Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase-like orphan receptor 1 (ROR1)

Abstract

Receptor tyrosine kinase-like orphan receptor 1 (ROR1)-binding molecules are provided, particularly human antibodies, e.g., antibody fragments, specific for ROR1. The present disclosure further relates to recombinant receptors, including chimeric antigen receptors (CARs), comprising such antibodies or fragments, and polynucleotides encoding antibodies, antigen-binding fragments, or receptors specific for ROR1. The present disclosure further relates to genetically engineered cells comprising such ROR1-binding proteins and receptors, and related methods and uses thereof in adoptive cell therapy. TIFF2022518925000036.tif80133

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 798,456, filed January 29, 2019, entitled "ANTIBODIES AND CHIMERIC ANTIGEN RECEPTORS SPECIFIC FOR RECEPTOR TYROSINE KINASE LIKE ORPHAN RECEPTOR 1 (ROR1)," the contents of which are incorporated by reference in their entirety.

[0002] INCORPORATION-BY-REFERENCE TO SEQUENCE LISTING This application is filed with an electronic Sequence Listing, which is provided in a file entitled 735042017740SeqList.txt, created on January 28, 2020, and is 225 kilobytes in size. The information in the electronic Sequence Listing is incorporated by reference in its entirety.

[0003] Field In some aspects, the present disclosure relates to receptor tyrosine kinase-like orphan receptor 1 (ROR1)-binding molecules, particularly human antibodies, e.g., antibody fragments, specific for ROR1. The disclosure further relates to recombinant receptors, including chimeric antigen receptors (CARs), comprising such antibodies or fragments, and polynucleotides encoding antibodies, antigen-binding fragments, or receptors specific for ROR1. The disclosure further relates to genetically engineered cells comprising such ROR1-binding proteins and receptors, and related methods and uses thereof in adoptive cell therapy. [Background technology]

[0004] background Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane receptor that is expressed during embryogenesis but typically not in normal cells of the body. However, ROR1 is expressed in a variety of cancer contexts and, in some cases, is involved in cell signaling to promote tumor cell survival. Based on its expression, ROR1 could be a tumor-specific and / or tumor-associated target for therapy. ROR1-binding molecules, receptors, and cells expressing such molecules are available. There is a need for improved ROR1-binding molecules and modified ROR1-binding receptor-expressing cells. Embodiments that meet this need are provided. Summary of the Invention

[0005] overview Heavy chain variable (V H ) region and the light chain variable (V L ) region, H The region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in SEQ ID NO: 67, 82, or 52, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in SEQ ID NO: 71, 86, 56, or 97, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99, and the V L or (ii) the V region comprises a light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or H The region comprises a CDR-H1 comprising the sequence shown in SEQ ID NO: 65, 80, or 50, a CDR-H2 comprising the sequence shown in SEQ ID NO: 69, 84, 54, or 95, and a CDR-H3 comprising the sequence shown in SEQ ID NO: 73, 88, 58, or 99, and Lor (iii) the V region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or H The region comprises a CDR-H1 comprising the sequence shown in SEQ ID NO: 66, 81, or 51, a CDR-H2 comprising the sequence shown in SEQ ID NO: 70, 85, 55, or 96, and a CDR-H3 comprising the sequence shown in SEQ ID NO: 73, 88, 58, or 99, and L the V region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or (iv) the V H The region comprises a CDR-H1 comprising the sequence shown in SEQ ID NO: 68, 83, or 53, a CDR-H2 comprising the sequence shown in SEQ ID NO: 72, 87, 57, or 98, and a CDR-H3 comprising the sequence shown in SEQ ID NO: 74, 89, 59, or 100, and L Provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, the region comprising: CDR-L1 comprising the sequence set forth in SEQ ID NO:76, 91, or 61; CDR-L2 comprising the sequence set forth in SEQ ID NO:78, 93, or 63; and CDR-L3 comprising the sequence set forth in SEQ ID NO:79, 94, or 64.

