Gpc3-targeted molecules and uses thereof

Abstract

The presently disclosed subject matter provides binding molecules for glypican-3 (GPC3), including antibodies or antigen-binding fragments thereof that bind to GPC3 and antigen recognizing receptors (e.g., CARs) that target GPC3. Also provided are cells and compositions comprising such binding molecules, and methods for treating diseases or disorders associated with GPC3, e.g., hepatocellular carcinoma.

Description

Attorney Docket No.14259-055-228 GPC3-TARGETED MOLECULES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No.63 / 510,323, filed June 26, 2023, the disclosure of which is incorporated by reference herein it its entirety. SEQUENCE LISTING This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14259-055-228_SEQLISTING.xml”, was created on June 21, 2024, and is 495,078 bytes in size. 1. TECHNICAL FIELD

[0001] The presently disclosed subject matter provides molecules that target glypican-3 (GPC3), cells comprising the molecules, and methods for treating GPC3-related diseases using such molecules and cells. 2. BACKGROUND

[0002] Cell-based immunotherapy is a therapy with curative potential for the treatment of cancer. T-cells and other immune cells may be modified to target tumor antigens through the introduction of genetic material coding for artificial or synthetic receptors for antigen, termed Chimeric Antigen Receptors (CARs), specific to selected antigens. Targeted T-cell therapy using CARs has shown recent clinical success in treating hematologic malignancies.

[0003] GPC3 is widely expressed in the placenta and fetal tissues, while its expression is significantly reduced in adult organs. In addition, significantly high expression levels of GPC3 have been found in hepatocellular carcinoma (HCC) cells compared to normal liver and non-neoplastic liver lesions. Thus, GPC3 is a promising tumor marker and a potential molecular target for therapeutic intervention in HCC. Thus, there are needs for GPC3-targeted molecules, e.g., CARs or antibodies, for treating tumors, e.g., HCC. 3. SUMMARY OF THE INVENTION

[0004] The presently disclosed subject matter provides GPC3-targeted molecules (e.g., antibodies, antigen-binding fragments, chimeric antigen receptor (CAR)s), cells comprising the GPC3-targeted molecules, and uses of the cells and antibodies, e.g., for treating a GPC3-related disease or disorder. NAI-1540294631v3 1

[0005] The presently disclosed subject matter provides GPC3-targeted CARs. In certain embodiments, the GPC3-targeted CAR comprises an extracellular domain that binds to GPC3, a transmembrane domain, and an intracellular domain, wherein the extracellular domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 29, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 30; (b) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 47, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 48; (c) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 62, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 63; (d) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 75, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 76; (e) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 89, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 90; (f) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 101, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 102; (g) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 119, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 120; (h) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 137, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 138; (i) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 155, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 156;NAI-1540294631v32(j) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 170, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 171; (k) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 183, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 184; (l) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 201, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 202; (m) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 215, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 216; (n) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 233, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 234; (o) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 246, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 247; or (p) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 262, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 263.

[0006] In certain embodiments, the VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3 are identified according to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the Contact numbering system, or the IMGT®Information System. In certain embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are identified according to the Kabat numbering system.

[0007] In certain embodiments, the VH and VL are characterized below: (a) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservativeNAI-1540294631v33modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof; (b) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (c) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (d) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (e) the VH 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: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservativeNAI-1540294631v34modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (f) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (g) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; (h) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof; (i) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153 or a conservativeNAI-1540294631v35modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof; (j) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; (k) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (l) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof; (m) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or aNAI-1540294631v36conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; (n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232 or a conservative modification thereof; (o) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; or (p) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a conservative modification thereof.

[0008] In certain embodiments, the VH and VL are characterized below: (a) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28;NAI-1540294631v37(b) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (c) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (d) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (e) the VHcomprises 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: 43; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (f) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (g) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VLcomprises a CDR1 comprising theNAI-1540294631v38amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; (h) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (i) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154; (j) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, 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; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169; (k) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (l) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200;NAI-1540294631v39(m) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, 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; and the VLcomprises 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: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169; (n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232; (o) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; or (p) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261.

[0009] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136.

[0010] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VLNAI-1540294631v310comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261.

[0011] In certain embodiments, the VH comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO: 262.

[0012] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO: 262.

[0013] In certain embodiments, the VL comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO: 263.

[0014] In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO: 263.

[0015] In certain embodiments, the VHand VLare characterized below: (a) the VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; (b) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 47; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 48; (c) the VH comprises the amino acid sequence set forth in SEQ ID NO: 62; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 63;NAI-1540294631v311(d) the VH comprises the amino acid sequence set forth in SEQ ID NO: 75; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 76; (e) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 89; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 90; (f) the VH comprises the amino acid sequence set forth in SEQ ID NO: 101; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 102; (g) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 119; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 120; (h) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 138; (i) the VH comprises the amino acid sequence set forth in SEQ ID NO: 155; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 156; (j) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 170; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 171; (k) the VH comprises the amino acid sequence set forth in SEQ ID NO: 183; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 184; (l) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 201; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 202; (m) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 215; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 216; (n) the VH comprises the amino acid sequence set forth in SEQ ID NO: 233; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 234; (o) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 246; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 247; or (p) the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 263.

[0016] In certain embodiments, the VH and VL are characterized below: (a) the VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; (b) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 47; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 48; (c) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 75; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 76;NAI-1540294631v312(d) the VH comprises the amino acid sequence set forth in SEQ ID NO: 137; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 138; (e) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 155; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 156; or (f) the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 263.

[0017] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 138.

[0018] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 262; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 263.

[0019] In certain embodiments, the VH and the VL are connected via a linker. In certain embodiments, the linker consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In certain embodiments, the linker consists of the amino acid sequence set forth in SEQ ID NO: 1.

[0020] In certain embodiments, the VH and the VL are positioned from the N- to the C-terminus: VL-VH. In certain embodiments, the VHand the VLare positioned from the N- to the C-terminus: VH-VL.

[0021] In certain embodiments, the extracellular domain comprises a variable fragment (Fv), a single-chain variable fragment (scFv), a Fab, or a F(ab)2. In certain embodiments, the extracellular domain comprises an scFv. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 264, or SEQ ID NO: 265. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 264, or SEQ ID NO: 265.

[0022] 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-3NAI-1540294631v313polypeptide, a 2B4 polypeptide, or a BTLA polypeptide. In certain embodiments, the transmembrane domain comprises a CD28 polypeptide. In certain embodiments, the CD28 polypeptide comprises amino acids 154 to 179 of the amino acid sequence set forth in SEQ ID NO: 308.

[0023] In certain embodiments, the intracellular domain comprises a CD3ζ polypeptide. In certain embodiments, the CD3ζ polypeptide is a modified CD3ζ polypeptide. In certain embodiments, the modified CD3ζ polypeptide comprises a native ITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 consisting of two loss-of-function mutations. In certain embodiments, the native ITAM1 consists of the amino acid sequence set forth in SEQ ID NO: 313. In certain embodiments, the ITAM2 variant consists of the amino acid sequence set forth in SEQ ID NO: 319. In certain embodiments, the ITAM3 variant consists of the amino acid sequence set forth in SEQ ID NO: 323. In certain embodiments, the modified CD3ζ polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 325. In certain embodiments, the intracellular domain further comprises at least one co-stimulatory signaling region. In certain embodiments, the at least one co-stimulatory signaling region comprises at least one intracellular signaling domain of a co-stimulatory molecule. In certain embodiments, the co- stimulatory molecule is selected from the group consisting of CD28, 4-1BB, OX40, ICOS, DAP-10, CD27, CD28, CD30, CD40, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CD8, CD4, B2C, CD80, CD86, DAP10, DAP12, MyD88, BTNL3, and NKG2D, and combinations thereof. In certain embodiments, the co-stimulatory molecule is CD28. In certain embodiments, the at least one co-stimulatory signaling region comprises amino acids 180 to 220 of the amino acid sequence set forth in SEQ ID NO: 308.

[0024] In certain embodiments, the CAR further comprises a signal peptide. In certain embodiments, the signal peptide comprises the amino acid sequence set forth in SEQ ID NO: 278. In certain embodiments, the CAR further comprises a self-cleaving P2A peptide. In certain embodiments, the self-cleaving P2A peptide comprises the amino acid sequence set forth in SEQ ID NO: 329.

[0025] In certain embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 333, SEQ ID NO: 335, SEQ ID NO: 337, SEQ ID NO: 339, SEQ ID NO: 341, SEQ ID NO: 343, SEQ ID NO: 345, SEQ ID NO: 347, SEQ ID NO: 349, SEQ ID NO: 351, SEQ ID NO: 353, or SEQ ID NO: 355.NAI-1540294631v314

[0026] In certain embodiments, the CAR is expressed from a vector. In certain embodiments, the vector is a viral vector. In certain embodiments, the viral vector is a retroviral vector.

[0027] The presently disclosed subject matter further provides nucleic acids encoding the GPC3- targeted CARs disclosed herein. In certain embodiments, the nucleic acid further comprises a promoter that is operably linked to the CAR. In certain embodiments, the promoter is endogenous or exogenous. In certain embodiments, the exogenous promoter is selected from the group consisting of an elongation factor (EF)-1 promoter, a cytomegalovirus immediate-early promoter (CMV) promoter, a simian virus 40 early promoter (SV40) promoter, a phosphoglycerate kinase (PGK) promoter, a metallothionein promoter, and Ubiquitin C promoter. In certain embodiments, the endogenous promoter is selected from the group consisting of a TCR alpha promoter, a TCR beta promoter, and a beta 2-microglobulin promoter. In certain embodiments, the promoter is an inducible promoter. In certain embodiments, the inducible promoter is selected from the group consisting of a NFAT transcriptional response element (TRE) promoter, a CD69 promoter, a CD25 promoter, an IL-2 promoter, a 4-1BB promoter, a PD1 promoter, and a LAG3 promoter. In certain embodiments, the nucleic acid comprises the nucleotide sequence set forth in SEQ ID NO: 334, SEQ ID NO: 336, SEQ ID NO: 338, SEQ ID NO: 340, SEQ ID NO: 342, SEQ ID NO: 344, SEQ ID NO: 346, SEQ ID NO: 348, SEQ ID NO: 350, SEQ ID NO: 352, SEQ ID NO: 354, or SEQ ID NO: 356.

[0028] The presently disclosed subject matter provides vectors comprising the nucleic acids disclosed herein. In certain embodiments, the vector is a viral vector. In certain embodiments, the viral vector is a retroviral vector.

[0029] The presently disclosed subject matter further provides cells comprising the CARs, nucleic acids, or vectors disclosed herein.

[0030] In certain embodiments, the cell is an immunoresponsive cell or an immune effector cell. In certain embodiments, the cell is a cell of the lymphoid lineage or a cell of the myeloid lineage. In certain embodiments, the cell is selected from the group consisting of a T cell, a B cell, a Natural Killer (NK) cell, macrophage, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a lymphokine activated killer (LAK) cell, a stem cell from which a lymphoid cell may be differentiated, a stem cell from which a myeloid cell may be differentiated, or a combination thereof. In certain embodiments, the cell is a T cell. In certain embodiments, the T cell is selected from the group consisting of helper T cells, cytotoxic T cells, memory T cells, regulatory T cells, tumor- infiltrating lymphocyte (TIL), Natural Killer T cells, mucosal associated invariant T cells, αβ T cells, and γδ T cells. In certain embodiments, the cell is a NK cell. In certain embodiments, the NK cell isNAI-1540294631v315derived from a stem cell. In certain embodiments, the stem cell is a pluripotent stem cell. In certain embodiments, the pluripotent stem cell is an embryoid stem cell or an induced pluripotent stem cell.

[0031] Furthermore, the presently disclosed subject matter provides anti-GPC3 antibodies or antigen-binding fragments thereof. In certain embodiments, the anti-GPC3 antibody or antigen- binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 29, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 30; (b) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 47, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 48; (c) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 62, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 63; (d) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 75, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 76; (e) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 89, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 90; (f) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 101, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 102; (g) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 119, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 120; (h) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 137, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 138; (i) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 155, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 156;NAI-1540294631v316(j) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 170, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 171; (k) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 183, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 184; (l) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 201, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 202; (m) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 215, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 216; (n) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 233, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 234; (o) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 246, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 247; or (p) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 262, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 263.

[0032] In certain embodiments, the VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3 are identified according to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the Contact numbering system, or the IMGT®Information System. In certain embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are identified according to the Kabat numbering system.

[0033] In certain embodiments, the VH and VL are characterized as below: (a) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservativeNAI-1540294631v317modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof; (b) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (c) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (d) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (e) the VH 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: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservativeNAI-1540294631v318modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (f) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (g) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; (h) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof; (i) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153 or a conservativeNAI-1540294631v319modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof; (j) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; (k) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; (l) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof; (m) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or aNAI-1540294631v320conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; (n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232 or a conservative modification thereof; (o) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; or (p) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a conservative modification thereof.

[0034] In certain embodiments, the VH and VL are characterized as below: (a) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28;NAI-1540294631v321(b) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (c) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (d) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (e) the VHcomprises 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: 43; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (f) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (g) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VLcomprises a CDR1 comprising theNAI-1540294631v322amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; (h) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (i) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154; (j) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, 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; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169; (k) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (l) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200;NAI-1540294631v323(m) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, 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; and the VLcomprises 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: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169; (n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232; (o) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; or (p) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261.

[0035] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136.

[0036] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VLNAI-1540294631v324comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261.

[0037] In certain embodiments, the VH comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO: 262. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO: 262.

[0038] In certain embodiments, the VL comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO: 263. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO: 263.

[0039] In certain embodiments, the VHand VLare characterized as below: (a) the VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; (b) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 47; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 48; (c) the VH comprises the amino acid sequence set forth in SEQ ID NO: 62; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 63;NAI-1540294631v325(d) the VH comprises the amino acid sequence set forth in SEQ ID NO: 75; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 76; (e) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 89; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 90; (f) the VH comprises the amino acid sequence set forth in SEQ ID NO: 101; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 102; (g) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 119; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 120; (h) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 138; (i) the VH comprises the amino acid sequence set forth in SEQ ID NO: 155; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 156; (j) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 170; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 171; (k) the VH comprises the amino acid sequence set forth in SEQ ID NO: 183; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 184; (l) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 201; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 202; (m) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 215; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 216; (n) the VH comprises the amino acid sequence set forth in SEQ ID NO: 233; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 234; (o) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 246; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 247; or (p) the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 263.

[0040] In certain embodiments, the VH and VL are characterized as below: (a) the VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; (b) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 47; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 48; (c) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 75; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 76;NAI-1540294631v326(d) the VH comprises the amino acid sequence set forth in SEQ ID NO: 137; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 138; (e) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 155; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 156; or (f) the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 263.

[0041] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 138.

[0042] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 262; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 263.

[0043] In certain embodiments, the antigen-binding fragment thereof is a variable fragment (Fv), a single-chain variable fragment (scFv), a Fab, or a F(ab)2. In certain embodiments, the antigen- binding fragment thereof is an scFv. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 264, or SEQ ID NO: 265. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 264, or SEQ ID NO: 265.

[0044] In certain embodiments, the VH is connected to the VL via a linker. In certain embodiments, the linker consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In certain embodiments, the linker consists of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the VH and the VL are positioned from the N- to the C-terminus: VL-VH. In certain embodiments, the VH and the VL are positioned from the N- to the C-terminus: VH-VL.

[0045] In certain embodiments, the antibody comprises a human variable region framework region. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a Fc region. In certain embodiments, the Fc region comprises the amino acid sequence set forth in SEQ ID NO: 357.NAI-1540294631v327

[0046] In certain embodiments, the antibody or antigen-binding fragment thereof is a fully human or an antigen-binding fragment thereof, a chimeric antibody or an antigen-binding fragment thereof, or a humanized antibody or an antigen-binding fragment thereof.

[0047] The presently disclosed subject matter further provides antibodies or antigen-binding fragments thereof that compete with any one of the anti-GPC3 antibodies or antigen-binding fragments thereof disclosed herein for binding to GPC3. And, the presently disclosed subject matter provides antibodies or antigen-binding fragments thereof that bind to essentially the same epitope region on GPC3 as any one of the anti-GPC3 antibodies or antigen-binding fragments thereof disclosed herein.

[0048] The presently disclosed subject matter further provides conjugates comprising the antibodies or antigen-binding fragments thereof disclosed herein. In certain embodiments, the antibody or antigen-binding fragment thereof is linked to a therapeutic agent, a detectable agent, or a diagnostic agent. In certain embodiments, the therapeutic agent is a chemotherapeutic agent, a cytotoxin, or a drug. In certain embodiments, the conjugate is an immunoconjugate.

[0049] The presently disclosed subject matter provides multispecific molecules comprising any one of the antibodies or antigen-binding fragments thereof disclosed herein that is linked to a second functional moiety. In certain embodiments, the second functional moiety has a different binding specificity than the antibody or antigen binding fragment thereof.

[0050] Furthermore, the presently disclosed subject matter provides nucleic acids that encode the antibodies or antigen-binding fragments thereof. In certain embodiments, the nucleic acid comprises a first polynucleotide that encodes a VH comprising the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO: 262; and / or a second polynucleotide that encodes a VL comprising the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO: 263.

[0051] In certain embodiments, the first polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO: 33, SEQ ID NO: 51, SEQ ID NO: 66, SEQ ID NO: 79, SEQ ID NO: 93, SEQ ID NO: 105, SEQ ID NO: 123, SEQ ID NO: 141, SEQ ID NO: 159, SEQ ID NO: 174, SEQ ID NO: 187, SEQ ID NO: 205, SEQ ID NO: 219, SEQ ID NO: 237, SEQ ID NO: 250, or SEQ ID NO: 266. In certain embodiments, the second polynucleotide comprises the nucleotide sequence set forth inNAI-1540294631v328SEQ ID NO: 35, SEQ ID NO: 53, SEQ ID NO: 68, SEQ ID NO: 81, SEQ ID NO: 95, SEQ ID NO: 107, SEQ ID NO: 125, SEQ ID NO: 143, SEQ ID NO: 161, SEQ ID NO: 176, SEQ ID NO: 189, SEQ ID NO: 207, SEQ ID NO: 221, SEQ ID NO: 239, SEQ ID NO: 252, or SEQ ID NO: 268.

[0052] The presently disclosed subject matter provides vectors comprising the nucleic acids disclosed herein. In certain embodiments, the vector is an expression vector.

[0053] The presently disclosed subject matter further provides host cells comprising the vectors disclosed herein.

[0054] The presently disclosed subject matter provides methods of producing a presently disclosed anti-GPC3 antibody or an antigen-binding fragment thereof. In certain embodiments, the method comprises culturing a presently disclosed host cell under conditions to induce expression of the antibody or antigen-binding fragment thereof from the host cell.

[0055] The presently disclosed subject matter provides methods for detecting GPC3 in a whole cell or tissue. In certain embodiments, the method comprises: (a) contacting a cell or tissue with a presently disclosed anti-GPC3 antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a detectable label; and (b) determining the amount of the labeled antibody or antigen-binding fragment thereof bound to the cell or tissue by measuring the amount of detectable label associated with the cell or tissue, wherein the amount of bound antibody or antigen-binding fragment thereof indicates the amount of GPC3 in the cell or tissue.

[0056] The presently disclosed composition comprises the cells, the antibodies or antigen- binding fragments, the conjugates, or the multispecific molecules disclosed herein. In certain embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In certain embodiments, the composition comprises between about 1 × 105and about 5 × 108cells.

[0057] The presently disclosed cells, antibodies or antigen-binding fragments thereof, conjugates, multispecific molecules, or compositions can be used in a therapy.

[0058] The presently disclosed cells, antibodies or antigen-binding fragments thereof, conjugates, multispecific molecules, or compositions can be used in a method for treating a disease or disorder associated with GPC3 in a subject.

[0059] The presently disclosed subject matter provides methods of treating a disease or disorder associated with GPC3 in a subject. In certain embodiments, the method comprises: administering to the subject cells comprising a presently disclosed GPC3-targeted CAR, the anti-GPC3 antibody orNAI-1540294631v329antigen-binding fragment thereof disclosed herein, the conjugate disclosed herein, the multispecific molecule disclosed herein, or the composition disclosed herein.

[0060] The presently disclosed subject matter provides uses of the presently disclosed cells, antibodies or antigen-binding fragments thereof, conjugates, multispecific molecules, or compositions in the manufacture of a medicament for treating a disease or disorder associated with GPC3.

[0061] In certain embodiments, the disease or disorder is a tumor. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the disease or disorder is selected from the group consisting of hepatocellular carcinoma, hepatoblastoma, lung squamous cell carcinoma, ovarian yolk sac tumor, melanoma, and urothelial carcinoma. In certain embodiments, the disease or disorder is hepatocellular carcinoma. In certain embodiments, the subject is a human subject.

[0062] The presently disclosed subject matter provides methods for producing a cell comprising a presently disclosed GPC3-targeted CAR. In certain embodiments, the method comprises: introducing into a cell a nucleic acid that encodes the presently disclosed GPC3-targeted CAR. 4. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figures 1A to 1E depict the binding activity of scFv-Fc fusion proteins of 16 binders to cells expressing human GPC3 using fluorescence-activated cell sorting (FACS) analysis. Each of the purified scFv-Fc proteins starting at a concentration of 45 μg / mL was serially diluted 12 times with a dilution factor of three, and incubated with CHO-K1 / human GPC3 clone 9(+) cells expressing human GPC3. An anti-hIgG GPC3 antibody was used as a positive control, and a human IgG was used as an isotype control, both of which were diluted in the same manner as the tested proteins. A PBS solution was used as a negative control. Each of the purified scFv-Fc fusion proteins was also tested for binding to a negative control cell line, CHO-K1(-). Plates were read by flow cytometry reader. Binding curves were plotted using the geometric-mean fluorescence intensity of the fluorescence signal on the cells, and the EC50 values were calculated.

[0064] Figures 2A and 2B depict the generation of the presently disclosed GPC3-targeted scFv CAR T Cells. Figure 2A depicts structures of CARs in accordance with certain embodiments of the presently disclosed subject matter. Figure 2B depicts the flow cytometric analysis showing the expression levels of LNGFR for the indicated constructs in the VH-VK and VK-VH orientation.

[0065] Figure 3 depicts the GPC3 expression levels of Nalm-6 GPC3+, Huh7, and PLC / PRF / 5 tumor cells.

[0066] Figures 4A and 4B depict the in vitro cytotoxicity of the presently disclosed GPC3- targeted CAR T cells against Nalm-6 GPC3+and Nalm-6 WT tumor cells. Figure 4A shows theNAI-1540294631v330results of 16 hour Cytotoxic T lymphocyte (CTL) mediated cytotoxicity using Nalm-6 GPC3+tumor cells. Figure 4B shows the results of 16 hour CTL using Nalm-6 wildtype (WT) tumor cells.

[0067] Figure 5 depicts the in vitro cytotoxicity of the presently disclosed GPC3-targeted CAR T cells against Huh-7 tumor cells. Figure 5 shows the results of 16 hour CTL using Huh-7 tumor cells.

[0068] Figure 6 depicts the in vitro cytotoxicity of the presently disclosed GPC3-targeted CAR T cells against PLC / PRF / 5 tumor cells. Figure 6 shows the results of 16 hour CTL using PLC / PRF / 5 tumor cells.

[0069] Figure 7 depicts an experimental layout of an assessment of the in vivo antitumor efficacy of the presently disclosed GPC3-targeted CAR T cells.

[0070] Figure 8 depicts the body weight changes of mice who received the presently disclosed GPC3-targeted CAR T cells.

[0071] Figure 9 depicts the in vivo antitumor efficacy of the presently disclosed GPC3-targeted CAR T cells.

[0072] Figure 10 depicts an experimental layout of an assessment of the in vivo safety and effective dose of the presently disclosed GPC3-targeted CAR with binders 8 and 16, respectively.

[0073] Figure 11 depicts the survival rates of mice treated with the presently disclosed GPC3- targeted CAR with binders 8 and 16, respectively, at difference doses.

[0074] Figure 12 depicts body weight changes of mice treated with the presently disclosed GPC3-targeted CAR with binders 8 and 16, respectively, at difference doses.

[0075] Figure 13 depicts the in vivo antitumor efficacy of the presently disclosed GPC3-targeted CAR with binders 8 and 16, respectively, at difference doses.

[0076] Figure 14 depicts the safety of the presently disclosed GPC3-targeted CAR with binders 8 and 16, respectively, at difference doses.

[0077] Figures 15A to 15C depict the restimulation assay with Huh7 tumor cells. Figure 15A depicts a scheme showing the principle of CAR T restimulation assay. Figure 15B shows the results of the Huh7 tumor cell lysis of the VH-VK GPC3 CAR T cells. Figure 15C shows the results of the proliferation of the CAR T cells.

[0078] Figure 16 depicts an assessment of the in vivo antitumor efficacy of the presently disclosed GPC3-targeted CAR T cells to orthotopically implanted Huh7 tumor cells in liver.

[0079] Figure 17 depicts an assessment of the in vivo antitumor efficacy of the presently disclosed GPC3-targeted CAR T cells to subcutaneously implanted Huh7 tumor cells.

