Anti-STEAP2 chimeric antigen receptor and uses thereof

Abstract

The present disclosure provides chimeric antigen receptors and antibodies comprising an antigen-binding domain that specifically binds human STEAP2, nucleotides encoding same, cells containing same, and methods of using same in the treatment of cancer (e.g., prostate cancer).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 262,602, filed October 15, 2021, which is incorporated by reference herein in its entirety.

[0002] References to sequence listings submitted electronically via EFS WEB The electronically submitted Sequence Listing (CARTSTEAP2-100-WO-PCT.xml; size: 144,481 bytes; and creation date: October 13, 2022) submitted with this application is hereby incorporated by reference in its entirety. [Background technology]

[0003] Immunotherapy has emerged as a powerful tool in the fight against various types of diseases, including cancer, by harnessing the power of a patient's own immune system to fight various types of tumors.

[0004] Chimeric antigen receptor (CAR) T cell therapy is a specific form of cell-based immunotherapy that uses genetically engineered T cells to combat cancer. In CAR T cell therapy, T cells are collected from the patient's blood, engineered ex vivo to express a CAR that contains both an antigen binding domain and a T cell activation domain, expanded into a larger population, and administered to the patient. CAR T cells act as a living drug, binding to cancer cells and causing their destruction. If successful, the effects of CAR T cell therapy tend to be long-lasting, as evidenced by the persistence and proliferation of CAR T cells detected in patients long after clinical remission. Summary of the Invention [Problem to be solved by the invention]

[0005] Although several promising CAR-therapies have been approved for use, there remains a need to develop CARs against novel targets to increase the number of indications that can be treated using this therapy. Described herein are novel CARs directed against human STEAP2 and methods of using them in the treatment of cancer, such as prostate cancer. [Means for solving the problem]

[0006] Some aspects of the present disclosure are directed to a polynucleotide comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR), the CAR comprising: (i) an antigen-binding domain that binds to an epitope on human prostate six-transmembrane epithelial antigen-2 (STEAP2); (ii) a transmembrane domain; and (iii) an intracellular domain. In some aspects, the antigen-binding domain binds to an epitope on an extracellular loop of human STEAP2.

[0007] In some embodiments, the antigen binding domain is a Fab, Fab', F(ab')2, Fd, Fv, single chain fragment variable (scFv), single chain antibody, V H H, vNAR, nanobody (single domain antibody) or any combination thereof. In some embodiments, the antigen binding domain comprises an scFv.

[0008] In some aspects, the antigen-binding domain comprises a variable heavy chain region (VH) and a variable light chain region (VL), where the VH comprises a VH complementarity determining region (CDR)1, a VH-CDR2, a VH-CDR3; and the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3.

[0009] In some embodiments, the antigen binding domain comprises a VH-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 6, 16, 26, 36, 46, and 96. In some embodiments, the antigen binding domain comprises a VH-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 5, 15, 25, 35, 45, and 95. In some embodiments, the antigen binding domain comprises a VH-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 4, 14, 24, 34, 44, and 94. In some embodiments, the antigen binding domain comprises a VL-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 3, 13, 23, 33, 43, and 93. In some embodiments, the antigen binding domain comprises a VL-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 2, 12, 22, 32, 42, and 92. In some embodiments, the antigen binding domain comprises a VL-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 1, 11, 21, 31, 41, and 91.

[0010] In some embodiments, the antigen-binding domain comprises: (a) a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23. (d) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36; (e) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46;or (f) a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96;

[0011] In some embodiments, the antigen binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47, and 97. In some embodiments, the antigen binding domain comprises a VH comprising an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47, and 97.

[0012] In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48, and 98. In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48, and 98.

[0013] In some embodiments, the antigen binding domain comprises: (a) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:17. (c) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28;(d) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 38; (e) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and or (f) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98;

[0014] In some embodiments, the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:57.

[0015] In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:58.

[0016] In some embodiments, the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:67.

[0017] In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:68.

[0018] In some embodiments, the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:77.

[0019] In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:78.

[0020] In some embodiments, the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:87.

[0021] In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:88.

[0022] In some embodiments, the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97.

[0023] In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:98.

[0024] In some embodiments, the antigen binding domain comprises: (a) a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (b) a VH comprising the amino acid sequence set forth in SEQ ID NO:17 and a VL comprising the amino acid sequence set forth in SEQ ID NO:18; (c) a VH comprising the amino acid sequence set forth in SEQ ID NO:27 and a VL comprising the amino acid sequence set forth in SEQ ID NO:28; (d) a VH comprising the amino acid sequence set forth in SEQ ID NO:37 and a VL comprising the amino acid sequence set forth in SEQ ID NO:38; (e) a VH comprising the amino acid sequence set forth in SEQ ID NO:47 and a VL comprising the amino acid sequence set forth in SEQ ID NO:48. (f) a VH comprising the amino acid sequence set forth in SEQ ID NO: 57 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 58; (g) a VH comprising the amino acid sequence set forth in SEQ ID NO: 67 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 68; (h) a VH comprising the amino acid sequence set forth in SEQ ID NO: 77 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 78; or (i) a VH comprising the amino acid sequence set forth in SEQ ID NO: 87 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 88; or (j) a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98.

[0025] In some embodiments, the antigen binding domain comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the antigen binding domain comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:99.

[0026] In some embodiments, the intracellular domain comprises a costimulatory domain or a portion thereof. In some embodiments, the intracellular domain comprises a costimulatory domain selected from the group consisting of an intracellular domain of CD3z, a CD28 costimulatory domain, a CD27 costimulatory domain, a 4-1BB costimulatory domain, an ICOS costimulatory domain, an OX-40 costimulatory domain, a GITR costimulatory domain, a CD2 costimulatory domain, an IL-2Rβ costimulatory domain, a MyD88 / CD40a CD28 costimulatory domain, and any combination thereof. In some embodiments, the intracellular domain comprises a 4-1BB costimulatory domain. In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a CD28 costimulatory domain. In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a 4-1BB costimulatory domain. In some embodiments, the intracellular domain of CD3z comprises SEQ ID NO: 131 and the 4-1BB costimulatory domain comprises SEQ ID NO: 130. In some embodiments, the intracellular domain comprising the intracellular domain of CD3z and a 4-1BB costimulatory domain comprises SEQ ID NO: 130. In some embodiments, the intracellular domain comprises the intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain.

[0027] In some embodiments, the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:10.

[0028] In some embodiments, the transmembrane domain comprises a transmembrane domain selected from a transmembrane domain of CD4, CD8α, or CD28. In some embodiments, the transmembrane domain comprises a transmembrane domain of CD28. In some embodiments, the transmembrane domain of CD28 comprises SEQ ID NO: 129.

[0029] In some embodiments, the CAR further comprises a hinge / spacer domain. In some embodiments, the hinge / spacer domain comprises an immunoglobulin hinge / spacer. In some embodiments, the hinge / spacer domain comprises an IgG hinge domain. In some embodiments, the hinge / spacer domain comprises an IgG1 hinge domain and an IgG2 hinge domain, an IgG3 hinge domain, or an IgG4 hinge domain. In some embodiments, the hinge / spacer domain comprises an IgG4 hinge domain. In some embodiments, the IgG4 hinge domain comprises SEQ ID NO: 128.

[0030] In some embodiments, the polynucleotide further encodes an Armoring molecule, which, when expressed on the surface of a cell, counters the immune suppression of cells in the tumor microenvironment. In some embodiments, the Armoring molecule comprises a function-inhibiting TGF-β receptor type 2 (TGFβRIIDN). In some embodiments, the Armoring molecule comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity with the amino acid sequence set forth in SEQ ID NO: 105. In some embodiments, the Armoring molecule comprises the amino acid sequence set forth in SEQ ID NO: 105.

[0031] In some embodiments, the nucleotide sequence encoding a CAR has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 101 or 103. In some embodiments, the nucleotide sequence encoding a CAR comprises the nucleotide sequence set forth in SEQ ID NO: 101 or 103.

[0032] In some embodiments, the polynucleotide further comprises a second nucleotide sequence encoding an Armouring molecule, wherein the second nucleotide sequence has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 104. In some embodiments, the second nucleotide sequence comprises the nucleotide sequence set forth in SEQ ID NO: 104. In some embodiments, the nucleotide sequence encoding the CAR comprises the nucleotide sequence set forth in SEQ ID NO: 101, and the second nucleotide sequence comprises the nucleotide sequence set forth in SEQ ID NO: 104. In some embodiments, the nucleotide sequence encoding the CAR comprises the nucleotide sequence set forth in SEQ ID NO: 103, and the second nucleotide sequence comprises the nucleotide sequence set forth in SEQ ID NO: 104.

[0033] In some embodiments, the nucleotide sequence encoding the CAR and the second nucleotide sequence are linked by a third nucleotide sequence, and the third nucleotide sequence encodes a cleavable peptide linker. In some embodiments, the cleavable peptide linker is a self-cleaving peptide linker. In some embodiments, the cleavable peptide linker comprises a T2A peptide. In some embodiments, the cleavable peptide linker comprises SEQ ID NO: 126.

[0034] In some embodiments, the polynucleotide comprises a nucleotide sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 107. In some embodiments, the polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO:107.

[0035] Some aspects of the present disclosure are directed to a vector or set of vectors comprising a polynucleotide disclosed herein. In some aspects, the vector is a viral vector.

[0036] Some aspects of the present disclosure are directed to a cell comprising a polynucleotide disclosed herein or a vector or set of vectors disclosed herein. In some aspects, the cell is an immune cell. In some aspects, the cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a tumor infiltrating lymphocyte, and any combination thereof.

[0037] Some aspects of the present disclosure are directed to a cell comprising (i) a polynucleotide encoding a chimeric antigen receptor (CAR) that binds to human STEAP2, and (ii) a polynucleotide encoding an armoring molecule. In some aspects, the cell is an immune cell. In some aspects, the cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a tumor infiltrating lymphocyte, and any combination thereof. In some aspects, the cell is a human cell.

[0038] In some aspects, a CAR comprises an antigen binding domain comprising a VH and a VL, wherein the VH comprises VH-CDR1, VH-CDR2, VH-CDR3, and the VL comprises VL-CDR1, VL-CDR2, and VL-CDR3; (a) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 3, and VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4. (b) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:11, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:12, and VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:13, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:14, and VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:15; (c) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 21, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 22, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 23, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 24, VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 25, and VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 26; (d) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 31, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 32, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 33, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 34, VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 35, and VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 36;(e) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 41, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 42, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 43, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 44, VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 45, and VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 46; or (f) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 91, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 92, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 93, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 94, VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 95, and VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 96;

[0039] In some embodiments, (a) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and the VL comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. (b) VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:17; and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; or (c) the VH comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27; or the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:28;(d) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:37, and the VL comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:38. %, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:47; (e) VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:47; and VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:48; or (f) VH comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97. and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:98;

[0040] In some aspects, the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:57, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:58.

