DLL3-Targeted Antigen Recognition Receptor and Uses Thereof

Abstract

The subject matter of the present disclosure provides an antigen recognition receptor that specifically targets DLL3, and a cell comprising such a DLL3-targeted antigen recognition receptor. The subject matter of the present disclosure further provides a use of the DLL3-targeted antigen recognition receptor for treatment. The subject matter of the present disclosure provides an antigen recognition receptor comprising an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular antigen binding domain specifically binds to DLL3. In certain embodiments, the extracellular antigen binding domain is a single chain variable fragment (scFv).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 240,189, 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 31, 2022, is named 0727341385.xml and is 264,802 bytes in size.

[0003] 1. Introduction The presently disclosed subject matter provides methods and compositions for immunotherapy, which relate to antigen-recognition receptors (e.g., chimeric antigen receptors (CARs)) that specifically target DLL3, cells containing such receptors, and methods of using such cells for therapy. [Background technology]

[0004] 2. Background technology Cell-based immunotherapy is a potentially curative therapy for the treatment of cancer. T cells and other immune cells can be engineered to target tumor antigens through the introduction of genetic material encoding an artificial or synthetic receptor for the antigen, called a chimeric antigen receptor (CAR), specific for the selected antigen. Targeted T cell therapy using CARs has recently shown clinical success in the treatment of hematological malignancies and solid tumors.

[0005] DLL3 is selectively expressed in high-grade lung neuroendocrine tumors (LU-NETs) and other neuroendocrine cancers. 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 SCLC and LCNEC patients 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 various diseases or disorders, immunotherapies (e.g., CARs) that target DLL3 are desirable. [Prior art documents] [Non-patent literature]

[0006] [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

[0007] 3. Summary of the Invention The presently disclosed subject matter provides antigen-recognition receptors that specifically target DLL3, and cells comprising such DLL3-targeted antigen-recognition receptors. The presently disclosed subject matter further provides uses of DLL3-targeted antigen-recognition receptors for therapy.

[0008] The presently disclosed subject matter provides an antigen-recognizing receptor comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular antigen-binding domain specifically binds to DLL3. In certain embodiments, the extracellular antigen-binding domain is a single-chain variable fragment (scFv). In certain embodiments, the extracellular antigen-binding domain is a human scFv. In certain embodiments, the extracellular antigen-binding domain is an optionally cross-linked Fab. In certain embodiments, the extracellular antigen-binding domain is a F(ab)2. In certain embodiments, one or more of the scFv, Fab, and F(ab)2 are included in a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain.

[0009] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 1 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 3 or a conservative modification thereof; (b) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof; (c) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 22 or a conservative modification thereof; (d) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 29 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 30 or a conservative modification thereof; (e) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 38 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 39 or a conservative modification thereof; (f) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 47 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 48 or a conservative modification thereof; (g) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 56 or a conservative modification thereof; (h) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 64 or a conservative modification thereof; (i) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 or a conservative modification thereof; (j) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 80 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 81 or a conservative modification thereof; (k) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 87 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 88 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 89 or a conservative modification thereof; (l) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 97 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 98 or a conservative modification thereof; (m) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 106 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 107 or a conservative modification thereof; (n) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 95 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof; (o) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 123 or a conservative modification thereof; (p) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 137 or a conservative modification thereof; (q) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 145 or a conservative modification thereof; (r) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof; (s) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof; (t) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; (u) a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 176 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 177 or a conservative modification thereof; (v) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 184 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 185 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186 or a conservative modification thereof; (w) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 194 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof; or (x) A heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 202 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203 or a conservative modification thereof.

[0010] In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region 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.

[0011] In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region 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.

[0012] In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region 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.

[0013] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 6 or a conservative modification thereof; (b) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or a conservative modification thereof, and CDR3 comprising SEQ ID NO: 16 or a conservative modification thereof; (c) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof; (d) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 31 or a conservative modification thereof, CDR2 having SEQ ID NO: 32 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 33 or a conservative modification thereof; (e) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof; (f) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 49 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 51 or a conservative modification thereof; (g) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof; (h) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 65 or a conservative modification thereof; (i) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 or a conservative modification thereof; (j) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof; (k) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 90 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 280 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 91 or a conservative modification thereof; (l) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 99 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 101 or a conservative modification thereof; (m) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 112 or a conservative modification thereof; (n) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 117 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 118 or a conservative modification thereof; (o) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof; (p) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 130 or a conservative modification thereof; (q) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 138 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 139 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof; (r) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof; (s) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof; (t) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof; (u) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 171 or a conservative modification thereof; (v) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 178 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 179 or a conservative modification thereof; (w) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 187 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 188 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 189 or a conservative modification thereof; (x) a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof; or (y) A light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 having the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 204 or a conservative modification thereof.

[0014] In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region 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.

[0015] In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region 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 SEQ ID NO: 16 or a conservative modification thereof.

[0016] In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region 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.

[0017] In certain embodiments, the extracellular antigen-binding domain 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: 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: 280, 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 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; (x) 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: 176, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178, 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: 79; (y) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 184, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 185, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186, and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189; (z) 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: 194, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195, 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: 196; or (aa) A heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 202, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203, 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: 204.

[0018] In certain embodiments, the extracellular antigen-binding domain comprises 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.

[0019] In certain embodiments, the extracellular antigen-binding domain comprises 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.

[0020] In certain embodiments, the extracellular antigen-binding domain comprises 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.

[0021] In certain embodiments, the extracellular antigen binding domain is selected from the group consisting of 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: The present invention also includes a heavy chain variable region 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:172, SEQ ID NO:180, SEQ ID NO:190, SEQ ID NO:197, or SEQ ID NO:205. In certain embodiments, the extracellular antigen-binding domain 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, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:190, SEQ ID NO:197, or SEQ ID NO:205. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:17. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:24.

[0022] In certain embodiments, the extracellular antigen binding domain is selected from the group consisting of 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: 181, SEQ ID NO: 191, SEQ ID NO: 198, or SEQ ID NO: 206. In certain embodiments, the extracellular antigen-binding domain 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, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:191, SEQ ID NO:198, or SEQ ID NO:206. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:18. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:25.

[0023] In certain embodiments, the extracellular antigen binding domain comprises (a) 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:1 63, SEQ ID NO: 172, SEQ ID NO: 180, SEQ ID NO: 190, SEQ ID NO: 197, or SEQ ID NO: 205. chain variable regions, and (b) 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:17 3. A light chain variable region 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:181, SEQ ID NO:191, SEQ ID NO:198, or SEQ ID NO:206.

[0024] In certain embodiments, the extracellular antigen-binding domain comprises (a) a overlapping 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, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:190, SEQ ID NO:197, or SEQ ID NO:205. In certain embodiments, the extracellular antigen-binding domain comprises (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, or SEQ ID NO:24, and (b) 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, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:191, SEQ ID NO:198, or SEQ ID NO:206. In certain embodiments, the extracellular antigen-binding domain comprises (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, or SEQ ID NO:24, and (b) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, or SEQ ID NO:25.

[0025] In certain embodiments, the extracellular antigen-binding domain comprises: (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: 180, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 181; (y) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 190, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 191; (z) 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; or (aa) A heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 205, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 206.

[0026] In certain embodiments, the extracellular antigen-binding domain comprises 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.

[0027] In certain embodiments, the extracellular antigen-binding domain comprises 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.

[0028] In certain embodiments, the extracellular antigen-binding domain comprises 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.

[0029] In certain embodiments, the extracellular antigen-binding domain comprises a linker between the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain, hi certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, or SEQ ID NO:214.

[0030] In certain embodiments, the extracellular antigen-binding domain comprises a signal peptide covalently linked to the 5' end of the extracellular antigen-binding domain. In certain embodiments, the transmembrane domain comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, or a combination thereof. In certain embodiments, the intracellular signaling domain comprises a CD3ζ polypeptide. In certain embodiments, the CD3ζ polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO:221.

[0031] In certain embodiments, the intracellular signaling domain further comprises at least one costimulatory signaling region. In certain embodiments, the at least one costimulatory signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, or a combination thereof. In certain embodiments, the at least one costimulatory signaling region comprises a CD28 polypeptide. In certain embodiments, the CD28 polypeptide comprises or consists of amino acids 180-220 of SEQ ID NO:7. In certain embodiments, the CD28 polypeptide comprises a mutated YMNM motif. In certain embodiments, the CD28 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO:275, SEQ ID NO:276, SEQ ID NO:277, SEQ ID NO:278, or SEQ ID NO:279.

[0032] In certain embodiments, the antigen-recognizing receptor is a chimeric antigen receptor (CAR) or a T-cell-like fusion protein. In certain embodiments, the antigen-recognizing receptor is a CAR.

[0033] In certain embodiments, the antigen-recognizing receptor is recombinantly expressed. In certain embodiments, the antigen-recognizing receptor is expressed from a vector. In certain embodiments, the vector is a gamma-retroviral vector.

[0034] The presently disclosed subject matter provides that a cell comprises an antigen-recognizing receptor of the present disclosure. In certain embodiments, the cell is transduced with the antigen-recognizing receptor. In certain embodiments, the antigen-recognizing receptor is constitutively expressed on the surface of the cell. In certain embodiments, the cell further comprises an exogenous IL-18 polypeptide. In certain embodiments, the exogenous IL-18 polypeptide is a human IL-18 polypeptide.

[0035] In certain embodiments, the cell is an immunoresponsive cell. In certain embodiments, the cell is a lymphoid lineage cell or a myeloid lineage cell. In certain embodiments, the cell is selected from the group consisting of a T cell, a natural killer (NK) cell, and a stem cell from which lymphocytes can be differentiated. In certain embodiments, the cell is a T cell. In certain embodiments, the T cell is a cytotoxic T lymphocyte (CTL) or a regulatory T cell. In certain embodiments, the stem cell is a pluripotent stem cell. In certain embodiments, the pluripotent stem cell is an embryonic-like stem cell or an induced pluripotent stem cell.

[0036] The presently disclosed subject matter further provides a nucleic acid encoding the antigen-recognizing receptor of the present disclosure. The presently disclosed subject matter further provides a vector comprising the nucleic acid molecule of the present disclosure. In certain embodiments, the vector is a viral vector. In certain embodiments, the vector is a gamma-retroviral vector.

[0037] Additionally, the presently disclosed subject matter provides host cells that express the nucleic acid molecules of the present disclosure. In certain embodiments, the host cell is a T cell.

[0038] The presently disclosed subject matter further provides a composition comprising the cells of the present disclosure. In some embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0039] The presently disclosed subject matter also provides lipid nanoparticles comprising a nucleic acid encoding the antigen-recognizing receptor of the present disclosure. Furthermore, the presently disclosed subject matter provides a composition comprising the lipid nanoparticles disclosed herein. In certain embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0040] The presently disclosed subject matter further provides methods of treating or alleviating a disease or disorder in a subject, hi certain embodiments, the methods comprise administering to the subject a cell or composition of the present disclosure.

[0041] 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 carcinoma. In certain embodiments, the tumor is small cell lung carcinoma.

[0042] The presently disclosed subject matter further provides kits for treating or ameliorating a disease or disorder in a subject, comprising a cell, nucleic acid, or composition of the present disclosure. In certain embodiments, the kit further comprises written instructions for using the cell or composition of the present disclosure to treat or ameliorate a disease or disorder in a subject.

[0043] Additionally, the presently disclosed subject matter provides a method for producing a DLL3-targeted antigen-recognizing receptor, the method comprising introducing into a cell a nucleic acid encoding the antigen-recognizing receptor.

[0044] Finally, the presently disclosed subject matter provides a cell and / or composition disclosed herein for use in treating or ameliorating a disease or disorder in a subject. 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 carcinoma. In certain embodiments, the tumor is small cell lung carcinoma.