[0080] Figure 18 depicts an assessment of the in vivo antitumor efficacy of the presently disclosed GPC3-targeted CAR T cells to Nalm-6 GPC3+ tumor cells injected via tail vein.NAI-1540294631v331

[0081] Figures 19A and 19B depict an analysis of GPC3 expression level in tumor liver samples versus normal liver samples. Figure 19A shows the density plot of upregulated membrane-bound proteins from mass spectrometry data obtained from the Chinese Human Proteome Project (CNHPP) (Jiang et al., 2019, Nature 567: 257–261) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) (Gao et al., 2019, Cell 179 (2): 561 - 577.e22), respectively. Proteins below the 98th percentile ranking of expression are colored in light color, and those in and above the 98th percentile ranking are colored in dark color. Figure 19B shows the density plot of upregulated membrane- bound transcripts from bulk RNAseq data obtained from The Cancer Genome Atlas (TCGA) (Ally et al., 2017, Cell 169 (7): 1327 - 1341.e23) and the CPTAC. Transcripts below the 98th percentile ranking of expression are colored in light color, and those in and above the 98th percentile ranking are colored in dark color. 5. DETAILED DESCRIPTION

[0082] The presently disclosed subject matter provides molecules that target GPC3 (referred to as “GPC3-targeted molecules”). In certain embodiments, the molecule is an antibody or an antigen- binding fragment thereof. In certain embodiments, the molecule is an antigen recognizing receptor. In certain embodiments, the antigen recognizing receptor is a chimeric antigen receptor (CAR). The presently disclosed subject matter further discloses cells comprising such GPC3-targeted molecules. The cells can be immunoresponsive cells and / or immune effector cells, e.g., genetically modified immunoresponsive cells (e.g., T cells or NK cells), or pluripotent stem cell that can differentiate into immunoresponsive cells and / or immune effector cells.

[0083] Non-limiting embodiments of the present disclosure are described by the present specification and Examples.

[0084] For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections: 5.1. Definitions; 5.2. GPC3; 5.3. Chimeric Antigen Receptors (CARs); 5.4. Cells; 5.5. Anti-GPC3 Antibodies; 5.6. Nucleic Acids and Vectors; 5.7. Methods of Detection; 5.8. Formulations and Administration; and 5.9. Methods of TreatmentNAI-1540294631v3325.1. Definitions

[0085] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which the presently disclosed subject matter belongs.

[0086] As used herein, the term “about” or “approximately” refers to within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend 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, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still 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.

[0087] As used herein, the term “immunoresponsive cell” refers to a cell that functions in an immune response or a progenitor, or progeny thereof. In certain embodiments, the immunoresponsive cell is a cell of lymphoid lineage. Non-limiting examples of cells of lymphoid lineage include T cells, Natural Killer (NK) cells, B cells, and stem cells from which lymphoid cells may be differentiated. In certain embodiments, the immunoresponsive cell is a cell of myeloid lineage.

[0088] As used herein, the term “activates an immunoresponsive cell” refers to induction of signal transduction or changes in protein expression in the cell resulting in initiation of an immune response. For example, when CD3 chains cluster in response to ligand binding and immunoreceptor tyrosine-based inhibition motifs (ITAMs) a signal transduction cascade is produced. In certain embodiments, when a CAR binds to an antigen, a formation of an immunological synapse occurs that includes clustering of many molecules near the bound receptor (e.g., CD4 or CD8, CD3γ / δ / є / ξ, etc.). This clustering of membrane bound signaling molecules allows for ITAM motifs contained within the CD3 chains to become phosphorylated. This phosphorylation in turn initiates a T cell activation pathway ultimately activating transcription factors, such as NF-κB and AP-1. These transcription factors induce global gene expression of the T cell to increase IL-2 production for proliferation and expression of master regulator T cell proteins in order to initiate a T cell mediated immune response.

[0089] As used herein, the term “stimulates an immunoresponsive cell” refers to a signal that results in a robust and sustained immune response. In certain embodiments, this occurs afterNAI-1540294631v333immunoresponsive cell (e.g., T cell) activation or concomitantly mediated through receptors including, but not limited to, CD28, 4-1BB, OX40, CD40 and ICOS. Receiving multiple stimulatory signals can be important to mount a robust and long-term T-cell mediated immune response. T cells can quickly become inhibited and unresponsive to antigen. While the effects of these co-stimulatory signals may vary, they generally result in increased gene expression in order to generate long lived, proliferative, and anti-apoptotic T cells that robustly respond to antigen for complete and sustained eradication.

[0090] The term “antibody” covers, for example polyclonal antibodies, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full length monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), synthetic antibodies, chimeric antibodies, humanized antibodies, or human versions of antibodies having full length heavy and / or light chains. The present disclosure also includes antibody fragments (and / or polypeptides that comprise antibody fragments) that retain α5 integrin binding characteristics. Non- limiting examples of antibody fragments include antigen-binding regions and / or effector regions of the antibody, e.g., Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single chain antibody molecule, dual variable region antibody, single variable region antibody, linear antibody, V region, a multispecific antibody formed from antibody fragments, F(ab)2, Fd, Fc, diabody, di-diabody, disulfide-linked Fvs (dsFv), single-domain antibody (e.g., VHH, nanobody) or other fragments (e.g., fragments consisting of the variable regions of the heavy and light chains that are non-covalently coupled). In general terms, a variable region domain may be any suitable arrangement of immunoglobulin heavy (VH) and / or light (VL) variable regions. For example, the presently disclosed subject matter also includes tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, and an antibody heavy chain monomer. Thus, for example, the variable region domain may be dimeric and contain VH-VH, VH-VL, or VL-VL dimers that bind α5 integrin. If desired, the VHand VLchains may be covalently coupled either directly or through a linker to form a single chain Fv (scFv). For ease of reference, scFv proteins are referred to herein as included in the category “antibody fragments.” Another form of an antibody fragment is a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs can be obtained by constructing polynucleotides that encode the CDR of interest. Such polynucleotides are prepared, for example, by using the polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, “Genetic Manipulation ofNAI-1540294631v334Monoclonal Antibodies,” in Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166, Cambridge University Press (1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies,” in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137, Wiley-Liss, Inc. (1995)). Antibody fragments may be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, variable domains of new antigen receptors (v-NAR), and bis-single chain Fv regions (see, e.g., Hollinger and Hudson, Nature Biotechnology, 23(9):1126-1136, 2005). The antibodies or antigen-binding fragments thereof, in certain embodiments, comprise a light chain and / or a heavy chain constant region, such as one or more constant regions, including one or more IgG1, IgG2, IgG3 and / or IgG4 constant regions. In certain embodiments, antibodies can include epitope-binding fragments of any of the above. The antibodies described herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule. Antibodies can be antagonistic antibodies or agonistic antibodies.

[0091] As used herein, the term “monospecific antibody” refers to an antibody that has one or more binding sites each of which bind to the same epitope of the same antigen, e.g., GPC3 (e.g., human GPC3).

[0092] As used herein, the term “multispecific molecule” refers to a molecule (e.g., an antibody) that is capable of binding to at least two distinct antigenic determinants, for example two binding sites each formed by a pair of an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) binding to different antigens or to different epitopes on the same antigen. Such a multispecific molecule may have a 1+1 format. Other multispecific molecule formats may be 2+1 or 1+2 formats (comprising two binding sites for a first antigen or epitope and one binding site for a second antigen or epitope) or 2+2 formats (comprising two binding sites for a first antigen or epitope and two binding sites for a second antigen or epitope). When a multispecific molecule comprises two antigen binding sites, each may bind to a different antigenic determinant. Such a multispecific molecule may bind to two different epitopes on the same antigen (e.g., epitopes on GPC3) or on different antigens (e.g., an epitope on GPC3 and an epitope on an antigen different from GPC3).

[0093] The term “epitope” refers to the region of an antigen to which an antibody binds preferentially and specifically. A monoclonal antibody binds preferentially to a single specific epitope of a molecule that can be molecularly defined. In the present invention, multiple epitopes can be recognized by a multispecific antibody.NAI-1540294631v335

[0094] As used herein, the term “antibody fragment” refers to any derivative of an antibody which is less than full-length. In exemplary embodiments, the antibody fragment retains at least a significant portion of the full-length antibody’s specific binding ability. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, scFv, Fv, dsFv diabody, Fc, and Fd fragments. The antibody fragment may be produced by any means. For instance, the antibody fragment may be enzymatically or chemically produced by fragmentation of an intact antibody, it may be recombinantly produced from a gene encoding the partial antibody sequence, or it may be wholly or partially synthetically produced. The antibody fragment may optionally be a single chain antibody fragment. Alternatively, the fragment may comprise multiple chains which are linked together, for instance, by disulfide linkages. The fragment may also optionally be a multimolecular complex. A functional antibody fragment will typically comprise at least about 50 amino acids and more typically will comprise at least about 200 amino acids.

[0095] As used herein, the term “Fab fragment” refers to a fragment of an antibody comprising an antigen-binding site generated by cleavage of the antibody with the enzyme papain, which cuts at the hinge region N-terminally to the inter-H-chain disulfide bond and generates two Fab fragments from one antibody molecule.

[0096] As used herein, the term “F(ab′)2 fragment” refers to a fragment of an antibody containing two antigen-binding sites, generated by cleavage of the antibody molecule with the enzyme pepsin which cuts at the hinge region C-terminally to the inter-H-chain disulfide bond.

[0097] As used herein, the term “Fc fragment” refers to the fragment of an antibody comprising the constant domain of its heavy chain.

[0098] As used herein, the term “Fv fragment” refers to the fragment of an antibody comprising the variable domains of its heavy chain and light chain.

[0099] The term “single chain variable fragment” or “scFv” refers to an Fv fragment in which the heavy chain domain and the light chain domain are linked. One or more scFv fragments may be linked to other antibody fragments (such as the constant domain of a heavy chain or a light chain) to form antibody constructs having one or more antigen recognition sites. The heavy chain domain and light chain domain are either joined directly or joined by a linker, which connects the N-terminus of the heavy chain domain with the C-terminus of the light chain domain, or the C-terminus of the heavy chain domain with the N-terminus of the light chain domain. As used herein, the term “linker” is art-recognized and refers to a molecule or group of molecules connecting twoNAI-1540294631v336compounds, such as two polypeptides. The linker may be comprised of a single linking molecule or may comprise a linking molecule and a spacer molecule, intended to separate the linking molecule and a compound by a specific distance. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility. In certain embodiments, the linker is a G4S linker.

[0100] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, which is provided below: GGGGSGGGGSGGGGS [SEQ ID NO: 1]

[0101] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 2, which is provided below: GGGGSGGGGSGGGSGGGGS [SEQ ID NO: 2]

[0102] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 3, which is provided below: GGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 3]

[0103] In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 4, which is provided below: GGGGSGGGGSGGGGSGGGGSGGGSGGGGS [SEQ ID NO: 4]

[0104] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 1 is set forth in SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, or SEQ ID NO: 21, which is provided below. GGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCT [SEQ ID NO: 5] GGCGGCGGAGGCAGCGGCGGCGGCGGCTCTGGCGGCGGCGGAAGC [SEQ ID NO: 6] GGCGGAGGAGGCAGCGGCGGCGGAGGCTCTGGCGGCGGCGGAAGT [SEQ ID NO: 7] GGCGGCGGAGGCAGCGGCGGCGGCGGCTCCGGCGGAGGCGGCTCT [SEQ ID NO: 8] GGCGGCGGAGGCTCTGGAGGCGGAGGCAGCGGCGGCGGCGGCTCC [SEQ ID NO: 9] GGCGGCGGCGGCAGCGGCGGCGGAGGTTCTGGAGGAGGCGGCAGC [SEQ ID NO: 10] GGCGGCGGCGGCAGCGGCGGAGGCGGCTCTGGCGGAGGCGGCAGC [SEQ ID NO: 11] GGCGGAGGCGGATCTGGCGGCGGCGGTTCAGGCGGAGGCGGCTCT [SEQ ID NO: 12] GGCGGAGGCGGATCTGGCGGAGGCGGCTCTGGAGGCGGCGGCTCA [SEQ ID NO: 13] GGAGGCGGCGGATCCGGCGGTGGCGGATCTGGCGGAGGCGGCAGC [SEQ ID NO: 14] GGCGGAGGCGGCTCTGGAGGAGGAGGGTCCGGAGGCGGCGGCAGC [SEQ ID NO: 15] GGCGGCGGCGGCAGCGGCGGAGGCGGCAGCGGCGGCGGAGGCAGC [SEQ ID NO: 16]NAI-1540294631v337GGCGGAGGCGGCAGCGGCGGCGGCGGAAGCGGCGGCGGAGGCAGC [SEQ ID NO: 17] GGCGGCGGAGGCTCTGGCGGTGGCGGAAGCGGCGGCGGCGGAAGC [SEQ ID NO: 18] GGAGGCGGCGGCAGCGGCGGCGGCGGCAGTGGCGGAGGCGGCAGC [SEQ ID NO: 19] GGCGGAGGCGGCAGCGGAGGAGGCGGCTCTGGCGGCGGCGGCTCA [SEQ ID NO: 20] GGCGGCGGCGGCAGCGGAGGCGGCGGCAGCGGAGGAGGTGGCAGC [SEQ ID NO: 21]

[0105] As used herein, “complementarity determining regions” or “CDRs” are defined as the complementarity determining region amino acid sequences of an antibody which are the hypervariable regions of immunoglobulin heavy and light chains. CDRs can be identified according to a number of known numbering systems. In certain embodiments, the CDRs are identified according to the Kabat numbering system. The Kabat CDRs are based on sequence variability and are the most commonly used (see e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). The CDRs can be identified according to the Chothia numbering system. Chothia refers to the location of the structural loops (see e.g., Chothia and Lesk, J. Mol. Biol.196:901-917 (1987)). The CDRs can be identified according to the AbM numbering system. The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software (see e.g., Martin, in Antibody Engineering, Vol.2, Chapter 3, Springer Verlag). The CDRs can be identified according to the Contact numbering system (see, e.g., MacCallum RM et al., 1996, J Mol Biol 5: 732-745). The Contact CDRs are based on an analysis of the available complex crystal structures. The CDRs can be identified according to the ImMunoGeneTics (IMGT)®Information System. A universal numbering system has been developed and widely adopted, IMGT®Information System (Lefranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003)). IMGT®is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates.

[0106] The term “amino acid sequence” refers to a list of abbreviations, letters, characters or words representing amino acid residues. The amino acid abbreviations used herein are conventional one letter codes for the amino acids and are expressed as follows: A, alanine; B, asparagine or aspartic acid; C, cysteine; D aspartic acid; E, glutamate, glutamic acid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine; Z, glutamine or glutamic acid.NAI-1540294631v338

[0107] The terms “peptide,” “protein,” and “polypeptide” are used interchangeably to refer to a natural or synthetic molecule comprising two or more amino acids linked by the carboxyl group of one amino acid to the alpha amino group of another.

[0108] The terms “polypeptide fragment” or “fragment”, when used in reference to a particular polypeptide, refers to a polypeptide in which amino acid residues are deleted as compared to the reference polypeptide itself, but where the remaining amino acid sequence is usually identical to that of the reference polypeptide. Such deletions may occur at the amino-terminus or carboxy-terminus of the reference polypeptide, or alternatively both. Fragments typically are at least about 5, 6, 8 or 10 amino acids long, at least about 14 amino acids long, at least about 20, 30, 40 or 50 amino acids long, at least about 75 amino acids long, or at least about 100, 150, 200, 300, 500 or more amino acids long. A fragment can retain one or more of the biological activities of the reference polypeptide. In various embodiments, a fragment may comprise an enzymatic activity and / or an interaction site of the reference polypeptide. In another embodiment, a fragment may have immunogenic properties.

[0109] As used herein, the term “substantially identical” or “substantially homologous” refers to a polypeptide or a nucleic acid molecule exhibiting at least about 50% identical or homologous to a reference amino acid sequence (for example, any of the amino acid sequences described herein) or a reference nucleotide sequence (for example, 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% identical or homologous to the amino acid sequence or the nucleic acid sequence used for comparison.

[0110] The term “identity” refers to sequence identity between two nucleic acid molecules or polypeptides. Identity can be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base, then the molecules are identical at that position. A degree of similarity or identity between nucleic acid or amino acid sequences is a function of the number of identical or matching nucleotides at positions shared by the nucleic acid sequences. Various alignment algorithms and / or programs may be used to calculate the identity between two sequences, including FASTA, or BLAST which are available as a part of the GCG sequence analysis package (University of Wisconsin, Madison, Wis.), and can be used with, e.g., default setting. When BLASTP is used, the percent similarity is based on the BLASTP positives score and the percent sequence identity is based on the BLASTP identities score. BLASTP “Identities” shows the number and fraction of totalNAI-1540294631v339residues in the high scoring sequence pairs which are identical; and BLASTP “Positives” shows the number and fraction of residues for which the alignment scores have positive values and which are similar to each other. Amino acid sequences having these degrees of identity or similarity or any intermediate degree of identity of similarity to the amino acid sequences disclosed herein are contemplated and encompassed by this disclosure. The polynucleotide sequences of similar polypeptides are deduced using the genetic code and may be obtained by conventional means, in particular by reverse translating its amino acid sequence using the genetic code.

[0111] The term “nucleic acid” refers to a natural or synthetic molecule comprising a single nucleotide or two or more nucleotides linked by a phosphate group at the 3’ position of one nucleotide to the 5’ end of another nucleotide. The nucleic acid is not limited by length, and thus the nucleic acid can include deoxyribonucleic acid (DNA) or ribonucleic acid (RNA).

[0112] The term “operably linked to” refers to the functional relationship of a nucleic acid with another nucleic acid sequence. Promoters, enhancers, transcriptional and translational stop sites, and other signal sequences are examples of nucleic acid sequences operably linked to other sequences. For example, operable linkage of DNA to a transcriptional control element refers to the physical and functional relationship between the DNA and promoter such that the transcription of such DNA is initiated from the promoter by an RNA polymerase that specifically recognizes, binds to and transcribes the DNA.

[0113] As used herein, the term “signal sequence” or “leader sequence” refers to a peptide sequence (e.g., 5, 10, 15, 20, 25 or 30 amino acids) present at the N-terminus of proteins that directs their entry to the secretory pathway.

[0114] The term “variant” refers to an amino acid or peptide sequence having conservative amino acid substitutions, non-conservative amino acid substitutions (i.e. a degenerate variant), substitutions within the wobble position of each codon (i.e. DNA and RNA) encoding an amino acid, amino acids added to the C-terminus of a peptide, or a peptide having 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% sequence identity to a reference sequence.

[0115] As used herein, the term “a conservative sequence modification” refers to an amino acid modification that does not significantly affect or alter the binding characteristics of the presently disclosed GPC3-targeted binding comprising the amino acid sequence. Conservative modifications can include amino acid substitutions, additions and deletions. Modifications can be introduced 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 their physicochemical properties such as charge and polarity. Conservative amino acid substitutions are ones in which theNAI-1540294631v340amino acid residue is replaced with an amino acid within the same group. For example, amino acids can be classified by charge: positively-charged amino acids include lysine, arginine, histidine, negatively-charged amino acids include aspartic acid, glutamic acid, neutral charge amino acids include alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In addition, amino acids can be classified by polarity: polar amino acids include arginine (basic polar), asparagine, aspartic acid (acidic polar), glutamic acid (acidic polar), glutamine, histidine (basic polar), lysine (basic polar), serine, threonine, and tyrosine; non-polar amino acids include alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine. Thus, one or more amino acid residues within 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 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, no more than five residues within a specified sequence or a CDR region are altered.

[0116] The term “vector” refers to a nucleic acid sequence capable of transporting into a cell another nucleic acid to which the vector sequence has been linked. The term “expression vector” includes any vector, (e.g., a plasmid, cosmid or phage chromosome) containing a gene construct in a form suitable for expression by a cell (e.g., linked to a transcriptional control element).

[0117] As used herein, the term “effective amount” refers to an amount sufficient to affect a beneficial or desired clinical result upon treatment. An effective amount can be administered to a subject in one or more doses. In certain embodiments, an effective amount can be an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of the disease, or otherwise reduce the pathological consequences of the disease. The effective amount can be determined by a physician on a case-by-case basis and is within the skill of one in the art. Several factors are typically taken into account when determining an appropriate dosage to achieve an effective amount. These factors include 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.

[0118] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.NAI-1540294631v341

[0119] The term “treatment” refers to the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

[0120] An “individual” or “subject” herein is a vertebrate, such as a human or a non-human animal, for example, 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, hamsters, and guinea pigs, rabbits, dogs, cats, sheep, pigs, goats, cattle, horses, and non-human primates such as apes and monkeys. In certain embodiment, the subject is a mammal. In certain embodiment, the subject is a human.

[0121] The term “GPC3 antigen” and, in particular, “GPC3” is intended to include fragments, variants (e.g., allelic variants), and derivatives of the antigen molecule, e.g., the GPC3 molecule.

[0122] The terms “comprises”, “comprising”, and are intended to have the broad meaning ascribed to them in U.S. Patent Law and can mean “includes”, “including” and the like. 5.2. GPC3

[0123] GPC3 is also known as glypican-3. Glypican-3 (GPC3) is a 70 kDa protein that is anchored to the cell surface via glycosylphosphatidylinositol (GPI). GPC3 is widely expressed in the placenta and fetal tissues such as liver, lung, and kidney, and it regulates morphogenesis or growth. However, its expression is significantly reduced in adult organs. On the other hand, significantly high levels of GPC3 are expressed in hepatocellular carcinoma (HCC) cells compared to normal liver and non-neoplastic liver lesions, making GPC3 a promising tumor marker and a potential molecular target for therapeutic intervention in HCC. GPC3 is a member of the heparan sulfate (HS) proteoglycan family that consists of six members, GPC1 to GPC6, which serve as receptors or coreceptors for a number of ligand molecules, including morphogens, growth factors, adhesion, and matrix molecules, to regulate their signaling and distribution.NAI-1540294631v342

[0124] The presently disclosed molecule binds to a GPC3 antigen. In certain embodiments, the presently disclosed binding molecule binds to a human GPC3 antigen. In certain embodiments, the GPC3 is a human GPC3. In certain embodiments, the GPC3 is a wild-type human GPC3. In certain embodiments, the GPC3 antigen comprises or consists of the amino acid sequence with a Uniprot Reference No: P51654-1 (SEQ ID NO: 22), which is provided below. MAGTVRTACLVVAMLLSLDFPGQAQPPPPPPDATCHQVRSFFQRLQPGLKWVPETPVPGSDLQVCLP KGPTCCSRKMEEKYQLTARLNMEQLLQSASMELKFLIIQNAAVFQEAFEIVVRHAKNYTNAMFKNNY PSLTPQAFEFVGEFFTDVSLYILGSDINVDDMVNELFDSLFPVIYTQLMNPGLPDSALDINECLRGA RRDLKVFGNFPKLIMTQVSKSLQVTRIFLQALNLGIEVINTTDHLKFSKDCGRMLTRMWYCSYCQGL MMVKPCGGYCNVVMQGCMAGVVEIDKYWREYILSLEELVNGMYRIYDMENVLLGLFSTIHDSIQYVQ KNAGKLTTTIGKLCAHSQQRQYRSAYYPEDLFIDKKVLKVAHVEHEETLSSRRRELIQKLKSFISFY SALPGYICSHSPVAENDTLCWNGQELVERYSQKAARNGMKNQFNLHELKMKGPEPVVSQIIDKLKHI NQLLRTMSMPKGRVLDKNLDEEGFESGDCGDDEDECIGGSGDGMIKVKNQLRFLAELAYDLDVDDAP GNSQQATPKDNEISTFHNLGNVHSPLKLLTSMAISVVCFFFLVH [SEQ ID NO: 22]

[0125] In certain embodiments, the GPC3 antigen 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%, at least about 99%, or at least about 100% identical to the amino acid sequence set forth in SEQ ID NO: 22 or a fragment thereof.

[0126] In certain embodiments, the presently disclosed binding molecule binds to an epitope of GPC3. In certain embodiments, the epitope is within amino acids 524 to 563 of SEQ ID NO: 22. In certain embodiments, the epitope is at the C-terminus of GPC3. 5.3. Chimeric Antigen Receptors (CARs)

[0127] The presently disclosed subject matter provides chimeric antigen receptors (CARs) that targets GPC3.

[0128] CARs are engineered receptors, which graft or confer a specificity of interest onto an immune effector cell. CARs can be used to graft the specificity of a monoclonal antibody onto a cell, e.g., an immunoresponsive cell, e.g., a T cell or a NK cell; with transferring of their coding sequence, e.g., facilitated by retroviral vectors.

[0129] In certain embodiments, the GPC3-targeted CAR comprises an extracellular domain that specifically binds to GPC3, a transmembrane domain, and an intracellular domain. In certain embodiments, the extracellular domain is fused to the transmembrane domain, which is fused to the intracellular domain.NAI-1540294631v343

[0130] In certain embodiments, the extracellular domain of the CAR comprises a GPC3-binding region, and is responsible for antigen recognition. In certain embodiments, the extracellular domain further comprise a signal peptide (SP) so that the CAR can be glycosylated and anchored in the cell membrane of a cell (e.g., an immunoresponsive cell).