[0041] In some embodiments, the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:67, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:68.

[0042] In some embodiments, the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:77, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:78.

[0043] In some embodiments, the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:87, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:88.

[0044] In some embodiments, the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:98.

[0045] In some embodiments, (a) a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (b) a VH comprising the amino acid sequence set forth in SEQ ID NO:17 and a VL comprising the amino acid sequence set forth in SEQ ID NO:18; (c) a VH comprising the amino acid sequence set forth in SEQ ID NO:27 and a VL comprising the amino acid sequence set forth in SEQ ID NO:28; (d) a VH comprising the amino acid sequence set forth in SEQ ID NO:37 and a VL comprising the amino acid sequence set forth in SEQ ID NO:38; (e) a VH comprising the amino acid sequence set forth in SEQ ID NO:47 and a VL comprising the amino acid sequence set forth in SEQ ID NO:48; (f ) a VH comprising the amino acid sequence set forth in SEQ ID NO: 57 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 58; (g) a VH comprising the amino acid sequence set forth in SEQ ID NO: 67 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 68; (h) a VH comprising the amino acid sequence set forth in SEQ ID NO: 77 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 78; (i) a VH comprising the amino acid sequence set forth in SEQ ID NO: 87 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 88; or (j) a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98.

[0046] In some embodiments, the Armouring molecule comprises a functionally inhibited TGF-β receptor type 2 (TGFβRIIDN). In some embodiments, the Armouring molecule comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105. In some embodiments, the Armouring molecule comprises the amino acid sequence set forth in SEQ ID NO: 105.

[0047] In some embodiments, a polynucleotide encoding a CAR comprises a nucleotide sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 101 or 103. In some embodiments, a polynucleotide encoding a CAR comprises the nucleotide sequence set forth in SEQ ID NO: 101 or 103.

[0048] In some embodiments, the polynucleotide encoding the Armouring molecule comprises a nucleotide sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 104. In some embodiments, the polynucleotide encoding the Armouring molecule comprises the nucleotide sequence set forth in SEQ ID NO: 104.

[0049] In some aspects, the polynucleotide encoding the CAR comprises the nucleotide sequence set forth in SEQ ID NO:101, and the polynucleotide encoding the armoring molecule comprises the nucleotide sequence set forth in SEQ ID NO:104.

[0050] In some aspects, the polynucleotide encoding the CAR comprises the nucleotide sequence set forth in SEQ ID NO:103, and the polynucleotide encoding the armoring molecule comprises the nucleotide sequence set forth in SEQ ID NO:104.

[0051] In some embodiments, the polynucleotide encoding the CAR and the polynucleotide encoding the Armouring molecule are operably linked under the control of a single promoter. In some embodiments, the polynucleotide encoding the CAR and the polynucleotide encoding the Armouring molecule are operably linked by an IRES. In some embodiments, the polynucleotide encoding the CAR and the polynucleotide encoding the Armouring molecule are linked by a nucleotide sequence encoding a cleavable peptide linker. In some embodiments, the cleavable peptide linker is a self-cleaving peptide linker. In some embodiments, the cleavable peptide linker comprises a T2A peptide. In some embodiments, the cleavable peptide linker comprises SEQ ID NO: 126.

[0052] Some aspects of the disclosure are directed to an antibody or antigen-binding portion thereof that specifically binds to human STEAP2, comprising a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH complementarity Determining Region (CDR) 1, a VH-CDR2, a VH-CDR3; the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3, wherein (i) the VL-CDR1 comprises an amino acid sequence selected from SEQ ID NOs: 1, 11, 21, 31, 41, and 91; (ii) the VL-CDR2 comprises an amino acid sequence selected from SEQ ID NOs: 2, 12, 22, 32, 42, and 51; and 92; (iii) VL-CDR3 comprises an amino acid sequence selected from SEQ ID NOs: 3, 13, 23, 33, 43 and 93; (iv) VH-CDR1 comprises an amino acid sequence selected from SEQ ID NOs: 4, 14, 24, 34, 44 and 94; (v) VH-CDR2 comprises an amino acid sequence selected from SEQ ID NOs: 5, 15, 25, 35, 45 and 95; and (vi) VH-CDR3 comprises an amino acid sequence selected from SEQ ID NOs: 6, 16, 26, 36, 46 and 96.

[0053] In some aspects, (a) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:1, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:2, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:3, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:4, VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:5, and VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:6; or (b) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:11, and VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: (c) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 21, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 22, and VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 23; or (b) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 24, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 25, and VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 26. (d) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 31, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 32, and VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 33, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 34, and VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 35; (e) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 41, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 42, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 43, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 44, VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 45, and VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 46;or (f) VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 91, VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 92, VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 93, VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 94, VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 95, and VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 96;

[0054] In some embodiments, the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, and 97. In some embodiments, the VH comprises an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, and 97.

[0055] In some embodiments, the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48, 58, 68, 78, 88, and 98. In some embodiments, the VL comprises an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48, 58, 68, 78, 88, and 98.

[0056] In some embodiments, (a) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; or (b) the VH has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:17. (c) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:27, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:28;(d) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:37, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:38; or (e) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:47. (f) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:57, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:58;(g) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:67, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:68; or (h) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:77. (i) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 87, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to SEQ ID NO: 88;or (j) the VH comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97, and the VL comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO:98;

[0057] In some embodiments, (a) the VH comprises the amino acid sequence set forth in SEQ ID NO:7, and the VL comprises the amino acid sequence set forth in SEQ ID NO:8; (b) the VH comprises the amino acid sequence set forth in SEQ ID NO:17, and the VL comprises the amino acid sequence set forth in SEQ ID NO:18; (c) the VH comprises the amino acid sequence set forth in SEQ ID NO:27, and the VL comprises the amino acid sequence set forth in SEQ ID NO:28; (d) the VH comprises the amino acid sequence set forth in SEQ ID NO:37, and the VL comprises the amino acid sequence set forth in SEQ ID NO:38; or (e) 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. (f) the VH comprises the amino acid sequence set forth in SEQ ID NO:57 and the VL comprises the amino acid sequence set forth in SEQ ID NO:58; (g) the VH comprises the amino acid sequence set forth in SEQ ID NO:67 and the VL comprises the amino acid sequence set forth in SEQ ID NO:68; (h) the VH comprises the amino acid sequence set forth in SEQ ID NO:77 and the VL comprises the amino acid sequence set forth in SEQ ID NO:78; (i) the VH comprises the amino acid sequence set forth in SEQ ID NO:87 and the VL comprises the amino acid sequence set forth in SEQ ID NO:88; or (j) the VH comprises the amino acid sequence set forth in SEQ ID NO:97 and the VL comprises the amino acid sequence set forth in SEQ ID NO:98.

[0058] Some aspects of the present disclosure are directed to a pharmaceutical composition comprising a polynucleotide disclosed herein, a vector disclosed herein, a cell disclosed herein, or an antibody or antigen-binding portion disclosed herein and a pharma- ceutical acceptable excipient.

[0059] Some aspects of the present disclosure are directed to a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a polynucleotide disclosed herein, a vector disclosed herein, a cell disclosed herein, an antibody or antigen-binding portion disclosed herein, or a pharmaceutical composition disclosed herein. In some aspects, the disease or condition comprises cancer.

[0060] Some aspects of the present disclosure are directed to a method of treating cancer in a subject in need thereof, comprising administering to the subject a polynucleotide disclosed herein, a vector disclosed herein, a cell disclosed herein, an antibody or antigen-binding portion disclosed herein, or a pharmaceutical composition disclosed herein. In some aspects, the cancer comprises prostate cancer. In some aspects, the prostate cancer is metastatic, recurrent, or relapsing.

[0061] Some aspects of the present disclosure are directed to the use of a polynucleotide disclosed herein, a vector disclosed herein, a cell disclosed herein, an antibody or antigen-binding portion disclosed herein, or a pharmaceutical composition disclosed herein in treating a disease or condition in a subject in need thereof. In some aspects, the disease or condition comprises cancer.

[0062] Some aspects of the present disclosure are directed to the use of a polynucleotide disclosed herein, a vector disclosed herein, a cell disclosed herein, an antibody or antigen-binding portion disclosed herein, or a pharmaceutical composition disclosed herein in treating cancer in a subject in need thereof. In some aspects, the cancer comprises prostate cancer. In some aspects, the prostate cancer is metastatic, recurrent, or relapsing. [Brief description of the drawings]