[0045] 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]

[0046] [Figure 1A] 1 shows a schematic diagram of a representative chimeric antigen receptor (CAR) disclosed herein. A shows a schematic diagram of the domains of a CAR disclosed herein co-expressed with a truncated EGFR domain. [Figure 1B] A shows a schematic diagram of a representative chimeric antigen receptor (CAR) disclosed herein. B shows a schematic diagram of the extracellular antigen-binding domain of three representative CARs disclosed herein, with a CD8 signal peptide and a flag tag for detection. VH: heavy chain, VL: light chain. [Figure 1C]

[0023] Figure 1 shows a schematic diagram of a representative chimeric antigen receptor (CAR) disclosed herein. C shows expression of the indicated CAR on transduced T cells as measured by flow cytometry. Grey: non-transduced T cells. [Figure 2A] Figure 1 shows the functional activity of T cells expressing the DLL3-targeting BBz CAR disclosed herein. A shows the cytotoxicity of human T cells expressing an antigen-recognizing receptor disclosed herein against the DLL3+ small cell lung cancer cell lines H82 and H69. [Figure 2B] A shows the functional activity of T cells expressing the DLL3-targeted BBz CAR disclosed herein. B shows a long-term proliferation assay. [Figure 2C] Figure 1 shows the functional activity of T cells expressing the DLL3-targeted BBz CAR disclosed herein.C shows the secretion of pro-inflammatory cytokines by stimulated human T cells expressing the DLL3-targeted CAR disclosed herein. [Figure 3A]

[0023] Figure 1 shows the in vivo activity of T cells expressing the DLL3-targeting 28z CAR disclosed herein. A shows metastatic H82-GFP-luciferase tumor growth in NSG mice receiving cells disclosed herein. [Figure 3B] A shows the in vivo activity of T cells expressing the DLL3-targeting 28z CAR disclosed herein. B shows the survival curve of NSG mice receiving cells disclosed herein. [Figure 4A] Figure 1 shows the activity of T cells expressing the DLL3-targeted 28z CAR disclosed herein, which comprises an IL-18 polypeptide. A shows a schematic diagram of a retroviral vector carrying a truncated EGFRt, 2J8-28z CAR, and an exogenous IL-18 polypeptide. [Figure 4B] A shows the activity of T cells expressing the DLL3-targeting 28z CAR disclosed herein, which comprises an IL-18 polypeptide. B shows CAR T cell proliferation in co-culture with H82 or H69 SCLC cells (E:T ratio of 1:5). [Figure 4C]Figure 1 shows the activity of T cells expressing the DLL3-targeted 28z CAR disclosed herein, which comprises an IL-18 polypeptide.C shows the mean radiance of H82 or H69 tumors in mice receiving T cells expressing the DLL3-targeted 28z CAR disclosed herein, which comprises an IL-18 polypeptide. [Figure 5A] 1A-1C show the activity of T cells expressing the DLL3-targeting 28z CAR disclosed herein, which comprises a CD28 mutant polypeptide designated "2J8-28YSNVz." A shows the effect of T cells expressing the 2J8-28YSNVz CAR disclosed herein in H82 tumor-bearing mice. [Figure 5B] (B) shows the activity of T cells expressing the DLL3-targeting 28z CAR disclosed herein, which comprises a CD28 mutant polypeptide designated "2J8-28YSNVz." (C) shows the mean radiance of metastatic SHP-77 SCLC tumors in mice receiving T cells expressing the 2J8-28YSNVz CAR disclosed herein, which comprises an exogenous IL-18 polypeptide. Crosses indicate death due to GvHD. DETAILED DESCRIPTION OF THE INVENTION

[0047] 5. MODE FOR CARRYING OUT THE INVENTION The presently disclosed subject matter provides antigen-recognition receptors (e.g., chimeric antigen receptors (CARs)) that specifically target DLL3. The presently disclosed subject matter further provides cells comprising such receptors. The cells can be immunoresponsive cells, e.g., genetically modified immunoresponsive cells (e.g., T cells or NK cells). The presently disclosed subject matter also provides methods of using such cells for therapy, e.g., treating and / or ameliorating a disease or disorder associated with DLL3.

[0048] Non-limiting embodiments of the present disclosure are illustrated in the specification and examples.

[0049] 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. Antigen-recognizing receptors, 5.4.Cells, 5.5. Compositions and Vectors 5.6. Polypeptides, 5.7. Formulation and Administration 5.8. Treatment method, 5.9. Kits, and 5.10. Exemplary Embodiments.

[0050] 5.1.Definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. The following references provide those skilled in the art with general definitions of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0051] 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.

[0052] "Immunoresponsive cell" refers to a cell that functions in an immune response or a precursor, or progeny thereof. In certain embodiments, an immunoresponsive cell is a cell of the lymphoid lineage. Non-limiting examples of cells of the lymphoid lineage include T cells, natural killer (NK) cells, B cells, and stem cells from which lymphoid cells can differentiate. In certain embodiments, an immunoresponsive cell is a cell of the myeloid lineage.

[0053] "Activating immunoresponsive cells" refers to the induction of intracellular signal transduction or changes in protein expression that result in the initiation of an immune response. For example, clustering of CD3 chains in response to ligand binding and immunoreceptor tyrosine-based inhibitory motifs (ITAMs) generates a signaling cascade. In certain embodiments, binding of an exogenous CAR to an antigen leads to the formation of an immunological synapse, involving the clustering of many molecules near the bound receptor (e.g., CD4 or CD8, CD3γ / δ / ε / ζ, etc.). This clustering of membrane-bound signaling molecules can phosphorylate the ITAM motifs contained within the CD3 chains. This phosphorylation, in turn, initiates the T cell activation pathway, ultimately activating transcription factors such as NF-κB and AP-1. These transcription factors induce global gene expression in T cells, increasing IL-2 production for proliferation and expression of master regulator T cell proteins, thereby initiating a T cell-mediated immune response.

[0054] "Stimulating immunoresponsive cells" refers to signals that result in a robust and sustained immune response. In various embodiments, this is mediated following immune cell (e.g., T cell) activation or simultaneously through receptors including, but not limited to, CD28, CD137 (4-1BB), OX40, CD40, and ICOS. Receiving multiple stimulatory signals can be important for mounting a robust, long-lasting T cell-mediated immune response. T cells can quickly become inhibited and unresponsive to antigen. While the effects of these costimulatory signals can vary, they generally result in increased gene expression to generate long-lived, proliferative, anti-apoptotic T cells that strongly respond to antigen for complete and sustained eradication.

[0055] As used herein, the term "antigen-recognizing receptor" refers to a receptor that can recognize a target antigen (e.g., DLL3). In certain embodiments, the antigen-recognizing receptor can activate an immune cell or immunoresponsive cell (e.g., a T cell) upon binding to the target antigen.

[0056] As used herein, the term "antibody" refers not only to intact antibody molecules but also to fragments of antibody molecules that retain immunogen-binding ability. Such fragments are well known in the art and are commonly used both in vitro and in vivo. Thus, as used herein, the term "antibody" refers not only to intact immunoglobulin molecules but also to the well-known active fragments F(ab')2 and Fab. F(ab')2 and Fab fragments, which lack the Fe fragment of intact antibodies, are cleared from the circulation more rapidly and may exhibit less nonspecific tissue binding than intact antibodies (Wahl et al., Nucl Med (1983); 24:316-325). As used herein, the term includes whole, native antibodies, bispecific antibodies, chimeric antibodies, Fab, Fab', single-chain V-region fragments (scFv), fusion polypeptides, and non-traditional antibodies. In certain embodiments, antibodies are glycoproteins 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 (referred to herein as V H ) and heavy chain constant (C H The heavy chain constant region is composed of three domains: CH1, CH2, and CH3. Each light chain contains a light chain variable region (referred to herein as V 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 Lis composed of three CDRs and four FRs, arranged from amino to 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.

[0057] As used herein, "CDR" is defined as the complementarity-determining region amino acid sequence of an antibody, which is the hypervariable region of an immunoglobulin heavy chain and light chain. See, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 4th USDapartment 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). Generally, an antibody contains 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 an antigen or epitope. In certain embodiments, the CDR regions are delineated using the IMGT numbering system. In certain embodiments, the CDR regions are delineated using the IMGT numbering system, accessible at http: / / www.imgt.org / IMGT_vquest / input.

[0058] As used herein, the term "single-chain variable fragment" or "scFv" refers to a V H heavy chains (V) of immunoglobulins (e.g., murine or human) covalently linked to form a VL heterodimer. H ) and light chain (V L ) is a fusion protein of the variable region of the heavy chain (V H ) and light chain (VL ) 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 typically rich in glycine for flexibility and rich in serine or threonine for solubility. The linker may connect the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain. Non-limiting examples of linkers are described in Shen et al., Anal. Chem. 80(6):1910-1917 (2008) and WO2014 / 087010, the contents of which are incorporated herein by reference in their entirety. In certain embodiments, the linker is a G4S linker.

[0059] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 209, provided below. GGGGSGGGGSGGGSGGGGS [SEQ ID NO: 209]

[0060] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 210, provided below. GGGGSGGGGSGGGGS [SEQ ID NO: 210]

[0061] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 211, provided below. GGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 211]

[0062] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 212, provided below. GGGGSGGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 212]

[0063] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 213, provided below. GGGGS [SEQ ID NO: 213]

[0064] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 214, provided below. GGGGSGGGGS [SEQ ID NO: 214]

[0065] Despite the removal of the constant region and the introduction of a linker, the scFv protein retains the specificity of the original immunoglobulin. Single-chain Fv polypeptide antibodies can be synthesized using the VFv polypeptide as described by Huston, et al. Proc. Nat. Acad. Sci. USA, (1988); 85:5879-5883, 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. H and V LThe scFv can be expressed from a nucleic acid containing a sequence encoding the scFv. Antagonistic scFvs with inhibitory 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 (Peter et al., J Biol 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).

[0066] As used herein, the term "chimeric antigen receptor" or "CAR" refers to a molecule comprising an extracellular antigen-binding domain fused to an intracellular signaling domain capable of activating or stimulating immunoresponsive cells, and a transmembrane domain. In certain embodiments, the extracellular antigen-binding domain of a CAR comprises an scFv. An scFv can be obtained by fusing the variable heavy and variable light regions of an antibody. Alternatively or additionally, an scFv can be derived from a Fab (e.g., obtained from a Fab library instead of from an antibody). In certain embodiments, an scFv is fused to a transmembrane domain and then to an intracellular signaling domain. The term "substantially identical" or "substantially homologous" refers to a polypeptide or nucleic acid molecule that exhibits at least about 50% homology or identity to a reference amino acid sequence (e.g., any of the amino acid sequences described herein) or a reference nucleic acid sequence (e.g., any of the nucleic acid sequences described herein). In certain embodiments, such a sequence is at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% homologous or identical to the amino acid or nucleic acid sequence used for comparison.

[0067] Sequence identity can be measured using sequence analysis software (e.g., Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, the BLAST program can be used, with a probability score of e-3 to e-100 indicating closely related sequences.

[0068] As used herein, the percent homology between two amino acid sequences corresponds to the percent identity between the two sequences. The percent identity 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 × 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. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.

[0069] The percent homology between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) 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. 48:444-453 (1970)) incorporated into the GAP program in the GCG software package (available at www.gcg.com) using either a Blossum62 matrix or a PAM250 matrix, gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6.

[0070] Additionally or alternatively, the amino acid sequences of the subject matter described herein can be further used as a "query sequence" to conduct searches 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. (1990) J. Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score=50, word length=3, to obtain amino acid sequences homologous to the specified sequences disclosed herein (e.g., the heavy and light chain variable region sequences of scFvs m903, m904, m905, m906, and m900). To obtain gapped alignments for comparison purposes, gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (eg, XBLAST and NBLAST) can be used.

[0071] An "effective amount" is an amount sufficient to produce beneficial or desired clinical results upon treatment. An effective amount may be administered to a subject in one or more doses. In certain embodiments, an effective amount may be 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 can be 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 when 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.

[0072] As used herein, the term "conservative sequence modification" refers to an amino acid modification that does not significantly affect or change the binding characteristics of the DLL3-targeting CAR (e.g., extracellular antigen-binding domain) of the present disclosure, including the amino acid sequence. Conservative modifications can include amino acid substitutions, additions, and deletions. Modifications can be introduced into the extracellular antigen-binding domain of the CAR of the present disclosure by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Amino acids can be classified into groups according to physicochemical properties, such as charge and polarity. A conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid within the same group. For example, amino acids can be classified by charge, with positively charged amino acids including lysine, arginine, and histidine, negatively charged amino acids including aspartic acid and glutamic acid, and neutrally charged amino acids including alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Additionally, amino acids can be classified by polarity, with polar amino acids including arginine (basic polar), asparagine, aspartic acid (acidic polar), glutamic acid (acidic polar), glutamine, histidine (basic polar), lysine (basic polar), serine, threonine, and tyrosine, and nonpolar amino acids including alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine. Thus, one or more amino acid residues in a CDR region can be replaced with other amino acid residues from the same group, and the altered antibody can be tested for retained function (i.e., the functions set forth in (c)-(l) above) using the functional assays described herein. In certain embodiments, no more than one, no more than two, no more than three, no more than four, or no more than five residues in a designated sequence or CDR region are altered.

[0073] As used herein, the term "endogenous" refers to a nucleic acid molecule or polypeptide that is normally expressed in a cell or tissue.

[0074] As used herein, the term "exogenous" refers to a nucleic acid molecule or polypeptide that is not endogenously present in a cell. Thus, the term "exogenous" encompasses foreign, heterologous, and any recombinant nucleic acid molecule or polypeptide expressed in a cell, such as overexpressed nucleic acid molecules and polypeptides. An "exogenous" nucleic acid refers to a nucleic acid that is not present in a native, wild-type cell; for example, an exogenous nucleic acid may differ from its endogenous counterpart by sequence, position / location, or both. For clarity, an exogenous nucleic acid may have the same or a different sequence compared to its native, endogenous counterpart, may be introduced into the cell itself or its precursor by genetic engineering, and may optionally be linked to alternative regulatory sequences, such as a non-native promoter or secretory sequence.

[0075] The term "heterologous nucleic acid molecule or polypeptide" means a nucleic acid molecule (e.g., a cDNA, DNA, or RNA molecule) or polypeptide that is not normally present in a cell or a sample obtained from a cell. The nucleic acid may be from another organism, or may be, for example, an mRNA molecule that is not normally expressed in the cell or sample.