[0131] In certain embodiments, the transmembrane domain (TD) connects the extracellular domain to the intracellular domain and resides within the cell membrane when expressed by a cell (e.g., an immunoresponsive cell).

[0132] In certain embodiments, the intracellular domain transmits an activation signal to the cell (e.g., an immunoresponsive cell) after antigen recognition. In certain embodiments, the intracellular domain comprises an intracellular signaling domain (ISD). In certain embodiments, the intracellular domain further comprises a co-stimulatory signaling region (CSR). A “signaling domain (SD)” generally comprises immunoreceptor tyrosine-based activation motifs (ITAMs) that activate a signaling cascade when the ITAM is phosphorylated. The term “co-stimulatory signaling region (CSR)” refers to an intracellular signaling domain from a costimulatory protein receptor, such as CD28, 41BB, and ICOS, that are able to enhance the activation of an immunoresponsive cell (e.g., a T cell).

[0133] In certain embodiments, the disclosed CAR is defined by the formula:

[0134] SP–ED-HG–TM–CSR–SD; or

[0135] SP– ED–HG–TM–SD–CSR; wherein “SP” represents an optional signal peptide, wherein “ED” represents an extracellular domain that binds to GPC3. wherein “HG” represents an optional hinge domain, wherein “TM” represents a transmembrane domain, wherein “CSR” represents one or more co-stimulatory signaling regions, wherein “SD” represents a signaling domain, and wherein “–” represents a peptide bond or linker.

[0136] Additional CAR constructs are described, for example, in Fresnak et al., Nat. Rev. Cancer 16(9):566-81 (2016), which is incorporated by reference in its entirety for the teaching of these CAR models.

[0137] In certain embodiments, the CAR can be for example (and without limitation), a TRUCK, Universal CAR, a Self-driving CAR, an Armored CAR, a Self-destruct CAR, a Conditional CAR, a Marked CAR, a TenCAR, a Dual CAR, or a sCAR.NAI-1540294631v344

[0138] TRUCKs (T cells redirected for universal cytokine killing) co-express a chimeric antigen receptor (CAR) and an antitumor cytokine. Cytokine expression may be constitutive or induced by T cell activation. Targeted by CAR specificity, localized production of pro-inflammatory cytokines recruits endogenous immune cells to tumor sites and may potentiate an antitumor response.

[0139] Universal, allogeneic CAR T cells are engineered to no longer express endogenous T cell receptor (TCR) and / or major histocompatibility complex (MHC) molecules, thereby preventing graft-versus-host disease (GVHD) or rejection, respectively.

[0140] Self-driving CARs co-express a CAR and a chemokine receptor, which binds to a tumor ligand, thereby enhancing tumor homing.

[0141] CAR T cells engineered to be resistant to immunosuppression (Armored CARs) may be genetically modified to no longer express various immune checkpoint molecules (e.g., cytotoxic T lymphocyte-associated antigen 4 (CTLA4) or programmed cell death protein 1 (PD-1)). Exemplary “Knockdown” and “Knockout” techniques include, but are not limited to, RNA interference (RNAi) (e.g., asRNA, miRNA, shRNA, siRNA, etc.) and CRISPR interference (CRISPRi) (e.g., CRISPR- Cas9). In certain embodiments, CAR T cells are engineered to express a dominant-negative form of a checkpoint molecule. In certain embodiments, the extracellular ligand-binding domain of the immune checkpoint molecule is fused to a transmembrane membrane in order to compete for ligand binding. For example, the extracellular ligand-binding domain of PD-1 may be fused to a CD8 transmembrane domain, thus competing for PD-1 ligand from the target cell. In certain embodiments, CAR T cells are engineered to express an immune checkpoint switch receptor to exploit the inhibitory immune checkpoint ligand present on a target cell. In certain embodiments, the extracellular ligand-binding domain of the immune checkpoint molecule is fused to a signaling, stimulatory, and / or co-stimulatory domain. For example, the extracellular ligand-binding domain of PD-1 may be fused to a CD28 domain, thus providing CD28 co-stimulation while blocking PD-1 signaling. In certain embodiments, the CAR T cells may be administered with an aptamer or a monoclonal antibody that blocks immune checkpoint signaling. In certain embodiments, the CAR T cells (e.g., CAR T cell therapy) are combined with a PD-1 blockade method, such as administration with PD-1 / PD-L1 antagonistic aptamers or anti-PD-1 / PD-L1 antibodies. In certain embodiments, the CAR T cells and PD-1 pathway-blocking antibodies are administered conjointly. In certain embodiments, the CAR T cells are engineered to express or express and secrete an immune checkpoint-blocking antibody, such as anti-PD-1 or anti-PD-L1, or fragments thereof. In certain embodiments, the CAR T cells are administered with a vector (e.g., an engineered virus) that expresses an immune checkpoint-blocking molecule described herein.NAI-1540294631v345

[0142] A self-destruct CAR may be designed using RNA delivered by electroporation to encode the CAR. Alternatively, inducible apoptosis of the T cell may be achieved based on ganciclovir binding to thymidine kinase in gene-modified lymphocytes or the more recently described system of activation of human caspase 9 by a small-molecule dimerizer.

[0143] A conditional CAR T cell is by default unresponsive, or switched “off”, until the addition of a small molecule to complete the circuit, enabling full transduction of both signal 1 and signal 2, thereby activating the CAR T cell. Alternatively, T cells may be engineered to express an adaptor- specific receptor with affinity for subsequently administered secondary antibodies directed at target antigen.

[0144] Marked CAR T cells express a CAR plus a tumor epitope to which an existing monoclonal antibody agent binds. In the setting of intolerable adverse effects, administration of the monoclonal antibody clears the CAR T cells and alleviates symptoms with no additional off-tumor effects.

[0145] A tandem CAR (TanCAR) T cell expresses a single CAR consisting of two linked single- chain variable fragments (scFvs) that have different affinities fused to intracellular co-stimulatory domain(s) and a CD3ζ domain. TanCAR T cell activation is achieved only when target cells co- express both targets.

[0146] A dual CAR T cell expresses two separate CARs with different ligand binding targets; one CAR includes only the CD3ζ domain and the other CAR includes only the co-stimulatory domain(s). Dual CAR T cell activation requires co-expression of both targets on the tumor.

[0147] A safety CAR (sCAR) consists of an extracellular scFv fused to an intracellular inhibitory domain. sCAR T cells co-expressing a standard CAR become activated only when encountering target cells that possess the standard CAR target but lack the sCAR target.

[0148] There are three generations of CARs. “First generation” CARs are typically composed of an extracellular antigen-binding domain (e.g., an scFv), which is fused to a transmembrane domain, which is fused to an intracellular domain. “First generation” CARs can provide de novo antigen recognition and cause activation of both CD4+and CD8+T-cells through their CD3ζ chain signaling domain in a single fusion molecule, independent of HLA-mediated antigen presentation. “Second generation” CARs add an intracellular signaling domain from a co-stimulatory molecule (e.g., CD28, 4-1BB, ICOS, OX40) to the intracellular domain of the CAR to provide additional signals to the cell. “Second generation” CARs comprise those that provide both co-stimulation (e.g., CD28 or 4-1BB) and activation (CD3ζ). “Third generation” CARs combine multiple signaling domains to further augment potency, e.g., are made by combining multiple signaling domains, such as CD3 ζ-NAI-1540294631v346CD28-OC40 or CD3ζ-CD28-4-1BB, to augment potency with stronger cytokine production and killing ability. In certain embodiments, the GPC3-targeted CAR is a first-generation CAR. In certain embodiments, the GPC3-targeted CAR is a second-generation CAR.

[0149] In certain embodiments, the CAR comprises one signaling domain. In certain embodiments, the CAR comprises one or more signaling domain (co-stimulatory signaling region). The one or more signaling domain may be a polypeptide selected from the group consisting of CD8, CD3ζ, CD3δ, CD3γ, CD3ε, FcγRI-γ, FcyRIII-y, FcεRIβ, FcεRIy, DAP10, DAP12, CD32, CD79a, CD79b, CD28, CD3C, CD4, B2C, 4-1BB (CD137), ICOS, CD27, CD288, CD80, NKp30, OX40, and mutants thereof. 5.3.1. Extracellular Domain of A CAR

[0150] The extracellular domain of the CARs disclosed herein generally comprise an antigen recognition domain that binds a GPC3 antigen. Such antigen-specific binding domains are typically derived from an antibody. In certain embodiments, the extracellular domain of the CAR comprises or is a functional antibody fragment or derivative thereof (e.g., a single chain variable fragment (scFv) or a Fab, or any suitable antigen binding fragment of an antibody).

[0151] In certain embodiments, the extracellular domain of the CAR comprises an scFv. In certain embodiments, the scFv is from a monoclonal antibody (mAb). The scFv can be a human scFv, a humanized scFv, or a murine scFv. In certain embodiments, the scFv is a human scFv. The scFv can be derived from fusing the heavy chain variable region (VH) and light chain variable region (VL) of an antibody. Alternatively or additionally, the scFv may be derived from Fab’s (instead of from an antibody, e.g., obtained from Fab libraries).

[0152] In certain embodiments, the extracellular domain of the CAR comprises a Fab. In certain embodiments, the Fab is crosslinked. In certain embodiments, the extracellular domain of the CAR comprises a F(ab)2.

[0153] Any of the foregoing molecules may be comprised in a fusion protein with a heterologous sequence to form the extracellular domain of the CAR.

[0154] In certain embodiments, the extracellular domain of the CAR binds to a GPC3 antigen (e.g., a human GPC3 antigen) with a EC50 of between about 1 ng / mL and about 600 ng / mL, between about 1 ng / mL and about 500 ng / mL, between about 1 ng / mL and about 400 ng / mL, between about 1 ng / mL and about 300 ng / mL, between about 1 ng / mL and about 200 ng / mL, between about 1 ng / mL and about 150 ng / mL between about 1 ng / mL and about 100 ng / mL, between about 1 ng / mL and about 60 ng / mL, between about 1 ng / mL and about 50 ng / mL, between about 1 ng / mL and about 40 ng / mL, between about 4 ng / mL and about 60 ng / mL, between about 4NAI-1540294631v347ng / mL and about 50 ng / mL, or between about 4 ng / mL and about 40 ng / mL. In certain embodiments, the extracellular domain of the CAR binds to GPC3 antigen (e.g., a human GPC3 antigen) with a EC50 of between about 1 ng / mL and about 60 ng / mL. In certain embodiments, the extracellular domain of the CAR binds to GPC3 antigen (e.g., a human GPC3 antigen) with a EC50 of between about 4 ng / mL and about 40 ng / mL.

[0155] Binding of the extracellular domain of the CAR can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay. Each of these assays generally detect the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody, or a scFv) specific for the complex of interest. For example, the scFv can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a γ counter or a scintillation counter or by autoradiography. In certain embodiments, the GPC3-targeted extracellular 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).

[0156] In certain embodiments, the extracellular domain of the CAR comprises a heavy chain variable region (VH) and a light chain variable region (VL).

[0157] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 29; and / or ii) the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 as set forth in a VLcomprising the amino acid sequence of SEQ ID NO: 30. SEQ ID NO: 29 and SEQ ID NO: 30 are disclosed in Table 1.

[0158] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25. SEQ ID NOs: 23-25 are provided in Table 1.NAI-1540294631v348

[0159] In certain embodiments, the VH 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 29. For example, the VHcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 29. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 29.

[0160] In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof. In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28. SEQ ID NOs: 26-28 are provided in Table 1.

[0161] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 30. For example, the VLcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 30. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 30.

[0162] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2NAI-1540294631v349comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28.

[0163] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 29, and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 30.

[0164] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VLor VL-VH.

[0165] In certain embodiments, the VH is positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the scFv comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 29, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 30. In certain embodiments, the VH and VL are linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31. SEQ ID NO: 31 is provided in Table 1.

[0166] In certain embodiments, the VL is positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the scFv comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 29, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 30. In certainNAI-1540294631v350embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 32. SEQ ID NO: 32 is provided in Table 1.

[0167] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 1 (ATA001 or ATA017) CDRs 1 2 3 VHDYAMH (SEQ ID NO:VISTYNGNTNYNRKFKD NDY (SEQ ID Q

[0168] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 29 is set forth in SEQ ID NO: 33, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACAAATTCACTGATTATGCTATGCACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACTACAACCGGAAGTTTAAGGACAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAAG ATTCTGCCATCTATTACTGTTTAAAGAACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC A (SEQ ID NO: 33)

[0169] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 29 is set forth in SEQ ID NO: 34, which is provided below. CAAGTGCAGCTGCAGCAGTCTGGTCCTGAGGTGGTGCGGCCCGGAGTGTCCGTGAAAATCTCCTGCA AAGGCAGCGGCTACAAGTTCACAGACTACGCCATGCACTGGGTGAAGCAGAGCCACGCCAAGAGCCT GGAATGGATCGGCGTGATTTCTACATATAATGGCAATACCAACTACAACCGGAAGTTTAAGGACAAGNAI-1540294631v351GCCACCATGACCGTGGACAAAAGCAGCAGCACCGCCTACATGGAACTGGCTAGACTGACCTCTGAGG ACAGCGCCATCTACTATTGTCTGAAGAACGACTACTGGGGCCAGGGCACAAGCGTCACCGTTTCCAG C (SEQ ID NO: 34)

[0170] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 30 is set forth in SEQ ID NO: 35, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCTTCTCTT GCAAGTCAAGTCAGAGTCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGGTGTTACAGAGGCC AGGCCAGTCGCCAAATCGCCTAATCTATCTGGTGTCTAAATTGGACTCTAGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACAGTTTCCTCACACGTTCGGAGGGGGGACCAAGCTGGAAATAAA A (SEQ ID NO: 35)

[0171] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 30 is set forth in SEQ ID NO: 36, which is provided below. GACGTGGTCATGACCCAGACCCCTCTGACACTGAGCGTGACCATCGGCCAGCCTGCTAGCTTCAGCT GCAAGAGCTCCCAGAGCCTGCTGGACTCTGATGGCAAGACCTACCTGAACTGGGTGCTGCAGAGACC TGGCCAATCTCCTAACAGACTGATCTACCTGGTGTCAAAGCTGGATTCTAGAGTGCCAGATAGATTC ACCGGCAGCGGCAGCGGAACCGATTTTACACTGAAGATCAGCCGGGTGGAAGCCGAGGACCTGGGAG TGTACTACTGCTGGCAGGGAACCCAGTTCCCCCACACATTCGGCGGCGGAACAAAGCTCGAGATCAA A (SEQ ID NO: 36)

[0172] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 31 is set forth in SEQ ID NO: 37, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACAAATTCACTGATTATGCTATGCACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACTACAACCGGAAGTTTAAGGACAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAAG ATTCTGCCATCTATTACTGTTTAAAGAACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATGTTGTGATGACCCAGACT CCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCTTCTCTTGCAAGTCAAGTCAGAGTCTCT TAGATAGTGATGGAAAGACATATTTGAATTGGGTGTTACAGAGGCCAGGCCAGTCGCCAAATCGCCT AATCTATCTGGTGTCTAAATTGGACTCTAGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACA GATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTA CACAGTTTCCTCACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA (SEQ ID NO: 37)NAI-1540294631v352

[0173] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 31 is set forth in SEQ ID NO: 38, which is provided below. CAAGTGCAGCTGCAGCAGTCTGGTCCTGAGGTGGTGCGGCCCGGAGTGTCCGTGAAAATCTCCTGCA AAGGCAGCGGCTACAAGTTCACAGACTACGCCATGCACTGGGTGAAGCAGAGCCACGCCAAGAGCCT GGAATGGATCGGCGTGATTTCTACATATAATGGCAATACCAACTACAACCGGAAGTTTAAGGACAAG GCCACCATGACCGTGGACAAAAGCAGCAGCACCGCCTACATGGAACTGGCTAGACTGACCTCTGAGG ACAGCGCCATCTACTATTGTCTGAAGAACGACTACTGGGGCCAGGGCACAAGCGTCACCGTTTCCAG CGGCGGCGGAGGCAGCGGCGGCGGCGGCTCTGGCGGCGGCGGAAGCGACGTGGTCATGACCCAGACC CCTCTGACACTGAGCGTGACCATCGGCCAGCCTGCTAGCTTCAGCTGCAAGAGCTCCCAGAGCCTGC TGGACTCTGATGGCAAGACCTACCTGAACTGGGTGCTGCAGAGACCTGGCCAATCTCCTAACAGACT GATCTACCTGGTGTCAAAGCTGGATTCTAGAGTGCCAGATAGATTCACCGGCAGCGGCAGCGGAACC GATTTTACACTGAAGATCAGCCGGGTGGAAGCCGAGGACCTGGGAGTGTACTACTGCTGGCAGGGAA CCCAGTTCCCCCACACATTCGGCGGCGGAACAAAGCTCGAGATCAAA (SEQ ID NO: 38)

[0174] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 32 is set forth in SEQ ID NO: 39, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCTTCTCTT GCAAGTCAAGTCAGAGTCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGGTGTTACAGAGGCC AGGCCAGTCGCCAAATCGCCTAATCTATCTGGTGTCTAAATTGGACTCTAGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACAGTTTCCTCACACGTTCGGAGGGGGGACCAAGCTGGAAATAAA AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTCCAGCTGCAGCAGTCT GGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCAAGGGTTCCGGCTACAAATTCA CTGATTATGCTATGCACTGGGTGAAGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAG TACTTACAATGGTAATACAAACTACAACCGGAAGTTTAAGGACAAGGCCACAATGACTGTAGACAAA TCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAAGATTCTGCCATCTATTACTGTT TAAAGAACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 39)

[0175] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 32 is set forth in SEQ ID NO: 40, which is provided below. GACGTGGTCATGACCCAGACCCCTCTGACACTGAGCGTGACCATCGGCCAGCCTGCTAGCTTCAGCT GCAAGAGCTCCCAGAGCCTGCTGGACTCTGATGGCAAGACCTACCTGAACTGGGTGCTGCAGAGACC TGGCCAATCTCCTAACAGACTGATCTACCTGGTGTCAAAGCTGGATTCTAGAGTGCCAGATAGATTC ACCGGCAGCGGCAGCGGAACCGATTTTACACTGAAGATCAGCCGGGTGGAAGCCGAGGACCTGGGAG TGTACTACTGCTGGCAGGGAACCCAGTTCCCCCACACATTCGGCGGCGGAACAAAGCTCGAGATCAANAI-1540294631v353AGGCGGCGGAGGCAGCGGCGGCGGCGGCTCTGGCGGCGGCGGAAGCCAAGTGCAGCTGCAGCAGTCT GGTCCTGAGGTGGTGCGGCCCGGAGTGTCCGTGAAAATCTCCTGCAAAGGCAGCGGCTACAAGTTCA CAGACTACGCCATGCACTGGGTGAAGCAGAGCCACGCCAAGAGCCTGGAATGGATCGGCGTGATTTC TACATATAATGGCAATACCAACTACAACCGGAAGTTTAAGGACAAGGCCACCATGACCGTGGACAAA AGCAGCAGCACCGCCTACATGGAACTGGCTAGACTGACCTCTGAGGACAGCGCCATCTACTATTGTC TGAAGAACGACTACTGGGGCCAGGGCACAAGCGTCACCGTTTCCAGC (SEQ ID NO: 40)

[0176] In certain embodiments, the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 47; and / or ii) the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 48. SEQ ID NO: 47 and SEQ ID NO: 48 are disclosed in Table 2.

[0177] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43. SEQ ID NOs: 41-43 are provided in Table 2.

[0178] In certain embodiments, the VH 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 47. For example, the VH comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 47. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 47.

[0179] In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45,NAI-1540294631v354and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. SEQ ID NOs: 44-46 are provided in Table 2.

[0180] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 48. For example, the VL comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 48.

[0181] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0182] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 47, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 48.

[0183] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VLor VL-VH.

[0184] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising theNAI-1540294631v355amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 47, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 49. SEQ ID NO: 49 is provided in Table 2.

[0185] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 47, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 50. SEQ ID NO: 50 is provided in Table 2.

[0186] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 2 (ATA002 or ATA018) CDRs 1 2 3 VI TYN NTNNN KFK TTY E IDNAI-1540294631v356VH-VLQVQLQQSGPEVVRPGVSVKISCKGSGYTFTDYAIHWVKQSHAKSLEWIGVISTY scFv NGNTNNNQKFKGKATMTVDKSSSTAYLELARLTSEDSAIYYCARSGTTYWGQGT A i TLTVSSGGGGSGGGGSGGGGSDVVMTQTPLTLSVTIGQPASISCKSSQSLLDSE, sequence of SEQ ID NO: 47 is set forth in SEQ ID NO: 51, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTATACACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACAACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTGCAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCA (SEQ ID NO: 51)

[0188] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 47 is set forth in SEQ ID NO: 52, which is provided below. CAAGTGCAGCTGCAGCAGAGCGGACCTGAGGTGGTGCGGCCTGGCGTGTCTGTGAAGATCAGCTGCA AGGGCTCTGGCTACACCTTTACCGACTACGCCATTCACTGGGTCAAGCAGAGCCACGCCAAGTCTCT GGAGTGGATCGGCGTGATCTCCACCTATAACGGCAATACCAACAACAACCAGAAGTTCAAGGGCAAG GCCACCATGACCGTGGATAAGAGCAGCAGCACCGCCTACCTGGAACTTGCTAGACTCACAAGCGAGG ACAGCGCCATCTACTATTGCGCCAGAAGCGGAACAACCTACTGGGGCCAAGGCACCACCCTGACCGT GTCCAGC (SEQ ID NO: 52)

[0189] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 48 is set forth in SEQ ID NO: 53, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCCTAGATAGTGAAGGAAAGACATATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTC AGTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGGTGGGACCAAGCTGGAGCTGAA A (SEQ ID NO: 53)

[0190] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 48 is set forth in SEQ ID NO: 54, which is provided below.NAI-1540294631v357GATGTGGTCATGACACAGACACCTCTGACACTGAGCGTGACAATCGGCCAGCCTGCTAGCATCAGCT GTAAAAGCAGCCAGAGCCTGCTGGACTCTGAGGGCAAAACATACCTGAACTGGCTGCTGCAGAGGCC CGGCCAGAGTCCTAAGCGGCTGATCTACCTGGTGTCCAAGGTGGACAGCGGTGTTCCAGATAGATTC AGCGGAAGCGGCTCCGGCACCGACTTCACCCTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGCG TGTACTACTGCTGGCAGGGCACCCACTTCCCCCATACCTTCGGCGGCGGCACAAAGCTGGAACTGAA G (SEQ ID NO: 54)

[0191] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 49 is set forth in SEQ ID NO: 55, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTATACACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACAACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTGCAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATGTTGTGATGACC CAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGA GCCTCCTAGATAGTGAAGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAA GCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTCAGTGGCAGTGGATCA GGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGC AAGGTACACATTTTCCTCACACGTTCGGTGGTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 55)

[0192] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 49 is set forth in SEQ ID NO: 56, which is provided below CAAGTGCAGCTGCAGCAGAGCGGACCTGAGGTGGTGCGGCCTGGCGTGTCTGTGAAGATCAGCTGCA AGGGCTCTGGCTACACCTTTACCGACTACGCCATTCACTGGGTCAAGCAGAGCCACGCCAAGTCTCT GGAGTGGATCGGCGTGATCTCCACCTATAACGGCAATACCAACAACAACCAGAAGTTCAAGGGCAAG GCCACCATGACCGTGGATAAGAGCAGCAGCACCGCCTACCTGGAACTTGCTAGACTCACAAGCGAGG ACAGCGCCATCTACTATTGCGCCAGAAGCGGAACAACCTACTGGGGCCAAGGCACCACCCTGACCGT GTCCAGCGGCGGAGGAGGCAGCGGCGGCGGAGGCTCTGGCGGCGGCGGAAGTGATGTGGTCATGACA CAGACACCTCTGACACTGAGCGTGACAATCGGCCAGCCTGCTAGCATCAGCTGTAAAAGCAGCCAGA GCCTGCTGGACTCTGAGGGCAAAACATACCTGAACTGGCTGCTGCAGAGGCCCGGCCAGAGTCCTAA GCGGCTGATCTACCTGGTGTCCAAGGTGGACAGCGGTGTTCCAGATAGATTCAGCGGAAGCGGCTCC GGCACCGACTTCACCCTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGCGTGTACTACTGCTGGCNAI-1540294631v358AGGGCACCCACTTCCCCCATACCTTCGGCGGCGGCACAAAGCTGGAACTGAAG (SEQ ID NO: 56)

[0193] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 50 is set forth in SEQ ID NO: 57, which is provided below GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCCTAGATAGTGAAGGAAAGACATATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTC AGTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGGTGGGACCAAGCTGGAGCTGAA AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTCCAGCTGCAGCAGTCT GGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCAAGGGTTCCGGCTACACATTCA CTGATTATGCTATACACTGGGTGAAGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAG TACTTACAATGGTAATACAAACAACAACCAGAAGTTTAAGGGCAAGGCCACAATGACTGTAGACAAA TCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGACATCTGAGGATTCTGCCATCTATTACTGTG CAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA (SEQ ID NO: 57)

[0194] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 50 is set forth in SEQ ID NO: 58, which is provided below. GATGTGGTCATGACACAGACACCTCTGACACTGAGCGTGACAATCGGCCAGCCTGCTAGCATCAGCT GTAAAAGCAGCCAGAGCCTGCTGGACTCTGAGGGCAAAACATACCTGAACTGGCTGCTGCAGAGGCC CGGCCAGAGTCCTAAGCGGCTGATCTACCTGGTGTCCAAGGTGGACAGCGGTGTTCCAGATAGATTC AGCGGAAGCGGCTCCGGCACCGACTTCACCCTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGCG TGTACTACTGCTGGCAGGGCACCCACTTCCCCCATACCTTCGGCGGCGGCACAAAGCTGGAACTGAA GGGCGGAGGAGGCAGCGGCGGCGGAGGCTCTGGCGGCGGCGGAAGTCAAGTGCAGCTGCAGCAGAGC GGACCTGAGGTGGTGCGGCCTGGCGTGTCTGTGAAGATCAGCTGCAAGGGCTCTGGCTACACCTTTA CCGACTACGCCATTCACTGGGTCAAGCAGAGCCACGCCAAGTCTCTGGAGTGGATCGGCGTGATCTC CACCTATAACGGCAATACCAACAACAACCAGAAGTTCAAGGGCAAGGCCACCATGACCGTGGATAAG AGCAGCAGCACCGCCTACCTGGAACTTGCTAGACTCACAAGCGAGGACAGCGCCATCTACTATTGCG CCAGAAGCGGAACAACCTACTGGGGCCAAGGCACCACCCTGACCGTGTCCAGC (SEQ ID NO: 58)

[0195] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 62; and / or ii) the VL comprisesNAI-1540294631v359a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 63. SEQ ID NO: 62 and SEQ ID NO: 63 are disclosed in Table 3.