[0063] [Figure 1] [Figures 1A-1H] STEAP2 expression and localization across various tumor types according to the Human Protein Atlas database of genomes (Figure 1A), cDNA array gene expression profiling (Figure 1B) and cell surface protein expression by immunohistochemistry (IHC) with application-specific polyclonal antibodies (Figure 1C). IHC on tissue microarrays containing decalcified en face sections of primary prostate cancer, castration resistant prostate cancer (CRPC) and prostate lymph node metastases and prostate cancer bone metastases for STEAP2 membrane expression (Figure 1D), corresponding images of STEAP2 in CRPC (Figure 1E) and bone metastases (Figure 1F). Summary of STEAP2 IHC and in-situ hybridization (ISH) and scoring criteria on normal human tissue microarrays (Figure 1G). Example of STEAP2 IHC staining in normal prostate tissue (Figure 1H). [Diagram 2][Figures 2A-2F] Figure 2A shows that 40A3 scFv-Fc was tested for binding to human STEAP family members (STEAP1, 2, 3 and 4) and mouse STEAP2. 40A3 scFv-Fc affinity was calculated from EC50 values ​​for sigmoidal dose-response curves in Graph Pad Prism and converted to molar concentrations. Figures 2B-2F show the results of multiple scFv-Fc and full-length IgG1 antibodies screened for binding to antigen-positive cell lines: Ad293 STEAP3-2 (Figure 2F), Ad293 STEAP3-2 mouse (Figure 2E) and LNCAP (Figure 2C) cells and antigen-negative cell lines: Ad293 (Figure 2D) and LNCAP STEAP2 CRISPR (Figure 2B). STEAP2 expression in the LNCAP cell line "LNCAP STEAP2 CRISPR" has been ablated via CRISPR knockout, and STEAP3-2 cells are a chimeric cell line with STEAP2 extracellular loops grafted onto the backbone of the STEAP3 protein to exploit the cell surface localization of STEAP3 and further elicit an immune response against STEAP2. Figures 2B-2F show binding curves for 40A3 scFv-Fc, 40A3 IgG1 and 14N scFv, known binders for STEAP2 as positive controls and non-binding IgG1 as a negative control. Alexa fluor 647 conjugated to an anti-human Fc secondary antibody was used for detection of scFv-Fc or IgG1 binding to cells by flow cytometry. [Diagram 3][Figures 3A-3E] Figure 3A shows the CAR design including the armouring strategy. Figures 3B-3D show the untransduced (Figure 3B), 40A3Bz (Figure 3C) and 40A3Bz dnTGFβRII (Figure 3D) transduced cell populations at day 10. Figure 3E shows western blots of pSMAD 2 / 3 and total SMAD 2 / 3 as indicators of acute signalling downstream of native TGFβRII in 40A3Bz and 40A3Bz dnTGFβRII CAR-T cells. A significant abrogation of TGFβ-mediated signalling in dnTGFβRII (40A3Bz) CAR-T cells compared to 40A3Bz CAR or untransduced cells alone was confirmed (Figure 3E). [Figure 4][Figures 4A-4P] Figure 4A shows robust CAR-T expansion after transformation. Figures 4B-4E show that CD8+CAR-T cells maintain a naive / stem cell-like phenotype. Figures 4F-4K show 40A3Bz STEAP2 CAR-T cells and 40A3Bz dnTGFβRII STEAP2 CAR-T cells from the same donor cells stained for phenotypic surface markers including CD45RO / CD62L / CD70 / CD27 and analyzed using flow cytometry and FlowJo. Key = naive (CD45RO-CD62L+), central memory (CD45RO+CD62L+), effector memory (CD45RO+CD62L-) and effector (CD45RO-CD62L-). CAR = chimeric antigen receptor; dnTGFβRII = functionally inhibited transforming growth factor beta receptor II; FACS = fluorescent activated cell sorting; STEAP2 = six transmembrane epithelial antigen 2 of the prostate; TGFβ = transforming growth factor beta. Figures 4L-4N show that 40A3Bz CAR-T and 40A3Bz dnTGFβRII CAR-T cells exhibit mixed CD4:CD8 ratios. Figure 4O shows that dnTGFβRII armouring enables CAR-T activity in the presence of TGFβ, as demonstrated by C4-2 tumor cell killing. Figure 4P shows various tumor cell lines that were characterized by FACS and STEAP2 cell surface IHC assessment with anti-STEAP2 antibody-alexa fluor 647 conjugates for antibody binding capacity using Bang's Beads Low Volume Easy Cell Kit (Figure 4P, left panel). Tumor cell lines were co-cultured with 40A3Bz dnTGFβRII CAR-T cells at an E:T ratio of 1:1, and media was analyzed at 24 h for levels of IFNγ released by CAR T-cells. 40A3Bz dnTGFβRII CAR-T induced significant IFNγ release in co-culture with C4-2, LNCAP, VCAP, and 22RV1 tumor cell lines ( Figure 4P , right panel). [Diagram 5][Figures 5A-5K] Figures 5A-5B and 5D-5E show STEAP2 expression in LNCAP STEAP2 CRISPR (Figures 5D-5E) and LNCAP (Figures 5A-5B) cell populations as determined by IHC (Figures 5A and 5D) and ISH (Figures 5B and 5E). 40A3Bz dnTGFβRII CAR-T and 40A3Bz dnTGFβRII STEAP2 CAR-T cells were co-cultured with antigen-positive cell lines ("Ad293 STEAP3-2" and "LNCAP") and antigen-negative cell lines ("Ad293" cells and "LNCAP STEAP2 CRISPR" cells). Function-inhibited 40A3Bz TGFβRII STEAP2 CAR-T cells grown for 10 days in human T cell medium (AIM-V medium supplemented with 5% human AB heat-inactivated serum and 300 U / mL IL-2) were shown to kill antigen-positive target cells in a manner similar to unarmored STEAP2 CAR-T cells, as shown for LNCAP (FIG. 5C) and Ad293 STEAP3-2 (FIG. 5G) in contrast to LNCAP STEAP2 CRISPR (FIG. 5F) and Ad293 cells (FIG. 5H). Target cell killing was measured over 100 hours using the xCELLigence impedance assay. Figures 5I-5K show supernatants from the same co-culture experiment taken 24 hours after addition of CAR-T cells and cytokines (IFNγ, TNFα, and IL-2) as measured using the MSD ECL assay: TNFα (Figure 5I), IFNγ (Figure 5J), IL-2 (Figure 5K). [Figure 6] We show that the STEAP2 CAR-T constructs tested demonstrate minimal on-target and off-target activity as assessed via IFNγ secretion after 24 hours of co-culture. [Figure 7][Figures 7A-7R] Figures 7A-7C show in vivo results where unarmed STEAP2 CAR-T cells were administered at three dose levels (3 / 7 / 21 x 106 cells) via tail vein injection into NSG mice engrafted with prostate cancer cell lines. Tumors were engrafted 1:1 in Cultrex BME in the flank. Tumor volumes (Figure 7A) were measured 35 days after engraftment in mice carrying the STEAP2 high expressing cell line C4-2. Mice were randomized and administered T cells when tumors reached 175 mm3. Mouse weights (Figure 7B) were measured up to day 28 after engraftment with the C4-2 cell line. Figure 7C shows STEAP2 expression as determined by IHC in the C4-2 model. Figures 7D-7F show tumor volumes (Figure 7D) measured 53 days after engraftment in mice carrying the cell line 22RV1 with moderate STEAP2 expression. Mice were randomized and administered T cells when tumors reached 175 mm3. Mouse weights (Figure 7E) were measured up to day 50 after implantation with the 22RV1 cell line. Figure 7F shows STEAP2 expression as determined by IHC in the 22RV1 xenograft model. Figure 7G shows the results of 22RV1 tumor-bearing mice bled 4, 7, 14, and 21 days after implantation with CAR-T cells. Serum samples were analyzed using an electrochemiluminescence (ECL) assay to assess cytokine production over time in vivo. Figure 7H shows Genevestigator analysis of 40A3Bz mouse biodistribution. Figures 7I-7K show STEAP2 expression 10 days after injection as assessed via ISH, with dose-dependent focal infiltration and no signs of damage. Figures 7L-7M show no evidence of CD3+ CAR-T infiltration into nerves at the base of the heart (21e6 cell dose at harvest 10 days after infusion). Figures 7N-7O show no evidence of CD3+ CAR-T infiltration into peripheral subcutaneous nerves (21e6 cell dose at harvest 10 days after infusion). Figures 7P-7R show subcutaneous tumor sample analysis after 40A3 CAR-T cells were administered at a concentration of 8e6 and assessed at harvest 14 days after infusion. Two small intact peripheral nerves and one non-infiltrated peripheral nerve can be seen trapped within the dense CAR-T infiltrate (Figure 7P, arrows).There are also some small blood vessels with minimal to mild STEAP2 staining (Figure 7R, arrows). Despite the very dense CD3+CAR-T infiltrate, the nerves are intact and do not appear affected (Figure 7Q). [Figure 8] [Figures 8A-8I] STEAP2-armored CAR-T cells demonstrate superior persistence and differentiation profiles, including those related to cytolysis and IFN-γ production. Figure 8A shows a schematic of five rounds of sequential killing. Figure 8B shows the T cell phenotype after treatment with 40A3Bz dnTGFβRII-armored CAR-T cells, CAR-T cells not armed with 40A3Bz, and control T cells. Figure 8C shows the cytolytic activity of 40A3Bz dnTGFβRII-armored CAR-T cells, CAR-T cells not armed with 40A3Bz, and control T cells. Figure 8D shows the cytokine release of 40A3Bz dnTGFβRII-armored CAR-T cells, CAR-T cells not armed with 40A3Bz, and control T cells. Figure 8E shows the tumor volume and Figure 8F shows the body weight of mice treated with 40A3Bz dnTGFβRII-armored CAR-T, 40A3Bz-unarmored CAR-T and control T cells. Figure 8G shows the cytokine release in mice treated with 2.5e^6 40A3Bz dnTGFβRII-armored CAR-T, 40A3B-unarmored CAR-T and control T cells per mouse. Figure 8H shows the fluorescent signal in mice transplanted with C4-2 luciferase expressing tumor cells and treated with untransduced T cells, 40A3Bz dnTGFβRII-armored CAR-T or 40A3Bz-unarmored CAR-T cells. Figure 8I shows the body weight of mice measured by day 22 after transplantation with luciferase expressing C4-2 cells. [Figure 9][Figures 9A-9F] Enhanced CAR-T production increases anti-tumor activity. Figure 9A shows 40A3Bz dnTGFβRII CAR-T cells produced according to the SMART process and phenotyped at day 4 expansion compared to untransduced T cells (UT) from the same donor. Figure 9B shows tumor volume (top) and body weight (bottom) measured up to 50 days after implantation of TGFβ-overexpressing 22Rv1 tumor cells into NSG MHC class 1 class 2 knockout mice treated with 40A3Bz dnTGFβRII SMART CAR-T cells administered at four concentrations (0.3, 1, 3, 6×e6 CAR-positive cells). Figure 9C shows tumor volumes (top) and body weights (bottom) of NSG class 1 class 2 knockout mice implanted with PDX fragments from frozen stocks of CTG-3610 prostate cancer cells, randomized when tumor volumes were in the range of 125-250 mm3, and treated as in B with 0.5e6 or 5e6 40A3Bz dnTGFβRII SMART CAR-T cells compared to 5e6 UT SMART control. IHC intensity and percentage scores for membrane STEAP2 and TGFβ of CTG-3610 tumor cells are displayed. Figure 9D shows tumor volumes (top) and body weights (bottom) of NSG class 1 class 2 knockout mice implanted with PDX fragments from frozen stocks of CTG-2440 prostate cancer cells, randomized when tumor volumes were in the range of 125-250 mm3, and treated as in B with 0.5e6 or 5e6 40A3Bz dnTGFβRII SMART CAR-T cells compared to 5e6 UT SMART control. IHC intensity and percentage scores for membrane STEAP2 and TGFβ of CTG-2440 cells are displayed. Figure 9E shows tumor volume (top) and body weight (bottom) of NSG Class 1 Class 2 knockout mice implanted with PDX fragments from a frozen stock of Lucap 147 prostate cancer cells, randomized when tumor volumes were in the range of 125-250 mm3, and treated as in B with 0.5e6 or 5e6 40A3Bz dnTGFβRII SMART CAR-T cells compared to 5e6 UT SMART control.IHC intensity and percentage scores for membrane STEAP2 and TGFβ of Lucap 147 cells are displayed. Figure 9F shows tumor volume (top) and body weight (bottom) of NSG class 1 class 2 knockout mice implanted with PDX fragments from frozen stocks of Lucap 73 prostate cancer cells, randomized when tumor volumes were in the range of 125-250 mm3, and treated as in B with 0.5e6 or 5e6 40A3Bz dnTGFβRII SMART CAR-T cells compared to 5e6 UT SMART control. IHC intensity and percentage scores for membrane STEAP2 and TGFβ of Lucap 73 cells are displayed. [Figure 10] [Figures 10A-10D] Figure 10A shows tumor cell line proliferation of co-cultures of LNCAP tumor cells and 40A3Bz dnTGFβRII CAR-T cells or non-transduced T cells at an E:T ratio of 0.3:1 in the presence of blocking anti-STEAP2 antibodies (0.2, 2, 20 or 200 μg / ml). Figure 10B shows IFNγ levels determined by MSD ECL assay in the supernatants of co-cultures of LNCAP tumor cells and 40A3Bz dnTGFβRII CAR-T cells or non-transduced T cells at an E:T ratio of 0.3:1 or 1:1 in the presence of blocking anti-STEAP2 antibodies or isotype blocking antibodies (0.2, 2, 20 or 200 μg / ml). Figure 10C shows tumor cell line growth of co-cultures of LNCAP STEAP2 CRISPR tumor cells and 40A3Bz dnTGFβRII CAR-T cells or non-transduced T cells at an E:T ratio of 0.3:1 in the presence of blocking anti-STEAP2 antibodies (0.2, 2, 20 or 200 μg / ml). Figure 10D shows IFNγ levels as determined by MSD ECL assay in the supernatants of co-cultures of LNCAP STEAP2 CRISPR tumor cells and 40A3Bz dnTGFβRII CAR-T cells or non-transduced T cells at an E:T ratio of 0.3:1 or 1:1 in the presence of blocking anti-STEAP2 antibodies or isotype blocking antibodies (0.2, 2, 20 or 200 μg / ml). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0064] The present disclosure relates to an antigen-binding moiety that specifically binds to an epitope on human prostate six-transmembrane epithelial antigen-2 (STEAP2). Some aspects of the present disclosure are directed to a polynucleotide comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR), the CAR comprising an antigen-binding domain that binds to an epitope on human STEAP2. Some aspects of the present disclosure are directed to a host cell comprising the polynucleotide. Other aspects of the present disclosure are directed to an antibody or antigen-binding portion thereof that specifically binds to an epitope on human STEAP2. In some aspects, the antigen-binding domain binds to an epitope on an extracellular loop of human STEAP2. Further aspects of the present disclosure are directed to a method of treating a subject in need thereof, comprising administering a polynucleotide, a cell and / or an antibody or antigen-binding portion thereof to the subject. In some aspects, the subject is afflicted with prostate cancer or a tumor derived from prostate cancer.