[0076] By "increase" is meant a positive change of at least about 5%. The change may be about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, about 100%, or more.

[0077] By "decreasing" is meant a negative change of at least about 5%. The change may be about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or even about 100%.

[0078] The terms "isolated," "purified," or "biologically pure" refer to material that is free to varying degrees from components that normally accompany it as found in its native state. "Isolated" refers to a degree of separation from the original source or surroundings. "Purified" refers to a degree of separation greater than isolation. A "purified" or "biologically pure" protein is sufficiently free from other materials so that any impurities do not substantially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide is purified when it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high-performance liquid chromatography. The term "purified" can indicate that a nucleic acid or protein yields essentially one band in an electrophoretic gel. For proteins that can be subject to modifications, such as phosphorylation or glycosylation, different modifications can yield different isolated proteins that can be purified separately.

[0079] The term "isolated cell" means a cell that is separated from molecules and / or cellular components that naturally accompany the cell.

[0080] As used herein, the term "antigen-binding domain" refers to a domain that is capable of specifically binding a particular antigenic determinant or set of antigenic determinants present on a cell.

[0081] "Recognize" means selectively binding to a target. T cells that recognize tumors can express receptors (e.g., CARs) that bind to tumor antigens.

[0082] By "signal sequence" or "leader sequence" is meant a peptide sequence (eg, 5, 10, 15, 20, 25, or 30 amino acids) present at the N-terminus of a newly synthesized protein that directs entry into the secretory pathway.

[0083] "Specifically binds" or "specifically binds to" or "specifically targets" means a polypeptide or fragment thereof that recognizes and / or binds to a biological molecule of interest (e.g., a polypeptide, e.g., a DLL3 polypeptide) but does not substantially recognize and / or bind to other molecules in a sample, e.g., a biological sample, which naturally includes a polypeptide of the present disclosure (e.g., a DLL3 polypeptide).

[0084] 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.

[0085] 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.

[0086] As used herein, the term "treatment" refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. The therapeutic effect of treatment includes, but is not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, and remission or improved prognosis. By preventing the progression of a disease or disorder, treatment can not only prevent deterioration due to the disorder in a subject affected or diagnosed with, or suspected of having, the disorder, but also prevent the onset of the disorder or symptoms of the disorder in a subject at risk of, or suspected of having, the disorder.

[0087] As used herein, an "individual" or "subject" refers to 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, as well as guinea pigs, rabbits, dogs, cats, sheep, pigs, goats, cows, horses, and non-human primates, such as apes and monkeys. As used herein, the term "immunocompromised" refers to a subject with an immunodeficiency. Subjects are highly vulnerable to opportunistic infections caused by organisms that typically do not cause disease in humans with healthy immune systems but can affect people with dysfunctional or suppressed immune systems.

[0088] 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.

[0089] 5.2.DLL3 DLL3 is selectively expressed in high-grade lung neuroendocrine tumors (LU-NETs) and other neuroendocrine cancers. 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 SCLC and LCNEC patients 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).

[0090] 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.

[0091] 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.

[0092] In certain embodiments, the antigen-recognizing receptor binds to human DLL3. In certain embodiments, human DLL3 comprises or consists of an amino acid sequence having UniProt Reference Number: Q9NYJ7-1 (SEQ ID NO: 215), or a fragment thereof. SEQ ID NO: 215 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: 215. In certain embodiments, the transmembrane domain comprises or consists of amino acids 493-513 of SEQ ID NO: 215. In certain embodiments, the cytoplasmic domain comprises or consists of amino acids 514-618 of SEQ ID NO: 215.

[0093] 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:215. In certain embodiments, the EGF-like 1 domain comprises or consists of amino acids 216-249 of SEQ ID NO:215. In certain embodiments, the EGF-like 2 domain comprises or consists of amino acids 274-310 of SEQ ID NO:215. In certain embodiments, the EGF-like 3 domain comprises or consists of amino acids 312-351 of SEQ ID NO:215. In certain embodiments, the EGF-like 4 domain comprises or consists of amino acids 353-389 of SEQ ID NO:215. In certain embodiments, the EGF-like 5 domain comprises or consists of amino acids 391-427 of SEQ ID NO:215. In certain embodiments, the EGF-like 6 domain comprises or consists of amino acids 429 to 465 of SEQ ID NO:215. [ka]

[0094] 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: 215 or a fragment thereof.

[0095] In certain embodiments, the antigen-recognizing receptor binds to a portion of human DLL3. In certain embodiments, the antigen-recognizing receptor binds to the extracellular domain of DLL3. In certain embodiments, the antigen-recognizing receptor binds to amino acids 27-492 of SEQ ID NO: 215.

[0096] 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: 215. 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: 215. 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: 215. 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: 215.

[0097] 5.3. Antigen Recognition Receptors The antigen-recognizing receptor of the present disclosure specifically targets or binds to DLL3. In certain embodiments, the antigen-recognizing receptor is a chimeric antigen receptor (CAR). In certain embodiments, the antigen-recognizing receptor is a TCR-like fusion molecule.

[0098] The subject matter of the present disclosure also provides a nucleic acid molecule encoding the antigen-recognizing receptor of the present disclosure. In certain embodiments, the nucleic acid molecule comprises a nucleotide sequence encoding the polypeptide of the DLL3-targeting antigen-recognizing receptor disclosed herein.

[0099] 5.3.1. Extracellular Antigen-Binding Domains In certain embodiments, the extracellular antigen-binding domain of the antigen-recognizing receptor binds to DLL3.

[0100] In certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is a human scFv. In certain embodiments, the scFv is a humanized scFv. In certain embodiments, the scFv is a mouse scFv. In certain embodiments, the scFv is identified by screening an scFv phage library with an antigen-Fc fusion protein.

[0101] In certain embodiments, the extracellular antigen-binding domain is a Fab. In certain embodiments, the Fab is cross-linked. In certain embodiments, the extracellular antigen-binding domain is a F(ab)2.

[0102] Any of the foregoing molecules can be included in a fusion protein with a heterologous sequence to form an extracellular antigen-binding domain. In certain embodiments, the extracellular antigen-binding domain (e.g., an embodied scFv) has 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, 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 DIn certain embodiments, the extracellular antigen-binding domain (e.g., the embodied scFv) binds to DLL3 (e.g., human DLL3) with 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 D In certain embodiments, the extracellular antigen-binding domain (e.g., the embodied scFv) binds 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 extracellular antigen-binding domain (e.g., the embodied scFv) binds 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 extracellular antigen-binding domain (e.g., the embodied scFv) binds 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 extracellular antigen-binding domain (e.g., the embodied scFv) binds 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 extracellular antigen-binding domain (e.g., the embodied scFv) binds 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).

[0103] Binding of the extracellular antigen-binding domain can be confirmed, for example, by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western blot assay. Each of these assays generally detects the presence of a particular protein-antibody complex of interest by using a labeled reagent (e.g., an antibody or scFv) specific to the complex of interest. For example, scFv can be radioactively labeled and used in a radioimmunoassay (RIA) (see, e.g., Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, incorporated herein by reference). Radioisotopes can be detected by means such as the use of a gamma counter or scintillation counter, or by autoradioactivity testing. In certain embodiments, the DLL3-targeting extracellular antigen-binding domain is labeled with a fluorescent marker. Non-limiting examples of fluorescent markers include green fluorescent protein (GFP), blue fluorescent protein (e.g., EBFP, EBFP2, Azurite, and mKalama1), cyan fluorescent protein (e.g., ECFP, Cerulean, and CyPet), and yellow fluorescent protein (e.g., YFP, Citrine, Venus, and YPet). In certain embodiments, the DLL3-targeting human scFv is labeled with GFP.

[0104] In certain embodiments, the CDRs are identified according to the IMGT numbering system.

[0105] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. HSEQ ID NOs: 1 to 3 are provided in Table 1.

[0106] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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:6 or a conservative modification thereof. L SEQ ID NOs: 4 to 6 are provided in Table 1.

[0107] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. 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:6 or a conservative modification thereof. L Includes:

[0108] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V domain 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. H and 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.

[0109] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:7. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to SEQ ID NO:7. H In certain embodiments, the extracellular antigen-binding domain comprises a V H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 7 is set forth in SEQ ID NO: 9. SEQ ID NOs: 7 and 9 are provided in Table 1 below.

[0110] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:8. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to SEQ ID NO:8. L In certain embodiments, the extracellular antigen-binding domain comprises a V 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: 8 and 10 are provided in Table 1 below.

[0111] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "J8". 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: 210.

[0112] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0113] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, the extracellular antigen-binding domain is an scFv, and the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 1]

[0114] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 11-13 are provided in Table 2.

[0115] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 14 to 16 are provided in Table 2.

[0116] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H and 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: 146 or a conservative modification thereof. L Includes:

[0117] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13. H and 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. L Includes:

[0118] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 17. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 17. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 17. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 17 is set forth in SEQ ID NO: 19. SEQ ID NOs: 17 and 19 are provided in Table 2 below.

[0119] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 18. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 18. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 16 and 20 are provided in Table 2 below.

[0120] In certain embodiments, the extracellular antigen-binding domain (e.g., 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "L22". 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: 210.

[0121] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0122] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 2]

[0123] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 2 and 22 are provided in Table 3.

[0124] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 23 or a conservative modification thereof. L SEQ ID NOs: 4, 5 and 23 are provided in Table 3.

[0125] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 23 or a conservative modification thereof. L Includes:

[0126] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V domain 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. 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:23. L Includes:

[0127] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:24. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:24. H In certain embodiments, the extracellular antigen-binding domain comprises a V 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. SEQ ID NOs: 24 and 26 are provided in Table 3 below.

[0128] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:25. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:25. L In certain embodiments, the extracellular antigen-binding domain 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: 25 and 27 are provided in Table 3 below.

[0129] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "B2". 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: 210.

[0130] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0131] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 3]

[0132] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 28-30 are provided in Table 4.

[0133] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 31-33 are provided in Table 4.

[0134] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H and 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. L Includes:

[0135] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 31, CDR2 having the amino acid sequence set forth in SEQ ID NO: 32, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 33. L Includes:

[0136] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 34. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 34. H In certain embodiments, the extracellular antigen-binding domain comprises a V 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. SEQ ID NOs: 34 and 36 are provided in Table 4 below.

[0137] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 35. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 35. L In certain embodiments, the extracellular antigen-binding domain 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: 35 and 37 are provided in Table 4 below.

[0138] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "A18". 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: 210.

[0139] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0140] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 4]

[0141] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 38, and 39 are provided in Table 5.

[0142] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 40, 5 and 41 are provided in Table 5.

[0143] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H and 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. L Includes:

[0144] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39. H and V 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. L Includes:

[0145] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:42. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:42. H In certain embodiments, the extracellular antigen-binding domain comprises a V 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. SEQ ID NOs: 42 and 44 are provided in Table 5 below.

[0146] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:43. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:43. L In certain embodiments, the extracellular antigen-binding domain 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: 43 and 45 are provided in Table 5 below.

[0147] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "E9". 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: 210.

[0148] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0149] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 5]

[0150] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 46-48 are provided in Table 6.

[0151] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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: 49 or a conservative modification thereof. L SEQ ID NOs: 49-51 are provided in Table 6.

[0152] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H and 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. L Includes:

[0153] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 49, CDR2 having the amino acid sequence set forth in SEQ ID NO: 50, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 51. L Includes:

[0154] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 52. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:52. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 52. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 52 is set forth in SEQ ID NO: 54. SEQ ID NOs: 52 and 54 are provided in Table 6 below.

[0155] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:53. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:51. L In certain embodiments, the extracellular antigen-binding domain 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: 53 and 55 are provided in Table 6 below.

[0156] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "G3". In certain embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 210.

[0157] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0158] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 6]

[0159] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 2 and 56 are provided in Table 7.

[0160] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof. L SEQ ID NOs: 57-59 are provided in Table 7.

[0161] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 59 or a conservative modification thereof. L Includes:

[0162] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V domain comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214, 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 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: 59. L Includes:

[0163] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:60. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:59. H In certain embodiments, the extracellular antigen-binding domain comprises a V H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 60 is set forth in SEQ ID NO: 62. SEQ ID NOs: 60 and 62 are provided in Table 7 below.

[0164] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:61. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:61. L In certain embodiments, the extracellular antigen-binding domain 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: 61 and 63 are provided in Table 7 below.

[0165] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "M11". 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: 210.

[0166] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0167] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 7]

[0168] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 2 and 64 are provided in Table 8.

[0169] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 65 or a conservative modification thereof. L SEQ ID NOs: 4, 5 and 65 are provided in Table 8.

[0170] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 65 or a conservative modification thereof. L Includes:

[0171] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V domain 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. 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:65. L Includes:

[0172] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:66. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:66. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 66. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 66 is set forth in SEQ ID NO: 68. SEQ ID NOs: 66 and 68 are provided in Table 8 below.

[0173] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:67. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:67. L In certain embodiments, the extracellular antigen-binding domain 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: 67 and 69 are provided in Table 8 below.