[0006] In addition, the heavy chain variable (V H ) region and the light chain variable (V L ) region, HThe V region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3), each of which comprises the sequence shown in SEQ ID NOs: 67, 71, and 73, respectively; L the V region comprises a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3) comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 82, 86, and 88, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 52, 56, and 58, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 52, 97, and 99, respectively; L (ii) the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 65, 69, and 73, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 80, 84, and 88, respectively; Lthe V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 50, 54, and 58, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 50, 95, and 99, respectively; L (iii) the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 66, 70, and 73, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 81, 85, and 88, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 51, 55, and 58, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 51, 96, and 99, respectively; L(iv) the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 68, 72, and 74, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 76, 78, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 83, 87, and 89, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 91, 93, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 53, 57, and 59, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 63, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 53, 98, and 100, respectively; L Provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, wherein the regions comprise CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 61, 63, and 64, respectively.

[0007] In some of any such embodiments, (i) V H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences shown in SEQ ID NOs: 67, 71, and 73, respectively, and V L (ii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively;H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences shown in SEQ ID NOs: 65, 69, and 73, respectively, and V L (iii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences set forth in SEQ ID NOs: 66, 70, and 73, respectively, and V L the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; or (iv) V H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences shown in SEQ ID NOs: 68, 72, and 74, respectively, and V L The regions include CDR-L1, CDR-L2, and CDR-L3, which contain the sequences shown in SEQ ID NOs: 76, 78, and 79, respectively.

[0008] In some of any such embodiments, (i) V H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences shown in SEQ ID NOs: 82, 86, and 88, respectively, and V L (ii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences shown in SEQ ID NOs: 80, 84, and 88, respectively, and V L (iii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences shown in SEQ ID NOs: 81, 85, and 88, respectively, and V L(iv) the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; or H The regions include CDR-H1, CDR-H2, and CDR-H3 containing the sequences set forth in SEQ ID NOs: 83, 87, and 89, respectively, and V L The regions include CDR-L1, CDR-L2, and CDR-L3, which contain the sequences shown in SEQ ID NOs: 91, 93, and 94, respectively.

[0009] In some of any of the embodiments, V H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 67, 71, and 73, respectively, and V L The regions include CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively. H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 82, 86, and 88, respectively, and V L The regions include CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively. H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 52, 56, and 58, respectively, and V L The regions include CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively. H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 52, 97, and 99, respectively, and V L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences shown in SEQ ID NOs: 60, 62, and 64, respectively.

[0010] In addition, the heavy chain variable (V H ) region and the light chain variable (V L ) region, H The region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained in SEQ ID NO: 112, 121, 103 or 130, and the V L Provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, the antibody comprising light chain complementarity-determining region 1 (CDR-L1), light chain complementarity-determining region 2 (CDR-L2) and light chain complementarity-determining region 3 (CDR-L3), the regions of which are contained in SEQ ID NO:115, 124, or 106.

[0011] In addition, the heavy chain variable (V H ) region and the light chain variable (V L ) region, H The region comprises heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2) and heavy chain complementarity determining region 3 (CDR-H3) contained in SEQ ID NO: 112, and L the region comprises light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3) contained in SEQ ID NO: 115; H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121, and L the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 124; H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 103, and L the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106; or HThe region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 130, and L Provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, the region comprising CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO:106.

[0012] In some of any such embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 112, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 115. In some of any such embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 124. In some of any of the embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 103, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106. In some of any of the embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 130, and L The region includes CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO:106.

[0013] In some of any such embodiments, V HThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 112, 121, 103, or 130, and L The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115, 124, or 106. In some of any such embodiments, V H The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 115; H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 124; HThe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:106; or H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106.

[0014] In some of any such embodiments, V H The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:115. HThe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:124. H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:106. H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106.

[0015] In addition, the heavy chain variable (V H ) region and the light chain variable (V L ) region, Hthe region is or comprises an amino acid sequence having at least 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 112, 121, 103, or 130, and L Provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, wherein a region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115, 124, or 106.

[0016] In addition, the heavy chain variable (V H ) region and the light chain variable (V L ) region, H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and Lthe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115; H wherein the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:124; Hthe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L or the V region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106; or H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and LProvided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, wherein the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106.

[0017] In some of any such embodiments, V H The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:115. HThe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:124.