[0065] I. Terminology In order that this description may be more readily understood, certain terms are defined first. Additional definitions are set forth throughout the detailed description.

[0066] It should be noted that the term "a" or "an" entity refers to one or more of that entity; for example, a "nucleotide sequence" is understood to represent one or more nucleotide sequences. Thus, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein.

[0067] Furthermore, "and / or" as used herein should be considered as a specific disclosure of each of the two particular features or components, with or without the other features or components. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (single) and "B" (single). Similarly, the term "and / or" when used in phrases such as "A, B and / or C" is intended to include each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0068] Whenever an embodiment is described herein using the term "comprising," it is understood that other similar embodiments are also provided that are described with the terms "consisting of" and / or "consisting essentially of." As used herein, the terms "comprise" and "include" and variations thereof (e.g., "comprises," "including," "includes" and "comprising") will be understood to indicate the inclusion of a stated component, feature, element or step or group of components, features, elements or steps, but not the exclusion of any other component, feature, element or step or group of components, features, elements or steps. Any of the terms "comprising," "essentially consisting of," and "consisting of" may be substituted with either of the other two terms while retaining their ordinary meaning.

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide those of ordinary skill in the art with a general dictionary of many of the terms used in this disclosure.

[0070] Units, prefixes, and symbols are written in their International System of Units (SI) accepted form. Numerical ranges include the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in a 5' to 3' orientation. Amino acid sequences are written left to right in an amino to carboxy orientation. The headings provided herein are not intended to limit the various aspects of the disclosure, which may be had by reference to the specification as a whole. Thus, the terms defined immediately below are more particularly defined by reference to the specification as a whole.

[0071] The term "about" is used herein to mean approximately, approximately, around, or within the region thereof. When the term "about" is used in conjunction with a numerical range, "about" modifies that range by extending the boundaries above and below the numerical values ​​set forth. In general, the term "about" can modify the numerical values ​​above and below the set forth value by, for example, a variance of 10 percent above or below (higher or lower).

[0072] The term "antibody" refers in some embodiments to a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH). In some antibodies, e.g., naturally occurring IgG antibodies, the heavy chain constant region is composed of a hinge and three domains, CH1, CH2 and CH3. In some antibodies, e.g., naturally occurring IgG antibodies, each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain (abbreviated herein as CL). The VH and VL regions may be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or elements, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The heavy chain may or may not have a C-terminal lysine. Unless otherwise specified herein, amino acids in the variable regions are numbered using the Kabat numbering system, and amino acids in the constant regions are numbered using the EU system.

[0073] Immunoglobulins may be from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. The IgG isotype is divided into subclasses in certain species: IgG1, IgG2, IgG3, and IgG4 in humans, and IgG1, IgG2a, IgG2b, and IgG3 in mice. In some embodiments, the antibodies described herein are of the IgG1 subtype. Immunoglobulins, such as IgG1, exist in several allotypes, which differ from each other in at most a small number of amino acids. "Antibody" includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human and non-human antibodies, as well as completely synthetic antibodies.

[0074] The term "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human STEAP2). The antigen-binding function of an antibody may be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody, such as the anti-STEAP2 antibodies described herein, include (i) Fab fragments (fragments from papain cleavage) or V L , V H (ii) a F(ab')2 fragment (a fragment resulting from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a V H and an Fd fragment consisting of the CH1 domain; (iv) a V of a single arm of an antibody. L and V H (v) Fv fragment consisting of V domains; H (vi) an isolated complementarity determining region (CDR); and (vii) a combination of two or more isolated CDRs, which may optionally be linked by a synthetic linker. In addition, the two domains of the Fv fragment, the V L and V HAlthough the V and VD are encoded by separate genes, they can be joined by a synthetic linker that allows them to be produced as a single protein chain using recombinant methods. L and V H The domains pair to form a monovalent molecule (known as a single chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.

[0075] The term "chimeric antigen receptor" or "CAR" as used herein refers to an engineered antigen-binding polypeptide comprising an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. Expression of a CAR on the surface of a cell, e.g., an immune cell, allows the cell to target and bind to a specific antigen. In some embodiments, the CAR is expressed by an immune cell, e.g., a T cell. In some embodiments, the antigen-binding domain comprises a Fab, Fab', F(ab')2, Fd, Fv, single-chain fragment variable (scFv), single-chain antibody, VHH, vNAR, nanobody (single domain antibody), or any combination thereof. In some embodiments, the transmembrane domain comprises a transmembrane domain selected from the transmembrane domains of CD4, CD8α, or CD28. In some embodiments, the intracellular domain comprises a costimulatory domain or a portion thereof. In some embodiments, the intracellular domain comprises a costimulatory domain selected from the group consisting of the intracellular domain of CD3z, CD28 costimulatory domain, CD27 costimulatory domain, 4-1BB costimulatory domain, ICOS costimulatory domain, OX-40 costimulatory domain, GITR costimulatory domain, CD2 costimulatory domain, IL-2Rβ costimulatory domain, MyD88 / CD40a CD28 costimulatory domain, and any combination thereof. The CAR may further comprise a "hinge" or "spacer" domain. Non-limiting examples of hinge / spacer domains include immunoglobulin hinge / spacer domains, such as IgG1 hinge domain and IgG2 hinge domain, IgG3 hinge domain, or IgG4 hinge domain.

[0076] As used herein, the term "armoring" refers to the molecular engineering of CAR-expressing cells (e.g., CAR-T cells) to further express one or more "armoring molecules" that can counteract immune suppression. For example, investigators have recently reported the modification of CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFvs), which improved the anti-tumor activity of CAR-T cells in mouse models of PD-L1+ hematological and solid tumors (Rafiq, S., Yeku, O., Jackson, H. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol 36, 847-856 (2018)). Other studies have demonstrated the efficacy of arming T cells with a function-inhibitory TGF-β receptor type 2 (TGFβRIIDN) arming molecule to neutralize the inhibitory effects of TGF-β on T cells (Bollard et al., Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma, J Clin Oncol 36(11):1128-1139(2018)). Currently, at least one clinical study is investigating the efficacy of arming anti-PSMA-CAR-T cells with a TGFβRIIDN arming molecule to treat castration-resistant prostate cancer (NCT03089203).

[0077] As used herein, the term "affinity" refers to a measure of the strength of binding of an antigen or target (such as an epitope) to its cognate binding domain (such as a paratope). As used herein, the term "avidity" refers to the overall stability of the complex between a population of epitopes and paratopes (i.e., antigens and antigen-binding domains).

[0078] The term "epitope" refers to a site on an antigen (e.g., STEAP2) to which a chimeric antigen receptor, immunoglobulin, or antibody specifically binds, for example, as defined by the particular method used to identify it. Epitopes can be formed both from contiguous amino acids (generally linear epitopes) or non-contiguous amino acids juxtaposed by tertiary folding of a protein (generally conformational epitopes). Epitopes formed from contiguous amino acids are typically, but not always, retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. Epitopes usually contain at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in a unique spatial conformation.

[0079] The term "binds to the same epitope," in the context of two or more antigen-binding moieties, means that the antigen-binding moieties bind to the same section of amino acid residues. An antigen-binding moiety that "competes with another antibody for binding to a target" refers to an antigen-binding moiety that inhibits (partially or completely) binding of the other antibody to the target.