[0174] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "O24." 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: 210.

[0175] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0176] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 8]

[0177] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 70-72 are provided in Table 9.

[0178] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 73-75 are provided in Table 9.

[0179] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H and 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. L Includes:

[0180] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 73, CDR2 having the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 75. L Includes:

[0181] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:76. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:76. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 76. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 76 is set forth in SEQ ID NO: 78. SEQ ID NOs: 76 and 78 are provided in Table 9 below.

[0182] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:77. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:77. L In certain embodiments, the extracellular antigen-binding domain 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: 77 and 79 are provided in Table 9 below.

[0183] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "P4". 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: 210.

[0184] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0185] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 9]

[0186] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 80 and 81 are provided in Table 10.

[0187] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof. L SEQ ID NOs: 57, 58 and 82 are provided in Table 10.

[0188] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 82 or a conservative modification thereof. L Includes:

[0189] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81. 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: 82. L Includes:

[0190] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a VH comprising an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 83. For example, the extracellular antigen-binding domain (e.g., scFv) comprises a VH 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 83. In certain embodiments, the extracellular antigen-binding domain comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 83. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 83 is set forth in SEQ ID NO: 85. SEQ ID NOs: 83 and 85 are provided in Table 10 below.

[0191] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 84. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:84. L In certain embodiments, the extracellular antigen-binding domain 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: 84 and 86 are provided in Table 10 below.

[0192] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "J23." 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: 210.

[0193] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0194] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 10]

[0195] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 87-89 are provided in Table 11.

[0196] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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: 280 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. L SEQ ID NOs: 90, 280 and 91 are provided in Table 11.

[0197] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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, a V comprising the amino acid sequence set forth in SEQ ID NO: 89 or a conservative modification thereof, and a V comprising the amino acid sequence set forth in SEQ ID NO: 90 or a conservative modification thereof. H V containing CDR3 H and 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: 280 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. L Includes:

[0198] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 90, CDR2 having the amino acid sequence set forth in SEQ ID NO: 280, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 91. L Includes:

[0199] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:92.H For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:92. H In certain embodiments, the extracellular antigen-binding domain comprises a V H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 92 is set forth in SEQ ID NO: 94. SEQ ID NOs: 92 and 94 are provided in Table 11 below.

[0200] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO:93. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:93. L In certain embodiments, the extracellular antigen-binding domain 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: 93 and 95 are provided in Table 11 below.

[0201] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "K19". 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: 210.

[0202] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0203] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 11]

[0204] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 96-98 are provided in Table 12.

[0205] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 99-101 are provided in Table 12.

[0206] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H and 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. L Includes:

[0207] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98. H and V 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. L Includes:

[0208] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 102. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 102. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 102. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 102 is set forth in SEQ ID NO: 104. SEQ ID NOs: 102 and 104 are provided in Table 12 below.

[0209] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 103. L For example, the extracellular antigen-binding domain (e.g., scFv) can comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 103. L In certain embodiments, the extracellular antigen-binding domain 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: 103 and 105 are provided in Table 12 below.

[0210] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V 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. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "N10." 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: 210.

[0211] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0212] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 12]

[0213] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 106 and 107 are provided in Table 13.

[0214] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof. L SEQ ID NOs: 57, 58 and 82 are provided in Table 13.

[0215] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 82 or a conservative modification thereof. L Includes:

[0216] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107. 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: 82. L Includes:

[0217] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 108. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 108 is set forth in SEQ ID NO: 110. SEQ ID NOs: 108 and 110 are provided in Table 13 below.

[0218] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 109. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 109. L In certain embodiments, the extracellular antigen-binding domain 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: 109 and 111 are provided in Table 13 below.

[0219] In certain embodiments, the extracellular antigen-binding domain (e.g., 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: 109 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "B16-v1." 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: 210.

[0220] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0221] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 13]

[0222] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 106 and 107 are provided in Table 14.

[0223] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 112 or a conservative modification thereof. L SEQ ID NOs: 4, 5 and 112 are provided in Table 14.

[0224] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 112 or a conservative modification thereof. L Includes:

[0225] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107. 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:112. L Includes:

[0226] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 108. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 108. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 108 is set forth in SEQ ID NO: 110. SEQ ID NOs: 108 and 110 are provided in Table 14 below.

[0227] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 113. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:113. L In certain embodiments, the extracellular antigen-binding domain 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: 113. SEQ ID NOs: 113 and 114 are provided in Table 14 below.

[0228] In certain embodiments, the extracellular antigen-binding domain (e.g., 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. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "B16-v2." 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: 210.

[0229] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0230] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L ) should be connected one after the other so that When the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: L -V H . [Table 14]

[0231] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 96, 115 and 116 are provided in Table 15.

[0232] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 117, 100 and 118 are provided in Table 15.

[0233] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H and 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. L Includes:

[0234] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116. H and V 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. L Includes:

[0235] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 119. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:119. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 119. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 119 is set forth in SEQ ID NO: 121. SEQ ID NOs: 119 and 121 are provided in Table 15 below.

[0236] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 120. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 120. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 120 and 122 are provided in Table 15 below.

[0237] In certain embodiments, the extracellular antigen-binding domain (e.g., 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. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "E23". 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: 210.

[0238] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0239] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 15]

[0240] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 2 and 123 are provided in Table 16.

[0241] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 124, 58 and 125 are provided in Table 16.

[0242] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H and 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. L Includes:

[0243] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:123. H and V 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. L Includes:

[0244] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 126. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 126. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 126. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 126 is set forth in SEQ ID NO: 128. SEQ ID NOs: 126 and 128 are provided in Table 16 below.

[0245] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 127. L For example, the extracellular antigen-binding domain (e.g., scFv) can comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 127. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 127 and 129 are provided in Table 16 below.

[0246] In certain embodiments, the extracellular antigen-binding domain (e.g., 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "F9". 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: 210.

[0247] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0248] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 16]

[0249] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 2 and 56 are provided in Table 17.

[0250] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 or a conservative modification thereof. L SEQ ID NOs: 57, 58 and 130 are provided in Table 17.

[0251] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 130 or a conservative modification thereof. L Includes:

[0252] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:56. 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: 130. L Includes:

[0253] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 131. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 131. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 131. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 131 is set forth in SEQ ID NO: 133. SEQ ID NOs: 131 and 133 are provided in Table 17 below.

[0254] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 132. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 132. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 132 and 134 are provided in Table 17 below.

[0255] In certain embodiments, the extracellular antigen-binding domain (e.g., 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. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "L12". 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: 210.

[0256] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0257] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 17]

[0258] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 135-137 are provided in Table 17.

[0259] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 139-140 are provided in Table 17.

[0260] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H and 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. L Includes:

[0261] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 138, CDR2 having the amino acid sequence set forth in SEQ ID NO: 139, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 140. L Includes:

[0262] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 141. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 141. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 141. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 141 is set forth in SEQ ID NO: 143. SEQ ID NOs: 141 and 143 are provided in Table 18 below.

[0263] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 142. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 142. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 142 and 144 are provided in Table 18 below.

[0264] In certain embodiments, the extracellular antigen-binding domain (e.g., 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "B22". 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: 210.

[0265] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0266] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 18]

[0267] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 2 and 145 are provided in Table 19.

[0268] In certain embodiments, the extracellular antigen-binding domain (e.g., 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: 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. L SEQ ID NOs: 57, 146 and 125 are provided in Table 19.

[0269] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. 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: 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. L Includes:

[0270] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V domain 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. H and V 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. L Includes:

[0271] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 147. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 147. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 147. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 147 is set forth in SEQ ID NO: 149. SEQ ID NOs: 147 and 149 are provided in Table 19 below.

[0272] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 148. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 148. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 148 and 150 are provided in Table 19 below.

[0273] In certain embodiments, the extracellular antigen-binding domain (e.g., 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "C22". 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: 210.

[0274] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0275] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 19]

[0276] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 151, 2 and 152 are provided in Table 20.

[0277] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof. L SEQ ID NOs: 57, 58 and 82 are provided in Table 20.

[0278] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. 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: 82 or a conservative modification thereof. L Includes:

[0279] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152. 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: 82. L Includes:

[0280] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 151. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 153. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 153. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 153 is set forth in SEQ ID NO: 155. SEQ ID NOs: 153 and 155 are provided in Table 20 below.

[0281] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 154. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 154. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 154 and 156 are provided in Table 20 below.

[0282] In certain embodiments, the extracellular antigen-binding domain (e.g., 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. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "D8". 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: 210.

[0283] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0284] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 20]

[0285] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 21, 2 and 123 are provided in Table 21.

[0286] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 124, 58 and 59 are provided in Table 21.

[0287] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H and 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. L Includes:

[0288] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:123. H and V 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. L Includes:

[0289] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 157. HFor example, the extracellular antigen-binding domain (e.g., scFv) can comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 157. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 157. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 157 is set forth in SEQ ID NO: 159. SEQ ID NOs: 157 and 159 are provided in Table 21 below.

[0290] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 158. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 158. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 158 and 160 are provided in Table 21 below.

[0291] In certain embodiments, the extracellular antigen-binding domain (e.g., 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "G16". 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: 210.

[0292] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0293] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 21]

[0294] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H SEQ ID NOs: 11, 136 and 161 are provided in Table 22.

[0295] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 73, 74 and 162 are provided in Table 22.

[0296] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 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. H and 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. L Includes:

[0297] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 73, CDR2 having the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 162. L Includes:

[0298] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 163. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 163. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 163. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 163 is set forth in SEQ ID NO: 165. SEQ ID NOs: 163 and 165 are provided in Table 22 below.

[0299] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 164. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 148. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 164 and 166 are provided in Table 22 below.

[0300] In certain embodiments, the extracellular antigen-binding domain (e.g., 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. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "F21". 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: 210.

[0301] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0302] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 22]

[0303] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H SEQ ID NOs: 96, 167 and 168 are provided in Table 23.

[0304] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. L SEQ ID NOs: 169-171 are provided in Table 23.

[0305] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises 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. H and 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. L Includes:

[0306] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168. H and V 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. L Includes:

[0307] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 172. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 172. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 172. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 172 is set forth in SEQ ID NO: 174. SEQ ID NOs: 172 and 174 are provided in Table 23 below.

[0308] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 173. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 173. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 173 and 175 are provided in Table 23 below.

[0309] In certain embodiments, the extracellular antigen-binding domain (e.g., 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "N12." 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: 210.

[0310] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0311] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 23]

[0312] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 176 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177 or a conservative modification thereof. H SEQ ID NOs: 21, 176 and 177 are provided in Table 24.

[0313] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 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: 179 or a conservative modification thereof. L SEQ ID NOs: 178, 50 and 179 are provided in Table 24.

[0314] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 176 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177 or a conservative modification thereof. H and a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 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: 179 or a conservative modification thereof. L Includes:

[0315] In certain embodiments, the extracellular antigen-binding domain (e.g., 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: 176, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177. H and V comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178, 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: 179. L Includes:

[0316] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 180. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 180. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 180. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 180 is set forth in SEQ ID NO: 182. SEQ ID NOs: 180 and 182 are provided in Table 24 below.

[0317] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 181. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 181. L In certain embodiments, the extracellular antigen-binding domain comprises a V L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 181 is set forth in SEQ ID NO: 183. SEQ ID NOs: 181 and 183 are provided in Table 24 below.

[0318] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 180. H and V comprising the amino acid sequence set forth in SEQ ID NO: 181. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "G23". 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: 210.

[0319] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0320] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 24]

[0321] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 184 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 185 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. H SEQ ID NOs: 184-186 are provided in Table 25.

[0322] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189 or a conservative modification thereof. L SEQ ID NOs: 187-189 are provided in Table 25.

[0323] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 184 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 185 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. H , a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189 or a conservative modification thereof. L Includes:

[0324] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 184, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 185, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186. H and V comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 187, CDR2 having the amino acid sequence set forth in SEQ ID NO: 188, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 189. L Includes:

[0325] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 190. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 190. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 190. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 190 is set forth in SEQ ID NO: 192. SEQ ID NOs: 190 and 192 are provided in Table 25 below.

[0326] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 191. L For example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 191. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 191. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 191 is set forth in SEQ ID NO: 193. SEQ ID NOs: 191 and 193 are provided in Table 25 below.

[0327] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 190. H and V comprising the amino acid sequence set forth in SEQ ID NO: 191. LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "I1". 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: 210.

[0328] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0329] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 25]

[0330] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 194 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof. H SEQ ID NOs: 11, 194 and 195 are provided in Table 26.

[0331] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 196 or a conservative modification thereof. L SEQ ID NOs: 4, 5 and 196 are provided in Table 26.

[0332] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 194 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195 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: 196 or a conservative modification thereof. L Includes:

[0333] In certain embodiments, the extracellular antigen-binding domain (e.g., 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: 194, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195. 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:196. L Includes:

[0334] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 197. HFor example, the extracellular antigen-binding domain (e.g., scFv) may comprise 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 197. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 197. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 197 is set forth in SEQ ID NO: 199. SEQ ID NOs: 197 and 199 are provided in Table 26 below.