[0018] In some of any such embodiments, V H The region is or includes the sequence set forth in SEQ ID NO: 112, 121, 103, or 130, and L The region is or comprises the sequence set forth in SEQ ID NO: 115, 124, or 106. In some of any such embodiments, V H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 112 and 115, respectively; H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 121 and 124, respectively; H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 103 and 106, respectively; or V H Area and V LThe regions are or include the sequences set forth in SEQ ID NOs: 130 and 106, respectively.

[0019] In addition, the heavy chain variable (V H ) region and the light chain variable (V L ) region, H The region is or comprises the sequence set forth in SEQ ID NO: 112, 121, 103, or 130, and the V L Provided herein are anti-ROR1 antibodies or antigen-binding fragments thereof, wherein the region is or comprises the sequence set forth in SEQ ID NO:115, 124, or 106.

[0020] In addition, the heavy chain variable (V H ) region and the light chain variable (V L ) region, H Area and V L the V region is or comprises the sequence shown in SEQ ID NO: 112 and 115, respectively; H Area and V L the V region is or comprises the sequence shown in SEQ ID NO: 121 and 124, respectively; H Area and V L or the V region is or comprises the sequence shown in SEQ ID NO: 103 and 106, respectively; or H Area and V L Provided herein are anti-ROR1 antibodies or antigen-binding fragments thereof, wherein the regions are or include the sequences set forth in SEQ ID NOs: 130 and 106, respectively.

[0021] In some of any such embodiments, V H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 112 and 115, respectively. H Area and VL The regions are or include the sequences set forth in SEQ ID NOs: 121 and 124, respectively. H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 103 and 106, respectively. H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 130 and 106, respectively.

[0022] In some of any such embodiments, V H The region may be identified by SEQ ID NO: 110, 119, 101, or 128, or by SEQ ID or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:110, 119, 101, or 128; LThe region is or comprises an amino acid sequence encoded by SEQ ID NO:113, 122, or 104, or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:113, 122, or 104. In some of any such embodiments, V H The region is or includes an amino acid sequence encoded by SEQ ID NO: 111, 120, 102, or 129, L The region is or comprises an amino acid sequence encoded by SEQ ID NO: 114, 123, 105, or 131. In some of any such embodiments, V H The region is or comprises an amino acid sequence encoded by SEQ ID NO:110 or by a nucleic acid sequence having at least at or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:110, LThe region is or comprises an amino acid sequence encoded by SEQ ID NO:113 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:113. H The region is or includes the amino acid sequence encoded by SEQ ID NO:111, L The region is or comprises the amino acid sequence encoded by SEQ ID NO: 114. In some of any such embodiments, V H The region is or comprises an amino acid sequence encoded by SEQ ID NO:119 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:119, LThe region is or comprises an amino acid sequence encoded by SEQ ID NO:122 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:122. H The region is or includes the amino acid sequence encoded by SEQ ID NO: 120, L The region is or includes the amino acid sequence encoded by SEQ ID NO:123.

[0023] In some of any of the embodiments, the antibody is a full-length antibody. In some of any of the embodiments, the antibody is an antigen-binding fragment. In some of any of such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof is isolated. In some of any of such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof is recombinant. In some of any of such embodiments, V H Area and V L At least a portion of the region is human or derived from a human protein. In some of any such embodiments, the antigen-binding fragment is or comprises a single-chain fragment. In some of any such embodiments, the antigen-binding fragment is or comprises a single-chain Fv (scFv).

[0024] In some of any such embodiments, V H The area is V L In some of any such embodiments, VH The area is V L In some of any such embodiments, V H Area and V L The regions are connected by a flexible linker. In some of any such embodiments, the flexible linker comprises the sequence shown in SEQ ID NO:41.

[0025] In some of any such embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO:118, 127, 109, or 134, or an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO:118, 127, 109, or 134. In some of any such embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO:118. In some of any such embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO: 127. In some of any embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO: 109. In some of any embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO: 134.

[0026] In some of any such embodiments, the scFv is identified by SEQ ID NO:116, 125, 107, or 132, or by SEQ ID or about 99% identity to NDC NO:116, 125, 107, or 132. In some of any such embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO:117, 126, 108, or 133. In some of any such embodiments, the scFv is or comprises an amino acid sequence encoded by SEQ ID NO:116 or by a nucleic acid sequence having at least at or about 80%, 81% or about 81%, 82% or about 82%, 83% or about 83%, 84% or about 84%, 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:116. In some of any such embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO:117.In some of any such embodiments, the scFv is or comprises an amino acid sequence encoded by SEQ ID NO:125 or by a nucleic acid sequence having at least at or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:125. In some of any such embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO:126.