[0080] As used herein, the terms "specific binding," "selective binding," "selectively binds," and "specifically binds" refer to an antigen-binding moiety (e.g., a CAR or an antibody) that binds to an epitope on a given antigen. Typically, an antigen-binding moiety (e.g., a CAR or an antibody) has (i) a binding affinity of approximately 10, as determined by, for example, surface plasmon resonance (SPR) techniques in a BIACORE® 2000 instrument using a given antigen, e.g., human STEAP2, as the analyte and an antibody as the ligand, or Scatchard analysis of the binding of the antibody to antigen-positive cells. -8 Less than M, 10 -9 Less than M or 10 -10 Less than M or less, about 10 -7 The equilibrium dissociation constant (K D) and (ii) binds to a given antigen with an affinity that is at least 2-fold greater than the affinity for binding to a non-specific antigen other than the given antigen or a closely related antigen (e.g., BSA, casein). Thus, an antigen-binding moiety (e.g., a CAR or antibody) that "specifically binds to human STEAP2" has an affinity of approximately 10 -8 Less than M, 10 -9 Less than M or 10 -10 M or less, etc., 10 -7 K below M D The term refers to an antigen-binding portion (e.g., a CAR or an antibody) that binds to human STEAP2.

[0081] A "polypeptide" refers to a chain comprising at least two contiguously linked amino acid residues, with no upper limit on the length of the chain. One or more amino acid residues in a protein may contain modifications, such as, but not limited to, glycosylation, phosphorylation, or disulfide bond formation. A "protein" may include one or more polypeptides.

[0082] The term "nucleic acid molecule" as used herein is intended to include DNA molecules and RNA molecules. A nucleic acid molecule can be single-stranded or double-stranded, and can be cDNA.

[0083] "Conservative amino acid substitution" refers to the replacement of an amino acid residue with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), amino acids with nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), amino acids with beta-branched side chains (e.g., threonine, valine, isoleucine) and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). In some aspects, a predicted non-essential amino acid residue in a STEAP2 binding moiety (e.g., an anti-STEAP2 CAR or antibody) is replaced with another amino acid residue from the same side chain family.

[0084] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = # of identical positions / total # of positions x 100) and takes into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0085] The percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at worldwideweb.gcg.com) using the NWSgapdna.CMP matrix and gap weights of 40, 50, 60, 70, or 80 and length weights of 1, 2, 3, 4, 5, or 6. The percent identity between two nucleotide or amino acid sequences may also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)), as incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Additionally, percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm as incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6.

[0086] The nucleic acid and protein sequences described herein can further be used as a "query sequence" to perform searches against public databases, for example, to identify related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12, to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See worldwideweb.ncbi.nlm.nih.gov.

[0087] The term "vector", as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, in which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomously replicating in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors"). In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" can be used interchangeably, as the plasmid is the most commonly used form of vector. However, other forms of expression vectors, such as viral vectors (eg, replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions are also included.

[0088] The term "recombinant host cell" (or simply "host cell"), as used herein, is intended to refer to a cell that contains a nucleic acid that does not naturally occur in the cell, and may be a cell into which a recombinant expression vector has been incorporated. It is understood that such terms are intended to refer not only to the particular subject cell, but to the progeny of such a cell. Because certain modifications may occur in successive generations due to either mutation or environmental influences, such progeny may not be, in fact, identical to the parent cell, but are still included within the scope of the term "host cell" as used herein.

[0089] "Immune response" as understood in the art generally refers to a biological response in a vertebrate to foreign pathogens or abnormal, e.g., cancerous, cells, which protects the organism against these pathogens and the diseases they cause. An immune response is mediated by the action of one or more cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, or neutrophils) and soluble macromolecules (including antibodies, cytokines, and complement) produced by either these cells or the liver, which result in the selective targeting, binding, damaging, destruction, and / or elimination from the vertebrate body of invading pathogens, pathogen-infected cells or tissues, cancerous or other abnormal cells, or in the case of autoimmunity or pathological inflammation, normal human cells or tissues. Immune responses include, for example, T cells, e.g., effector T cells, Th cells, CD4 T ... + cells, CD8 + This includes the activation or inhibition of T cells or Treg cells or any other cell of the immune system, such as NK cells.

[0090] "Immunotherapy" refers to the treatment of a subject afflicted with a disease or at risk of contracting a disease or at risk of recurrence of a disease by methods involving inducing, enhancing, suppressing or otherwise modifying the immune system or immune response.

[0091] As used herein, the term "linked" refers to the association of two or more molecules. Linkages can be covalent or non-covalent. Linkages can also be genetic (i.e., recombinantly fused). Such linkages can be achieved using a variety of art-recognized techniques, such as chemical conjugation and recombinant protein production.

[0092] As used herein, the terms "treat", "treatment" or "treatment of", when used in the context of cancer treatment, refer to alleviating disease pathology, reducing or eliminating disease symptoms, promoting increased survival and / or reducing discomfort. For example, treatment can refer to the ability of a therapy to alleviate symptoms, signs or causes of a disease when administered to a subject. Treatment also refers to alleviating or reducing at least one clinical symptom and / or inhibiting or slowing the progression of a pathological condition and / or preventing or delaying the onset of a disease or condition.

[0093] As used herein, "cancer" refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division can lead to the formation of malignant tumors or cells that can invade adjacent tissues and metastasize to distant parts of the body via the lymphatic system or bloodstream.

[0094] As used herein, the term "effective amount" or "therapeutically effective amount" of an administered therapeutic agent, e.g., CAR-T cells, is an amount sufficient to carry out a specifically stated or intended purpose, such as treating or curing cancer. An "effective amount" can be determined based on routine experimentation for the stated purpose.

[0095] As used herein, the terms "subject," "individual," or "patient" refer to any subject for which diagnosis, prognosis, or treatment is desired, particularly mammalian subjects. Mammalian subjects include, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, bears, etc.

[0096] As used herein, the terms "ug" and "uM" are used interchangeably with "μg" and "μM," respectively.

[0097] The various aspects described herein are described in further detail in the subsections below.

[0098] I. Polynucleotides of the Disclosure Some aspects of the present disclosure are directed to a polynucleotide comprising a nucleotide sequence encoding a CAR that specifically binds to human STEAP2. In some aspects, the CAR comprises (i) an antigen-binding domain that binds to an epitope on STEAP2, (ii) a transmembrane domain, and (iii) an intracellular domain. In some aspects, the CAR further comprises a hinge / spacer domain. In some aspects, the hinge / spacer domain is disposed between the antigen-binding domain and the transmembrane domain.

[0099] In some embodiments, the polynucleotide further comprises a nucleotide sequence encoding an armoring molecule. In some embodiments, the nucleotide sequence encoding the CAR and the nucleotide sequence encoding the armoring portion are expressed under the control of the same promoter. In some embodiments, the nucleotide sequence encoding the CAR and the nucleotide sequence encoding the armoring portion are expressed under the control of two promoters. In some embodiments, the two promoters are different promoters. In some embodiments, the nucleotide sequence encoding the CAR and the nucleotide sequence encoding the armoring portion are expressed as a single continuous polypeptide. In some embodiments, the nucleotide sequence encoding the CAR and the nucleotide sequence encoding the armoring portion are expressed as two separate polypeptides. In some embodiments, the nucleotide sequence encoding the CAR and the armoring portion are linked by a nucleotide sequence encoding a linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker is a self-cleaving peptide linker, including, for example, a T2A peptide.

[0100] IA antigen-binding domain Disclosed herein is a polynucleotide comprising a nucleotide sequence encoding a CAR, the CAR comprising (i) an antigen-binding domain that binds to an epitope on human STEAP2, (ii) an intracellular signaling domain, and (iii) a transmembrane domain. Any antigen-binding domain may be used in the compositions disclosed herein. In some aspects, the antigen-binding domain comprises a Fab, Fab', F(ab')2, Fd, Fv, single-chain fragment variable (scFv), single-chain antibody, VHH, vNAR, nanobody (single domain antibody), or any combination thereof. In some aspects, the antigen-binding domain comprises a scFv.

[0101] In some embodiments, the antigen binding domain of the CAR comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH complementarity determining region (CDR)1, a VH-CDR2, a VH-CDR3; and the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3. In some embodiments, the antigen binding domain comprises a VH-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 6, 16, 26, 36, 46, and 96. In some embodiments, the antigen binding domain comprises a VH-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 5, 15, 25, 35, 45, and 95. In some embodiments, the antigen binding domain comprises a VH-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 4, 14, 24, 34, 44, and 94.

[0102] In some embodiments, the antigen binding domain comprises a VL-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 3, 13, 23, 33, 43, and 93. In some embodiments, the antigen binding domain comprises a VL-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 2, 12, 22, 32, 42, and 92. In some embodiments, the antigen binding domain comprises a VL-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 1, 11, 21, 31, 41, and 91.

[0103] In some embodiments, the antigen-binding domain comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6.

[0104] In some embodiments, the antigen-binding domain comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0105] In some embodiments, the antigen-binding domain comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:22, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:23, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:24, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:25, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:26.

[0106] In some embodiments, the antigen-binding domain comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36.

[0107] In some embodiments, the antigen-binding domain comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0108] In some embodiments, the antigen-binding domain comprises VL-CDR1, VL-CDR2 and VL-CDR3 present in a VL region having the amino acid sequence set forth in SEQ ID NO:58; and VH-CDR1, VH-CDR2 and VH-CDR3 present in a VH region having the amino acid sequence set forth in SEQ ID NO:57.

[0109] In some embodiments, the antigen-binding domain comprises VL-CDR1, VL-CDR2 and VL-CDR3 present in a VL region having the amino acid sequence set forth in SEQ ID NO:68; and VH-CDR1, VH-CDR2 and VH-CDR3 present in a VH region having the amino acid sequence set forth in SEQ ID NO:67.

[0110] In some embodiments, the antigen-binding domain comprises VL-CDR1, VL-CDR2 and VL-CDR3 present in a VL region having the amino acid sequence set forth in SEQ ID NO:78; and VH-CDR1, VH-CDR2 and VH-CDR3 present in a VH region having the amino acid sequence set forth in SEQ ID NO:77.

[0111] In some embodiments, the antigen-binding domain comprises VL-CDR1, VL-CDR2 and VL-CDR3 present in a VL region having the amino acid sequence set forth in SEQ ID NO:88; and VH-CDR1, VH-CDR2 and VH-CDR3 present in a VH region having the amino acid sequence set forth in SEQ ID NO:87.

[0112] In some embodiments, the antigen-binding domain comprises VL-CDR1, VL-CDR2 and VL-CDR3 present in a VL region having the amino acid sequence set forth in SEQ ID NO:98; and VH-CDR1, VH-CDR2 and VH-CDR3 present in a VH region having the amino acid sequence set forth in SEQ ID NO:97.

[0113] In some embodiments, the CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, and 97. In some embodiments, the antigen binding domain comprises a VH comprising an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, and 97.