[0196] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61. SEQ ID NOs: 59-61 are provided in Table 3.

[0197] In certain embodiments, the VH 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 62. For example, the VHcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 62. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 62.

[0198] In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. SEQ ID NOs: 26, 27, and 46 are provided in Table 3.

[0199] In certain embodiments, the VL 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 63. For example, the VLcomprises an amino acid sequence that is 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% identical or homologousNAI-1540294631v360to the amino acid sequence set forth in SEQ ID NO: 63. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 63.

[0200] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61 or a conservative modification thereof; and VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0201] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 62, and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 63.

[0202] The VH the VL can be linked one after another, e.g., by a linker. In certain embodiments, the VHand VLare linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VL or VL-VH.

[0203] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VHand the VLare positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 62, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 63. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acidNAI-1540294631v361sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 64. SEQ ID NO: 64 is provided in Table 3.

[0204] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 62, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 63. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 65. SEQ ID NO: 65 is provided in Table 3.

[0205] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 3 (ATA003) CDRs 1 2 3 VHDYAVH (SEQ ID NO:VISTYNGNTNYNQKFKG SGTSY (SEQ ID QNAI-1540294631v362

[0206] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 62 is set forth in SEQ ID NO: 66, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTGTGCACTGGGTGAAACAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTGCAAGATCGGGGACGAGCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCA (SEQ ID NO: 66)

[0207] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 62 is set forth in SEQ ID NO: 67, which is provided below. CAAGTGCAGCTGCAGCAGAGCGGTCCTGAGGTGGTGCGGCCTGGAGTGTCCGTGAAGATTAGCTGCA AGGGCAGCGGATATACATTTACCGACTACGCCGTGCACTGGGTTAAGCAGAGCCACGCCAAGTCTCT GGAATGGATCGGCGTGATCAGCACCTACAACGGCAACACCAACTACAATCAGAAATTCAAGGGCAAG GCCACCATGACCGTGGACAAGAGCAGCAGCACCGCCTACATGGAACTGGCCAGGCTGACCAGCGAGG ATTCCGCCATCTACTACTGCGCCAGAAGCGGAACCTCATATTGGGGCCAGGGCACTACACTGACAGT GTCCAGC (SEQ ID NO: 67)

[0208] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 63 is set forth in SEQ ID NO: 68, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGTTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGTCTCTTAGATAGTGATGGAAAGACCTATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTTTCTGGTGTCTAAACTGGACTCTGGAGCCCCTGACAGGTTC TCTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGCTGGGACCAAGCTGGAGCTGAA A (SEQ ID NO: 68)

[0209] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 63 is set forth in SEQ ID NO: 69, which is provided below GATGTGGTCATGACACAGACCCCTCTGACCCTTTCTTTTACCATCGGACAGCCTGCTAGCATCAGCT GCAAGAGCTCTCAGAGCCTGCTGGACAGCGACGGCAAAACCTACCTGAACTGGCTGCTGCAAAGACC CGGCCAGTCTCCAAAGCGGCTGATCTTCCTGGTGTCCAAGCTGGACAGCGGCGCTCCTGATAGATTC AGCGGCAGCGGAAGCGGCACAGACTTCACACTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGCG TGTACTACTGTTGGCAGGGCACCCATTTCCCCCACACCTTCGGCGCCGGCACAAAGCTCGAGCTGAA G (SEQ ID NO: 69)NAI-1540294631v363

[0210] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 64 is set forth in SEQ ID NO: 70, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTGTGCACTGGGTGAAACAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTGCAAGATCGGGGACGAGCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATGTTGTGATGACC CAGACTCCACTCACTTTGTCGTTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGA GTCTCTTAGATAGTGATGGAAAGACCTATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAA GCGCCTAATCTTTCTGGTGTCTAAACTGGACTCTGGAGCCCCTGACAGGTTCTCTGGCAGTGGATCA GGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGC AAGGTACACATTTTCCTCACACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 70)

[0211] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 64 is set forth in SEQ ID NO: 71, which is provided below CAAGTGCAGCTGCAGCAGAGCGGTCCTGAGGTGGTGCGGCCTGGAGTGTCCGTGAAGATTAGCTGCA AGGGCAGCGGATATACATTTACCGACTACGCCGTGCACTGGGTTAAGCAGAGCCACGCCAAGTCTCT GGAATGGATCGGCGTGATCAGCACCTACAACGGCAACACCAACTACAATCAGAAATTCAAGGGCAAG GCCACCATGACCGTGGACAAGAGCAGCAGCACCGCCTACATGGAACTGGCCAGGCTGACCAGCGAGG ATTCCGCCATCTACTACTGCGCCAGAAGCGGAACCTCATATTGGGGCCAGGGCACTACACTGACAGT GTCCAGCGGCGGCGGAGGCAGCGGCGGCGGCGGCTCCGGCGGAGGCGGCTCTGATGTGGTCATGACA CAGACCCCTCTGACCCTTTCTTTTACCATCGGACAGCCTGCTAGCATCAGCTGCAAGAGCTCTCAGA GCCTGCTGGACAGCGACGGCAAAACCTACCTGAACTGGCTGCTGCAAAGACCCGGCCAGTCTCCAAA GCGGCTGATCTTCCTGGTGTCCAAGCTGGACAGCGGCGCTCCTGATAGATTCAGCGGCAGCGGAAGC GGCACAGACTTCACACTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGCGTGTACTACTGTTGGC AGGGCACCCATTTCCCCCACACCTTCGGCGCCGGCACAAAGCTCGAGCTGAAG (SEQ ID NO: 71)

[0212] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 65 is set forth in SEQ ID NO: 72, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGTTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGTCTCTTAGATAGTGATGGAAAGACCTATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTTTCTGGTGTCTAAACTGGACTCTGGAGCCCCTGACAGGTTCNAI-1540294631v364TCTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGCTGGGACCAAGCTGGAGCTGAA AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTCCAGCTGCAGCAGTCT GGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCAAGGGTTCCGGCTACACATTCA CTGATTATGCTGTGCACTGGGTGAAACAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAG TACTTACAATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAGGCCACAATGACTGTAGACAAA TCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGGATTCTGCCATCTATTACTGTG CAAGATCGGGGACGAGCTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA (SEQ ID NO: 72)

[0213] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 65 is set forth in SEQ ID NO: 73, which is provided below. GATGTGGTCATGACACAGACCCCTCTGACCCTTTCTTTTACCATCGGACAGCCTGCTAGCATCAGCT GCAAGAGCTCTCAGAGCCTGCTGGACAGCGACGGCAAAACCTACCTGAACTGGCTGCTGCAAAGACC CGGCCAGTCTCCAAAGCGGCTGATCTTCCTGGTGTCCAAGCTGGACAGCGGCGCTCCTGATAGATTC AGCGGCAGCGGAAGCGGCACAGACTTCACACTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGCG TGTACTACTGTTGGCAGGGCACCCATTTCCCCCACACCTTCGGCGCCGGCACAAAGCTCGAGCTGAA GGGCGGCGGAGGCAGCGGCGGCGGCGGCTCCGGCGGAGGCGGCTCTCAAGTGCAGCTGCAGCAGAGC GGTCCTGAGGTGGTGCGGCCTGGAGTGTCCGTGAAGATTAGCTGCAAGGGCAGCGGATATACATTTA CCGACTACGCCGTGCACTGGGTTAAGCAGAGCCACGCCAAGTCTCTGGAATGGATCGGCGTGATCAG CACCTACAACGGCAACACCAACTACAATCAGAAATTCAAGGGCAAGGCCACCATGACCGTGGACAAG AGCAGCAGCACCGCCTACATGGAACTGGCCAGGCTGACCAGCGAGGATTCCGCCATCTACTACTGCG CCAGAAGCGGAACCTCATATTGGGGCCAGGGCACTACACTGACAGTGTCCAGC (SEQ ID NO: 73)

[0214] In certain embodiments, the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 75; and / or ii) the VLcomprises a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 76. SEQ ID NO: 75 and SEQ ID NO: 76 are disclosed in Table 4.

[0215] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60,NAI-1540294631v365and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25. SEQ ID NOs: 23, 60, and 25 are provided in Table 4.

[0216] In certain embodiments, the VHcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 75. For example, the VH comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 75. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 75.

[0217] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. SEQ ID NOs: 74, 45, and 46 are provided in Table 4.

[0218] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 76. For example, the VL comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 76. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 76.

[0219] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification, and a CDR3 comprising the amino acid sequence setNAI-1540294631v366forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0220] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 75, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 76.

[0221] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VHand VLare linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VL or VL-VH.

[0222] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 75, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 76. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 77. SEQ ID NO: 77 is provided in Table 4.

[0223] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certainNAI-1540294631v367embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 75, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 76. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 78. SEQ ID NO: 78 is provided in Table 4.

[0224] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 4 (ATA004 or ATA019) CDRs 1 2 3 VHDYAMH (SEQ ID NO:VISTYNGNTNYNQKFKG NDY (SEQ ID Q N V L E N V L C L E K I

[0225] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 75 is set forth in SEQ ID NO: 79, which is provided below CAGGTCCAACTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTATGCACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATCAGTACTTACAATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTCTAAAGAACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC A (SEQ ID NO: 79)

[0226] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 75 is set forth in SEQ ID NO: 80, which is provided belowNAI-1540294631v368CAGGTGCAGCTGCAGCAGAGCGGTCCTGAGGTGGTTAGACCTGGCGTGTCTGTGAAGATTAGCTGCA AAGGCAGCGGCTACACCTTTACCGACTACGCCATGCATTGGGTCAAGCAGAGCCACGCCAAGTCTCT GGAATGGATCGGCGTGATCTCTACATATAATGGCAACACCAACTACAACCAGAAGTTCAAGGGCAAG GCCACCATGACCGTGGATAAGAGCTCCAGCACCGCCTACATGGAACTGGCTAGACTGACAAGCGAGG ATAGCGCCATCTACTACTGTCTGAAGAACGACTACTGGGGCCAGGGCACCAGCGTGACCGTGAGCAG C (SEQ ID NO: 80)

[0227] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 76 is set forth in SEQ ID NO: 81, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCTTAAATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGAG TTTTTTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGAGGGGGGACCAAGCTGGAAATAAA A (SEQ ID NO: 81)

[0228] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 76 is set forth in SEQ ID NO: 82, which is provided below. GACGTGGTGATGACACAGACCCCTCTGACCCTGAGCGTGACAATCGGCCAACCTGCTAGCATCTCTT GCAAGTCCTCCCAGAGCCTGCTGAACAGCGACGGCAAAACCTACCTGAATTGGCTGCTCCAGCGGCC TGGACAATCTCCAAAGCGGCTGATCTACCTGGTGAGCAAGGTGGACAGCGGCGTCCCCGATAGATTT ACCGGCAGCGGAAGCGGCACAGACTTCACTCTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGAG TGTTCTACTGCTGGCAGGGAACCCACTTCCCCCACACATTCGGCGGCGGAACAAAGCTGGAGATCAA G (SEQ ID NO: 82)

[0229] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 77 is set forth in SEQ ID NO: 83, which is provided below. CAGGTCCAACTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTATGCACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATCAGTACTTACAATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTCTAAAGAACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATGTTGTGATGACCCAGACT CCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCT TAAATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCT AATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACANAI-1540294631v369GATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGAGTTTTTTATTGCTGGCAAGGTA CACATTTTCCTCACACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA (SEQ ID NO: 83)

[0230] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 77 is set forth in SEQ ID NO: 84, which is provided below CAGGTGCAGCTGCAGCAGAGCGGTCCTGAGGTGGTTAGACCTGGCGTGTCTGTGAAGATTAGCTGCA AAGGCAGCGGCTACACCTTTACCGACTACGCCATGCATTGGGTCAAGCAGAGCCACGCCAAGTCTCT GGAATGGATCGGCGTGATCTCTACATATAATGGCAACACCAACTACAACCAGAAGTTCAAGGGCAAG GCCACCATGACCGTGGATAAGAGCTCCAGCACCGCCTACATGGAACTGGCTAGACTGACAAGCGAGG ATAGCGCCATCTACTACTGTCTGAAGAACGACTACTGGGGCCAGGGCACCAGCGTGACCGTGAGCAG CGGCGGCGGAGGCTCTGGAGGCGGAGGCAGCGGCGGCGGCGGCTCCGACGTGGTGATGACACAGACC CCTCTGACCCTGAGCGTGACAATCGGCCAACCTGCTAGCATCTCTTGCAAGTCCTCCCAGAGCCTGC TGAACAGCGACGGCAAAACCTACCTGAATTGGCTGCTCCAGCGGCCTGGACAATCTCCAAAGCGGCT GATCTACCTGGTGAGCAAGGTGGACAGCGGCGTCCCCGATAGATTTACCGGCAGCGGAAGCGGCACA GACTTCACTCTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGAGTGTTCTACTGCTGGCAGGGAA CCCACTTCCCCCACACATTCGGCGGCGGAACAAAGCTGGAGATCAAG (SEQ ID NO: 84)

[0231] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 78 is set forth in SEQ ID NO: 85, which is provided below GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCTTAAATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAAGATTTGGGAG TTTTTTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGAGGGGGGACCAAGCTGGAAATAAA AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTCCAACTGCAGCAGTCT GGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCAAGGGTTCCGGCTACACATTCA CTGATTATGCTATGCACTGGGTGAAGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATCAG TACTTACAATGGTAATACAAACTACAACCAGAAGTTTAAGGGCAAGGCCACAATGACTGTAGACAAA TCCTCCAGCACAGCCTATATGGAACTTGCCAGATTGACATCTGAGGATTCTGCCATCTATTACTGTC TAAAGAACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 85)

[0232] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 78 is set forth in SEQ ID NO: 86, which is provided below. GACGTGGTGATGACACAGACCCCTCTGACCCTGAGCGTGACAATCGGCCAACCTGCTAGCATCTCTT GCAAGTCCTCCCAGAGCCTGCTGAACAGCGACGGCAAAACCTACCTGAATTGGCTGCTCCAGCGGCC TGGACAATCTCCAAAGCGGCTGATCTACCTGGTGAGCAAGGTGGACAGCGGCGTCCCCGATAGATTTNAI-1540294631v370ACCGGCAGCGGAAGCGGCACAGACTTCACTCTGAAAATCTCTAGAGTGGAAGCCGAGGACCTGGGAG TGTTCTACTGCTGGCAGGGAACCCACTTCCCCCACACATTCGGCGGCGGAACAAAGCTGGAGATCAA GGGCGGCGGAGGCTCTGGAGGCGGAGGCAGCGGCGGCGGCGGCTCCCAGGTGCAGCTGCAGCAGAGC GGTCCTGAGGTGGTTAGACCTGGCGTGTCTGTGAAGATTAGCTGCAAAGGCAGCGGCTACACCTTTA CCGACTACGCCATGCATTGGGTCAAGCAGAGCCACGCCAAGTCTCTGGAATGGATCGGCGTGATCTC TACATATAATGGCAACACCAACTACAACCAGAAGTTCAAGGGCAAGGCCACCATGACCGTGGATAAG AGCTCCAGCACCGCCTACATGGAACTGGCTAGACTGACAAGCGAGGATAGCGCCATCTACTACTGTC TGAAGAACGACTACTGGGGCCAGGGCACCAGCGTGACCGTGAGCAGC (SEQ ID NO: 86)

[0233] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 89; and / or ii) the VL comprises a VLCDR1, a VLCDR2, and a VLCDR3 as set forth in a VLcomprising the amino acid sequence of SEQ ID NO: 90. SEQ ID NO: 89 and SEQ ID NO: 90 are disclosed in Table 5.

[0234] In certain embodiments, the VH 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: 43 or a conservative modification thereof. In certain embodiments, the VH 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: 43. SEQ ID NOs: 87, 88, and 43 are provided in Table 5.

[0235] In certain embodiments, the VHcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 89. For example, the VH comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 89. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 89.

[0236] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence setNAI-1540294631v371forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. SEQ ID NOs: 26, 27, and 46 are provided in Table 5.

[0237] In certain embodiments, the VL 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 90. For example, the VLcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 90. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 90.

[0238] In certain embodiments, the VH 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: 43 or a conservative modification thereof; and VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VHcomprises 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: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0239] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 89, and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 90.

[0240] The VH the VL can be linked one after another, e.g., by a linker. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VLor VL-VH.

[0241] In certain embodiments, the VH is positioned at the N-terminus of the extracellular domain, i.e., the VHand the VLare positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising aNAI-1540294631v372CDR1 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: 43; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 89, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 90. In certain embodiments, the VH and VL are linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 91. SEQ ID NO: 91 is provided in Table 5.

[0242] In certain embodiments, the VL is positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising 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: 43; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 89, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 90. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 92. SEQ ID NO: 92 is provided in Table 5.

[0243] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 5 (ATA005) CDRs 1 2 3 D Q N L L ENAI-1540294631v373VH-VLQVQLQQSGPEVERPGVSVKISCKGSGYTFTDFAIHWVIQSHAKSLEWIGVISTYN scFv GHTNYNQKFKGKATMTVDKSSSTAYLELARLISEDSGIYYCARSGTTYWGQGTTL A i TVSSGGGGSGGGGSGGGGSDVVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKT Y L E I I, sequence of SEQ ID NO: 89 is set forth in SEQ ID NO: 93, which is provided below. CAGGTCCAACTGCAGCAGTCTGGGCCTGAGGTGGAGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTTTGCTATACACTGGGTGATTCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTCATACAAACTACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGATATCTGAGG ATTCTGGCATCTATTACTGTGCAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCC (SEQ ID NO: 93)

[0245] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 89 is set forth in SEQ ID NO: 94, which is provided below CAGGTGCAGCTGCAGCAGTCCGGCCCCGAGGTGGAAAGACCTGGCGTTAGCGTGAAGATCAGCTGCA AGGGCTCTGGCTACACATTCACAGACTTTGCCATCCACTGGGTGATCCAGAGCCACGCCAAGAGCCT GGAATGGATCGGCGTGATCAGCACCTATAACGGCCACACCAACTACAACCAGAAGTTCAAGGGAAAA GCTACAATGACCGTGGACAAGTCCTCTTCTACCGCCTACCTCGAGCTGGCCAGACTGATTAGCGAGG ACAGCGGAATCTACTATTGCGCCCGGAGCGGCACCACCTACTGGGGCCAGGGCACAACCCTGACCGT GTCCAGC (SEQ ID NO: 94)

[0246] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 90 is set forth in SEQ ID NO: 95, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTCCAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTAGTGTCTAAATTGGACTCTGGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGCTGGGACCAAGCTGGAGCTGAA A (SEQ ID NO: 95)

[0247] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 90 is set forth in SEQ ID NO: 96, which is provided below.NAI-1540294631v374GATGTGGTGATGACACAGACCCCTCTGACCCTGAGCGTGACAATCGGACAACCTGCTAGCATCAGCT GTAAAAGCTCTCAGAGCCTGCTGGACAGCGACGGCAAGACCTACCTGAATTGGCTGTTCCAGAGACC AGGGCAAAGCCCCAAGCGGCTGATCTACCTGGTGTCCAAGCTGGATTCTGGCGTGCCTGACAGGTTC ACCGGCAGCGGATCAGGCACAGATTTCACCCTTAAAATCAGCAGAGTGGAGGCCGAGGACCTGGGCG TCTACTACTGCTGGCAGGGCACACATTTCCCTCACACCTTTGGCGCCGGCACCAAGCTGGAACTGAA G (SEQ ID NO: 96)

[0248] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 91 is set forth in SEQ ID NO: 97, which is provided below. CAGGTCCAACTGCAGCAGTCTGGGCCTGAGGTGGAGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTTTGCTATACACTGGGTGATTCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTCATACAAACTACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGATATCTGAGG ATTCTGGCATCTATTACTGTGCAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCCGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATGTTGTGATGACC CAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGA GCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTCCAGAGGCCAGGCCAGTCTCCAAA GCGCCTAATCTATCTAGTGTCTAAATTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCA GGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGC AAGGTACACATTTTCCTCACACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 97)

[0249] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 91 is set forth in SEQ ID NO: 98, which is provided below. CAGGTGCAGCTGCAGCAGTCCGGCCCCGAGGTGGAAAGACCTGGCGTTAGCGTGAAGATCAGCTGCA AGGGCTCTGGCTACACATTCACAGACTTTGCCATCCACTGGGTGATCCAGAGCCACGCCAAGAGCCT GGAATGGATCGGCGTGATCAGCACCTATAACGGCCACACCAACTACAACCAGAAGTTCAAGGGAAAA GCTACAATGACCGTGGACAAGTCCTCTTCTACCGCCTACCTCGAGCTGGCCAGACTGATTAGCGAGG ACAGCGGAATCTACTATTGCGCCCGGAGCGGCACCACCTACTGGGGCCAGGGCACAACCCTGACCGT GTCCAGCGGCGGCGGCGGCAGCGGCGGCGGAGGTTCTGGAGGAGGCGGCAGCGATGTGGTGATGACA CAGACCCCTCTGACCCTGAGCGTGACAATCGGACAACCTGCTAGCATCAGCTGTAAAAGCTCTCAGA GCCTGCTGGACAGCGACGGCAAGACCTACCTGAATTGGCTGTTCCAGAGACCAGGGCAAAGCCCCAA GCGGCTGATCTACCTGGTGTCCAAGCTGGATTCTGGCGTGCCTGACAGGTTCACCGGCAGCGGATCA GGCACAGATTTCACCCTTAAAATCAGCAGAGTGGAGGCCGAGGACCTGGGCGTCTACTACTGCTGGCNAI-1540294631v375AGGGCACACATTTCCCTCACACCTTTGGCGCCGGCACCAAGCTGGAACTGAAG (SEQ ID NO: 98)

[0250] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 92 is set forth in SEQ ID NO: 99, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTCCAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTAGTGTCTAAATTGGACTCTGGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGCTGGGACCAAGCTGGAGCTGAA AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTCCAACTGCAGCAGTCT GGGCCTGAGGTGGAGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCAAGGGTTCCGGCTACACATTCA CTGATTTTGCTATACACTGGGTGATTCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAG TACTTACAATGGTCATACAAACTACAACCAGAAGTTTAAGGGCAAGGCCACAATGACTGTAGACAAA TCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGATATCTGAGGATTCTGGCATCTATTACTGTG CAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCC (SEQ ID NO: 99)

[0251] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 92 is set forth in SEQ ID NO: 100, which is provided below. GATGTGGTGATGACACAGACCCCTCTGACCCTGAGCGTGACAATCGGACAACCTGCTAGCATCAGCT GTAAAAGCTCTCAGAGCCTGCTGGACAGCGACGGCAAGACCTACCTGAATTGGCTGTTCCAGAGACC AGGGCAAAGCCCCAAGCGGCTGATCTACCTGGTGTCCAAGCTGGATTCTGGCGTGCCTGACAGGTTC ACCGGCAGCGGATCAGGCACAGATTTCACCCTTAAAATCAGCAGAGTGGAGGCCGAGGACCTGGGCG TCTACTACTGCTGGCAGGGCACACATTTCCCTCACACCTTTGGCGCCGGCACCAAGCTGGAACTGAA GGGCGGCGGCGGCAGCGGCGGCGGAGGTTCTGGAGGAGGCGGCAGCCAGGTGCAGCTGCAGCAGTCC GGCCCCGAGGTGGAAAGACCTGGCGTTAGCGTGAAGATCAGCTGCAAGGGCTCTGGCTACACATTCA CAGACTTTGCCATCCACTGGGTGATCCAGAGCCACGCCAAGAGCCTGGAATGGATCGGCGTGATCAG CACCTATAACGGCCACACCAACTACAACCAGAAGTTCAAGGGAAAAGCTACAATGACCGTGGACAAG TCCTCTTCTACCGCCTACCTCGAGCTGGCCAGACTGATTAGCGAGGACAGCGGAATCTACTATTGCG CCCGGAGCGGCACCACCTACTGGGGCCAGGGCACAACCCTGACCGTGTCCAGC (SEQ ID NO: 100)

[0252] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 101; and / or ii) the VLNAI-1540294631v376comprises a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 102. SEQ ID NO: 101 and SEQ ID NO: 102 are disclosed in Table 6.