[0027] In some of any such embodiments, the anti-ROR1 antibody or fragment further comprises at least a portion of an immunoglobulin constant region, or a variant thereof. In some of any such embodiments, the portion of the immunoglobulin constant region comprises at least a portion of a hinge region, or a variant thereof. In some of any such embodiments, the at least a portion of the immunoglobulin constant region, or a variant thereof, comprises at least a portion of a hinge region, or a variant thereof, H In some of any such embodiments, the at least a portion of an immunoglobulin constant region or variant thereof comprises at least a portion of a C H In some of any such embodiments, the at least a portion of an immunoglobulin constant region or variant thereof comprises at least a portion of a C3 region. H 2nd area and / or C H In some of any such embodiments, the at least a portion of the immunoglobulin constant region or variant thereof is human or derived from a human protein or variant thereof.

[0028] In some of any such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof specifically binds to receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein. In some of any such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof specifically binds to human ROR1 protein. In some of any such embodiments, the human ROR1 protein comprises the amino acid sequence set forth in SEQ ID NO:144, 145, or 146.

[0029] In some of any of the embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof specifically binds to an epitope consisting of or present within the sequence set forth in SEQ ID NO: 199. In some of any of the embodiments, the antibody or antigen-binding fragment thereof further binds to one or more epitopes consisting of or present within a sequence selected from among any one of SEQ ID NOs: 200-214. In some of any of the embodiments, the one or more epitopes comprise a structural epitope.

[0030] In some of any such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof does not bind, does not cross-react, or binds at a lower level, degree, or affinity to receptor tyrosine kinase-like orphan receptor 2 (ROR2) protein. In some of any such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof does not bind, does not cross-react, or binds at a lower level, degree, or affinity to human ROR2 protein. In some of any such embodiments, the degree, level, or degree, or affinity of binding of the anti-ROR1 antibody or antigen-binding fragment thereof to human ROR2 is at least 75% or about 75%, 80% or about 80%, 90% or about 90%, 95% or about 95%, or 99% or about 99% lower than the degree, level, or degree, or affinity of binding to human ROR1 protein.

[0031] In some of either embodiment, the antibody or antigen-binding fragment thereof binds to human ROR1 protein at a concentration of about 1×10 -11 M ~ approx. 1×10 -7 The equilibrium dissociation constant (K D In some of any of the embodiments, the antibody or antigen-binding fragment thereof binds to human ROR1 protein at about 1 x 10 -8 M ~ approx. 1×10 -7 The equilibrium dissociation constant (K D In some of any of the embodiments, the antibody or antigen-binding fragment thereof binds to human ROR1 protein at about 5×10 -11 M ~ approx. 1×10 -10 The equilibrium dissociation constant (K D ) to join them.

[0032] In some of either embodiment, the antibody or antigen-binding fragment thereof binds to human ROR1 protein at a concentration of about 1×10 -5 1 / s ~ approx. 1×10 -2 Dissociation rate constant (k d or k offIn some of any of the embodiments, the antibody or antigen-binding fragment thereof binds to human ROR1 protein at about 1 x 10 -3 1 / s~approx. 1×10 -2 Dissociation rate constant (k d or k off In some of any of the embodiments, the antibody or antigen-binding fragment thereof binds to human ROR1 protein at about 1 x 10 -5 1 / s~approx. 1×10 -4 Dissociation rate constant (k d or k off ) to join them.

[0033] Also provided herein is a single-chain cell surface protein comprising an anti-ROR1 antibody, or antigen-binding fragment thereof, of any of the embodiments provided herein.

[0034] Also provided herein is a conjugate comprising an anti-ROR1 antibody or antigen-binding fragment thereof of any of the embodiments provided herein and a heterologous molecule or heterologous moiety. In some of any such embodiments, the heterologous molecule or heterologous moiety is a therapeutic moiety.