[0114] In some embodiments, the CAR comprises an antigen binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48, 58, 68, 78, 88, and 98. In some embodiments, the antigen binding domain comprises a VL comprising an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48, 58, 68, 78, 88, and 98.

[0115] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0116] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18.

[0117] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 27, and a VL comprising the amino acid sequence set forth in SEQ ID NO:28.

[0118] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 38. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 37, and a VL comprising the amino acid sequence set forth in SEQ ID NO:38.

[0119] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 48. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 47, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 48.

[0120] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 57, and a VL comprising the amino acid sequence set forth in SEQ ID NO:58.

[0121] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 67, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 67, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 68.

[0122] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 77, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 78. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 77, and a VL comprising the amino acid sequence set forth in SEQ ID NO: 78.

[0123] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 87, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 87, and a VL comprising the amino acid sequence set forth in SEQ ID NO:88.

[0124] In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98. In some embodiments, a CAR comprises an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97, and a VL comprising the amino acid sequence set forth in SEQ ID NO:98.

[0125] In some embodiments, a CAR comprises an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, a CAR comprises an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9.

[0126] In some embodiments, a CAR comprises an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 99. In some embodiments, a CAR comprises an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:99.

[0127] IB intracellular domain Disclosed herein is a polynucleotide comprising a nucleotide sequence encoding a CAR, the CAR comprising (i) an antigen-binding domain that binds to an epitope on human STEAP2, (ii) an intracellular signaling domain, and (iii) a transmembrane domain. Any intracellular signaling domain may be used in the compositions disclosed herein. In some aspects, the intracellular signaling domain comprises a co-stimulatory domain or a portion thereof.

[0128] In some embodiments, the intracellular domain comprises a costimulatory domain selected from the group consisting of an intracellular domain of CD3z, a CD28 costimulatory domain, a CD27 costimulatory domain, a 4-1BB costimulatory domain, an ICOS costimulatory domain, an OX-40 costimulatory domain, a GITR costimulatory domain, a CD2 costimulatory domain, an IL-2Rβ costimulatory domain, a MyD88 / CD40a CD28 costimulatory domain, and any combination thereof.

[0129] In some embodiments, the intracellular domain comprises a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen-binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; and (ii) a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and (ii) a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. , at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130; and (ii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8; and (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0130] In some embodiments, a CAR comprises (i) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9; and (ii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, a CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO: 9; and (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0131] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a CD28 costimulatory domain. In some embodiments, the CAR comprises (i) an antigen-binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; and (ii) an intracellular domain of CD3z and a CD28 costimulatory domain. In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. and (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131, and a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133.

[0132] In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; and (ii) an antigen-binding domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131. The CAR comprises an intracellular domain of CD3z comprising an amino acid sequence having about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity, and a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% to the amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO: 9; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133.

[0133] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; and (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. and (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131, and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130.

[0134] In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; and (ii) an antigen-binding domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131. The CAR comprises an intracellular domain of CD3z comprising an amino acid sequence having about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity, and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% to the amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO: 9; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0135] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; and (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain.In some embodiments, the CAR comprises an antigen-binding domain comprising: (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; and (ii) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131. %, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% to the amino acid sequence set forth in SEQ ID NO:130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130.

[0136] In some embodiments, the CAR comprises: (i) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; and (ii) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131. The intracellular domain comprises a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133, and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130.

[0137] In some embodiments, the intracellular domain comprises a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen-binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; and (ii) a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:17, and (ii) a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:18. %, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130; and (ii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; and (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0138] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a CD28 costimulatory domain. In some embodiments, the CAR comprises (i) an antigen-binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; and (ii) an intracellular domain of CD3z and a CD28 costimulatory domain. In some embodiments, the CAR comprises an antigen-binding domain comprising: (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18. and (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131, and a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133.

[0139] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen-binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; and (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises an antigen-binding domain comprising: (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18. and (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131, and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0140] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; and (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain.In some embodiments, the CAR comprises an antigen-binding domain comprising: (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; and (ii) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131. the intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and the 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0141] In some embodiments, the intracellular domain comprises a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and (ii) a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97; and (ii) a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:98. 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; and (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; and (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0142] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a CD28 costimulatory domain. In some embodiments, the CAR comprises (i) an antigen-binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and (ii) an intracellular domain of CD3z and a CD28 costimulatory domain. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98; and and (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131, and a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133.

[0143] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises an antigen-binding domain comprising (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:98. and (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131, and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0144] In some embodiments, the intracellular domain comprises an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain. In some embodiments, the CAR comprises an antigen binding domain comprising: (i) a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; and (ii) an antigen binding domain comprising 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131. the intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; and the 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130.In some embodiments, the CAR comprises an antigen-binding domain comprising: (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98; and (ii) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131. the intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and the 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; and (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130.

[0145] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO: 10.

[0146] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO: 108.

[0147] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 109. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO: 109.

[0148] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 110. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO: 110.

[0149] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 111. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO:111.

[0150] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO:112.

[0151] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 113. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO:113.

[0152] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO:114.

[0153] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO: 115.

[0154] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 116. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO:116.

[0155] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 118. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO:118.

[0156] In some embodiments, a CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 119. In some embodiments, a CAR comprises the amino acid sequence set forth in SEQ ID NO:119.

[0157] IC transmembrane domain Disclosed herein is a polynucleotide comprising a nucleotide sequence encoding a CAR, the CAR comprising (i) an antigen-binding domain that binds to an epitope on human STEAP2, (ii) an intracellular signaling domain, and (iii) a transmembrane domain. Any transmembrane domain may be used in the compositions disclosed herein. In some aspects, the transmembrane domain comprises a transmembrane domain selected from the transmembrane domains of CD4, CD8α, or CD28. In some aspects, the transmembrane domain comprises a CD28 transmembrane domain.

[0158] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28. In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. (ii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129.

[0159] In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; (ii) an antigen-binding domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, and (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO: 9; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0160] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) an intracellular domain of CD3z and a CD28 costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; (ii) an antigen binding domain comprising a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131; and (iii) an intracellular domain of CD3z comprising an amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and (iv) a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129.

[0161] In some embodiments, a CAR comprises: (i) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9; (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; and (iii) a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; and (iv) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129.

[0162] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; (ii) an antigen binding domain comprising a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131; and (iii) an intracellular domain of CD3z comprising an amino acid sequence having at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iv) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129.

[0163] In some embodiments, the CAR comprises: (i) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131. domain and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129.

[0164] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and (ii) a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 100%, at least about 15 ... (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and a CD28 costimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:130. and (iii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129.

[0165] In some embodiments, the CAR comprises: (i) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131; 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iii) a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iv) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% to the amino acid sequence set forth in SEQ ID NO:129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129.

[0166] In some embodiments, the CAR comprises (i) an antigen-binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28. In some embodiments, the CAR comprises an antigen-binding domain comprising: (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18. (ii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0167] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) an intracellular domain of CD3z and a CD28 costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; (ii) an antigen-binding domain comprising an VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% and (iii) a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and (iv) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0168] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; (ii) an antigen-binding domain comprising an VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% and (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iv) an intracellular domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0169] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:17, and (ii) a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 100%, at least about 15 ... (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a CD28 co-stimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and a CD28 co-stimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 100%, at least about 150%, at least about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:130. and (iii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0170] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28. In some embodiments, the CAR comprises an antigen-binding domain comprising (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:98. (ii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0171] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) an intracellular domain of CD3z and a CD28 costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98; (ii) an antigen binding domain comprising an VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% and (iii) a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and (iv) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0172] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98; (ii) an antigen binding domain comprising an VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% and (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; and (iv) an intracellular domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0173] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain; and (iii) a transmembrane domain comprising the transmembrane domain of CD28.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97; and (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a CD28 co-stimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; and a CD28 co-stimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 100%, at least about 150%, at least about 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:130. and (iii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; and (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129.

[0174] In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 109. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 110. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 111. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 113. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 116. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 118. In some embodiments, the CAR comprises the amino acid sequence set forth in SEQ ID NO: 119.

[0175] ID spacer / hinge domain Disclosed herein is a polynucleotide comprising a nucleotide sequence encoding a CAR, the CAR comprising (i) an antigen binding domain that binds to an epitope on human STEAP2, (ii) an intracellular signaling domain, (iii) a transmembrane domain, and (iv) a hinge / spacer domain. Any hinge / spacer domain may be used in the compositions disclosed herein. In some aspects, the hinge / spacer domain comprises a human immunoglobulin hinge / spacer domain. In some aspects, the hinge / spacer domain comprises an IgG hinge domain. In some aspects, the hinge / spacer domain comprises an IgG1 hinge domain and an IgG2 hinge domain, an IgG3 hinge domain, or an IgG4 hinge domain. In some aspects, the hinge / spacer domain comprises an IgG4 hinge domain. In some aspects, the IgG hinge domain is a variant hinge domain. In some aspects, the IgG4 hinge domain is a variant IgG4 hinge domain. In some embodiments, the variant IgG4 hinge domain comprises a S228P mutation. In some embodiments, the IgG4 hinge domain comprises the amino acid sequence set forth in SEQ ID NO: 128.

[0176] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; (ii) an antigen binding domain comprising a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:130; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO:128.

[0177] In some embodiments, the CAR comprises: (i) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; (ii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130. (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO: 9; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128.

[0178] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) an intracellular domain of CD3z and a CD28 costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; (iii) a CD28 costimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO:131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO:133; (iii) a transmembrane comprising the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO:128.

[0179] In some embodiments, the CAR comprises: (i) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131; and %, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% to the amino acid sequence set forth in SEQ ID NO:128. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z and a CD28 costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.

[0180] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a main and a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130; (iii) a 4-1BB costimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129; , at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.

[0181] In some embodiments, the CAR comprises: (i) an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131; and %, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% to the amino acid sequence set forth in SEQ ID NO:128. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.

[0182] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8;(ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain;

[0183] In some embodiments, a CAR comprises: (i) an antigen-binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; (ii) an antigen-binding domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:131; an intracellular domain of CD3z comprising an amino acid sequence having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:133; (iii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129; %, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128.In some embodiments, the CAR comprises (i) an antigen binding domain comprising the amino acid sequence set forth in SEQ ID NO:9; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.

[0184] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; (ii) an antigen binding domain comprising an VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 128. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 131; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128.

[0185] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) an intracellular domain of CD3z and a CD28 costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:17, and (ii) a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 100%, at least about 15 ... (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; (iii) a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; (iv) a CD28 costimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129; , at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128.

[0186] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:17, and (ii) a VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 100%, at least about 15 ... (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; (iii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:130; (iv) a 4-1BB costimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; , at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.

[0187] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18;(ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129;and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128.