[0253] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43. SEQ ID NOs: 41-43 are provided in Table 6.

[0254] In certain embodiments, the VH 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 101. For example, the VHcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 101. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 101.

[0255] In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. SEQ ID NOs: 44-46 are provided in Table 6.

[0256] In certain embodiments, the VL 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 102. For example, the VLcomprises an amino acid sequence that is 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% identical orNAI-1540294631v377homologous to the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 102.

[0257] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0258] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 101, and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 102.

[0259] The VH the VL can be linked one after another, e.g., by a linker. In certain embodiments, the VHand VLare linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VL or VL-VH.

[0260] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VHand the VLare positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 101, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acidNAI-1540294631v378sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 103. SEQ ID NO: 103 is provided in Table 6.

[0261] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 101, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 104. SEQ ID NO: 104 is provided in Table 6.

[0262] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 6 (ATA006) CDRs 1 2 3 VHDYAIH (SEQ ID NO:VISTYNGNTNNNQKFKG SGTTY (SEQ ID Q N L L E N L T Y L E M INAI-1540294631v379

[0263] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 101 is set forth in SEQ ID NO: 105, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTATACACTGGGTGATGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACAACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTGCAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCA (SEQ ID NO: 105)

[0264] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 101 is set forth in SEQ ID NO: 106, which is provided below. CAAGTGCAGCTGCAGCAGAGCGGCCCTGAGGTGGTGCGGCCCGGAGTGTCCGTGAAGATCAGCTGCA AGGGCTCTGGCTACACCTTTACCGACTACGCCATCCACTGGGTGATGCAGAGCCATGCCAAGAGCCT GGAGTGGATCGGAGTGATCTCTACATACAACGGCAACACCAACAACAATCAGAAGTTCAAGGGAAAA GCCACAATGACCGTGGATAAGTCCTCCAGCACCGCCTACCTGGAACTGGCTAGACTGACTAGCGAGG ATAGCGCTATTTACTATTGCGCCAGAAGCGGCACCACATACTGGGGCCAGGGAACAACACTGACCGT GTCAAGC (SEQ ID NO: 106)

[0265] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 102 is set forth in SEQ ID NO: 107, which is provided below. GATGTTGTGATGACCCAGTCTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCCTAGATAGTGAAGGAAAGACATATCTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTC AGTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGGTGGGACCAAGCTGGAGCTGAA A (SEQ ID NO: 107)

[0266] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 102 is set forth in SEQ ID NO: 108, which is provided below. GACGTGGTCATGACCCAGAGTCCTCTGACCCTGAGCGTCACAATCGGCCAGCCTGCCAGCATCAGCT GTAAAAGCAGCCAGAGCCTGCTGGACTCTGAGGGCAAAACCTACCTGAACTGGCTGCTGCAAAGACC TGGACAGTCTCCAAAGCGGCTGATCTACCTGGTTTCCAAGGTGGACTCTGGCGTGCCTGATAGATTC AGCGGCTCCGGCAGCGGCACCGACTTCACCCTGAAGATCAGCCGCGTGGAAGCCGAGGACCTGGGAG TGTACTACTGCTGGCAGGGCACCCACTTCCCCCACACATTCGGCGGCGGTACCAAGCTGGAACTCAA G (SEQ ID NO: 108)NAI-1540294631v380

[0267] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 103 is set forth in SEQ ID NO: 109, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGATTATGCTATACACTGGGTGATGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACAACAACCAGAAGTTTAAGGGCAAG GCCACAATGACTGTAGACAAATCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGACATCTGAGG ATTCTGCCATCTATTACTGTGCAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGT CTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATGTTGTGATGACC CAGTCTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGA GCCTCCTAGATAGTGAAGGAAAGACATATCTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAA GCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTCAGTGGCAGTGGATCA GGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGC AAGGTACACATTTTCCTCACACGTTCGGTGGTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 109)

[0268] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 103 is set forth in SEQ ID NO: 110, which is provided below. CAAGTGCAGCTGCAGCAGAGCGGCCCTGAGGTGGTGCGGCCCGGAGTGTCCGTGAAGATCAGCTGCA AGGGCTCTGGCTACACCTTTACCGACTACGCCATCCACTGGGTGATGCAGAGCCATGCCAAGAGCCT GGAGTGGATCGGAGTGATCTCTACATACAACGGCAACACCAACAACAATCAGAAGTTCAAGGGAAAA GCCACAATGACCGTGGATAAGTCCTCCAGCACCGCCTACCTGGAACTGGCTAGACTGACTAGCGAGG ATAGCGCTATTTACTATTGCGCCAGAAGCGGCACCACATACTGGGGCCAGGGAACAACACTGACCGT GTCAAGCGGCGGCGGCGGCAGCGGCGGAGGCGGCTCTGGCGGAGGCGGCAGCGACGTGGTCATGACC CAGAGTCCTCTGACCCTGAGCGTCACAATCGGCCAGCCTGCCAGCATCAGCTGTAAAAGCAGCCAGA GCCTGCTGGACTCTGAGGGCAAAACCTACCTGAACTGGCTGCTGCAAAGACCTGGACAGTCTCCAAA GCGGCTGATCTACCTGGTTTCCAAGGTGGACTCTGGCGTGCCTGATAGATTCAGCGGCTCCGGCAGC GGCACCGACTTCACCCTGAAGATCAGCCGCGTGGAAGCCGAGGACCTGGGAGTGTACTACTGCTGGC AGGGCACCCACTTCCCCCACACATTCGGCGGCGGTACCAAGCTGGAACTCAAG (SEQ ID NO: 110)

[0269] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 104 is set forth in SEQ ID NO: 111, which is provided below. GATGTTGTGATGACCCAGTCTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTT GCAAGTCAAGTCAGAGCCTCCTAGATAGTGAAGGAAAGACATATCTGAATTGGTTGTTACAGAGGCC AGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAAGTGGACTCTGGAGTCCCTGACAGGTTCNAI-1540294631v381AGTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGTACACATTTTCCTCACACGTTCGGTGGTGGGACCAAGCTGGAGCTGAA AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTCCAGCTGCAGCAGTCT GGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCAAGGGTTCCGGCTACACATTCA CTGATTATGCTATACACTGGGTGATGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAG TACTTACAATGGTAATACAAACAACAACCAGAAGTTTAAGGGCAAGGCCACAATGACTGTAGACAAA TCCTCCAGCACAGCCTATCTGGAACTTGCCAGATTGACATCTGAGGATTCTGCCATCTATTACTGTG CAAGATCGGGGACGACCTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA (SEQ ID NO: 111)

[0270] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 104 is set forth in SEQ ID NO: 112, which is provided below. GACGTGGTCATGACCCAGAGTCCTCTGACCCTGAGCGTCACAATCGGCCAGCCTGCCAGCATCAGCT GTAAAAGCAGCCAGAGCCTGCTGGACTCTGAGGGCAAAACCTACCTGAACTGGCTGCTGCAAAGACC TGGACAGTCTCCAAAGCGGCTGATCTACCTGGTTTCCAAGGTGGACTCTGGCGTGCCTGATAGATTC AGCGGCTCCGGCAGCGGCACCGACTTCACCCTGAAGATCAGCCGCGTGGAAGCCGAGGACCTGGGAG TGTACTACTGCTGGCAGGGCACCCACTTCCCCCACACATTCGGCGGCGGTACCAAGCTGGAACTCAA GGGCGGCGGCGGCAGCGGCGGAGGCGGCTCTGGCGGAGGCGGCAGCCAAGTGCAGCTGCAGCAGAGC GGCCCTGAGGTGGTGCGGCCCGGAGTGTCCGTGAAGATCAGCTGCAAGGGCTCTGGCTACACCTTTA CCGACTACGCCATCCACTGGGTGATGCAGAGCCATGCCAAGAGCCTGGAGTGGATCGGAGTGATCTC TACATACAACGGCAACACCAACAACAATCAGAAGTTCAAGGGAAAAGCCACAATGACCGTGGATAAG TCCTCCAGCACCGCCTACCTGGAACTGGCTAGACTGACTAGCGAGGATAGCGCTATTTACTATTGCG CCAGAAGCGGCACCACATACTGGGGCCAGGGAACAACACTGACCGTGTCAAGC (SEQ ID NO: 112)

[0271] In certain embodiments, the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 119; and / or ii) the VLcomprises a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 120. SEQ ID NO: 119 and SEQ ID NO: 120 are disclosed in Table 7.

[0272] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:NAI-1540294631v382114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115. SEQ ID NOs: 113-115 are provided in Table 7.

[0273] In certain embodiments, the VHcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 119. For example, the VH comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 119. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 119.

[0274] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118. SEQ ID NOs: 116-118 are provided in Table 7.

[0275] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 120. For example, the VL comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 120. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 120.

[0276] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 or a conservative modification, and a CDR3 comprising the amino acid sequenceNAI-1540294631v383set forth in SEQ ID NO: 118 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118.

[0277] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 119, and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 120.

[0278] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VLor VL-VH.

[0279] In certain embodiments, the VH is positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118. In certain embodiments, the scFv comprises a VHcomprising the amino acid sequence set forth in SEQ ID NO: 119, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 120. In certain embodiments, the VH and VL are linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 121. SEQ ID NO: 121 is provided in Table 7.

[0280] In certain embodiments, the VL is positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116; a CDR2 comprising the amino acid sequence setNAI-1540294631v384forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 119, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 120. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 122. SEQ ID NO: 122 is provided in Table 7.

[0281] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 7 (ATA007) CDRs 1 2 3 VHTYGVH (SEQ ID NO:VIWSGGSTDYNASFIS RGNDGPPFAY Q G Q D G Q Y Y D G K R

[0282] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 119 is set forth in SEQ ID NO: 123, which is provided below. CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTCTCATTAACTACCTATGGTGTTCACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGTGATATGGAGTGGTGGAAGCACAGACTATAATGCATCTTTCATATCCAGACTG ACCATCAGCAAGGACAATTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGCTAATGACA CAGCCATATATTACTGTGCCAGAAGAGGGAATGATGGTCCTCCGTTTGCTTACTGGGGCCAAGGGAC TCTGGTCACTGTCTCTGCA (SEQ ID NO: 123)NAI-1540294631v385

[0283] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 119 is set forth in SEQ ID NO: 124, which is provided below. CAAGTGCAGCTGAAGCAGAGCGGACCTGGCCTGGTCCAGCCTAGCCAAAGCCTGAGCATCACATGCA CCGTGTCCGGCTTCAGCCTGACAACATACGGCGTGCACTGGGTGCGGCAGAGCCCCGGCAAGGGCCT GGAATGGCTGGGCGTTATCTGGAGCGGCGGATCTACCGACTACAACGCCAGCTTTATCTCTAGACTG ACCATCAGCAAGGACAACTCTAAAAGCCAGGTGTTCTTCAAGATGAACAGCCTTCAGGCCAACGACA CCGCCATCTACTATTGTGCCAGGCGGGGCAATGACGGCCCTCCTTTCGCCTACTGGGGCCAGGGCAC CCTGGTGACCGTGTCCGCC (SEQ ID NO: 124)

[0284] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 120 is set forth in SEQ ID NO: 125, which is provided below. GACATCCAGATGACCCAGTCTCCATCCTCCTTATCTGCCTCTCTGGGAGAAAGAGTCAGTCTCACTT GTCGGGCAAGTCAGGAAATTAGTGGTTACTTAAGCTGGCTTCAGCAGAAACCAGATGGAACTATTAA ACGCCTGATCTACGCCGCATCCACTTTAGATTCTGGTGTCCCAAAAAGGTTCAGTGGCAGTAGGTCT GGGTCAGATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGATTTTGCAGACTATTACTGTCTAC AATATGTTAGTTATCCTCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 125)

[0285] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 120 is set forth in SEQ ID NO: 126, which is provided below. GATATCCAGATGACCCAGTCTCCCAGCAGCCTGAGCGCTTCTCTCGGCGAGAGAGTGTCCCTGACCT GCAGAGCCAGCCAGGAGATCAGCGGCTACCTGTCCTGGCTGCAGCAGAAGCCTGATGGCACAATTAA GCGGCTGATCTATGCCGCTAGCACCCTGGACAGCGGCGTGCCAAAGAGATTTAGCGGAAGCAGAAGC GGCAGCGACTACAGCCTGACCATCAGCTCTCTGGAAAGCGAGGACTTCGCTGATTACTACTGCCTGC AGTACGTGTCCTACCCCCTGACATTCGGCGCCGGAACAAAGCTGGAGCTGAAA (SEQ ID NO: 126)

[0286] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 121 is set forth in SEQ ID NO: 127, which is provided below. CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTCTCATTAACTACCTATGGTGTTCACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGTGATATGGAGTGGTGGAAGCACAGACTATAATGCATCTTTCATATCCAGACTG ACCATCAGCAAGGACAATTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGCTAATGACA CAGCCATATATTACTGTGCCAGAAGAGGGAATGATGGTCCTCCGTTTGCTTACTGGGGCCAAGGGAC TCTGGTCACTGTCTCTGCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGAC ATCCAGATGACCCAGTCTCCATCCTCCTTATCTGCCTCTCTGGGAGAAAGAGTCAGTCTCACTTGTCNAI-1540294631v386GGGCAAGTCAGGAAATTAGTGGTTACTTAAGCTGGCTTCAGCAGAAACCAGATGGAACTATTAAACG CCTGATCTACGCCGCATCCACTTTAGATTCTGGTGTCCCAAAAAGGTTCAGTGGCAGTAGGTCTGGG TCAGATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGATTTTGCAGACTATTACTGTCTACAAT ATGTTAGTTATCCTCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 127)

[0287] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 121 is set forth in SEQ ID NO: 128, which is provided below. CAAGTGCAGCTGAAGCAGAGCGGACCTGGCCTGGTCCAGCCTAGCCAAAGCCTGAGCATCACATGCA CCGTGTCCGGCTTCAGCCTGACAACATACGGCGTGCACTGGGTGCGGCAGAGCCCCGGCAAGGGCCT GGAATGGCTGGGCGTTATCTGGAGCGGCGGATCTACCGACTACAACGCCAGCTTTATCTCTAGACTG ACCATCAGCAAGGACAACTCTAAAAGCCAGGTGTTCTTCAAGATGAACAGCCTTCAGGCCAACGACA CCGCCATCTACTATTGTGCCAGGCGGGGCAATGACGGCCCTCCTTTCGCCTACTGGGGCCAGGGCAC CCTGGTGACCGTGTCCGCCGGCGGAGGCGGATCTGGCGGCGGCGGTTCAGGCGGAGGCGGCTCTGAT ATCCAGATGACCCAGTCTCCCAGCAGCCTGAGCGCTTCTCTCGGCGAGAGAGTGTCCCTGACCTGCA GAGCCAGCCAGGAGATCAGCGGCTACCTGTCCTGGCTGCAGCAGAAGCCTGATGGCACAATTAAGCG GCTGATCTATGCCGCTAGCACCCTGGACAGCGGCGTGCCAAAGAGATTTAGCGGAAGCAGAAGCGGC AGCGACTACAGCCTGACCATCAGCTCTCTGGAAAGCGAGGACTTCGCTGATTACTACTGCCTGCAGT ACGTGTCCTACCCCCTGACATTCGGCGCCGGAACAAAGCTGGAGCTGAAA (SEQ ID NO: 128)

[0288] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 122 is set forth in SEQ ID NO: 129, which is provided below. GACATCCAGATGACCCAGTCTCCATCCTCCTTATCTGCCTCTCTGGGAGAAAGAGTCAGTCTCACTT GTCGGGCAAGTCAGGAAATTAGTGGTTACTTAAGCTGGCTTCAGCAGAAACCAGATGGAACTATTAA ACGCCTGATCTACGCCGCATCCACTTTAGATTCTGGTGTCCCAAAAAGGTTCAGTGGCAGTAGGTCT GGGTCAGATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGATTTTGCAGACTATTACTGTCTAC AATATGTTAGTTATCCTCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAAGGTGGAGGTGGATC AGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTG CAGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTACCTATGGTGTTC ACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAGCAC AGACTATAATGCATCTTTCATATCCAGACTGACCATCAGCAAGGACAATTCCAAGAGCCAAGTTTTC TTTAAAATGAACAGTCTGCAAGCTAATGACACAGCCATATATTACTGTGCCAGAAGAGGGAATGATG GTCCTCCGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA (SEQ ID NO: 129)

[0289] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 122 is set forth in SEQ ID NO: 130, which is provided below.NAI-1540294631v387GATATCCAGATGACCCAGTCTCCCAGCAGCCTGAGCGCTTCTCTCGGCGAGAGAGTGTCCCTGACCT GCAGAGCCAGCCAGGAGATCAGCGGCTACCTGTCCTGGCTGCAGCAGAAGCCTGATGGCACAATTAA GCGGCTGATCTATGCCGCTAGCACCCTGGACAGCGGCGTGCCAAAGAGATTTAGCGGAAGCAGAAGC GGCAGCGACTACAGCCTGACCATCAGCTCTCTGGAAAGCGAGGACTTCGCTGATTACTACTGCCTGC AGTACGTGTCCTACCCCCTGACATTCGGCGCCGGAACAAAGCTGGAGCTGAAAGGCGGAGGCGGATC TGGCGGCGGCGGTTCAGGCGGAGGCGGCTCTCAAGTGCAGCTGAAGCAGAGCGGACCTGGCCTGGTC CAGCCTAGCCAAAGCCTGAGCATCACATGCACCGTGTCCGGCTTCAGCCTGACAACATACGGCGTGC ACTGGGTGCGGCAGAGCCCCGGCAAGGGCCTGGAATGGCTGGGCGTTATCTGGAGCGGCGGATCTAC CGACTACAACGCCAGCTTTATCTCTAGACTGACCATCAGCAAGGACAACTCTAAAAGCCAGGTGTTC TTCAAGATGAACAGCCTTCAGGCCAACGACACCGCCATCTACTATTGTGCCAGGCGGGGCAATGACG GCCCTCCTTTCGCCTACTGGGGCCAGGGCACCCTGGTGACCGTGTCCGCC (SEQ ID NO: 130)

[0290] In certain embodiments, the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 137; and / or ii) the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 138. SEQ ID NO: 137 and SEQ ID NO: 138 are disclosed in Table 8.

[0291] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133. SEQ ID NOs: 131-133 are provided in Table 8.

[0292] In certain embodiments, the VH 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 137. For example, the VH comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 137. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137.

[0293] In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the aminoNAI-1540294631v388acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof. In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136. SEQ ID NOs: 134-136 are provided in Table 8.

[0294] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 138. For example, the VLcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 138. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 138.

[0295] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof; and VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136.

[0296] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137, and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 138.

[0297] The VH the VL can be linked one after another, e.g., by a linker. In certain embodiments, the VHand VLare linked via a linker. In certain embodiments, the linker comprises or consists ofNAI-1540294631v389the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VL or VL-VH.

[0298] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 137, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 138. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 139. SEQ ID NO: 139 is provided in Table 8.

[0299] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VHand the VLare positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 137, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 138. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 140. SEQ ID NO: 140 is provided in Table 8.

[0300] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 8 (ATA008 or ATA020) CDRs 1 2 3 DN - 5 0 9 63 v390VLRASGNIHNYLA (SEQNAKTLAD (SEQ ID NO: QHFWTTPFT (SEQ ID NO: 134) 135) ID NO: 136) V LK SGPGLV PS SLSITCTVSGFSLNSYGVHWVR SPGKGLEWLGAIWSSG M A G M G D A G K Nsequence of SEQ ID NO: 137 is set forth in SEQ ID NO: 141, which is provided below. CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTCTCATTAAATAGCTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGCGATATGGAGTAGTGGAAGCACAGACTATAATGCACCTTTCATATCCAGACTG AGCATCAGCAAGGACAACTCCAAGAACCAAGTTTTCTTTAAAATGAACAGTCTGCAAGTTGATGACA CAGCCATATATTTTTGTGCCGGAAATCCAGAATCGGATCATTACTACGGCTACGAGGCCATGGACTC CTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 141)

[0302] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 137 is set forth in SEQ ID NO: 142, which is provided below. CAAGTGCAGCTGAAGCAGAGCGGTCCTGGCCTGGTTCAGCCATCTCAGAGCCTGAGCATCACATGCA CCGTGTCCGGCTTTAGCCTGAACAGCTATGGCGTGCATTGGGTGCGGCAGTCTCCTGGCAAAGGCCT GGAATGGCTGGGCGCCATTTGGTCCAGCGGCTCCACCGACTACAACGCCCCTTTCATCTCTAGACTG AGCATCAGCAAGGACAACAGCAAGAACCAGGTCTTTTTCAAGATGAACAGCCTGCAAGTGGACGACA CCGCCATCTACTTCTGCGCCGGCAACCCCGAGAGCGACCACTACTACGGCTACGAGGCCATGGACAG CTGGGGCCAGGGCACCAGCGTGACAGTGTCCAGC (SEQ ID NO: 142)

[0303] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 138 is set forth in SEQ ID NO: 143, which is provided below. GACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACAT GTCGAGCAAGTGGGAATATTCACAATTATTTAGCATGGTATCAGCAGAGACAGGGAAAATCTCCTCANAI-1540294631v391GCTCCTGGTCTATAATGCAAAAACCTTAGCCGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCA GGAACACAATATTCTCTCAAGATCATCAGCCTTCAGCCTGAAGATTTTGGGAGTTATTACTGTCAAC ATTTTTGGACTACTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA (SEQ ID NO: 143)

[0304] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 138 is set forth in SEQ ID NO: 144, which is provided below. GATATCCAGATGACACAGAGCCCTGCTTCTCTCTCCGCCAGCGTGGGCGAGACAGTGACCATCACCT GTAGAGCCAGCGGAAATATCCACAACTACCTGGCCTGGTACCAGCAGCGGCAAGGCAAGAGCCCCCA GCTGCTGGTGTACAATGCCAAGACCCTGGCTGATGGCGTGCCCAGCAGATTCAGCGGATCCGGCTCT GGCACACAGTACAGCCTGAAAATCATCAGCCTGCAGCCTGAGGATTTCGGAAGCTACTATTGCCAGC ACTTCTGGACCACCCCTTTCACCTTCGGCTCTGGCACTAAGCTGGAAATCAAG (SEQ ID NO: 144)

[0305] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 139 is set forth in SEQ ID NO: 145, which is provided below. CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTCTCATTAAATAGCTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGCGATATGGAGTAGTGGAAGCACAGACTATAATGCACCTTTCATATCCAGACTG AGCATCAGCAAGGACAACTCCAAGAACCAAGTTTTCTTTAAAATGAACAGTCTGCAAGTTGATGACA CAGCCATATATTTTTGTGCCGGAAATCCAGAATCGGATCATTACTACGGCTACGAGGCCATGGACTC CTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGT GGAGGTGGATCTGACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTG TCACCATCACATGTCGAGCAAGTGGGAATATTCACAATTATTTAGCATGGTATCAGCAGAGACAGGG AAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTAGCCGATGGTGTGCCATCAAGGTTCAGT GGCAGTGGATCAGGAACACAATATTCTCTCAAGATCATCAGCCTTCAGCCTGAAGATTTTGGGAGTT ATTACTGTCAACATTTTTGGACTACTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA (SEQ ID NO: 145)