[0335] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 198. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 198. L In certain embodiments, the extracellular antigen-binding domain 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. SEQ ID NOs: 198 and 200 are provided in Table 26 below.

[0336] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "C8". 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: 210.

[0337] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0338] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 26]

[0339] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 202 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. H SEQ ID NOs: 201-203 are provided in Table 27.

[0340] In certain embodiments, the extracellular antigen-binding domain (e.g., 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, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204 or a conservative modification thereof. L SEQ ID NOs: 57, 58 and 204 are provided in Table 27.

[0341] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 202 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. 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: 204 or a conservative modification thereof. L Includes:

[0342] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) 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: 202, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203. 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: 204. L Includes:

[0343] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 205. HFor example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:205. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 205. H An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 205 is set forth in SEQ ID NO: 207. SEQ ID NOs: 205 and 207 are provided in Table 27 below.

[0344] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 206. L For example, the extracellular antigen-binding domain (e.g., scFv) 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%, about 99%, or about 100% homologous or identical to the amino acid sequence set forth in SEQ ID NO:206. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 206. L An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 206 is set forth in SEQ ID NO: 208. SEQ ID NOs: 206 and 208 are provided in Table 27 below.

[0345] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 205. H and V comprising the amino acid sequence set forth in SEQ ID NO: 206 LIn certain embodiments, the extracellular antigen-binding domain is an scFv. In certain embodiments, the scFv is designated "O18." 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: 210.

[0346] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0347] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H . [Table 27]

[0348] Specific sequences (SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:153, 154, SEQ ID NO:157, SEQ ID NO:158, SEQ ID NO:163, SEQ ID NO:164, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:205, or SEQ ID NO:206) H Amino acid sequence and / or V L The amino acid sequence may contain substitutions (eg, conservative substitutions), insertions, or deletions relative to the specified sequence(s), yet retain the ability to bind to DLL3.

[0349] In certain embodiments, a total of 1 to 10 amino acids are selected from a specific sequence (e.g., SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 153, SEQ ID NO: 154, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 205, or SEQ ID NO: 206). In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs of the extracellular antigen-binding domain (e.g., FRs). In certain embodiments, the extracellular antigen-binding domain is selected from the group consisting of the sequences (SEQ ID NOs: 7, 8, 17, 18, 24, 25, 34, 35, 42, 43, 52, 53, 60, 61, 66, 67, 76, 77, 83, 84, 92, 93, 102, 103, 108, 109, 113, 119, 120, 126, 127, 131, 132, 141, 142, 147, 148, 153, 154, 157, 158, 163, 164, 172, 173, 180, 181, 190, 191, 197, 198, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 253, 254, 255, 256, 257, 258, 26 7, 8, 17, 18, 24, 25, 34, 35, 42, 43, 52, 53, 60, 61, 66, 67, 76, 77, 83, 84, 92, 93, 102, 103, 108, 109, 113, 119, 120, 126, 127, 131, 132, 141, 142, 147, 148, 153, 154, 157, 158, 163, 164, 172, 173, 180, 181, 190, 191, 197, 198, 205, or 206, comprising a post-translational modification of H Sequence and / or V L Contains arrays.

[0350] In certain embodiments, the extracellular antigen-binding domain of a CAR of the present disclosure is selected for binding to DLL3 (e.g., human DLL3), e.g., from the V of any one of the scFvs of the present disclosure (e.g., H CDR1 sequence, V H CDR2 sequence, and V H CDR3 sequence, and V L CDR1 sequence, V L CDR2 sequence, and V L In certain embodiments, the extracellular antigen-binding domain of a CAR of the disclosure cross-competes with a reference antibody or antigen-binding fragment thereof comprising the CDR3 sequence of any one of the V and CDR3 sequences of any one of the scFvs of the disclosure (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, and G23) for binding to DLL3 (e.g., human DLL3). H Sequence and V L cross-compete with a reference antibody or antigen-binding portion thereof comprising the sequence

[0351] In certain embodiments, the extracellular antigen-binding domain of a CAR of the present disclosure comprises the V of scFv J8 for binding to DLL3 (e.g., human DLL3). H CDR1 sequence, V H CDR2 sequence, and V H CDR3 sequence, and V L CDR1 sequence, V L CDR2 sequence, and V L For example, the extracellular antigen-binding domain of a CAR of the present disclosure may comprise a V CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 1 for binding to DLL3 (e.g., human DLL3). H CDR1, V comprising the amino acid sequence set forth in SEQ ID NO:2 H CDR2, V comprising the amino acid sequence set forth in SEQ ID NO:3 H CDR3, V comprising the amino acid sequence set forth in SEQ ID NO:4 LCDR1, V comprising amino acids having the sequence set forth in SEQ ID NO:5 L CDR2, and V comprising amino acids having the sequence set forth in SEQ ID NO:6 L In certain embodiments, the extracellular antigen-binding domain of a CAR of the present disclosure cross-competes with the V CDR3 of scFv J8 for binding to DLL3 (e.g., human DLL3). H Sequence and V L For example, the extracellular antigen-binding domain of a CAR of the present disclosure may comprise a V comprising amino acids having the sequence set forth in SEQ ID NO: 7 for binding to DLL3 (e.g., human DLL3). H and V comprising an amino acid sequence set forth in SEQ ID NO:8 L or an antigen-binding portion thereof.

[0352] In certain embodiments, the extracellular antigen-binding domain binds to the same epitope region on DLL3 (e.g., human DLL3) as the reference antibody or antigen-binding portion thereof. For example, the extracellular antigen-binding domain of a CAR of the disclosure can be, for example, any one of the V of the scFvs of the disclosure (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, and G23). H CDR1 sequence, V H CDR2 sequence, and V H CDR3 sequence, and V L CDR1 sequence, V L CDR2 sequence, and V L The CAR binds to the same epitope region on DLL3 (e.g., human DLL3) as a reference antibody or antigen-binding portion thereof comprising the CDR3 sequence. In certain embodiments, the extracellular antigen-binding domain of a CAR of the disclosure comprises, for example, any one of the V of the scFvs of the disclosure (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, and G23).H Sequence and V L It binds to the same epitope region on DLL3 (e.g., human DLL3) as a reference antibody or antigen-binding portion thereof that comprises the sequence.

[0353] In certain embodiments, the extracellular antigen-binding domain cross-competes with a reference antibody or antigen-binding portion thereof for binding to DLL3 (e.g., human DLL3). For example, the extracellular antigen-binding domain of a CAR of the disclosure cross-competes with, for example, the V of any one of the scFvs of the disclosure (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, and G23) for binding to DLL3 (e.g., human DLL3). H CDR1 sequence, V H CDR2 sequence, and V H CDR3 sequence, and V L CDR1 sequence, V L CDR2 sequence, and V L In certain embodiments, the extracellular antigen-binding domain of a CAR of the disclosure cross-competes with a reference antibody or antigen-binding portion thereof comprising the CDR3 sequence. In certain embodiments, the extracellular antigen-binding domain of a CAR of the disclosure comprises, for example, any one of the V of any one of the scFvs of the disclosure (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, and G23). H Sequence and V L It binds to the same epitope region on DLL3 (e.g., human DLL3) as a reference antibody or antigen-binding portion thereof that comprises the sequence.

[0354] Extracellular antigen-binding domains that cross-compete or compete with a reference antibody or antigen-binding portion thereof for binding to DLL3 (e.g., human DLL3) can be identified by using routine methods known in the art, including, but not limited to, ELISA, radioimmunoassay (RIA), Biacore, flow cytometry, Western blotting, and any other suitable quantitative or qualitative antibody binding assay. Competitive ELISA is described in Morris, "Epitope Mapping of Protein Antigens by Competition ELISA," The Protein Protocols Handbook (1996), edited by J. Walker, pp. 595-600, which is incorporated by reference in its entirety. In certain embodiments, the antibody binding assay includes measuring initial binding of a reference antibody to a DLL3 polypeptide, mixing the reference antibody with a test extracellular antigen-binding domain, measuring secondary binding of the reference antibody to the DLL3 polypeptide in the presence of the test extracellular antigen-binding domain, and comparing the initial binding to the secondary binding of the reference antibody. A decrease in the secondary binding of the reference antibody to the DLL3 polypeptide compared to the initial binding indicates that the test extracellular antigen-binding domain cross-competes with the reference antibody, e.g., an antibody that recognizes the same or substantially the same epitope, an overlapping epitope, or an adjacent epitope, for binding to DLL3. In certain embodiments, the reference antibody is labeled, e.g., with a fluorescent dye, biotin, or peroxidase. In certain embodiments, the DLL3 polypeptide is expressed intracellularly, e.g., in a flow cytometry assay. In certain embodiments, the DLL3 polypeptide is immobilized on a surface comprising a Biacore™ (e.g., in a Biacore™ assay) or other medium suitable for surface plasmon resonance analysis. Binding of the reference antibody in the presence of a completely irrelevant antibody (that does not bind to DLL3) can serve as a high control. A low control can be obtained by incubating a labeled reference antibody with an unlabeled reference antibody, which will result in competition and reduced binding of the labeled reference antibody.In certain embodiments, a test extracellular antigen-binding domain that reduces binding of the reference antibody to a DLL3 polypeptide by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% is considered to be an extracellular antigen-binding domain that cross-competes with the reference antibody for binding to DLL3. In certain embodiments, the assay is performed at room temperature.

[0355] In certain embodiments, the antibody binding assay comprises measuring initial binding of a test extracellular antigen-binding domain to a DLL3 polypeptide, mixing the test extracellular antigen-binding domain with a reference antibody, measuring second binding of the test extracellular antigen-binding domain to the DLL3 polypeptide in the presence of the reference antibody, and comparing the initial binding of the test extracellular antigen-binding domain to the second binding of the test extracellular antigen-binding domain, wherein a decrease in second binding of the test extracellular antigen-binding domain to the DLL3 polypeptide compared to the initial binding indicates that the test extracellular antigen-binding domain cross-competes with the reference antibody, e.g., an antibody that recognizes the same or substantially the same epitope, an overlapping epitope, or an adjacent epitope, for binding to DLL3. In certain embodiments, the test extracellular antigen-binding domain is labeled, e.g., with a fluorescent dye, biotin, or peroxidase. In certain embodiments, the DLL3 polypeptide is expressed intracellularly, e.g., in a flow cytometry assay. In certain embodiments, the DLL3 polypeptide is immobilized on a surface comprising a Biacore™ (e.g., in a Biacore™ assay) or other medium suitable for surface plasmon resonance analysis. Binding of the test extracellular antigen-binding domain in the presence of a completely irrelevant antibody (that does not bind to DLL3) can serve as a high control. A low control can be obtained by incubating a labeled test extracellular antigen-binding domain with an unlabeled test extracellular antigen-binding domain, resulting in competition and reduced binding of the labeled test extracellular antigen-binding domain. In certain embodiments, a test extracellular antigen-binding domain whose binding to the DLL3 polypeptide is reduced by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% in the presence of the reference antibody is considered to be an extracellular antigen-binding domain that cross-competes with the reference antibody for binding to DLL3. In certain embodiments, the assay is performed at room temperature.

[0356] In certain non-limiting embodiments, the extracellular antigen-binding domain of a CAR of the present disclosure comprises a linker connecting the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 209. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 210. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 211. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 212. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 213. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 214.

[0357] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a heavy chain variable region (V H In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V H -V L .

[0358] In certain embodiments, the variable region within the extracellular antigen-binding domain comprises a light chain variable region (V L In certain embodiments, when the extracellular antigen-binding domain is an scFv, the variable regions are arranged from the N-terminus to the C-terminus: V L -V H .

[0359] Chimeric Antigen Receptors (CARs) In certain embodiments, the antigen-recognition receptor is a CAR. A CAR is an engineered receptor that transfers or confers a desired specificity onto immune effector cells. CARs can be used to transfer the specificity of monoclonal antibodies into T cells, and the transfer of their coding sequences is facilitated by retroviral vectors.

[0360] There are three generations of CARs. "First generation" CARs are typically composed of an extracellular antigen-binding domain (e.g., scFv) fused to a transmembrane domain, which is fused to a cytoplasmic / intracellular signaling domain. "First generation" CARs can provide novel antigen recognition and bind to CD4 ζ chains via the CD3ζ chain signaling domain in a single fusion molecule, independent of HLA-mediated antigen presentation. + and CD8 + The antigen-recognizing receptor can induce both activation and activation of T cells. "Second-generation" CARs add intracellular signaling domains from various costimulatory molecules (e.g., CD28, 4-1BB, ICOS, OX40) to the cytoplasmic tail of the CAR to provide additional signals to T cells. "Second-generation" CARs include those that provide both costimulation (e.g., CD28 or 4-1BB) and activation (CD3ζ). "Third-generation" CARs include those that provide multiple costimulations (e.g., CD28 and 4-1BB) and activation (CD3ζ). In certain embodiments, the antigen-recognizing receptor is a first-generation CAR. In certain embodiments, the antigen-recognizing receptor is a CAR that does not include the intracellular signaling domain of a costimulatory molecule or a fragment thereof. In certain embodiments, the antigen-recognizing receptor is a second-generation CAR.