[0188] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98; (ii) an antigen binding domain comprising an VH comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 90% (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 128. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128.

[0189] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) an intracellular domain of CD3z and a CD28 costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97; and (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; (iii) a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; (iv) a CD28 costimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129; , at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133; (iii) a transmembrane domain comprising the transmembrane domain of CD28 comprising the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128.

[0190] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) an intracellular domain of CD3z and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain.In some embodiments, the CAR comprises (i) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97; and (ii) an antigen-binding domain comprising a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; (iii) a 4-1BB costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 130; (iv) a 4-1BB costimulatory domain comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 129; (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128.In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131 and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129; and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128.

[0191] In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain, and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98;(ii) an intracellular domain of CD3z comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 131; a CD28 costimulatory domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 133; (iii) a transmembrane domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:129; and (iv) an IgG hinge domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:128. In some embodiments, the CAR comprises: (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) an intracellular domain of CD3z comprising the amino acid sequence set forth in SEQ ID NO: 131, a CD28 costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 133, and a 4-1BB costimulatory domain comprising the amino acid sequence set forth in SEQ ID NO: 130; (iii) a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO: 129;and (iv) an IgG hinge domain comprising the amino acid sequence set forth in SEQ ID NO: 128. In some embodiments, the CAR comprises (i) an antigen binding domain comprising a VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 98; (ii) an intracellular domain of CD3z, a CD28 costimulatory domain and a 4-1BB costimulatory domain; (iii) a transmembrane domain comprising the transmembrane domain of CD28; and (iv) an IgG hinge domain;

[0192] In some embodiments, the nucleotide sequence encoding a CAR has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 101. In some embodiments, the nucleotide sequence encoding a CAR comprises the nucleotide sequence set forth in SEQ ID NO:101.

[0193] In some embodiments, the nucleotide sequence encoding a CAR has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 102. In some embodiments, the nucleotide sequence encoding a CAR comprises the nucleotide sequence set forth in SEQ ID NO:102.

[0194] In some embodiments, the nucleotide sequence encoding a CAR has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 103. In some embodiments, the nucleotide sequence encoding a CAR comprises the nucleotide sequence set forth in SEQ ID NO:103.

[0195] IE Armoring Molecule Disclosed herein is a polynucleotide comprising (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen-binding domain that binds to an epitope on human STEAP2), and (b) a nucleotide sequence encoding an armoring molecule. One approach to making CAR-T cells more resistant to tumor-associated immune suppression is called "armoring". Armoring is the molecular engineering of CAR-T cells to express one or more "armoring molecules" that can counteract immune suppression. For example, investigators have reported modification of CAR-T cells to secrete a PD-1-blocking single-chain variable fragment (scFv), which improved the anti-tumor activity of CAR-T cells in mouse models of PD-1+ hematological and solid tumors (Rafiq, S., Yeku, O., Jackson, H. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol 36, 847-856 (2018)). Other studies have demonstrated the efficacy of arming T cells with a function-inhibitory TGF-β receptor type 2 (TGFβRIIDN) arming molecule to neutralize the inhibitory effects of TGF-β on T cells (Bollard et al., Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma, J Clin Oncol 36(11):1128-1139(2018)). Currently, at least one clinical study is investigating the efficacy of arming anti-PSMA-CAR-T cells with a TGFβRIIDN arming molecule (NCT03089203) to treat castration-resistant prostate cancer.

[0196] In some embodiments, the Armouring molecule comprises a functionally inhibited TGF-β receptor type 2 (TGFβRIIDN). In some embodiments, the Armouring molecule comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105. In some embodiments, the Armouring molecule comprises the amino acid sequence set forth in SEQ ID NO: 105.

[0197] In some aspects, the polynucleotide comprises (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6); and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6); and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6); and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0198] In some aspects, the polynucleotide comprises (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16); and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16); and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105. In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16); and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0199] In some aspects, the polynucleotide comprises (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96); and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96); and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105. In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96); and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0200] In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and (b) an antigen-binding domain comprising a VL comprising an amino acid sequence having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105; and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105.In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, the CAR comprising an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0201] In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17; and (b) an antigen-binding domain comprising a VL having an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105.In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, the CAR comprising an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0202] In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 97, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 98; and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97; and (b) an antigen-binding domain comprising a VL having an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105.In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, the CAR comprising an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:98; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0203] In some embodiments, the Armouring molecule comprises a functionally inhibited TGF-β receptor type 2 (TGFβRIIDN). In some embodiments, the Armouring molecule comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105. In some embodiments, the Armouring molecule comprises the amino acid sequence set forth in SEQ ID NO: 105.

[0204] In some aspects, the polynucleotide comprises (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6); and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6); and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6); and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0205] In some aspects, the polynucleotide comprises (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16); and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16); and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105. In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR (the CAR comprises an antigen binding domain comprising a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16); and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0206] In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and (b) an antigen-binding domain comprising a VL comprising an amino acid sequence having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105; and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105.In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, the CAR comprising an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0207] In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17; and (b) an antigen-binding domain comprising a VL having an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 105.In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, the CAR comprising an antigen binding domain comprising a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0208] In some embodiments, the polynucleotide comprises (a) a nucleotide sequence encoding a CAR, wherein the CAR comprises an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:99; and (b) a nucleotide sequence encoding a TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, the CAR comprising an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:99; and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR, the CAR comprising an antigen binding domain comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 99; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0209] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:10; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:10; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:10; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0210] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 108; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:108; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:108; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0211] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 109; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:109; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:109; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0212] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:110; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:110; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:110; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0213] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:111; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:111; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:111; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0214] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:112; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:112; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:112; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0215] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:113; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:113; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:113; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0216] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:114; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:114; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:114; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0217] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:115; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:115; and (b) an armoring molecule comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:115; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0218] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:116; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:116; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:116; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0219] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98% or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:118; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:118; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:118; and (b) an armoring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0220] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:119; and (b) a nucleotide sequence encoding TGFβRIIDN. In some embodiments, the polynucleotide comprises an Armouring molecule comprising: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:119; and (b) an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:105. In some embodiments, the polynucleotide comprises: (a) a nucleotide sequence encoding an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:119; and (b) an Armouring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0221] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR comprising the nucleotide sequence set forth in SEQ ID NO:101; and (b) a nucleotide sequence encoding an Armouring molecule comprising the nucleotide sequence set forth in SEQ ID NO:104.

[0222] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR comprising the nucleotide sequence set forth in SEQ ID NO: 102; and (b) a nucleotide sequence encoding an Armouring molecule comprising the nucleotide sequence set forth in SEQ ID NO: 104.

[0223] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR comprising the nucleotide sequence set forth in SEQ ID NO: 103; and (b) a nucleotide sequence encoding an Armouring molecule comprising the nucleotide sequence set forth in SEQ ID NO: 104.

[0224] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR comprising the nucleotide sequence set forth in SEQ ID NO:101; and (b) a nucleotide sequence encoding an Armouring molecule comprising the amino acid sequence set forth in SEQ ID NO:105.

[0225] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR comprising the nucleotide sequence set forth in SEQ ID NO: 102; and (b) a nucleotide sequence encoding an Armouring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0226] In some aspects, the polynucleotide comprises: (a) a nucleotide sequence encoding a CAR comprising the nucleotide sequence set forth in SEQ ID NO: 103; and (b) a nucleotide sequence encoding an Armouring molecule comprising the amino acid sequence set forth in SEQ ID NO: 105.

[0227] In some embodiments, the nucleotides encoding the CAR and the nucleotides encoding the Armouring molecule are linked by a third nucleotide sequence, which encodes a cleavable peptide linker. In some embodiments, the cleavable peptide linker comprises a T2A peptide. In some embodiments, the cleavable peptide linker comprises SEQ ID NO: 126.

[0228] In some embodiments, the polynucleotide comprises a nucleotide sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 107. In some embodiments, the polynucleotide comprises the nucleotide sequence set forth in SEQ ID NO:107.

[0229] II. Anti-STEAP2 Antibodies of the Present Disclosure Some aspects of the disclosure are directed to an antibody or antigen-binding portion thereof that specifically binds to human STEAP2. In some aspects, the antibody or antigen-binding portion thereof comprises a variable heavy chain region (VH) and a variable light chain region (VL), where the VH comprises a VH complementarity Determining Region (CDR)1, a VH-CDR2, a VH-CDR3; and the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3. In some aspects, the antibody or antigen-binding portion thereof comprises a VH-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 6, 16, 26, 36, 46, and 96. In some aspects, the antibody or antigen-binding portion thereof comprises a VH-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 5, 15, 25, 35, 45, and 95. In some aspects, the antibody or antigen-binding domain thereof comprises a VH-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 4, 14, 24, 34, and 44 and 94.

[0230] In some embodiments, the antibody, or antigen-binding portion thereof, comprises a VL-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 3, 13, 23, 33, 43, and 93. In some embodiments, the antibody, or antigen-binding portion thereof, comprises a VL-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 2, 12, 22, 32, 42, and 92. In some embodiments, the antibody, or antigen-binding portion thereof, comprises a VL-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 1, 11, 21, 31, 41, and 91.

[0231] In some embodiments, the antibody or antigen-binding portion thereof comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6.

[0232] In some embodiments, the antibody or antigen-binding portion thereof comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:11, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:12, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:13, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:14, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:15, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:16.

[0233] In some embodiments, the antibody or antigen-binding portion thereof comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:21, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:22, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:23, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:24, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:25, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:26.

[0234] In some embodiments, the antibody or antigen-binding portion thereof comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:33, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO:35, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:36.

[0235] In some embodiments, the antibody or antigen-binding portion thereof comprises a VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, a VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, a VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.

[0236] In some embodiments, the antibody or antigen-binding portion thereof comprises a VL-CDR1, a VL-CDR2 and a VL-CDR3 present in a VL region having the amino acid sequence set forth in SEQ ID NO:58; and a VH-CDR1, a VH-CDR2 and a VH-CDR3 present in a VH region having the amino acid sequence set forth in SEQ ID NO:57.

[0237] In some embodiments, the antibody or antigen-bindin...

Claims

1. A polynucleotide comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR), the CAR comprising: (i) an antigen-binding domain that binds to an epitope on human prostate six-transmembrane epithelial antigen-2 (STEAP2); (ii) a transmembrane domain; and (iii) intracellular domain A polynucleotide comprising:

2. The polynucleotide of claim 1 , wherein the antigen-binding domain binds to an epitope on an extracellular loop of human STEAP2.