[0035] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain comprising an anti-ROR1 antibody or antigen-binding fragment thereof of any of the embodiments provided herein, and an intracellular signaling region.

[0036] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any of the embodiments provided herein, a transmembrane region, and an intracellular signaling region.

[0037] In addition, the heavy chain variable (V H ) region and the light chain variable (V L an anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, wherein: (i) the V regionH The region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in SEQ ID NO: 67, 82, or 52, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in SEQ ID NO: 71, 86, 56, or 97, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99, and L or (ii) the V region comprises a light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or H The region comprises a CDR-H1 comprising the sequence shown in SEQ ID NO: 65, 80, or 50, a CDR-H2 comprising the sequence shown in SEQ ID NO: 69, 84, 54, or 95, and a CDR-H3 comprising the sequence shown in SEQ ID NO: 73, 88, 58, or 99, and L or (iii) the V region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or H The region comprises a CDR-H1 comprising the sequence shown in SEQ ID NO: 66, 81, or 51, a CDR-H2 comprising the sequence shown in SEQ ID NO: 70, 85, 55, or 96, and a CDR-H3 comprising the sequence shown in SEQ ID NO: 73, 88, 58, or 99, and L or (iv) the V region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or HThe region comprises a CDR-H1 comprising the sequence shown in SEQ ID NO: 68, 83, or 53, a CDR-H2 comprising the sequence shown in SEQ ID NO: 72, 87, 57, or 98, and a CDR-H3 comprising the sequence shown in SEQ ID NO: 74, 89, 59, or 100, and L Provided herein is an anti-ROR1 chimeric antigen receptor (CAR), the region comprising: a CDR-L1 comprising the sequence set forth in SEQ ID NO: 76, 91, or 61; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 78, 93, or 63; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64.

[0038] In addition, the heavy chain variable (V H ) region and the light chain variable (V L 1. An anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, wherein: (i) the V region H The V region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3), each of which comprises the sequence shown in SEQ ID NOs: 67, 71, and 73, respectively; L the V region comprises a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3) comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 82, 86, and 88, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 52, 56, and 58, respectively; Lor the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 52, 97, and 99, respectively; L (ii) the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 65, 69, and 73, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 80, 84, and 88, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 50, 54, and 58, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 50, 95, and 99, respectively; L (iii) the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 66, 70, and 73, respectively;L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 81, 85, and 88, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 51, 55, and 58, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 51, 96, and 99, respectively; L (iv) the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 68, 72, and 74, respectively; L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 76, 78, and 79, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 83, 87, and 89, respectively; L the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 91, 93, and 94, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 53, 57, and 59, respectively;L or the V region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 60, 63, and 64, respectively; H The V region comprises CDR-H1, CDR-H2, and CDR-H3 having the sequences shown in SEQ ID NOs: 53, 98, and 100, respectively; L Provided herein is an anti-ROR1 chimeric antigen receptor (CAR), which comprises CDR-L1, CDR-L2, and CDR-L3 regions comprising the sequences set forth in SEQ ID NOs: 61, 63, and 64, respectively.

[0039] In some of any such embodiments, (i) V H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 67, 71, and 73, respectively; L (ii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 65, 69, and 73, respectively; L (iii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 66, 70, and 73, respectively; L the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; or (iv) V H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 68, 72, and 74, respectively; L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences shown in SEQ ID NOs: 76, 78, and 79, respectively.

[0040] In some of any such embodiments, (i) V H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 82, 86, and 88, respectively; L (ii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 80, 84, and 88, respectively; L (iii) the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences set forth in SEQ ID NOs: 81, 85, and 88, respectively; L the region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; or (iv) V H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences set forth in SEQ ID NOs: 83, 87, and 89, respectively; L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences shown in SEQ ID NOs: 91, 93, and 94, respectively.

[0041] In addition, the heavy chain variable (V H ) region and the light chain variable (V L an anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, H The region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) contained in SEQ ID NO: 112, 121, 103 or 130, and the V LProvided herein is an anti-ROR1 chimeric antigen receptor (CAR), comprising a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3), the regions of which are contained in SEQ ID NO: 115, 124, or 106.