[0361] In certain embodiments, the CAR comprises an extracellular antigen-binding domain that specifically binds to DLL3, a transmembrane domain, and an intracellular signaling domain.

[0362] 5.3.2.1. Extracellular Antigen-Binding Domain of the CAR The extracellular antigen-binding domain of the CAR can be any extracellular antigen-binding domain disclosed herein, e.g., in Section 4.3.1.

[0363] In certain embodiments, the CAR comprises an extracellular antigen-binding domain disclosed in Section 4.3.1.

[0364] In addition, the extracellular antigen-binding domain can comprise a leader or signal peptide that directs the nascent protein into the endothelial endoplasmic reticulum. A signal peptide or leader may be essential if the CAR is glycosylated and anchored in the cell membrane. The signal sequence or leader can be a peptide sequence (about 5, about 10, about 15, about 20, about 25, or about 30 amino acids in length) present at the N-terminus of a newly synthesized protein that directs entry into the secretory pathway. In certain embodiments, the signal peptide is covalently linked to the 5' end of the extracellular antigen-binding domain. In certain embodiments, the signal peptide comprises a CD8 polypeptide, e.g., the CAR comprises a truncated CD8 signal peptide.

[0365] 5.3.2.2. CAR Transmembrane Domain In certain non-limiting embodiments, the transmembrane domain of the CAR comprises a hydrophobic alpha helix that spans at least a portion of the membrane. Different transmembrane domains result in different receptor stabilities. After antigen recognition, the receptors cluster and transmit a signal to the cell. According to the presently disclosed subject matter, the transmembrane domain of the CAR can comprise a native or modified transmembrane domain of CD8 or a fragment thereof, a native or modified transmembrane domain of CD28 or a fragment thereof, a native or modified transmembrane domain of CD3ζ or a fragment thereof, a native or modified transmembrane domain of CD4 or a fragment thereof, a native or modified transmembrane domain of 4-1BB or a fragment thereof, a native or modified transmembrane domain of OX40 or a fragment thereof, a fragment thereof, a native or modified transmembrane domain of ICOS or a fragment thereof, a native or modified transmembrane domain of CD84 or a fragment thereof, a native or modified transmembrane domain of CD166 or a fragment thereof, a native or modified transmembrane domain of CD8a or a fragment thereof, a native or modified transmembrane domain of CD8b or a fragment thereof, a native or modified transmembrane domain of ICAM-1 or a fragment thereof, a native or modified transmembrane domain of CTLA-4 or a fragment thereof, a native or modified transmembrane domain of CD27 or a fragment thereof, a native or modified transmembrane domain of CD40 or a fragment thereof, NKGD2 or a fragment thereof, or a combination thereof.

[0366] In certain embodiments, the transmembrane domain of the CAR comprises a CD8 polypeptide (e.g., the transmembrane domain of CD8 or a fragment thereof). In certain embodiments, the transmembrane domain of the CAR comprises the transmembrane domain of human CD8 or a fragment thereof. In certain embodiments, the CD8 polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% homologous or identical to the amino acid sequence having NCBI reference number NP_001139345.1 (SEQ ID NO: 216) or a fragment thereof, and / or may optionally contain up to one, or up to two, or up to three conservative amino acid substitutions. In certain embodiments, the CD8 polypeptide comprises or consists of an amino acid sequence that is at least 20, or at least 30, or at least 40, or at least 50, and up to 235 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the CD8 polypeptide comprises or consists of the amino acid sequence of amino acids 1-235, 1-50, 50-100, 100-150, 150-200, 137-209, or 200-235 of SEQ ID NO: 216. In certain embodiments, the transmembrane domain of the CAR comprises a CD8 polypeptide comprising or consisting of amino acids 137-209 of SEQ ID NO: 216. SEQ ID NO: 216 is provided below. MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPTSGCSWLFQPRGAAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLTLSDFRRENEGYYFCSALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRRVCKCPRPVVKSGDKPSLSARYV [SEQ ID NO: 216]

[0367] In certain embodiments, the transmembrane domain of the CAR comprises the transmembrane domain of murine CD8 or a fragment thereof. In certain embodiments, the CD8 polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% homologous or identical to the amino acid sequence having NCBI reference number AAA92533.1 (SEQ ID NO: 217) or a fragment thereof, and / or may optionally contain up to one, up to two, or up to three conservative amino acid substitutions. In certain embodiments, the CD8 polypeptide comprises or consists of an amino acid sequence that is a contiguous portion of SEQ ID NO: 217 and is at least about 20, or at least about 30, or at least about 40, or at least about 50, or at least about 60, or at least about 70, or at least about 100, or at least about 200, and up to 247 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the CD8 polypeptide comprises or consists of the amino acid sequence of amino acids 1-247, 1-50, 50-100, 100-150, 150-200, 151-219, or 200-247 of SEQ ID NO: 217. In certain embodiments, the transmembrane domain of the CAR comprises a CD8 polypeptide comprising or consisting of amino acids 151-219 of SEQ ID NO: 217. SEQ ID NO: 217 is provided below. [ka]

[0368] In certain embodiments, the transmembrane domain of a CAR of the present disclosure comprises a CD28 polypeptide (e.g., the transmembrane domain of CD28 or a fragment thereof).

[0369] In certain embodiments, the transmembrane domain of the CAR comprises the transmembrane domain of human CD28 or a fragment thereof. In certain embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% homologous or identical to the amino acid sequence having NCBI reference number NP_006130 (SEQ ID NO: 218), or a fragment thereof, and / or may optionally contain up to one, or up to two, or up to three conservative amino acid substitutions. In certain non-limiting embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence that is a contiguous portion of SEQ ID NO: 218 that is at least 20, or at least 30, or at least 40, or at least 50, and up to 220 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the CD28 polypeptide comprises or consists of the amino acid sequence of amino acids 1-220, 1-50, 50-100, 100-150, 150-200, 153-179, or 200-220 of SEQ ID NO: 218. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide comprising or consisting of amino acids 153-179 of SEQ ID NO: 218. SEQ ID NO: 218 is provided below. [ka]

[0370] In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide (e.g., the transmembrane domain of murine CD28 or a fragment thereof). In certain embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% homologous or identical to the amino acid sequence having NCBI reference number NP_031668.3 (SEQ ID NO: 219), or a fragment thereof, and / or may optionally contain up to one, or up to two, or up to three conservative amino acid substitutions. In certain non-limiting embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence that is at least 20, or at least 30, or at least 40, or at least 50, and up to 218 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the CD28 polypeptide comprises or consists of the amino acid sequence of amino acids 1-220, 1-50, 50-100, 100-150, 150-200, 151-177, or 200-218 of SEQ ID NO: 219. In certain embodiments, the transmembrane domain of the CAR comprises a CD28 polypeptide comprising or consisting of amino acids 151-177 of SEQ ID NO: 219. SEQ ID NO: 219 is provided below. [ka]

[0371] In certain non-limiting embodiments, the CAR further comprises a spacer region linking the extracellular antigen-binding domain to the transmembrane domain. The spacer region can be flexible enough to orient the antigen-binding domain in different directions to facilitate antigen recognition while maintaining the activation activity of the CAR.

[0372] In certain embodiments, the hinge / spacer region of the CAR is selected from the group consisting of a native or modified hinge region of CD8 or a fragment thereof, a native or modified hinge region of CD28 or a fragment thereof, a native or modified hinge region of CD3ζ or a fragment thereof, a native or modified hinge region of CD40 or a fragment thereof, a native or modified hinge region of 4-1BB or a fragment thereof, a native or modified hinge region of OX40 or a fragment thereof, a native or modified hinge region of CD84 or a fragment thereof, a native or modified hinge region of CD166 or a fragment thereof, a native or modified hinge region of CD8a, The hinge region may be a decorative hinge region or fragment thereof, a native or modified hinge region of CD8b or fragment thereof, a native or modified hinge region of ICOS or fragment thereof, a native or modified hinge region of ICAM-1 or fragment thereof, a native or modified hinge region of CTLA-4 or fragment thereof, a native or modified hinge region of CD27 or fragment thereof, a native or modified hinge region of CD40 or fragment thereof, a native or modified hinge region of NKGD2 or fragment thereof, a synthetic polypeptide (not based on a protein associated with an immune response), or a combination thereof. The hinge / spacer region can be a hinge region from IgG1, or an immunoglobulin CH2CH3 region and a portion of CD3, a portion of a CD28 polypeptide (e.g., a portion of SEQ ID NO: 218 or 219), a portion of a CD8 polypeptide (e.g., a portion of SEQ ID NO: 216 or 217), a variation of any of the foregoing that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% homologous or identical thereto, or a synthetic spacer sequence.

[0373] 5.3.2.3. CAR Intracellular Signaling Domain In certain embodiments, the CAR comprises an intracellular signaling domain. In certain non-limiting embodiments, the intracellular signaling domain of the CAR comprises a CD3ζ polypeptide. CD3ζ can activate or stimulate cells (e.g., lymphoid cells, e.g., T cells). Wild-type ("native") CD3ζ contains three functional immunoreceptor tyrosine-based activation motifs (ITAMs), three functional basic-rich stretch (BRS) regions (BRS1, BRS2, ​​and BRS3). CD3ζ transmits activation signals to cells (e.g., lymphoid cells, e.g., T cells) after antigen binding. The intracellular signaling domain of the CD3ζ chain is the primary transmitter of signals from endogenous TCRs.

[0374] In certain embodiments, the intracellular signaling domain of the CAR comprises native CD3ζ. In certain embodiments, the CD3ζ polypeptide comprises or consists of an amino acid sequence that is at least about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% homologous or identical to the amino acid sequence having NCBI reference number NP_932170 (SEQ ID NO: 220), or a fragment thereof, and / or may optionally contain up to one, up to two, or up to three conservative amino acid substitutions. In certain non-limiting embodiments, the CD3ζ polypeptide comprises or consists of an amino acid sequence that is a contiguous portion of SEQ ID NO: 220 that is at least 20, or at least 30, or at least 40, or at least 50, and up to 164 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the CD3ζ polypeptide comprises or consists of the amino acid sequence of amino acids 1-164, 1-50, 50-100, 52-164, 100-150, or 150-164 of SEQ ID NO: 220. In certain embodiments, the intracellular signaling domain of a CAR comprises a CD3ζ polypeptide comprising or consisting of amino acids 52-164 of SEQ ID NO: 220. SEQ ID NO: 220 is provided below. [ka]

[0375] In certain embodiments, the intracellular signaling domain of the CAR comprises a CD3 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 221. SEQ ID NO: 221 is provided below. RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR [SEQ ID NO: 221]

[0376] An exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO:221 is set forth in SEQ ID NO:222, provided below. AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCC TGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC [SEQ ID NO: 222]

[0377] In certain embodiments, the intracellular signaling domain of the CAR further comprises at least a costimulatory signaling region. In certain embodiments, the costimulatory signaling region comprises at least one costimulatory molecule or a fragment thereof. In certain embodiments, the costimulatory signaling region comprises the intracellular domain of at least one costimulatory molecule or a fragment thereof.

[0378] As used herein, a "costimulatory molecule" refers to a cell surface molecule other than an antigen receptor or its ligand that can provide an efficient lymphocyte response to an antigen. In certain embodiments, a costimulatory molecule can provide optimal lymphocyte activation. Non-limiting examples of costimulatory molecules include CD28, 4-1BB, OX40, ICOS, DAP-10, CD27, CD40, NKGD2, CD2, FN14, HVEM, LTBR, ​​CD28H, TNFR1, TNFR2, BAFF-R, BCMA, TACI, TROY, RANK, CD40, CD27, CD30, EDAR, XEDAR, GITR, DR6, and NGFR, and combinations thereof. A costimulatory molecule can bind to a costimulatory ligand, which is a protein expressed on the cell surface that, upon binding to its receptor, generates a costimulatory response, i.e., an intracellular response that affects the stimulation provided when an antigen-recognizing receptor (e.g., a chimeric antigen receptor (CAR)) binds to its target antigen. As an example, 4-1BB ligand (i.e., 4-1BBL) can be used in combination with a CAR signal to induce CAR + It can bind to 4-1BB to provide an intracellular signal that induces effector cell function in T cells.

[0379] In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising a CD28 polypeptide, e.g., the intracellular domain of CD28, or a fragment thereof. In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising a CD28 polypeptide, e.g., the intracellular domain of human CD28, or a fragment thereof. In certain embodiments, the CD28 polypeptide 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% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 218, or a fragment thereof, and / or may optionally comprise up to one, or up to two, or up to three conservative amino acid substitutions. In certain non-limiting embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence that is a contiguous portion of SEQ ID NO: 218 that is at least 20, or at least 30, or at least 40, or at least 50, and up to 220 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the CD28 polypeptide comprises or consists of the amino acid sequence of amino acids 1-220, 1-50, 50-100, 100-150, 114-220, 150-200, 180-220, or 200-220 of SEQ ID NO: 218. In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising a CD28 polypeptide that comprises or consists of the amino acid sequence of amino acids 180-220 of SEQ ID NO: 218.