3. The antigen-binding domain can be Fab, Fab', F(ab'), Fd, Fv, single chain fragment variable (scFv), single chain antibody, V Ｈ 2. The polynucleotide of claim 1, comprising a H, a vNAR, a nanobody (single domain antibody), or any combination thereof.

4. The polynucleotide of claim 3 , wherein the antigen-binding domain comprises an scFv.

5. The polynucleotide of claim 1, wherein the antigen-binding domain comprises a variable heavy chain region (VH) and a variable light chain region (VL), wherein the VH comprises a VH complementarity-determining region (CDR) 1, a VH-CDR2, and a VH-CDR3; and the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3.

6. The polynucleotide of claim 5, wherein the antigen-binding domain comprises a VH-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 6, 16, 26, 36, 46 and 96.

7. The polynucleotide of claim 5, wherein the antigen-binding domain comprises a VH-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 5, 15, 25, 35, 45 and 95.

8. The polynucleotide of claim 5, wherein the antigen-binding domain comprises a VH-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 4, 14, 24, 34, 44 and 94.

9. The polynucleotide of claim 5, wherein the antigen-binding domain comprises a VL-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 3, 13, 23, 33, 43 and 93.

10. The polynucleotide of claim 5, wherein the antigen-binding domain comprises a VL-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 2, 12, 22, 32, 42 and 92.

11. The polynucleotide of claim 5, wherein the antigen-binding domain comprises a VL-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 1, 11, 21, 31, 41 and 91.

12. The antigen-binding domain comprises: (a) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15, VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 22, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 23, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 25, VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26; (d) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36; (e) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; or (f) VL-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 91, VL-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 92, VL-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 93, VH-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94, VH-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95, VH-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96 The polynucleotide of claim 1, comprising:

13. 13. The polynucleotide of claim 12, wherein the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47, and 97.

14. The polynucleotide of claim 12 , wherein the antigen-binding domain comprises a VH comprising an amino acid sequence selected from SEQ ID NOs: 7, 17, 27, 37, 47 and 97.

15. 13. The polynucleotide of claim 12, wherein the antigen-binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48, and 98.

16. The polynucleotide of claim 12 , wherein the antigen-binding domain comprises a VL comprising an amino acid sequence selected from SEQ ID NOs: 8, 18, 28, 38, 48 and 98.

17. The antigen-binding domain comprises: (a) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8; (b) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 17, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 18; (c) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28; (d) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 38; (e) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 48; or (f) a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity with the amino acid sequence set forth in SEQ ID NO: 97; and a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity with the amino acid sequence set forth in SEQ ID NO:

98. The polynucleotide of claim 12, comprising:

18. The polynucleotide of claim 1, wherein the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

57.

19. The polynucleotide of claim 18, wherein the antigen-binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

58.

20. The polynucleotide of claim 1, wherein the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

67.

21. The polynucleotide of claim 20, wherein the antigen-binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

68.

22. The polynucleotide of claim 1, wherein the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

77.

23. The polynucleotide of claim 22, wherein the antigen-binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

78.

24. The polynucleotide of claim 1, wherein the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

87.

25. The polynucleotide of claim 24, wherein the antigen-binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

88.

26. The polynucleotide of claim 1, wherein the antigen-binding domain comprises a VH comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

97.

27. 27. The polynucleotide of claim 26, wherein the antigen-binding domain comprises a VL comprising an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

98.

28. The antigen-binding domain comprises: (a) a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8; (b) a VH comprising the amino acid sequence set forth in SEQ ID NO: 17 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 18; (c) a VH comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 28; (d) a VH comprising the amino acid sequence set forth in SEQ ID NO: 37 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 38; (e) a VH comprising the amino acid sequence set forth in SEQ ID NO: 47 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 48; (f) a VH comprising the amino acid sequence set forth in SEQ ID NO: 57 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 58; (g) a VH comprising the amino acid sequence set forth in SEQ ID NO: 67 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 68; (h) VH comprising the amino acid sequence set forth in SEQ ID NO: 77 and VL comprising the amino acid sequence set forth in SEQ ID NO: 78; (i) a VH comprising the amino acid sequence set forth in SEQ ID NO: 87 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 88; or (j) VH comprising the amino acid sequence set forth in SEQ ID NO: 97 and VL comprising the amino acid sequence set forth in SEQ ID NO: 98 The polynucleotide of claim 1, comprising:

29. The polynucleotide of claim 1, wherein the antigen-binding domain comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

9.

30. 2. The polynucleotide of claim 1, wherein the antigen-binding domain comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

99.

31. The polynucleotide of claim 12 , wherein the intracellular domain comprises a costimulatory domain or a portion thereof.

32. 32. The polynucleotide of claim 31, wherein the intracellular domain comprises a costimulatory domain selected from the group consisting of an intracellular domain of CD3z, a CD28 costimulatory domain, a CD27 costimulatory domain, a 4-1BB costimulatory domain, an ICOS costimulatory domain, an OX-40 costimulatory domain, a GITR costimulatory domain, a CD2 costimulatory domain, an IL-2Rβ costimulatory domain, a MyD88 / CD40a CD28 costimulatory domain, and any combination thereof.

33. The polynucleotide of claim 32, wherein the intracellular domain comprises a 4-1BB costimulatory domain.

34. The polynucleotide of claim 32, wherein the intracellular domain comprises the intracellular domain of CD3z and the CD28 costimulatory domain.

35. The polynucleotide of claim 32, wherein the intracellular domain comprises an intracellular domain of CD3z comprising SEQ ID NO: 131 and a 4-1BB costimulatory domain comprising SEQ ID NO:

130.

36. The polynucleotide of claim 35, wherein the intracellular domain comprises the intracellular domain of CD3z, the CD28 costimulatory domain, and the 4-1BB costimulatory domain.

37. 13. The polynucleotide of claim 12, wherein the transmembrane domain comprises a transmembrane domain selected from the transmembrane domains of CD4, CD8α, or CD28.

38. 38. The polynucleotide of claim 37, wherein the transmembrane domain comprises the transmembrane domain of CD28 and comprises SEQ ID NO:

129.

39. The polynucleotide of claim 12, wherein the CAR further comprises a hinge / spacer domain.

40. 40. The polynucleotide of claim 39, wherein the hinge / spacer domain comprises an immunoglobulin hinge / spacer.

41. 41. The polynucleotide of claim 40, wherein the hinge / spacer domain comprises an IgG hinge domain.

42. 42. The polynucleotide of claim 41 , wherein the hinge / spacer domain comprises an IgG1 hinge domain, an IgG2 hinge domain, an IgG3 hinge domain, or an IgG4 hinge domain.

43. 43. The polynucleotide of claim 42, wherein the hinge / spacer domain comprises an IgG4 hinge domain and comprises SEQ ID NO:

128.

44. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

10.

45. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

108.

46. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

109.

47. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

110.

48. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

111.

49. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

112.

50. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

113.

51. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

114.

52. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

115.

53. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

116.

54. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

118.

55. 2. The polynucleotide of claim 1, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

119.

56. The polynucleotide of claim 12, further encoding an armoring molecule, which, when expressed on the surface of a cell, counters immune suppression of the cell in the tumor microenvironment.

57. 57. The polynucleotide of claim 56, wherein the armoring molecule comprises a function-inhibiting TGF-β receptor type 2 (TGFβRIIDN).

58. The polynucleotide of claim 57, wherein the armoring molecule comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

105.

59. 59. The polynucleotide of claim 58, wherein the armoring molecule comprises the amino acid sequence set forth in SEQ ID NO:

105.

60. 60. The polynucleotide of claim 59, wherein the nucleotide sequence encoding the CAR has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 101 or 103.

61. 61. The polynucleotide of Claim 60, wherein the nucleotide sequence encoding the CAR comprises the nucleotide sequence set forth in SEQ ID NO: 101 or 103.

62. 62. The polynucleotide of claim 61, further comprising a second nucleotide sequence encoding an Armoring molecule, wherein the second nucleotide sequence has 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO:

104.

63. 63. The polynucleotide of claim 62, wherein the second nucleotide comprises the nucleotide sequence set forth in SEQ ID NO:

104.

64. 64. The polynucleotide of Claim 63, wherein the nucleotide sequence encoding the CAR comprises the nucleotide sequence set forth in SEQ ID NO: 101, and the second nucleotide sequence comprises the nucleotide sequence set forth in SEQ ID NO:

104.

65. 64. The polynucleotide of Claim 63, wherein the nucleotide sequence encoding the CAR comprises the nucleotide sequence set forth in SEQ ID NO: 103, and the second nucleotide sequence comprises the nucleotide sequence set forth in SEQ ID NO:

104.

66. 57. The polynucleotide of Claim 56, wherein the nucleotide sequence encoding the CAR and the second nucleotide sequence are linked by a third nucleotide sequence, wherein the third nucleotide sequence encodes a cleavable peptide linker.

67. 67. The polynucleotide of claim 66, wherein the cleavable peptide linker is a self-cleaving peptide linker.

68. 68. The polynucleotide of claim 67, wherein the cleavable peptide linker comprises a T2A peptide.

69. 69. The polynucleotide of claim 68, wherein the cleavable peptide linker comprises SEQ ID NO:

126.

70. 13. The polynucleotide of claim 12, comprising a nucleotide sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the nucleotide sequence set forth in SEQ ID NO:

107.

71. 71. The polynucleotide of claim 70, comprising the nucleotide sequence set forth in SEQ ID NO:

107.

72. 13. The polynucleotide of claim 12, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

117.

73. 73. The polynucleotide of claim 72, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

117.

74. 13. The polynucleotide of claim 12, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

120.

75. 75. The polynucleotide of claim 74, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

120.

76. 13. The polynucleotide of claim 12, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

121.

77. 77. The polynucleotide of claim 76, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

121.

78. 13. The polynucleotide of claim 12, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

122.

79. 79. The polynucleotide of claim 78, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

122.

80. 13. The polynucleotide of claim 12, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

123.

81. 81. The polynucleotide of claim 80, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

123.

82. 13. The polynucleotide of claim 12, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

124.

83. 83. The polynucleotide of claim 82, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

124.

84. 13. The polynucleotide of claim 12, wherein the CAR comprises an amino acid sequence having 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 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

125.

85. 85. The polynucleotide of claim 84, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

125.

86. A vector or set of vectors comprising the polynucleotide of any one of claims 1 to 85.

87. 87. The vector or set of vectors of claim 86, which is a viral vector.

88. A cell comprising the polynucleotide of any one of claims 1 to 85.

89. 89. The cell of claim 88, which is an immune cell.

90. 90. The cell of claim 89, selected from the group consisting of T cells, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), regulatory T cells, tumor-infiltrating lymphocytes, and any combination thereof.

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