[0306] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 139 is set forth in SEQ ID NO: 146, which is provided below. CAAGTGCAGCTGAAGCAGAGCGGTCCTGGCCTGGTTCAGCCATCTCAGAGCCTGAGCATCACATGCA CCGTGTCCGGCTTTAGCCTGAACAGCTATGGCGTGCATTGGGTGCGGCAGTCTCCTGGCAAAGGCCT GGAATGGCTGGGCGCCATTTGGTCCAGCGGCTCCACCGACTACAACGCCCCTTTCATCTCTAGACTG AGCATCAGCAAGGACAACAGCAAGAACCAGGTCTTTTTCAAGATGAACAGCCTGCAAGTGGACGACA CCGCCATCTACTTCTGCGCCGGCAACCCCGAGAGCGACCACTACTACGGCTACGAGGCCATGGACAGNAI-1540294631v392CTGGGGCCAGGGCACCAGCGTGACAGTGTCCAGCGGCGGAGGCGGATCTGGCGGAGGCGGCTCTGGA GGCGGCGGCTCAGATATCCAGATGACACAGAGCCCTGCTTCTCTCTCCGCCAGCGTGGGCGAGACAG TGACCATCACCTGTAGAGCCAGCGGAAATATCCACAACTACCTGGCCTGGTACCAGCAGCGGCAAGG CAAGAGCCCCCAGCTGCTGGTGTACAATGCCAAGACCCTGGCTGATGGCGTGCCCAGCAGATTCAGC GGATCCGGCTCTGGCACACAGTACAGCCTGAAAATCATCAGCCTGCAGCCTGAGGATTTCGGAAGCT ACTATTGCCAGCACTTCTGGACCACCCCTTTCACCTTCGGCTCTGGCACTAAGCTGGAAATCAAG (SEQ ID NO: 146)

[0307] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 140 is set forth in SEQ ID NO: 147, which is provided below. GACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACAT GTCGAGCAAGTGGGAATATTCACAATTATTTAGCATGGTATCAGCAGAGACAGGGAAAATCTCCTCA GCTCCTGGTCTATAATGCAAAAACCTTAGCCGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCA GGAACACAATATTCTCTCAAGATCATCAGCCTTCAGCCTGAAGATTTTGGGAGTTATTACTGTCAAC ATTTTTGGACTACTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAAGGTGGAGGTGGATC AGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTG CAGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAAATAGCTATGGTGTAC ACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGCGATATGGAGTAGTGGAAGCAC AGACTATAATGCACCTTTCATATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAACCAAGTTTTC TTTAAAATGAACAGTCTGCAAGTTGATGACACAGCCATATATTTTTGTGCCGGAAATCCAGAATCGG ATCATTACTACGGCTACGAGGCCATGGACTCCTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 147)

[0308] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 140 is set forth in SEQ ID NO: 148, which is provided below. GATATCCAGATGACACAGAGCCCTGCTTCTCTCTCCGCCAGCGTGGGCGAGACAGTGACCATCACCT GTAGAGCCAGCGGAAATATCCACAACTACCTGGCCTGGTACCAGCAGCGGCAAGGCAAGAGCCCCCA GCTGCTGGTGTACAATGCCAAGACCCTGGCTGATGGCGTGCCCAGCAGATTCAGCGGATCCGGCTCT GGCACACAGTACAGCCTGAAAATCATCAGCCTGCAGCCTGAGGATTTCGGAAGCTACTATTGCCAGC ACTTCTGGACCACCCCTTTCACCTTCGGCTCTGGCACTAAGCTGGAAATCAAGGGCGGAGGCGGATC TGGCGGAGGCGGCTCTGGAGGCGGCGGCTCACAAGTGCAGCTGAAGCAGAGCGGTCCTGGCCTGGTT CAGCCATCTCAGAGCCTGAGCATCACATGCACCGTGTCCGGCTTTAGCCTGAACAGCTATGGCGTGC ATTGGGTGCGGCAGTCTCCTGGCAAAGGCCTGGAATGGCTGGGCGCCATTTGGTCCAGCGGCTCCAC CGACTACAACGCCCCTTTCATCTCTAGACTGAGCATCAGCAAGGACAACAGCAAGAACCAGGTCTTT TTCAAGATGAACAGCCTGCAAGTGGACGACACCGCCATCTACTTCTGCGCCGGCAACCCCGAGAGCGNAI-1540294631v393ACCACTACTACGGCTACGAGGCCATGGACAGCTGGGGCCAGGGCACCAGCGTGACAGTGTCCAGC (SEQ ID NO: 148)

[0309] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 155; and / or ii) the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 as set forth in a VLcomprising the amino acid sequence of SEQ ID NO: 156. SEQ ID NO: 155 and SEQ ID NO: 156 are disclosed in Table 9.

[0310] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151. SEQ ID NOs: 149-151 are provided in Table 9.

[0311] In certain embodiments, the VH 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 155. For example, the VHcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 155. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 155.

[0312] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof. In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154. SEQ ID NOs: 152-154 are provided in Table 9.

[0313] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 156. For example, the VL comprises an aminoNAI-1540294631v394acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 156. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 156.

[0314] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof; and VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154.

[0315] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 155, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 156.

[0316] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VHand VLare linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VL or VL-VH.

[0317] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154. In certainNAI-1540294631v395embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 155, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 156. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 157. SEQ ID NO: 157 is provided in Table 9.

[0318] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VHand the VLare positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 155, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 156. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 158. SEQ ID NO: 158 is provided in Table 9.

[0319] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 9 (ATA009 or ATA021) CDRs 1 2 3 VDAYIH (SEQ ID NO:GIDPENDNTEYDPKFPG RPLGLPFDY : : N Q F L N Q S ENAI-1540294631v396VL-VHDIVLSQSPSSLAVSVGENVTMNCKSSQRLLDSSNQRNYLAWYQQKPGQSPQLLIF scFv WASTRESGVPDRFTGSGSGTDFTLTIRSVKAEDLAVYYCQQYYSYPFTFGSGTKL A i EIKGGGGSGGGGSGGGGSEVQLQQSGAEHVKPGTSVRLSCTASGFNIKDAYIHWV Asequence of SEQ ID NO: 155 is set forth in SEQ ID NO: 159, which is provided below. GAGGTTCAGCTTCAGCAGTCTGGGGCAGAGCATGTGAAGCCAGGGACCTCAGTCAGGTTGTCCTGCA CAGCTTCTGGCTTTAACATTAAAGACGCCTATATACACTGGGTGAAGCAGAGGCCTGAACAGGGCCT GGAGTGGATTGGAGGGATTGATCCTGAGAATGACAATACTGAATATGACCCTAAATTCCCCGGCAAG GCCACTGTTGTGGCCGACACATCCTCCAACACAGCCTACCTGCAACTCAGCAGCCTGACATCTGAGG ACACTGCCGTCTATTACTGTGCTAGAAGACCTCTCGGACTACCTTTTGACTACTGGGGCCAAGGCAC CACTCTCACAGTCTCCTCA (SEQ ID NO: 159)

[0321] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 155 is set forth in SEQ ID NO: 160, which is provided below. GAAGTGCAGCTTCAACAATCTGGCGCCGAGCACGTGAAGCCTGGCACAAGCGTGCGGCTGAGCTGCA CCGCCAGCGGATTTAACATCAAGGACGCCTATATCCACTGGGTCAAGCAGAGACCTGAGCAGGGACT GGAATGGATCGGCGGCATCGACCCCGAGAACGACAACACCGAGTACGACCCTAAGTTCCCTGGCAAG GCCACCGTTGTGGCCGATACATCTTCTAATACCGCCTACCTGCAGCTGTCCTCCCTGACCAGCGAGG ACACCGCTGTGTACTATTGTGCCAGACGGCCTCTGGGCCTGCCTTTCGACTACTGGGGCCAGGGCAC AACCCTCACAGTGTCCAGC (SEQ ID NO: 160)

[0322] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 156 is set forth in SEQ ID NO: 161, which is provided below. GACATTGTGCTGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAACGTTACTATGAACT GCAAGTCCAGTCAGAGACTTTTAGATAGTAGCAATCAAAGGAACTATTTGGCCTGGTACCAGCAGAA ACCAGGGCAGTCTCCTCAACTGCTGATTTTCTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGC TTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGAAGTGTGAAGGCTGAAGACCTGG CAGTTTATTACTGTCAGCAATATTATAGCTATCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAAT AAAA (SEQ ID NO: 161)

[0323] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 156 is set forth in SEQ ID NO: 162, which is provided below. GACATCGTGCTGAGCCAGAGCCCTAGCAGCCTGGCCGTGTCTGTGGGCGAGAATGTGACAATGAACT GCAAGAGCTCTCAGAGGCTGCTGGACAGCAGCAACCAGCGGAACTACCTGGCTTGGTACCAGCAAAA GCCCGGCCAGAGCCCCCAGCTGCTGATTTTCTGGGCCTCCACCAGAGAGAGCGGCGTGCCAGATAGANAI-1540294631v397TTCACCGGCAGCGGCAGCGGCACTGATTTCACCCTGACCATCAGAAGCGTGAAAGCTGAAGATCTGG CCGTGTACTACTGCCAGCAGTACTACAGCTACCCCTTTACATTCGGCAGCGGCACCAAGCTGGAAAT CAAA (SEQ ID NO: 162)

[0324] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 157 is set forth in SEQ ID NO: 163, which is provided below. GAGGTTCAGCTTCAGCAGTCTGGGGCAGAGCATGTGAAGCCAGGGACCTCAGTCAGGTTGTCCTGCA CAGCTTCTGGCTTTAACATTAAAGACGCCTATATACACTGGGTGAAGCAGAGGCCTGAACAGGGCCT GGAGTGGATTGGAGGGATTGATCCTGAGAATGACAATACTGAATATGACCCTAAATTCCCCGGCAAG GCCACTGTTGTGGCCGACACATCCTCCAACACAGCCTACCTGCAACTCAGCAGCCTGACATCTGAGG ACACTGCCGTCTATTACTGTGCTAGAAGACCTCTCGGACTACCTTTTGACTACTGGGGCCAAGGCAC CACTCTCACAGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGAC ATTGTGCTGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAACGTTACTATGAACTGCA AGTCCAGTCAGAGACTTTTAGATAGTAGCAATCAAAGGAACTATTTGGCCTGGTACCAGCAGAAACC AGGGCAGTCTCCTCAACTGCTGATTTTCTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTC ACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGAAGTGTGAAGGCTGAAGACCTGGCAG TTTATTACTGTCAGCAATATTATAGCTATCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAA A (SEQ ID NO: 163)

[0325] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 157 is set forth in SEQ ID NO: 164, which is provided below. GAAGTGCAGCTTCAACAATCTGGCGCCGAGCACGTGAAGCCTGGCACAAGCGTGCGGCTGAGCTGCA CCGCCAGCGGATTTAACATCAAGGACGCCTATATCCACTGGGTCAAGCAGAGACCTGAGCAGGGACT GGAATGGATCGGCGGCATCGACCCCGAGAACGACAACACCGAGTACGACCCTAAGTTCCCTGGCAAG GCCACCGTTGTGGCCGATACATCTTCTAATACCGCCTACCTGCAGCTGTCCTCCCTGACCAGCGAGG ACACCGCTGTGTACTATTGTGCCAGACGGCCTCTGGGCCTGCCTTTCGACTACTGGGGCCAGGGCAC AACCCTCACAGTGTCCAGCGGAGGCGGCGGATCCGGCGGTGGCGGATCTGGCGGAGGCGGCAGCGAC ATCGTGCTGAGCCAGAGCCCTAGCAGCCTGGCCGTGTCTGTGGGCGAGAATGTGACAATGAACTGCA AGAGCTCTCAGAGGCTGCTGGACAGCAGCAACCAGCGGAACTACCTGGCTTGGTACCAGCAAAAGCC CGGCCAGAGCCCCCAGCTGCTGATTTTCTGGGCCTCCACCAGAGAGAGCGGCGTGCCAGATAGATTC ACCGGCAGCGGCAGCGGCACTGATTTCACCCTGACCATCAGAAGCGTGAAAGCTGAAGATCTGGCCG TGTACTACTGCCAGCAGTACTACAGCTACCCCTTTACATTCGGCAGCGGCACCAAGCTGGAAATCAA A (SEQ ID NO: 164)

[0326] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 158 is set forth in SEQ ID NO: 165, which is provided below.NAI-1540294631v398GACATTGTGCTGTCACAGTCTCCATCCTCCCTAGCTGTGTCAGTTGGAGAGAACGTTACTATGAACT GCAAGTCCAGTCAGAGACTTTTAGATAGTAGCAATCAAAGGAACTATTTGGCCTGGTACCAGCAGAA ACCAGGGCAGTCTCCTCAACTGCTGATTTTCTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGC TTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGAAGTGTGAAGGCTGAAGACCTGG CAGTTTATTACTGTCAGCAATATTATAGCTATCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAAT AAAAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGAGGTTCAGCTTCAGCAG TCTGGGGCAGAGCATGTGAAGCCAGGGACCTCAGTCAGGTTGTCCTGCACAGCTTCTGGCTTTAACA TTAAAGACGCCTATATACACTGGGTGAAGCAGAGGCCTGAACAGGGCCTGGAGTGGATTGGAGGGAT TGATCCTGAGAATGACAATACTGAATATGACCCTAAATTCCCCGGCAAGGCCACTGTTGTGGCCGAC ACATCCTCCAACACAGCCTACCTGCAACTCAGCAGCCTGACATCTGAGGACACTGCCGTCTATTACT GTGCTAGAAGACCTCTCGGACTACCTTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTC A (SEQ ID NO: 165)

[0327] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 158 is set forth in SEQ ID NO: 166, which is provided below. GACATCGTGCTGAGCCAGAGCCCTAGCAGCCTGGCCGTGTCTGTGGGCGAGAATGTGACAATGAACT GCAAGAGCTCTCAGAGGCTGCTGGACAGCAGCAACCAGCGGAACTACCTGGCTTGGTACCAGCAAAA GCCCGGCCAGAGCCCCCAGCTGCTGATTTTCTGGGCCTCCACCAGAGAGAGCGGCGTGCCAGATAGA TTCACCGGCAGCGGCAGCGGCACTGATTTCACCCTGACCATCAGAAGCGTGAAAGCTGAAGATCTGG CCGTGTACTACTGCCAGCAGTACTACAGCTACCCCTTTACATTCGGCAGCGGCACCAAGCTGGAAAT CAAAGGAGGCGGCGGATCCGGCGGTGGCGGATCTGGCGGAGGCGGCAGCGAAGTGCAGCTTCAACAA TCTGGCGCCGAGCACGTGAAGCCTGGCACAAGCGTGCGGCTGAGCTGCACCGCCAGCGGATTTAACA TCAAGGACGCCTATATCCACTGGGTCAAGCAGAGACCTGAGCAGGGACTGGAATGGATCGGCGGCAT CGACCCCGAGAACGACAACACCGAGTACGACCCTAAGTTCCCTGGCAAGGCCACCGTTGTGGCCGAT ACATCTTCTAATACCGCCTACCTGCAGCTGTCCTCCCTGACCAGCGAGGACACCGCTGTGTACTATT GTGCCAGACGGCCTCTGGGCCTGCCTTTCGACTACTGGGGCCAGGGCACAACCCTCACAGTGTCCAG C (SEQ ID NO: 166)

[0328] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 170; and / or ii) the VLcomprises a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 171. SEQ ID NO: 170 and SEQ ID NO: 171 are disclosed in Table 10.

[0329] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 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 CDR3NAI-1540294631v399comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 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. SEQ ID NOs: 131, 167, and 168 are provided in Table 10.

[0330] In certain embodiments, the VHcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 170. For example, the VH comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 170. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 170.

[0331] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169. SEQ ID NOs: 134, 135, and 169 are provided in Table 10.

[0332] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 171. For example, the VL comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 171. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 171.

[0333] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 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 modificationNAI-1540294631v3100thereof; and VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, 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; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169.

[0334] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 170, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 171.

[0335] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VLor VL-VH.

[0336] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, 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; and a VLcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 170, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 171. In certain embodiments, the VH and VL are linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 172. SEQ ID NO: 172 is provided in Table 10.

[0337] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2NAI-1540294631v3101comprising 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; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 170, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 171. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 173. SEQ ID NO: 173 is provided in Table 10.

[0338] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 10 (ATA0010) CDRs 1 2 3 VHSYGVH (SEQ ID NO:VVWSGGGTDYNAPFIS NPDSDHYYGYEAMD Q G M A G M G D A G K N

[0339] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 170 is set forth in SEQ ID NO: 174, which is provided below. CAGGTGCAGCTAAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTCTCATTAAATAGCTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGTGGTATGGAGTGGTGGAGGCACAGACTATAATGCACCTTTCATATCCAGACTG AGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGTTGATGACANAI-1540294631v3102CAGCCATATATTATTGTGCCGGAAATCCAGACTCGGATCATTATTACGGCTACGAGGCTATGGACTA CTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 174)

[0340] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 170 is set forth in SEQ ID NO: 175, which is provided below. CAGGTCCAGCTGAAGCAGAGCGGCCCTGGCCTGGTGCAACCTAGCCAGTCCCTGAGCATCACCTGCA CCGTGTCCGGATTTAGCCTGAATAGCTACGGCGTGCATTGGGTGCGGCAAAGCCCCGGCAAAGGCCT GGAATGGCTGGGCGTGGTGTGGAGCGGCGGCGGCACAGACTACAATGCCCCTTTCATCTCTCGGCTG AGCATCAGCAAGGACAACAGTAAGTCTCAGGTTTTCTTCAAGATGAACAGCCTGCAGGTGGACGACA CAGCCATCTACTATTGCGCCGGCAACCCAGACAGCGATCACTACTACGGCTACGAGGCCATGGACTA CTGGGGACAGGGCACCAGCGTGACCGTGTCTAGC (SEQ ID NO: 175)

[0341] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 171 is set forth in SEQ ID NO: 176, which is provided below. GACTTCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACAT GTCGAGCAAGTGGAAATATTCACAATTATTTAGCATGGTATCAGCAGAGACAGGGAAAATCTCCTCA GCTCCTGGTCTATAATGCAAAAACCTTAGCCGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCA GGACCACAATATTCTCTCAAGATCATCAGCCTTCAGCCTGAGGATTTTGGGACTTATTACTGTCAAC ATTTTTGGACTATTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA (SEQ ID NO: 176)

[0342] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 171 is set forth in SEQ ID NO: 177, which is provided below. GACTTCCAGATGACACAGAGCCCTGCCAGCCTCTCCGCCTCTGTGGGCGAGACAGTGACCATTACCT GTAGAGCTTCTGGCAACATCCACAACTACCTGGCCTGGTACCAGCAGAGACAGGGCAAGAGCCCTCA GCTGCTGGTGTACAACGCCAAGACACTGGCTGATGGCGTCCCATCTAGATTCAGCGGCTCCGGCAGC GGCCCCCAGTACAGCCTTAAAATCATCAGCCTGCAACCTGAAGATTTCGGCACCTACTATTGCCAGC ACTTCTGGACCATCCCCTTCACCTTTGGCAGCGGAACCAAGCTGGAGATCAAG (SEQ ID NO: 177)

[0343] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 172 is set forth in SEQ ID NO: 178, which is provided below. CAGGTGCAGCTAAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTCTCATTAAATAGCTATGGTGTACACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGTGGTATGGAGTGGTGGAGGCACAGACTATAATGCACCTTTCATATCCAGACTG AGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAACAGTCTGCAAGTTGATGACA CAGCCATATATTATTGTGCCGGAAATCCAGACTCGGATCATTATTACGGCTACGAGGCTATGGACTANAI-1540294631v3103CTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGT GGAGGTGGATCTGACTTCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTG TCACCATCACATGTCGAGCAAGTGGAAATATTCACAATTATTTAGCATGGTATCAGCAGAGACAGGG AAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTAGCCGATGGTGTGCCATCAAGGTTCAGT GGCAGTGGATCAGGACCACAATATTCTCTCAAGATCATCAGCCTTCAGCCTGAGGATTTTGGGACTT ATTACTGTCAACATTTTTGGACTATTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA (SEQ ID NO: 178)

[0344] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 172 is set forth in SEQ ID NO: 179, which is provided below. CAGGTCCAGCTGAAGCAGAGCGGCCCTGGCCTGGTGCAACCTAGCCAGTCCCTGAGCATCACCTGCA CCGTGTCCGGATTTAGCCTGAATAGCTACGGCGTGCATTGGGTGCGGCAAAGCCCCGGCAAAGGCCT GGAATGGCTGGGCGTGGTGTGGAGCGGCGGCGGCACAGACTACAATGCCCCTTTCATCTCTCGGCTG AGCATCAGCAAGGACAACAGTAAGTCTCAGGTTTTCTTCAAGATGAACAGCCTGCAGGTGGACGACA CAGCCATCTACTATTGCGCCGGCAACCCAGACAGCGATCACTACTACGGCTACGAGGCCATGGACTA CTGGGGACAGGGCACCAGCGTGACCGTGTCTAGCGGCGGAGGCGGCTCTGGAGGAGGAGGGTCCGGA GGCGGCGGCAGCGACTTCCAGATGACACAGAGCCCTGCCAGCCTCTCCGCCTCTGTGGGCGAGACAG TGACCATTACCTGTAGAGCTTCTGGCAACATCCACAACTACCTGGCCTGGTACCAGCAGAGACAGGG CAAGAGCCCTCAGCTGCTGGTGTACAACGCCAAGACACTGGCTGATGGCGTCCCATCTAGATTCAGC GGCTCCGGCAGCGGCCCCCAGTACAGCCTTAAAATCATCAGCCTGCAACCTGAAGATTTCGGCACCT ACTATTGCCAGCACTTCTGGACCATCCCCTTCACCTTTGGCAGCGGAACCAAGCTGGAGATCAAG (SEQ ID NO: 179)

[0345] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 173 is set forth in SEQ ID NO: 180, which is provided below. GACTTCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACAT GTCGAGCAAGTGGAAATATTCACAATTATTTAGCATGGTATCAGCAGAGACAGGGAAAATCTCCTCA GCTCCTGGTCTATAATGCAAAAACCTTAGCCGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCA GGACCACAATATTCTCTCAAGATCATCAGCCTTCAGCCTGAGGATTTTGGGACTTATTACTGTCAAC ATTTTTGGACTATTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAAGGTGGAGGTGGATC AGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTGCAGCTAAAGCAGTCAGGACCTGGCCTAGTG CAGCCCTCACAGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAAATAGCTATGGTGTAC ACTGGGTTCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGGTATGGAGTGGTGGAGGCAC AGACTATAATGCACCTTTCATATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTC TTTAAAATGAACAGTCTGCAAGTTGATGACACAGCCATATATTATTGTGCCGGAAATCCAGACTCGGNAI-1540294631v3104ATCATTATTACGGCTACGAGGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 180)

[0346] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 173 is set forth in SEQ ID NO: 181, which is provided below. GACTTCCAGATGACACAGAGCCCTGCCAGCCTCTCCGCCTCTGTGGGCGAGACAGTGACCATTACCT GTAGAGCTTCTGGCAACATCCACAACTACCTGGCCTGGTACCAGCAGAGACAGGGCAAGAGCCCTCA GCTGCTGGTGTACAACGCCAAGACACTGGCTGATGGCGTCCCATCTAGATTCAGCGGCTCCGGCAGC GGCCCCCAGTACAGCCTTAAAATCATCAGCCTGCAACCTGAAGATTTCGGCACCTACTATTGCCAGC ACTTCTGGACCATCCCCTTCACCTTTGGCAGCGGAACCAAGCTGGAGATCAAGGGCGGAGGCGGCTC TGGAGGAGGAGGGTCCGGAGGCGGCGGCAGCCAGGTCCAGCTGAAGCAGAGCGGCCCTGGCCTGGTG CAACCTAGCCAGTCCCTGAGCATCACCTGCACCGTGTCCGGATTTAGCCTGAATAGCTACGGCGTGC ATTGGGTGCGGCAAAGCCCCGGCAAAGGCCTGGAATGGCTGGGCGTGGTGTGGAGCGGCGGCGGCAC AGACTACAATGCCCCTTTCATCTCTCGGCTGAGCATCAGCAAGGACAACAGTAAGTCTCAGGTTTTC TTCAAGATGAACAGCCTGCAGGTGGACGACACAGCCATCTACTATTGCGCCGGCAACCCAGACAGCG ATCACTACTACGGCTACGAGGCCATGGACTACTGGGGACAGGGCACCAGCGTGACCGTGTCTAGC (SEQ ID NO: 181)

[0347] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 183; and / or ii) the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 as set forth in a VLcomprising the amino acid sequence of SEQ ID NO: 184. SEQ ID NO: 183 and SEQ ID NO: 184 are disclosed in Table 11.

[0348] In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182. SEQ ID NOs: 41, 24, and 182 are provided in Table 11.

[0349] In certain embodiments, the VHcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 183. For example, the VHcomprises an amino acid sequence that is 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%, aboutNAI-1540294631v310594%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 183. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 183.

[0350] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. SEQ ID NOs: 26, 27, and 46 are provided in Table 11.

[0351] In certain embodiments, the VL 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 184. For example, the VL comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 184. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 184.

[0352] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof; and VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.NAI-1540294631v3106

[0353] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 183, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 184.

[0354] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VLor VL-VH.

[0355] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 183, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 184. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 185. SEQ ID NO: 185 is provided in Table 11.

[0356] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 183, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 184. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 186. SEQ ID NO: 186 is provided in Table 11.