[0380] In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising the intracellular domain of a CD28 polypeptide, e.g., mouse CD28, or a fragment thereof. In certain embodiments, the CD28 polypeptide 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% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 219 or a fragment thereof, and / or may optionally contain up to one, or up to two, or up to three conservative amino acid substitutions. In certain non-limiting embodiments, the CD28 polypeptide comprises or consists of an amino acid sequence that is at least about 20, or at least about 30, or at least about 40, or at least about 50, and up to 218 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the CD28 polypeptide comprises or consists of the amino acid sequence of amino acids 1-218, 1-50, 50-100, 100-150, 150-218, 178-218, or 200-218 of SEQ ID NO: 219. In certain embodiments, the costimulatory signaling region of a CAR of the disclosure comprises a CD28 polypeptide comprising or consisting of amino acids 178-218 of SEQ ID NO: 219.

[0381] In certain embodiments, the costimulatory signaling region of a CAR of the present disclosure comprises a CD28 polypeptide containing a mutated YMNM motif. CD28 is a transmembrane protein that plays an important role in T cell activation through its function as a costimulatory molecule. CD28 has an intracellular domain containing an intracellular motif important for effective CD28 signal transduction. In certain embodiments, the CD28 intracellular domain contains an intracellular subdomain (also known as an "intracellular motif") that regulates signal transduction pathways following TCR stimulation. CD28 contains three intracellular motifs: the YMNM motif, and two proline-rich motifs: the PRRP motif and the PYAP motif. The CD28 intracellular motifs can serve as docking sites for numerous adaptor molecules that interact with these motifs via their SH2 or SH3 domains. Such interactions transmit downstream signals that terminate on transcription factors that regulate gene expression. For example, the native YMNM motif binds to the p85 subunit of phosphoinositide 3-kinase (PI3K). The natural YMNM motif also binds to growth factor receptor-bound protein 2 (Grb2) and / or Grb2-associated adaptor protein 2 (GADS). Grb2 binds to Gab1 and Gab2, which can then recruit the p85 subunit of PI3K.

[0382] In certain embodiments, the naturally occurring YMNM motif consists of the amino acid sequence set forth in YMNM (SEQ ID NO: 224). In certain embodiments, the naturally occurring YMNM motif binds to the p85 subunit of PI3K via the consensus sequence YMxM (SEQ ID NO: 225), where x is not aspartic acid (N). In certain embodiments, the naturally occurring YMNM motif binds to Grb2 and / or GAD via the consensus sequence YxNx (SEQ ID NO: 226), where x is not methionine (M).

[0383] In certain embodiments, CD28 polypeptides containing a mutated YMNM motif of the present disclosure exhibit reduced recruitment of the p85 subunit of PI3K compared to CD28 molecules containing a native YMNM motif. In certain embodiments, the p85 subunit of PI3K does not bind to the mutated YMNM motif, thereby reducing recruitment of the p85 subunit of PI3K to the CD28 polypeptide. Mutated YMNM motifs that block binding of the p85 subunit of PI3K retain binding to Grb2 and / or GADS. Thus, downstream signaling of Grb2 / GADS remains intact, e.g., downstream signaling leading to IL-2 secretion remains intact. Such mutated YMNM motifs are referred to as "GADS / Grb2-permissive mutants."

[0384] In certain embodiments, the mutated YMNM motif binds to the p85 subunit of PI3K but not to Grb2 and / or GADS. Because PI3K p85 binding is maintained, downstream PI3K signaling remains intact. Because Grb2 / GADS binding is blocked, recruitment of the PI3K p85 subunit induced by Grb2 binding to Gab1 and Gab2 is reduced or blocked. In addition, downstream Grb2 / GADS signaling is blocked. Such mutated YMNM motifs are referred to as "PI3K-permissive mutants."

[0385] In certain embodiments, the mutated YMNM motif does not bind to the p85 subunit of PI3K and does not bind to Grb2 and / or GADS. Such mutated YMNM motifs are referred to as "non-functional mutants." Non-functional mutants do not provide for binding of PI3K, Grb2, or GADS to CD28 at the YMNM motif, but do not prevent these signaling molecules from binding elsewhere within the CD28 molecule.

[0386] In certain embodiments, the mutated YMNM motif retains only one of the two methionine residues present in the YMNM motif, i.e., YMxx or YxxM. These motifs potentially regulate PI3K-mediated signaling by limiting the number of methionine residues that can bind to the p85 subunit of PI3K. Such mutated YMNM motifs are referred to as "hybrid 'HEMI' mutants."

[0387] In certain embodiments, the mutated YMNM motif is a GADS / Grb-2 permissive mutant. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YxNx (SEQ ID NO: 226), where x is not methionine (M). In certain embodiments, x is selected from the group consisting of the amino acids A, R, N, D, C, E, Q, G, H, I, K, F, P, S, T, W, Y, V, and L. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YENV (SEQ ID NO: 227), YSNV (SEQ ID NO: 228), YKNL (SEQ ID NO: 229), YENQ (SEQ ID NO: 230), YKNI (SEQ ID NO: 231), YINQ (SEQ ID NO: 232), YHNK (SEQ ID NO: 233), YVNQ (SEQ ID NO: 234), YLNP (SEQ ID NO: 235), YLNT (SEQ ID NO: 236), YDND (SEQ ID NO: 237), YENI (SEQ ID NO: 238), YENL (SEQ ID NO: 239), YKNQ (SEQ ID NO: 240), YKNV (SEQ ID NO: 241), or YANG (SEQ ID NO: 242). In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YSNV (SEQ ID NO: 228). In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YKNI (SEQ ID NO: 231). In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YENV (SEQ ID NO: 227). In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YKNL (SEQ ID NO: 229).

[0388] In certain embodiments, the mutated YMNM motif is a PI3K-permissive mutant. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YMxM (SEQ ID NO: 225), where x is not aspartic acid (N). In certain embodiments, x is selected from the group consisting of the amino acids A, R, D, C, E, Q, G, H, I, K, M, F, P, S, T, W, Y, V, and L. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YMDM (SEQ ID NO: 243), YMPM (SEQ ID NO: 244), YMRM (SEQ ID NO: 245), or YMSM (SEQ ID NO: 246). In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YMDM (SEQ ID NO: 243).

[0389] In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YbxM (SEQ ID NO:247), where x is not aspartic acid (N) and b is not methionine (M). In certain embodiments, x is selected from the group consisting of the amino acids A, R, D, C, E, Q, G, H, I, K, M, F, P, S, T, W, Y, V, and L. In certain embodiments, b is selected from the group consisting of the amino acids A, R, N, C, E, Q, G, H, I, K, N, F, P, S, T, W, Y, V, and L. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YTHM (SEQ ID NO:248), YVLM (SEQ ID NO:249), YIAM (SEQ ID NO:250), YVEM (SEQ ID NO:251), YVKM (SEQ ID NO:252), or YVPM (SEQ ID NO:253).

[0390] In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YMxb (SEQ ID NO: 254), where x is not aspartic acid (N) and b is not methionine (M). In certain embodiments, x is selected from the group consisting of the amino acids A, R, D, C, E, Q, G, H, I, K, M, F, P, S, T, W, Y, V, and L. In certain embodiments, b is selected from the group consisting of the amino acids A, R, N, C, E, Q, G, H, I, K, N, F, P, S, T, W, Y, V, and L. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YMAP (SEQ ID NO: 255).

[0391] Certain mutated YMNM motifs are described in Mol Cell Proteomics. 2010 Nov;9(11):2391-404, Virology. 2015 May;0:568-577, both of which are incorporated herein by reference in their entireties.

[0392] In certain embodiments, the mutated YMNM motif is a hybrid "HEMI" mutant. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YMNx (SEQ ID NO: 256) or YxNM (SEQ ID NO: 257), where x is not methionine (M). In certain embodiments, x is selected from the group consisting of the amino acids A, R, N, C, E, Q, G, H, I, K, N, F, P, S, T, W, Y, V, and L. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YMNV (SEQ ID NO: 258), YENM (SEQ ID NO: 259), YMNQ (SEQ ID NO: 260), YMNL (SEQ ID NO: 261), or YSNM (SEQ ID NO: 262).

[0393] In certain embodiments, the mutated YMNM motif is a non-functional variant. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence Ybxb (SEQ ID NO: 263), where x is not aspartic acid (N) and b is not methionine (M). In certain embodiments, x is selected from the group consisting of A, R, D, C, E, Q, G, H, I, K, M, F, P, S, T, W, Y, V, and L. In certain embodiments, b is selected from the group consisting of A, R, N, D, C, E, Q, G, H, I, K, F, P, S, T, W, Y, V, and L. In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YGGG (SEQ ID NO: 264), YAAA (SEQ ID NO: 265), YFFF (SEQ ID NO: 266), YETV (SEQ ID NO: 267), YQQQ (SEQ ID NO: 268), YHAE (SEQ ID NO: 269), YLDL (SEQ ID NO: 270), YLIP (SEQ ID NO: 271), YLRV (SEQ ID NO: 272), YTAV (SEQ ID NO: 273), or YVHV (SEQ ID NO: 274). In certain embodiments, the mutated YMNM motif consists of the amino acid sequence set forth in YGGG (SEQ ID NO: 264).

[0394] In specific embodiments, the intracellular signaling domain of a chimeric receptor of the present disclosure comprises a costimulatory signaling domain comprising a CD28 polypeptide comprising a mutated YMNM motif consisting of the amino acid sequence set forth in YENV (SEQ ID NO: 227), wherein the CD28 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 275. SEQ ID NO: 275 is provided below. RSKRSRLLHSDYENVTPRRPGPTRKHYQPYAPPRDFAAYRS [SEQ ID NO: 275]

[0395] In specific embodiments, the intracellular signaling domain of a chimeric receptor of the present disclosure comprises a costimulatory signaling domain comprising a CD28 polypeptide comprising a mutated YMNM motif consisting of the amino acid sequence set forth in YKNI (SEQ ID NO: 231), wherein the CD28 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 276. SEQ ID NO: 276 is provided below. RSKRSRLLHSDYKNITPRRPGPTRKHYQPYAPPRDFAAYRS [SEQ ID NO: 276]

[0396] In specific embodiments, the intracellular signaling domain of a chimeric receptor of the present disclosure comprises a costimulatory signaling domain comprising a CD28 polypeptide comprising a mutated YMNM motif consisting of the amino acid sequence set forth in YMDM (SEQ ID NO: 243), wherein the CD28 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 277. SEQ ID NO: 277 is provided below. RSKRSRLLHSDYMDMTPRRPGPTRKHYQPYAPPRDFAAYRS [SEQ ID NO: 277]

[0397] In specific embodiments, the intracellular signaling domain of a chimeric receptor of the present disclosure comprises a costimulatory signaling domain comprising a CD28 polypeptide comprising a mutated YMNM motif consisting of the amino acid sequence set forth in YGGG (SEQ ID NO: 264), wherein the CD28 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 278. SEQ ID NO: 278 is provided below. RSKRSRLLHSDYGGGTPRRPGPTRKHYQPYAPPRDFAAYRS [SEQ ID NO: 278]

[0398] In specific embodiments, the intracellular signaling domain of a chimeric receptor of the present disclosure comprises a costimulatory signaling domain comprising a CD28 polypeptide comprising a mutated YMNM motif consisting of the amino acid sequence set forth in YSNV (SEQ ID NO: 228), wherein the CD28 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 279. SEQ ID NO: 279 is provided below. RSKRSRLLHSDYSNVTPRRPGPTRKHYQPYAPPRDFAAYRS [SEQ ID NO: 279]

[0399] In certain embodiments, the intracellular signaling domain of a CAR of the present disclosure comprises a first costimulatory signaling domain comprising a CD28 polypeptide comprising a mutated YMNM motif (disclosed herein), and a second costimulatory signaling domain comprising the intracellular domain of a costimulatory molecule. Additional information regarding CARs comprising a CD28 polypeptide comprising a mutated YMNM motif can be found in International Patent Publication No. WO 2021 / 158850, which is incorporated by reference in its entirety.

[0400] In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising a 4-1BB polypeptide, e.g., the intracellular domain of 4-1BB, or a fragment thereof. In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising a 4-1BB polypeptide, e.g., the intracellular domain of human 4-1BB, or a fragment thereof. In certain embodiments, the 4-1BB polypeptide 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%, at least about 100% homologous or identical to the amino acid sequence having NCBI reference number NP_001552 (SEQ ID NO: 221), or a fragment thereof, and / or may optionally comprise up to one, or up to two, or up to three conservative amino acid substitutions. In certain non-limiting embodiments, the 4-1BB polypeptide comprises or consists of an amino acid sequence that is a contiguous portion of SEQ ID NO: 223 that is at least 20, or at least 30, or at least 40, or at least 50, or at least 100, or at least 150, or at least 150, and up to 255 amino acids in length. Alternatively or additionally, in various non-limiting embodiments, the 4-1BB polypeptide comprises or consists of the amino acid sequence of amino acids 1-255, 1-50, 50-100, 100-150, 150-200, or 200-255 of SEQ ID NO: 223. In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising a 4-1BB polypeptide that comprises or consists of the amino acid sequence of amino acids 214-255 of SEQ ID NO: 223. SEQ ID NO: 223 is provided below. [ka]

[0401] In certain embodiments, the intracellular signaling domain of the CAR comprises a costimulatory signaling region comprising the intracellular domains of two or more costimulatory molecules or portions thereof (e.g., the intracellular domain of CD28 or a fragment thereof and the intracellular domain of 4-1BB or a fragment thereof, or the intracellular domain of CD28 or a fragment thereof and the intracellular domain of OX40 or a fragment thereof). 【0...