[0357] In certain embodiments, the CDRs are identified according to the Kabat numbering system.NAI-1540294631v3107Table 11 (ATA011) CDRs 1 2 3 VHDYAIH (SEQ ID NO:VISTYNGNTNYNRKFKD DDY (SEQ ID Q N V L E N V L C L E K I

[0358] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 183 is set forth in SEQ ID NO: 187, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGACTATGCTATACACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACTACAACCGGAAGTTTAAGGACAAG GCCACAATGACTGTTGACAAATCCTCCAGCACAGTTTATATGGAACTTGCCAGATTGACATCTGAGG AATCTGCCATCTATTACTGTGTAAAGGACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC A (SEQ ID NO: 187)

[0359] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 183 is set forth in SEQ ID NO: 188, which is provided below. CAGGTGCAGCTGCAGCAGAGCGGTCCTGAGGTGGTGCGGCCTGGCGTGTCCGTGAAGATCTCTTGCA AGGGCAGCGGATATACCTTTACCGACTACGCCATCCACTGGGTGAAGCAGAGCCACGCCAAGTCCCT CGAGTGGATCGGCGTTATCAGCACATACAACGGCAACACCAACTACAATAGAAAGTTCAAGGACAAA GCCACAATGACCGTGGACAAGAGCAGCAGCACCGTGTACATGGAGCTGGCCAGACTGACCAGCGAGG AAAGCGCTATCTACTACTGCGTGAAAGACGACTACTGGGGCCAGGGCACCAGCGTCACTGTGTCCAG C (SEQ ID NO: 188)NAI-1540294631v3108

[0360] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 184 is set forth in SEQ ID NO: 189, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCTTCTCTT GCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCGCCAAAGCGCCTAATCTATTTGGTGTCTAAACTGGACTCTAGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGCACACATTTTCCTCATACGTTCGGAGGAGGGACCAAGTTGGAAATAAA A (SEQ ID NO: 189)

[0361] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 184 is set forth in SEQ ID NO: 190, which is provided below. GACGTGGTCATGACCCAGACCCCTCTGACACTGAGCGTGACCATCGGACAACCTGCTTCTTTTAGCT GTAAAAGCAGCCAGTCTCTGCTGGATTCTGATGGCAAGACCTACCTGAACTGGCTGCTGCAAAGACC TGGACAGTCCCCAAAGCGGCTGATCTACCTGGTGTCTAAGCTGGACAGCCGGGTGCCCGATAGATTC ACCGGCAGCGGCTCTGGCACAGATTTCACACTGAAAATTTCTAGAGTGGAAGCCGAGGACCTGGGCG TGTACTATTGCTGGCAGGGCACACATTTCCCCCACACCTTCGGCGGAGGAACAAAGCTGGAAATCAA G (SEQ ID NO: 190)

[0362] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 185 is set forth in SEQ ID NO: 191, which is provided below. CAGGTCCAGCTGCAGCAGTCTGGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCA AGGGTTCCGGCTACACATTCACTGACTATGCTATACACTGGGTGAAGCAGAGTCATGCAAAGAGTCT AGAGTGGATTGGAGTTATTAGTACTTACAATGGTAATACAAACTACAACCGGAAGTTTAAGGACAAG GCCACAATGACTGTTGACAAATCCTCCAGCACAGTTTATATGGAACTTGCCAGATTGACATCTGAGG AATCTGCCATCTATTACTGTGTAAAGGACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTGATGTTGTGATGACCCAGACT CCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCTTCTCTTGCAAGTCAAGTCAGAGCCTCT TAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCGCCAAAGCGCCT AATCTATTTGGTGTCTAAACTGGACTCTAGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACA GATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGCA CACATTTTCCTCATACGTTCGGAGGAGGGACCAAGTTGGAAATAAAA (SEQ ID NO: 191)

[0363] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 185 is set forth in SEQ ID NO: 192, which is provided below. CAGGTGCAGCTGCAGCAGAGCGGTCCTGAGGTGGTGCGGCCTGGCGTGTCCGTGAAGATCTCTTGCA AGGGCAGCGGATATACCTTTACCGACTACGCCATCCACTGGGTGAAGCAGAGCCACGCCAAGTCCCTNAI-1540294631v3109CGAGTGGATCGGCGTTATCAGCACATACAACGGCAACACCAACTACAATAGAAAGTTCAAGGACAAA GCCACAATGACCGTGGACAAGAGCAGCAGCACCGTGTACATGGAGCTGGCCAGACTGACCAGCGAGG AAAGCGCTATCTACTACTGCGTGAAAGACGACTACTGGGGCCAGGGCACCAGCGTCACTGTGTCCAG CGGCGGCGGCGGCAGCGGCGGAGGCGGCAGCGGCGGCGGAGGCAGCGACGTGGTCATGACCCAGACC CCTCTGACACTGAGCGTGACCATCGGACAACCTGCTTCTTTTAGCTGTAAAAGCAGCCAGTCTCTGC TGGATTCTGATGGCAAGACCTACCTGAACTGGCTGCTGCAAAGACCTGGACAGTCCCCAAAGCGGCT GATCTACCTGGTGTCTAAGCTGGACAGCCGGGTGCCCGATAGATTCACCGGCAGCGGCTCTGGCACA GATTTCACACTGAAAATTTCTAGAGTGGAAGCCGAGGACCTGGGCGTGTACTATTGCTGGCAGGGCA CACATTTCCCCCACACCTTCGGCGGAGGAACAAAGCTGGAAATCAAG (SEQ ID NO: 192)

[0364] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 186 is set forth in SEQ ID NO: 193, which is provided below. GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCTTCTCTT GCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTGTTACAGAGGCC AGGCCAGTCGCCAAAGCGCCTAATCTATTTGGTGTCTAAACTGGACTCTAGAGTCCCTGACAGGTTC ACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAG TTTATTATTGCTGGCAAGGCACACATTTTCCTCATACGTTCGGAGGAGGGACCAAGTTGGAAATAAA AGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCTCAGGTCCAGCTGCAGCAGTCT GGGCCTGAGGTGGTGAGGCCTGGGGTCTCAGTGAAGATTTCCTGCAAGGGTTCCGGCTACACATTCA CTGACTATGCTATACACTGGGTGAAGCAGAGTCATGCAAAGAGTCTAGAGTGGATTGGAGTTATTAG TACTTACAATGGTAATACAAACTACAACCGGAAGTTTAAGGACAAGGCCACAATGACTGTTGACAAA TCCTCCAGCACAGTTTATATGGAACTTGCCAGATTGACATCTGAGGAATCTGCCATCTATTACTGTG TAAAGGACGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 193)

[0365] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 186 is set forth in SEQ ID NO: 194, which is provided below. GACGTGGTCATGACCCAGACCCCTCTGACACTGAGCGTGACCATCGGACAACCTGCTTCTTTTAGCT GTAAAAGCAGCCAGTCTCTGCTGGATTCTGATGGCAAGACCTACCTGAACTGGCTGCTGCAAAGACC TGGACAGTCCCCAAAGCGGCTGATCTACCTGGTGTCTAAGCTGGACAGCCGGGTGCCCGATAGATTC ACCGGCAGCGGCTCTGGCACAGATTTCACACTGAAAATTTCTAGAGTGGAAGCCGAGGACCTGGGCG TGTACTATTGCTGGCAGGGCACACATTTCCCCCACACCTTCGGCGGAGGAACAAAGCTGGAAATCAA GGGCGGCGGCGGCAGCGGCGGAGGCGGCAGCGGCGGCGGAGGCAGCCAGGTGCAGCTGCAGCAGAGC GGTCCTGAGGTGGTGCGGCCTGGCGTGTCCGTGAAGATCTCTTGCAAGGGCAGCGGATATACCTTTA CCGACTACGCCATCCACTGGGTGAAGCAGAGCCACGCCAAGTCCCTCGAGTGGATCGGCGTTATCAG CACATACAACGGCAACACCAACTACAATAGAAAGTTCAAGGACAAAGCCACAATGACCGTGGACAAGNAI-1540294631v3110AGCAGCAGCACCGTGTACATGGAGCTGGCCAGACTGACCAGCGAGGAAAGCGCTATCTACTACTGCG TGAAAGACGACTACTGGGGCCAGGGCACCAGCGTCACTGTGTCCAGC (SEQ ID NO: 194)

[0366] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 201; and / or ii) the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 as set forth in a VLcomprising the amino acid sequence of SEQ ID NO: 202. SEQ ID NO: 201 and SEQ ID NO: 202 are disclosed in Table 12.

[0367] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197. SEQ ID NOs: 195-197 are provided in Table 12.

[0368] In certain embodiments, the VH 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 201. For example, the VHcomprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 201. In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 201.

[0369] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof. In certain embodiments, the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200. SEQ ID NOs: 198-200 are provided in Table 12.

[0370] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 202. For example, the VL comprises an aminoNAI-1540294631v3111acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 202. In certain embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO: 202.

[0371] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof; and VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof. In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200.

[0372] In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 201, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 202.

[0373] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VHand VLare linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VL or VL-VH.

[0374] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200. In certainNAI-1540294631v3112embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 201, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 202. In certain embodiments, the VHand VLare linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 203. SEQ ID NO: 203 is provided in Table 12.

[0375] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VHand the VLare positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VH comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197; and a VL comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 201, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 202. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 204. SEQ ID NO: 204 is provided in Table 12.

[0376] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 12 (ATA012) CDRs 1 2 3 VSYYMS (SEQ ID NO:AINFYGGLAYYPDTVKG HYRYDNAMDY Q G G Y G G T Y Y G113Amino GSGGGGSGGGGSDVKLVESGGGLVKLGGSLKLSCAASGFTFSSYYMSWVRQTPEK Acid RLDLVAAINFYGGLAYYPDTVKGRFTISRDNAKNTLYLQMNSLKSEDTALYYCVR HYRYDNAMDYWGQGTSVTVSS (SEQ ID NO 204)sequence of SEQ ID NO: 201 is set forth in SEQ ID NO: 205, which is provided below. GACGTTAAGCTCGTGGAGTCTGGGGGAGGCTTAGTGAAGCTTGGAGGGTCCCTGAAACTCTCCTGTG CAGCCTCTGGATTCACTTTCAGTAGCTATTACATGTCTTGGGTTCGCCAGACTCCAGAGAAGAGGCT GGACTTGGTCGCAGCCATAAATTTTTATGGTGGTCTTGCCTACTATCCAGACACTGTGAAGGGCCGA TTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTGCAAATGAACAGTCTGAAGTCTGAGG ACACAGCCTTGTATTACTGTGTGAGACATTATAGGTACGACAATGCTATGGACTACTGGGGTCAAGG AACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 205)

[0378] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 201 is set forth in SEQ ID NO: 206, which is provided below. GACGTGAAACTGGTTGAGAGCGGAGGCGGCCTGGTGAAACTGGGAGGAAGCCTGAAACTGTCTTGTG CCGCCAGCGGCTTCACCTTTAGCAGCTATTACATGTCCTGGGTGCGGCAGACACCAGAGAAGAGACT GGACCTGGTGGCCGCTATCAACTTCTACGGCGGCCTGGCCTACTACCCTGACACCGTGAAGGGCAGA TTCACCATCAGCAGAGACAACGCCAAGAACACCCTGTACCTGCAGATGAACAGCCTCAAGAGCGAGG ACACTGCCCTGTATTACTGCGTGAGGCACTACCGGTACGACAACGCCATGGACTACTGGGGCCAGGG CACCAGCGTGACCGTGTCCTCT (SEQ ID NO: 206)

[0379] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 202 is set forth in SEQ ID NO: 207, which is provided below. GACATTGTGATGACCCAGTCTCAAAAATTCATGTCCACATCAATTAGAGACAGGGTCAACATCACCT GCAAGGCCAGTCAGAATGTGGGTACTGCTGTAGCCTGGTATCAACAGAGACCAGGACAATCTCCTAA ACTACTGATTTACTCGGCATCCAATCGGTACAGTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCT GGGACAGATTTCACTCTCACCATCAGCAATATGCAGTCTGAAGACCTGACAAGTTATTTCTGCCAGC AATATAGTAGTTATCCTCTCACGTTCGGTGTTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 207)

[0380] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 202 is set forth in SEQ ID NO: 208, which is provided below. GATATCGTGATGACCCAGAGCCAGAAGTTCATGAGCACAAGCATCAGAGATAGAGTGAACATCACCT GCAAGGCTTCCCAGAACGTGGGCACAGCCGTGGCTTGGTACCAGCAAAGACCTGGCCAGTCCCCTAA GCTGCTGATCTACAGCGCCAGCAATAGATACTCTGGGGTCCCCGACCGGTTTACCGGCAGCGGCAGC GGCACAGATTTCACCCTGACCATTTCTAATATGCAGAGCGAAGATCTGACAAGCTACTTCTGCCAGCNAI-1540294631v3114AATACTCTTCTTACCCCCTGACATTCGGCGTGGGAACCAAGCTGGAACTGAAG (SEQ ID NO: 208)

[0381] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 203 is set forth in SEQ ID NO: 209, which is provided below. GACGTTAAGCTCGTGGAGTCTGGGGGAGGCTTAGTGAAGCTTGGAGGGTCCCTGAAACTCTCCTGTG CAGCCTCTGGATTCACTTTCAGTAGCTATTACATGTCTTGGGTTCGCCAGACTCCAGAGAAGAGGCT GGACTTGGTCGCAGCCATAAATTTTTATGGTGGTCTTGCCTACTATCCAGACACTGTGAAGGGCCGA TTCACCATCTCCAGAGACAATGCCAAGAACACCCTGTACCTGCAAATGAACAGTCTGAAGTCTGAGG ACACAGCCTTGTATTACTGTGTGAGACATTATAGGTACGACAATGCTATGGACTACTGGGGTCAAGG AACCTCAGTCACCGTCTCCTCAGGTGGAGGTGGATCAGGTGGAGGTGGATCTGGTGGAGGTGGATCT GACATTGTGATGACCCAGTCTCAAAAATTCATGTCCACATCAATTAGAGACAGGGTCAACATCACCT GCAAGGCCAGTCAGAATGTGGGTACTGCTGTAGCCTGGTATCAACAGAGACCAGGACAATCTCCTAA ACTACTGATTTACTCGGCATCCAATCGGTACAGTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCT GGGACAGATTTCACTCTCACCATCAGCAATATGCAGTCTGAAGACCTGACAAGTTATTTCTGCCAGC AATATAGTAGTTATCCTCTCACGTTCGGTGTTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 209)

[0382] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 203 is set forth in SEQ ID NO: 210, which is provided below. GACGTGAAACTGGTTGAGAGCGGAGGCGGCCTGGTGAAACTGGGAGGAAGCCTGAAACTGTCTTGTG CCGCCAGCGGCTTCACCTTTAGCAGCTATTACATGTCCTGGGTGCGGCAGACACCAGAGAAGAGACT GGACCTGGTGGCCGCTATCAACTTCTACGGCGGCCTGGCCTACTACCCTGACACCGTGAAGGGCAGA TTCACCATCAGCAGAGACAACGCCAAGAACACCCTGTACCTGCAGATGAACAGCCTCAAGAGCGAGG ACACTGCCCTGTATTACTGCGTGAGGCACTACCGGTACGACAACGCCATGGACTACTGGGGCCAGGG CACCAGCGTGACCGTGTCCTCTGGCGGAGGCGGCAGCGGCGGCGGCGGAAGCGGCGGCGGAGGCAGC GATATCGTGATGACCCAGAGCCAGAAGTTCATGAGCACAAGCATCAGAGATAGAGTGAACATCACCT GCAAGGCTTCCCAGAACGTGGGCACAGCCGTGGCTTGGTACCAGCAAAGACCTGGCCAGTCCCCTAA GCTGCTGATCTACAGCGCCAGCAATAGATACTCTGGGGTCCCCGACCGGTTTACCGGCAGCGGCAGC GGCACAGATTTCACCCTGACCATTTCTAATATGCAGAGCGAAGATCTGACAAGCTACTTCTGCCAGC AATACTCTTCTTACCCCCTGACATTCGGCGTGGGAACCAAGCTGGAACTGAAG (SEQ ID NO: 210)

[0383] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 204 is set forth in SEQ ID NO: 211, which is provided below.NAI-1540294631v3115GACATTGTGATGACCCAGTCTCAAAAATTCATGTCCACATCAATTAGAGACAGGGTCAACATCACCT GCAAGGCCAGTCAGAATGTGGGTACTGCTGTAGCCTGGTATCAACAGAGACCAGGACAATCTCCTAA ACTACTGATTTACTCGGCATCCAATCGGTACAGTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCT GGGACAGATTTCACTCTCACCATCAGCAATATGCAGTCTGAAGACCTGACAAGTTATTTCTGCCAGC AATATAGTAGTTATCCTCTCACGTTCGGTGTTGGGACCAAGCTGGAGCTGAAAGGTGGAGGTGGATC AGGTGGAGGTGGATCTGGTGGAGGTGGATCTGACGTTAAGCTCGTGGAGTCTGGGGGAGGCTTAGTG AAGCTTGGAGGGTCCCTGAAACTCTCCTGTGCAGCCTCTGGATTCACTTTCAGTAGCTATTACATGT CTTGGGTTCGCCAGACTCCAGAGAAGAGGCTGGACTTGGTCGCAGCCATAAATTTTTATGGTGGTCT TGCCTACTATCCAGACACTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACACCCTG TACCTGCAAATGAACAGTCTGAAGTCTGAGGACACAGCCTTGTATTACTGTGTGAGACATTATAGGT ACGACAATGCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 211)

[0384] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 204 is set forth in SEQ ID NO: 212, which is provided below. GATATCGTGATGACCCAGAGCCAGAAGTTCATGAGCACAAGCATCAGAGATAGAGTGAACATCACCT GCAAGGCTTCCCAGAACGTGGGCACAGCCGTGGCTTGGTACCAGCAAAGACCTGGCCAGTCCCCTAA GCTGCTGATCTACAGCGCCAGCAATAGATACTCTGGGGTCCCCGACCGGTTTACCGGCAGCGGCAGC GGCACAGATTTCACCCTGACCATTTCTAATATGCAGAGCGAAGATCTGACAAGCTACTTCTGCCAGC AATACTCTTCTTACCCCCTGACATTCGGCGTGGGAACCAAGCTGGAACTGAAGGGCGGAGGCGGCAG CGGCGGCGGCGGAAGCGGCGGCGGAGGCAGCGACGTGAAACTGGTTGAGAGCGGAGGCGGCCTGGTG AAACTGGGAGGAAGCCTGAAACTGTCTTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTATTACATGT CCTGGGTGCGGCAGACACCAGAGAAGAGACTGGACCTGGTGGCCGCTATCAACTTCTACGGCGGCCT GGCCTACTACCCTGACACCGTGAAGGGCAGATTCACCATCAGCAGAGACAACGCCAAGAACACCCTG TACCTGCAGATGAACAGCCTCAAGAGCGAGGACACTGCCCTGTATTACTGCGTGAGGCACTACCGGT ACGACAACGCCATGGACTACTGGGGCCAGGGCACCAGCGTGACCGTGTCCTCT (SEQ ID NO: 212)

[0385] In certain embodiments, the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VHcomprising the amino acid sequence of SEQ ID NO: 215; and / or ii) the VLcomprises a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO: 216. SEQ ID NO: 215 and SEQ ID NO: 216 are disclosed in Table 13.

[0386] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 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 CDR3NAI-1540294631v3116comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, 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. SEQ ID NOs: 213, 167, and 168 are provided in Table 13.

[0387] In certain embodiments, the VHcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 215. For example, the VH comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 215. In certain embodiments, the VHcomprises the amino acid sequence set forth in SEQ ID NO: 215.

[0388] In certain embodiments, the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof. In certain embodiments, the VL comprises 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: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169. SEQ ID NOs: 214, 135, and 169 are provided in Table 13.

[0389] In certain embodiments, the VLcomprises 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%) identical or homologous to the amino acid sequence set forth in SEQ ID NO: 216. For example, the VL comprises an amino acid sequence that is 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 216. In certain embodiments, the VLcomprises the amino acid sequence set forth in SEQ ID NO: 216.

[0390] In certain embodiments, the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 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 modificationNAI-1540294631v3117thereof; and VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof. In certain embodiments, the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, 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; and the VLcomprises 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: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169.

[0391] In certain embodiments, the VH comprises the amino acid sequence set forth in SEQ ID NO: 215, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 216.

[0392] The VHthe VLcan be linked one after another, e.g., by a linker. In certain embodiments, the VH and VL are linked via a linker. In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO : 4. The variable regions from the N- to the C-terminus can be VH-VLor VL-VH.

[0393] In certain embodiments, the VHis positioned at the N-terminus of the extracellular domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VH-VL. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, 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; and a VLcomprising 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: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 215, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 216. In certain embodiments, the VH and VL are linked via a linker comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 217. SEQ ID NO: 217 is provided in Table 13.

[0394] In certain embodiments, the VLis positioned at the N-terminus of the extracellular antigen-binding domain, i.e., the VH and the VL are positioned from the N- to the C-terminus as VL- VH. In certain embodiments, the extracellular domain of the CAR is an scFv that comprises a VHcomprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, a CDR2NAI-1540294631v3118comprising 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; and a VL 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: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169. In certain embodiments, the scFv comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 215, and a VLcomprising the amino acid sequence set forth in SEQ ID NO: 216. In certain embodiments, the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 218. SEQ ID NO: 218 is provided in Table 13.

[0395] In certain embodiments, the CDRs are identified according to the Kabat numbering system. Table 13 (ATA013) CDRs 1 2 3 VHNYGIN (SEQ ID NO:VVWSGGGTDYNAPFIS NPDSDHYYGYEAMD Q G M A G M G D A G K N

[0396] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 215 is set forth in SEQ ID NO: 219, which is provided below. CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTTTCATTAAATAACTATGGTATAAACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGTGGTATGGAGTGGTGGAGGCACAGACTATAATGCACCTTTCATATCCAGACTG AGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAGCAGTCTGCAAGTTGATGACANAI-1540294631v3119CAGCCATATATTATTGTGCCGGAAATCCAGACTCGGATCATTACTACGGCTACGAGGCTATGGACTA CTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 219)

[0397] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 215 is set forth in SEQ ID NO: 220, which is provided below. CAAGTGCAGCTGAAGCAGAGCGGACCTGGCCTGGTGCAGCCTAGCCAGTCCCTGAGCATCACCTGTA CCGTGAGCGGATTTTCTCTGAACAACTACGGCATCAACTGGGTGCGGCAGAGCCCCGGCAAGGGCCT GGAATGGCTGGGCGTGGTGTGGTCCGGCGGCGGCACTGATTATAATGCCCCTTTCATCTCCAGACTG TCCATTTCTAAGGACAACAGCAAGAGCCAGGTGTTCTTCAAGATGAGCAGCCTGCAGGTGGACGACA CCGCCATCTACTATTGCGCCGGCAACCCCGACAGCGACCACTACTACGGCTACGAGGCCATGGACTA CTGGGGCCAGGGCACAAGCGTGACCGTGTCCAGC (SEQ ID NO: 220)

[0398] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 216 is set forth in SEQ ID NO: 221, which is provided below. GACTTCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCTTCACTT GTCGAGCAAGTGGAGATATTCACAATTTTTTAGCATGGTATCAGCAGAGACAGGGAAAGTCTCCTCA GCTCCTGGTCTATAATGCAAAAACCTTAGCCGATGGTGTGCCATCAAGGTTCAGTGGCAGTGCATCA GGAACACAATATTCTCTCAAGATCATCAGCCTTCAGCCTGAGGATTTTGGGACTTATTACTGTCAAC ATTTTTGGACTATTCCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA (SEQ ID NO: 221)

[0399] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 216 is set forth in SEQ ID NO: 222, which is provided below. GATTTCCAGATGACCCAGTCTCCAGCCAGCCTGTCTGCTTCTGTGGGCGAGACAGTCACCTTTACAT GCAGAGCCAGCGGCGACATCCACAACTTCCTGGCCTGGTACCAGCAGCGGCAGGGAAAAAGCCCTCA GCTGCTGGTTTACAATGCCAAGACCCTGGCTGATGGAGTGCCTAGCAGATTCAGCGGCAGCGCCTCT GGCACACAGTACAGCCTGAAAATCATCAGCCTCCAACCTGAGGATTTCGGCACCTACTACTGCCAAC ACTTCTGGACCATCCCCTTCACATTTGGCAGCGGCACCAAGCTGGAAATCAAG (SEQ ID NO: 222)

[0400] In certain embodiments, an exemplary nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 217 is set forth in SEQ ID NO: 223, which is provided below. CAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCACAGAGCCTGTCCATCACCTGCA CAGTCTCTGGTTTTTCATTAAATAACTATGGTATAAACTGGGTTCGCCAGTCTCCAGGAAAGGGTCT GGAGTGGCTGGGAGTGGTATGGAGTGGTGGAGGCACAGACTATAATGCACCTTTCATATCCAGACTG AGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTTAAAATGAGCAGTCTGCAAGTTGATGACA CAGCCATATATTATTGTGCCGGAAATCCAGACTCGGATCA...

Claims

WHAT IS CLAIMED IS:

1. A chimeric antigen receptor (CAR), comprising an extracellular domain that binds to GPC3, a transmembrane domain, and an intracellular domain, wherein the extracellular domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein a) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 29, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 30; b) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 47, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 48; c) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 62, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 63; d) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 75, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 76; e) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 89, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 90; f) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 101, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 102; g) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 119, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 120; h) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 137, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 138; 1540294631v3246i) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 155, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 156; j) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 170, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 171; k) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 183, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 184; l) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 201, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 202; m) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 215, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 216; n) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 233, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 234; o) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 246, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 247; or p) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 262, and the VLcomprises a VLCDR1, a VLNAI-1540294631v3247CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO:

263.

2. The CAR of claim 1, wherein the VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VL CDR3 are identified according to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the Contact numbering system, or the IMGT®Information System.

3. The CAR of claim 1, wherein the VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VL CDR3 are identified according to the Kabat numbering system.

4. The CAR of claim 1, wherein: a) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof; b) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; c) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61 or a conservative modification thereof; and theNAI-1540294631v3248VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; d) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; e) the VHcomprises 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: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; f) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; g) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 or a conservative modification thereof, and a CDR3 comprising theNAI-1540294631v3249amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; h) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof; i) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof; j) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; k) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequenceNAI-1540294631v3250set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; l) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof; m) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232 or a conservative modification thereof;NAI-1540294631v3251o) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; or p) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a conservative modification thereof.

5. The CAR of any one of claims 1-4, wherein: a) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28; b) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; c) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and aNAI-1540294631v3252CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; d) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; e) the VH 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: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; f) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; g) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; h) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VL comprises aNAI-1540294631v3253CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; i) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154; j) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, 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; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169; k) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; l) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200; m) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, 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; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214, a CDR2 comprisingNAI-1540294631v3254the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169; n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232; o) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; or p) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

261.

6. The CAR of claim 5, wherein the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

136.

7. The CAR of claim 5, wherein the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:NAI-1540294631v3255230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

261.

8. The CAR of any one of claims 1-7, wherein VHcomprises 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO:

262.

9. The CAR of any one of claims 1-8, wherein VH comprises the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO:

262.

10. The CAR of any one of claims 1-9, wherein VLcomprises 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO:

263.

11. The CAR of any one of claims 1-10, wherein VL comprises the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO: 263.NAI-1540294631v325612. The CAR of any one of claims 1-11, wherein: a) the VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 30; b) the VH comprises the amino acid sequence set forth in SEQ ID NO: 47; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 48; c) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 62; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 63; d) the VH comprises the amino acid sequence set forth in SEQ ID NO: 75; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 76; e) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 89; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 90; f) the VH comprises the amino acid sequence set forth in SEQ ID NO: 101; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 102; g) the VH comprises the amino acid sequence set forth in SEQ ID NO: 119; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 120; h) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 138; i) the VH comprises the amino acid sequence set forth in SEQ ID NO: 155; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 156; j) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 170; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 171; k) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 183; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 184; l) the VH comprises the amino acid sequence set forth in SEQ ID NO: 201; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 202; m) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 215; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 216; n) the VH comprises the amino acid sequence set forth in SEQ ID NO: 233; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 234; o) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 246; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 247; orNAI-1540294631v3257p) the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VL comprises the amino acid sequence set forth in SEQ ID NO:

263.

13. The CAR of claim 12, wherein: a) the VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; b) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 47; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 48; c) the VH comprises the amino acid sequence set forth in SEQ ID NO: 75; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 76; d) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 138; e) the VH comprises the amino acid sequence set forth in SEQ ID NO: 155; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 156; or f) the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VL comprises the amino acid sequence set forth in SEQ ID NO:

263.

14. The CAR of claim 13, wherein the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VLcomprises the amino acid sequence set forth in SEQ ID NO:

138.

15. The CAR of claim 13, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VLcomprises the amino acid sequence set forth in SEQ ID NO:

263.

16. The CAR of any one of claims 1-15, wherein the extracellular domain comprises a variable fragment (Fv), a single-chain variable fragment (scFv), a Fab, or a F(ab)2.

17. The CAR of claim 16, wherein the extracellular domain comprises an scFv.

18. The CAR of any one of claims 1-17, wherein the extracellular domain comprises a linker between the VH and the VL.

19. The CAR of claim 18, wherein the linker consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.NAI-1540294631v325820. The CAR of any one of claims 1-19, wherein the VH and the VL are positioned from the N- to the C-terminus: VL-VH.

21. The CAR of any one of claims 1-19, wherein the VHand the VLare positioned from the N- to the C-terminus: VH-VL.

22. The CAR of any one of claims 1-21, wherein the extracellular domain comprises or is an scFv, which comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 264, or SEQ ID NO:

265.

23. The CAR of claim 22, wherein the extracellular domain comprises or is an scFv, which comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 264, or SEQ ID NO:

265.

24. The CAR of any one of claims 1-23, 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, or a BTLA polypeptide.

25. The CAR of claim 24, wherein the transmembrane domain comprises a CD28 polypeptide.

26. The CAR of claim 25, wherein the CD28 polypeptide comprises the amino acid sequence set forth in amino acids 154 to 179 of SEQ ID NO:

308.

27. The CAR of any one of claims 1-26, wherein the intracellular domain comprises a CD3ζ polypeptide.

28. The CAR of claim 27, wherein the CD3ζ polypeptide is a modified CD3ζ polypeptide.NAI-1540294631v325929. The CAR of claim 28, wherein the modified CD3ζ polypeptide comprises a native ITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 consisting of two loss-of-function mutations.

30. The CAR of claim 29, wherein the native ITAM1 consists of the amino acid sequence set forth in SEQ ID NO:

313.

31. The CAR of claim 29, wherein the ITAM2 variant consists of the amino acid sequence set forth in SEQ ID NO:

319.

32. The CAR of claim 29, wherein the ITAM3 variant consists of the amino acid sequence set forth in SEQ ID NO:

323.

33. The CAR of any one of claims 28-32, wherein the modified CD3ζ polypeptide comprises or consists of the amino acid sequence set forth in SEQ ID NO:

325.

34. The CAR of any one of claims 1-33, wherein the intracellular domain further comprises at least one co-stimulatory signaling region.

35. The CAR of claim 34, wherein the at least one co-stimulatory signaling region comprises at least one intracellular signaling domain of a co-stimulatory molecule.

36. The CAR of claim 35, wherein the co-stimulatory molecule is selected from the group consisting of CD28, 4-1BB, OX40, ICOS, DAP-10, CD27, CD28, CD30, CD40, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CD8, CD4, B2C, CD80, CD86, DAP10, DAP12, MyD88, BTNL3, and NKG2D, and combinations thereof.

37. The CAR of claim 36, wherein the co-stimulatory molecule is CD28.

38. The CAR of any one of claims 34-37, wherein the at least one co-stimulatory signaling region comprises amino acids 180 to 220 of SEQ ID NO:

308.

39. The CAR of any one of claims 1-38, further comprising a signal peptide.NAI-1540294631v326040. The CAR of claim 39, wherein the signal peptide comprises the amino acid sequence set forth in SEQ ID NO:

278.

41. The CAR of any one of claims 1-40, further comprising a self-cleaving P2A peptide.

42. The CAR of claim 41, wherein the self-cleaving P2A peptide comprises the amino acid sequence set forth in SEQ ID NO:

329.

43. The CAR of any one of claims 1-42, comprising the amino acid sequence set forth in SEQ ID NO: 333, SEQ ID NO: 335, SEQ ID NO: 337, SEQ ID NO: 339, SEQ ID NO: 341, SEQ ID NO: 343, SEQ ID NO: 345, SEQ ID NO: 347, SEQ ID NO: 349, SEQ ID NO: 351, SEQ ID NO: 353, or SEQ ID NO:

355.

44. The CAR of any one of claims 1-43, wherein the CAR is expressed from a vector.

45. The CAR of claim 44, wherein the vector is a viral vector.

46. The CAR of claim 45, wherein the viral vector is a retroviral vector.

47. A nucleic acid encoding the CAR of any one of claims 1-46.

48. The nucleic acid of claim 47, comprising the nucleotide sequence set forth in SEQ ID NO: 334, SEQ ID NO: 336, SEQ ID NO: 338, SEQ ID NO: 340, SEQ ID NO: 342, SEQ ID NO: 344, SEQ ID NO: 346, SEQ ID NO: 348, SEQ ID NO: 350, SEQ ID NO: 352, SEQ ID NO: 354, or SEQ ID NO:

356.

49. The nucleic acid of claim 47 or 48, further comprising a promoter that is operably linked to the CAR.

50. The nucleic acid of claim 49, wherein the promoter is endogenous or exogenous.

51. The nucleic acid of claim 50, wherein the exogenous promoter is selected from the group consisting of an elongation factor (EF)-1 promoter, a cytomegalovirus immediate-early promoter (CMV) promoter, a simian virus 40 early promoter (SV40) promoter, a phosphoglycerate kinase (PGK) promoter, a metallothionein promoter, and Ubiquitin C promoter.NAI-1540294631v326152. The nucleic acid of claim 50, wherein the endogenous promoter is selected from a TCR alpha promoter, a TCR beta promoter, and a beta 2-microglobulin promoter.

53. The nucleic acid of claim 49, wherein the promoter is an inducible promoter.

54. The nucleic acid of claim 53, wherein the inducible promoter is selected from the group consisting of a NFAT transcriptional response element (TRE) promoter, a CD69 promoter, a CD25 promoter, an IL-2 promoter, a 4-1BB promoter, a PD1 promoter, and a LAG3 promoter.

55. A vector comprising the nucleic acid of any one of claims 47-54.

56. The vector of claim 55, wherein the vector is a viral vector.

57. The vector of claim 56, wherein the viral vector is a retroviral vector.

58. A cell comprising the CAR of any one of claims 1-46, the nucleic acid of any one of claims 47-54, or the vector of any one of claims 55-57.

59. The cell of claim 58, wherein the cell is transduced with the CAR, the nucleic acid, or the vector.

60. The cell of claim 58 or claim 59, wherein the CAR is constitutively expressed on the surface of the cell.

61. The cell of any one of claims 58-60, wherein the cell is an immunoresponsive cell or an immune effector cell.

62. The cell of any one of claims 58-61, wherein the cell is a cell of the lymphoid lineage or a cell of the myeloid lineage.

63. The cell of any one of claims 58-62, wherein the cell is selected from the group consisting of a T cell, a B cell, a Natural Killer (NK) cell, macrophage, innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a lymphokine activated killer (LAK) cell, a stem cell from which a lymphoid cell may be differentiated, a stem cell from which a myeloid cell may be differentiated, or a combination thereof.NAI-1540294631v326264. The cell of claim 63, wherein the cell is a T cell.

65. The cell of claim 63 or claim 64, wherein the T cell is selected from the group consisting of helper T cells, cytotoxic T cells, memory T cells, regulatory T cells, tumor-infiltrating lymphocytes (TILs), Natural Killer T cells, mucosal associated invariant T cells, αβ T cells, and γδ T cells.

66. The cell of claim 63, wherein the cell is a NK cell.

67. The cell of claim 66, wherein the NK cell is derived from a stem cell.

68. The cell of claim 63 or 67, wherein the stem cell is a pluripotent stem cell.

69. The cell of claim 68, wherein the pluripotent stem cell is an embryoid stem cell or an induced pluripotent stem cell.

70. An anti-GPC3 antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein a) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 29, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 30; b) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 47, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 48; c) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 62, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 63; d) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 75, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 76; e) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 89, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 90;NAI-1540294631v3263f) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 101, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 102; g) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 119, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 120; h) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 137, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 138; i) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 155, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 156; j) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 170, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 171; k) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 183, and the VLcomprises a VLCDR1, a VLCDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 184; l) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 201, and the VLcomprises a VLCDR1, a VLCDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 202; m) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 215, and the VLcomprises a VLCDR1, a VLNAI-1540294631v3264CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 216; n) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 233, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of a VL comprising the amino acid sequence set forth in SEQ ID NO: 234; o) the VHcomprises a VHCDR1, a VHCDR2, and a VHCDR3 of a VHcomprising the amino acid sequence set forth in SEQ ID NO: 246, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO: 247; or p) the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH comprising the amino acid sequence set forth in SEQ ID NO: 262, and the VL comprises a VL CDR1, a VL CDR2, and a VLCDR3 of a VLcomprising the amino acid sequence set forth in SEQ ID NO:

263.

71. The antibody or antigen-binding fragment thereof of claim 70, wherein the VH CDR1, VH CDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3 are identified according to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the Contact numbering system, or the IMGT®Information System.

72. The antibody or antigen-binding fragment thereof of claim 71, wherein the VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3 are identified according to the Kabat numbering system.

73. The antibody or antigen-binding fragment thereof of any one of claims 70-72, wherein: a) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQNAI-1540294631v3265ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a conservative modification thereof; b) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; c) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; d) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; e) the VH 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: 43 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or aNAI-1540294631v3266conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; f) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; g) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; h) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a conservative modification thereof; i) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof; andNAI-1540294631v3267the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof; j) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; k) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46 or a conservative modification thereof; l) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof; m) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213 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 theNAI-1540294631v3268amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 214 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232 or a conservative modification thereof; o) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115 or a conservative modification thereof; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117 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; or p) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260 or a conservative modification thereof; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a conservative modification thereof.

74. The antibody or antigen-binding fragment thereof of any one of claims 70-73, wherein:NAI-1540294631v3269a) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28; b) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; c) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 59, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 61; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; d) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 60, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 25; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; e) the VH 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: 43; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46;NAI-1540294631v3270f) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; g) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; h) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; i) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 149, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 150, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 151; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 152, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 153, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 154; j) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, 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; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169;NAI-1540294631v3271k) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 182; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; l) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 195, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 196, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 197; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 198, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 199, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 200; m) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 213, 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; and the VL comprises 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: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 169; n) the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 227, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 228, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 229; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 232; o) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 117, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 118; orNAI-1540294631v3272p) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

261.

75. The antibody or antigen-binding fragment thereof of claim 74, wherein the VHcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 131, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 132, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 133; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

136.

76. The antibody or antigen-binding fragment thereof of claim 74, wherein the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 258, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 259, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 260; and the VLcomprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 230, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 231, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

261.

77. The antibody or antigen-binding fragment thereof of any one of claims 70-76, wherein VHcomprises 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO: 262.NAI-1540294631v327378. The antibody or antigen-binding fragment thereof of any one of claims 70-77, wherein VH comprises the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO:

262.

79. The antibody or antigen-binding fragment thereof of any one of claims 70-78, wherein VLcomprises 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% identical or homologous to the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO:

263.

80. The antibody or antigen-binding fragment thereof of any one of claims 70-79, wherein VL comprises the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO:

263.

81. The antibody or antigen-binding fragment thereof of any one of claims 70-80, wherein: a) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; b) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 47; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 48; c) the VH comprises the amino acid sequence set forth in SEQ ID NO: 62; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 63; d) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 75; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 76; e) the VH comprises the amino acid sequence set forth in SEQ ID NO: 89; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 90;NAI-1540294631v3274f) the VH comprises the amino acid sequence set forth in SEQ ID NO: 101; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 102; g) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 119; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 120; h) the VH comprises the amino acid sequence set forth in SEQ ID NO: 137; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 138; i) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 155; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 156; j) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 170; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 171; k) the VH comprises the amino acid sequence set forth in SEQ ID NO: 183; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 184; l) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 201; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 202; m) the VH comprises the amino acid sequence set forth in SEQ ID NO: 215; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 216; n) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 233; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 234; o) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 246; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 247; or p) the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VLcomprises the amino acid sequence set forth in SEQ ID NO:

263.

82. The antibody or antigen-binding fragment thereof of claim 81, wherein: a) the VH comprises the amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 30; b) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 47; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 48; c) the VH comprises the amino acid sequence set forth in SEQ ID NO: 75; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 76; d) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 137; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 138;NAI-1540294631v3275e) the VH comprises the amino acid sequence set forth in SEQ ID NO: 155; and the VL comprises the amino acid sequence set forth in SEQ ID NO: 156; or f) the VHcomprises the amino acid sequence set forth in SEQ ID NO: 262; and the VL comprises the amino acid sequence set forth in SEQ ID NO:

263.

83. The antibody or antigen-binding fragment thereof of claim 82, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 137; and the VLcomprises the amino acid sequence set forth in SEQ ID NO:

138.

84. The antibody or antigen-binding fragment thereof of claim 82, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 262; and the VLcomprises the amino acid sequence set forth in SEQ ID NO: 263, 85. The antibody or antigen-binding fragment thereof of any one of claims 70-84, wherein the antigen-binding fragment thereof is a variable fragment (Fv), a single-chain variable fragment (scFv), a Fab, or a F(ab)2.

86. The antibody or antigen-binding fragment thereof of claim 85, wherein the antigen- binding fragment thereof is an scFv.

87. The antibody or antigen-binding fragment thereof of claim 86, wherein the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 264, or SEQ ID NO:

265.

88. The antibody or antigen-binding fragment thereof of claim 87, wherein the scFv comprises or consists of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 264, or SEQ ID NO: 265.NAI-1540294631v327689. The antibody or antigen-binding fragment thereof of any one of claims 70-88, wherein the VH is connected to the VL via a linker.

90. The antibody or antigen-binding fragment thereof of claim 89, wherein the linker consists of the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO:

4.

91. The antibody or antigen-binding fragment thereof of any one of claims 70-90, wherein the VHand the VLare positioned from the N- to the C-terminus: VL-VH.

92. The antibody or antigen-binding fragment thereof of any one of claims 70-90, wherein the VHand the VLare positioned from the N- to the C-terminus: VH-VL.

93. The antibody or antigen-binding fragment thereof of any one of claims 70-92, wherein the antibody comprises a human variable region framework region.

94. The antibody or antigen-binding fragment thereof of any one of claims 70-83, wherein the antibody or antigen-binding fragment thereof comprises a Fc region.

95. The antibody or antigen-binding fragment thereof of claim 94, wherein the Fc region is a IgG1 Fc region.

96. The antibody or antigen-binding fragment thereof of claim 94 or 95, wherein the Fc region comprises the amino acid sequence set forth in SEQ ID NO:

357.

97. The antibody or antigen-binding fragment thereof of any one of claims 70-96, which is a fully human or an antigen-binding fragment thereof, a chimeric antibody or an antigen-binding fragment thereof, or a humanized antibody or an antigen-binding fragment thereof.

98. An antibody or an antigen-binding fragment thereof that competes with the antibody or antigen-binding fragment thereof of any one of claims 70-97 for binding to GPC3.

99. An antibody or an antigen-binding fragment thereof that binds to essentially the same epitope region on GPC3 as the antibody or antigen-binding fragment thereof of any one of claims 70-97.NAI-1540294631v3277100. A conjugate comprising the antibody or antigen-binding fragment thereof of any one of claims 70-97.

101. The conjugate of claim 100, wherein the antibody or antigen-binding fragment thereof is linked to a therapeutic agent, a detectable agent, or a diagnostic agent.

102. The conjugate of claim 101, wherein the therapeutic agent is a chemotherapeutic agent, a cytotoxin, or a drug.

103. The conjugate of any one of claims 100-102, which is an immunoconjugate.

104. A multispecific molecule comprising the antibody or the antigen-binding fragment thereof of any one of claims 70-97, linked to a second functional moiety.

105. The multispecific molecule of claim 104, wherein the second functional moiety has a different binding specificity than the antibody or antigen binding fragment thereof.

106. A nucleic acid that encodes the antibody or antigen-binding fragment thereof of any one of claims 70-97.

107. The nucleic acid of claim 106, which comprises a first polynucleotide that encodes a VH comprising the amino acid sequence set forth in SEQ ID NO: 29, SEQ ID NO: 47, SEQ ID NO: 62, SEQ ID NO: 75, SEQ ID NO: 89, SEQ ID NO: 101, SEQ ID NO: 119, SEQ ID NO: 137, SEQ ID NO: 155, SEQ ID NO: 170, SEQ ID NO: 183, SEQ ID NO: 201, SEQ ID NO: 215, SEQ ID NO: 233, SEQ ID NO: 246, or SEQ ID NO: 262; and / or a second polynucleotide that encodes a VLcomprising the amino acid sequence set forth in SEQ ID NO: 30, SEQ ID NO: 48, SEQ ID NO: 63, SEQ ID NO: 76, SEQ ID NO: 90, SEQ ID NO: 102, SEQ ID NO: 120, SEQ ID NO: 138, SEQ ID NO: 156, SEQ ID NO: 171, SEQ ID NO: 184, SEQ ID NO: 202, SEQ ID NO: 216, SEQ ID NO: 234, SEQ ID NO: 247, or SEQ ID NO:

263.

108. The nucleic acid of claim 107, wherein the first polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO: 33, SEQ ID NO: 51, SEQ ID NO: 66, SEQ ID NO: 79, SEQ ID NO: 93, SEQ ID NO: 105, SEQ ID NO: 123, SEQ ID NO: 141, SEQ ID NO: 159, SEQ ID NO: 174, SEQ ID NO: 187, SEQ ID NO: 205, SEQ ID NO: 219, SEQ ID NO: 237, SEQ ID NO: 250, or SEQ ID NO: 266.NAI-1540294631v3278109. The nucleic acid of claim 107 or 108, wherein the second polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO: 35, SEQ ID NO: 53, SEQ ID NO: 68, SEQ ID NO: 81, SEQ ID NO: 95, SEQ ID NO: 107, SEQ ID NO: 125, SEQ ID NO: 143, SEQ ID NO: 161, SEQ ID NO: 176, SEQ ID NO: 189, SEQ ID NO: 207, SEQ ID NO: 221, SEQ ID NO: 239, SEQ ID NO: 252, or SEQ ID NO:

268.

110. A vector comprising the nucleic acid of any one of claims 106-109.

111. The vector of claim 110, which is an expression vector.

112. A host cell comprising the vector of claim 110 or 111.

113. A method of producing an anti-GPC3 antibody or an antigen-binding fragment thereof, wherein the method comprises culturing the host cell of claim 111 under conditions to induce expression of the antibody or antigen-binding fragment thereof from the host cell.

114. A method for detecting GPC3 in a whole cell or tissue, comprising: a) contacting a cell or tissue with the antibody or antigen-binding fragment thereof of any one of claims 70-97, wherein the antibody or antigen-binding fragment thereof comprises a detectable label; and b) determining the amount of the labeled antibody or antigen-binding fragment thereof bound to said cell or tissue by measuring the amount of detectable label associated with the cell or tissue, wherein the amount of bound antibody or antigen-binding fragment thereof indicates the amount of GPC3 in the cell or tissue.

115. A composition comprising the cell of any one of claims 58-69, the antibody or antigen- binding fragment thereof of any one of claims 70-97, the conjugate of any one of claims 100- 103, or the multispecific molecule of claim 104 or claim 105.

116. The composition of claim 115, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

117. The composition of claim 115 or claim 116, comprising between about 1 × 105and about 5 × 108cells.NAI-1540294631v3279118. A method of treating a disease or disorder associated with GPC3 in a subject, comprising administering to the subject the cell of any one of claims 58-69, the antibody or antigen-binding fragment thereof of any one of claims 70-97, the conjugate of any one of claims 100-103, the multispecific molecule of claim 104 or claim 105, or the composition of any one of claims 115- 117.

119. The method of claim 118, wherein the disease or disorder is a tumor.

120. The method of claim 118 or claim 119, wherein the disease or disorder is cancer.

121. The method of any one of claims 118-120, wherein the disease or disorder is selected from the group consisting of hepatocellular carcinoma, hepatoblastoma, lung squamous cell carcinoma, ovarian yolk sac tumor, melanoma, and urothelial carcinoma.

122. The method of claim 121, wherein the disease or disorder is hepatocellular carcinoma.

123. The method of any one of claims 118-122, wherein the subject is a human subject.

124. A method for producing a cell comprising the CAR of any one of claims 1-46, comprising introducing into a cell a nucleic acid that encodes the CAR of any one of claims 1- 46.

125. The cell of any one of claims 58-69, the antibody or antigen-binding fragment thereof of any one of claims 70-97, the conjugate of any one of claims 100-103, the multispecific molecule of claim 104 or claim 105, or the composition of any one of claims 115-117 for use in a therapy.

126. The cell of any one of claims 58-69, the antibody or antigen-binding fragment thereof of any one of claims 70-97, the conjugate of any one of claims 100-103, the multispecific molecule of claim 104 or claim 105, or the composition of any one of claims 115-117 for use in a method for treating a disease or disorder associated with GPC3 in a subject.

127. The use of claim 126, wherein the disease or disorder is a tumor.

128. The use of claim 126 or claim 127, wherein the disease or disorder is cancer.NAI-1540294631v3280129. The use of any one of claims 126-128, wherein the disease or disorder is selected from the group consisting of hepatocellular carcinoma, hepatoblastoma, lung squamous cell carcinoma, ovarian yolk sac tumor, melanoma, and urothelial carcinoma.

130. The use of claim 129, wherein the disease or disorder is hepatocellular carcinoma.

131. The use of any one of claims 126-130, wherein the subject is a human subject.NAI-1540294631v3281

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