Claims

1. An antigen recognition receptor comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular antigen-binding domain specifically binds to DLL3, and the extracellular antigen-binding domain (a) a heavy chain variable region 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; (b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof; (c) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 or a conservative modification thereof; (d) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a conservative modification thereof; (e) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39 or a conservative modification thereof; (f) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 or a conservative modification thereof; (g) a heavy chain variable region 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; (h) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 or a conservative modification thereof; (i) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 or a conservative modification thereof; (j) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 80 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 81 or a conservative modification thereof; (k) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 87 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 88 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 89 or a conservative modification thereof; (l) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 97 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 98 or a conservative modification thereof; (m) a heavy chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107 or a conservative modification thereof; (n) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 95 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof; (o) a heavy chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123 or a conservative modification thereof; (p) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 137 or a conservative modification thereof; (q) a heavy chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 145 or a conservative modification thereof; (r) a heavy chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof; (s) a heavy chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof; (t) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; (u) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 176 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177 or a conservative modification thereof; (v) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 184 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 185 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186 or a conservative modification thereof; (w) a heavy chain variable region 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: 194 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof; or (x) An antigen-recognizing receptor comprising a heavy chain variable region including CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 202 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 203 or a conservative modification thereof.

2. The antigen-recognizing receptor of claim 1 , wherein the extracellular antigen-binding domain is a single-chain variable fragment (scFv).

3. The antigen-recognizing receptor according to claim 2 , wherein the extracellular antigen-binding domain is a human scFv.

4. The antigen-recognizing receptor of claim 1, wherein the extracellular antigen-binding domain is an optionally cross-linked Fab.

5. The extracellular antigen-binding domain is F(ab) ２ The antigen-recognition receptor according to claim 1,

6. The scFv, Fab, and F(ab) ２ The antigen-recognizing receptor according to any one of claims 2 to 5, wherein one or more of the following are included in a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain.

7. the extracellular antigen-binding domain (a) a heavy chain variable region 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; (b) a heavy chain variable region 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; or (c) an antigen-recognizing receptor according to claim 1, comprising a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 or a conservative modification thereof.

8. the extracellular antigen-binding domain (a) a light chain variable region 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; (b) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or a conservative modification thereof, and CDR3 comprising SEQ ID NO: 16 or a conservative modification thereof; (c) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof; (d) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31 or a conservative modification thereof, CDR2 comprising SEQ ID NO: 32 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33 or a conservative modification thereof; (e) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof; (f) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51 or a conservative modification thereof; (g) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof; (h) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 65 or a conservative modification thereof; (i) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75 or a conservative modification thereof; (j) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 82 or a conservative modification thereof; (k) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 280 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91 or a conservative modification thereof; (l) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 99 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 101 or a conservative modification thereof; (m) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 or a conservative modification thereof; (n) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 117 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 100 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118 or a conservative modification thereof; (o) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof; (p) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 130 or a conservative modification thereof; (q) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof; (r) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof; (s) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof; (t) a light chain variable region comprising: CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73 or a conservative modification thereof; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof; (u) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 171 or a conservative modification thereof; (v) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 179 or a conservative modification thereof; (w) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189 or a conservative modification thereof; (x) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof; or (y) The antigen-recognizing receptor according to claim 1, comprising a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204 or a conservative modification thereof.

9. the extracellular antigen-binding domain (a) a light chain variable region 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; (b) a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or a conservative modification thereof, and CDR3 comprising SEQ ID NO: 16 or a conservative modification thereof; (c) an antigen-recognizing receptor according to claim 1, comprising a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof.

10. the extracellular antigen-binding domain (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: 280, 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 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, and 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; (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; (p) 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, and 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; (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 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, and 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; (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 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, and 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; (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 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; (x) 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: 176, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177; and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 178, 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: 79; (y) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 184, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 185, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 186; and a light chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 187, CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 188, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 189; (z) 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: 194, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 195, 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: 196; or (aa) An antigen-recognizing receptor according to claim 1, comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 201, CDR2 having the amino acid sequence set forth in SEQ ID NO: 202, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 203, 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:

204.

11. the extracellular antigen-binding domain (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; or (c) an antigen-recognizing receptor according to claim 1, comprising 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.

12. the extracellular antigen-binding domain is selected from the group consisting of 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:180, 2. The antigen-recognizing receptor of claim 1, comprising a heavy chain variable region 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: 190, SEQ ID NO: 197, or SEQ ID NO:

205.

13. The antigen recognition receptor of claim 1, wherein the extracellular antigen-binding domain 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, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:190, SEQ ID NO:197, or SEQ ID NO:

205.

14. The antigen-recognizing receptor of claim 1, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 17, or SEQ ID NO:

24.

15. The extracellular antigen-binding domain is selected from the group consisting of 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: 181, SEQ ID NO: 191, SEQ ID NO: 198, or SEQ ID NO:

206. The antigen-recognizing receptor of claim 1, comprising a light chain variable region 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: 181, SEQ ID NO: 191, SEQ ID NO: 198, or SEQ ID NO:

206.

16. The antigen recognition receptor of claim 1, wherein the extracellular antigen-binding domain 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, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:191, SEQ ID NO:198, or SEQ ID NO:

206.

17. The antigen-recognizing receptor of claim 1, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8, SEQ ID NO: 18, or SEQ ID NO:

25.

18. The extracellular antigen-binding domain comprises (a) the amino acid sequence of 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:180, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:188, SEQ ID NO:189, SEQ ID NO:190, SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:200, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:224, SEQ ID NO:225, SEQ ID a heavy chain variable region 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 selected amino acid sequence set forth in SEQ ID NO:180, SEQ ID NO:190, SEQ ID NO:197, or SEQ ID NO:205; and ) 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:181, SEQ ID NO:

2. The antigen-recognizing receptor of claim 1, comprising a light chain variable region 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: 191, SEQ ID NO: 198, or SEQ ID NO:

206.

19. the extracellular antigen-binding domain comprises (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, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:190, SEQ ID NO:197, or SEQ ID NO:205; and (b) a heavy chain variable region comprising the amino acid sequence set forth in the sequence 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: 181, SEQ ID NO: 191, SEQ ID NO: 198, or SEQ ID NO:

206. The antigen recognition receptor of claim 1, 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, SEQ ID NO: 173, SEQ ID NO: 181, SEQ ID NO:

20. The antigen-recognizing receptor of claim 1, wherein the extracellular antigen-binding domain comprises: (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:7, SEQ ID NO:17, or SEQ ID NO:24; and (b) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:18, or SEQ ID NO:

25.

21. the extracellular antigen-binding domain (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; and (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: 180, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 181; (y) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 190, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 191; (z) 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; or (aa) The antigen-recognizing receptor of claim 1, comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 205, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:

206.

22. the extracellular antigen-binding domain (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; or (c) an antigen-recognizing receptor according to claim 1, comprising 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.

23. The antigen-recognizing receptor according to claim 1 , wherein the extracellular antigen-binding domain comprises a linker between the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain.

24. 24. The antigen recognition receptor of claim 23, wherein the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, or SEQ ID NO:

214.

25. The antigen-recognizing receptor according to claim 1 , wherein the extracellular antigen-binding domain comprises a signal peptide covalently linked to the 5′ end of the extracellular antigen-binding domain.

26. The antigen-recognizing receptor of claim 1, wherein the transmembrane domain comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, or a combination thereof.

27. The antigen-recognition receptor of claim 1, wherein the intracellular signaling domain comprises a CD3ζ polypeptide.

28. The antigen recognition receptor of claim 27, wherein the CD3ζ polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO:

221.

29. The antigen-recognizing receptor of claim 1, wherein the intracellular signaling domain further comprises at least one costimulatory signaling region.

30. 30. The antigen recognition receptor of claim 29, wherein the at least one costimulatory signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, or a combination thereof.

31. The antigen-recognizing receptor of claim 30, wherein the at least one costimulatory signaling region comprises a CD28 polypeptide.

32. The antigen recognition receptor of claim 31, wherein the CD28 polypeptide comprises or consists of amino acids 180 to 220 of SEQ ID NO:

7.

33. The antigen-recognizing receptor of claim 31 , wherein the CD28 polypeptide comprises a mutated YMNM motif.

34. 32. The antigen-recognition receptor of claim 31 , wherein the CD28 polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 277, SEQ ID NO: 278, or SEQ ID NO:

279.

35. The antigen recognition receptor according to claim 1 , wherein the antigen recognition receptor is a chimeric antigen receptor (CAR) or a T cell-like fusion protein.

36. The antigen recognition receptor according to claim 1 , wherein the antigen recognition receptor is a CAR.

37. The antigen-recognizing receptor of claim 1 , wherein the antigen-recognizing receptor is recombinantly expressed.

38. The antigen-recognizing receptor of claim 1 , wherein the antigen-recognizing receptor is expressed from a vector.

39. The antigen-recognizing receptor according to claim 38, wherein the vector is a gamma-retroviral vector.

40. A cell comprising the antigen-recognizing receptor according to any one of claims 1 to 5 and 7 to 39.

41. The cell of claim 40, wherein the cell is transduced with the antigen-recognizing receptor.

42. The cell of claim 40, wherein the antigen-recognizing receptor is constitutively expressed on the surface of the cell.

43. The cell of claim 40, further comprising an exogenous IL-18 polypeptide.

44. The cell of claim 43, wherein the exogenous IL-18 polypeptide is a human IL-18 polypeptide.

45. 41. The cell of claim 40, wherein the cell is an immunoresponsive cell.

46. 41. The cell of claim 40, wherein the cell is a lymphoid or myeloid lineage cell.

47. 41. The cell of claim 40, wherein the cell is selected from the group consisting of a T cell, a natural killer (NK) cell, and a stem cell from which a lymphoid cell can be differentiated.

48. 41. The cell of claim 40, wherein the cell is a T cell.

49. 48. The method of claim 47, wherein the T cells are cytotoxic T lymphocytes (CTLs) or regulatory T cells.

50. 48. The cell of claim 47, wherein the stem cell is a pluripotent stem cell.

51. 51. The cell of claim 50, wherein the pluripotent stem cell is an embryonic-like stem cell or an induced pluripotent stem cell.

52. A nucleic acid encoding the antigen-recognizing receptor according to any one of claims 1 to 5 and 7 to 39.

53. A vector comprising the nucleic acid of claim 52.

54. 54. The vector of claim 53, wherein the vector is a gamma-retroviral vector.

55. A host cell expressing the nucleic acid of claim 52.

56. 56. The host cell of claim 55, wherein the host cell is a T cell.

57. A composition comprising the cells of claim 40.

58. 58. The composition of claim 57, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

59. A lipid nanoparticle comprising the nucleic acid of claim 52.

60. 60. A composition comprising the lipid nanoparticle of claim 59.

61. 61. The composition of claim 60, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

62. 1. A composition for treating or ameliorating a disease or disorder in a subject, said composition comprising: A cell comprising the antigen-recognizing receptor according to any one of claims 1 to 5 and 7 to 39, or Lipid nanoparticles containing nucleic acids encoding the antigen-recognizing receptor contains, or The composition comprises: the cells and a pharmaceutically acceptable carrier; or The lipid nanoparticles and pharmaceutically acceptable carriers The composition, which is a pharmaceutical composition comprising:

63. 63. The composition of claim 62, wherein the disease or disorder is a tumor.

64. 64. The composition of claim 63, wherein the tumor is a cancer.

65. 63. The composition of claim 62, 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.

66. 66. The composition of claim 65, wherein the lung neuroendocrine tumor is selected from the group consisting of lung neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and small cell lung carcinoma.

67. 60. The composition of claim 59, wherein the tumor is small cell lung cancer.

68. 63. The composition of claim 62, wherein the subject is a human.

69. A kit for treating or ameliorating a disease or disorder in a subject, the kit comprising: a cell comprising an antigen-recognition receptor according to any one of claims 1 to 5 and 7 to 39; a nucleic acid encoding the antigen-recognition receptor; a lipid nanoparticle comprising the nucleic acid; a composition comprising the cell, the nucleic acid, or the lipid nanoparticle; or a pharmaceutical composition comprising the cell, the nucleic acid, or the lipid nanoparticle and a pharmaceutically acceptable carrier.

70. 70. The kit of claim 69, wherein the kit further comprises written instructions for using the cells or composition to treat or ameliorate a disease or disorder in a subject.

71. A method for producing the DLL3-targeting antigen-recognizing receptor of any one of claims 1 to 5 and 7 to 39, comprising introducing into the cell a nucleic acid encoding the antigen-recognizing receptor.

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