[0042] In addition, the heavy chain variable (V H ) region and the light chain variable (V L an anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, H The region comprises heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2) and heavy chain complementarity determining region 3 (CDR-H3) contained in SEQ ID NO: 112, and L the region comprises light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3) contained in SEQ ID NO: 115; H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121, and L the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 124; H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 103, and L the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106; or H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 130, and L Provided herein is an anti-ROR1 chimeric antigen receptor (CAR), the region comprising CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106.

[0043] In some of any such embodiments, V HThe region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 112, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 115. In some of any such embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121, and L The region includes CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO:124.

[0044] In some of any such embodiments, V H The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 112, 121, 103, or 130, and L The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115, 124, or 106. In some of any such embodiments, V HThe region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 115; H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 124; H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:106; or Hthe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106.

[0045] In some of any such embodiments, V H The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:115. H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:124.

[0046] In addition, the heavy chain variable (V H ) region and the light chain variable (V L an anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, Hthe region is or comprises an amino acid sequence having at least 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 112, 121, 103, or 130, and L Provided herein is an anti-ROR1 chimeric antigen receptor (CAR), wherein the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 115, 124, or 106.

[0047] In addition, the heavy chain variable (V H ) region and the light chain variable (V L an anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and Lthe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115; H wherein the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:124; Hthe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L or the V region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106; ... H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and LProvided herein is an anti-ROR1 chimeric antigen receptor (CAR), wherein the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106.

[0048] In some of any such embodiments, V H The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:115. HThe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:124.

[0049] In some of any such embodiments, V H The region is or includes the sequence set forth in SEQ ID NO: 112, 121, 103, or 130, L The region is or includes the sequence shown in SEQ ID NO:115, 124, or 106.

[0050] In some of any such embodiments, V H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 112 and 115, respectively; H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 121 and 124, respectively; H Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 103 and 106, respectively; or VH Area and V L The regions are or include the sequences set forth in SEQ ID NOs: 130 and 106, respectively.

[0051] In addition, the heavy chain variable (V H ) region and the light chain variable (V L an anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, H The region is or comprises the sequence set forth in SEQ ID NO: 112, 121, 103, or 130, and the V L Provided herein is an anti-ROR1 chimeric antigen receptor (CAR), wherein the region is or comprises the sequence set forth in SEQ ID NO:115, 124, or 106.

[0052] In addition, the heavy chain variable (V H ) region and the light chain variable (V L an anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising a V region and an intracellular signaling region, H Area and V L the V region is or comprises the sequence shown in SEQ ID NO: 112 and 115, respectively; H Area and V L the V region is or comprises the sequence shown in SEQ ID NO: 121 and 124, respectively; H Area and V L or the V region is or comprises the sequence shown in SEQ ID NO: 103 and 106, respectively; or H Area and V L Provided herein are anti-ROR1 chimeric antigen receptors (CARs), the regions of which are or comprise the sequences set forth in SEQ ID NOs: 130 and 106, respectively.

[0053] In some of any such embodiments, V H Area and V LThe regions are or include the sequences set forth in SEQ ID NOs: 112 and 115, respectively. H Area and V L The regions are or include the sequences shown in SEQ ID NOs: 121 and 124, respectively.

[0054] In some of any such embodiments, V H The region may be identified by SEQ ID NO: 110, 119, 101, or 128, or by SEQ ID or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:110, 119, 101, or 128; L The region is or comprises an amino acid sequence encoded by SEQ ID NO:113, 122, or 104, or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:113, 122, or 104. In some of any such embodiments, V HThe region is or includes an amino acid sequence encoded by SEQ ID NO: 111, 120, 102, or 129, L The region is or comprises an amino acid sequence encoded by SEQ ID NO: 114, 123, 105, or 131. In some of any such embodiments, V H The region is or comprises an amino acid sequence encoded by SEQ ID NO:110 or by a nucleic acid sequence having at least at or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:110, and L The region is or comprises an amino acid sequence encoded by SEQ ID NO:113 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:113. H The region is or includes the amino acid sequence encoded by SEQ ID NO:111 and LThe region is or comprises the amino acid sequence encoded by SEQ ID NO: 114. In some of any such embodiments, V H The region is or comprises an amino acid sequence encoded by SEQ ID NO:119 or by a nucleic acid sequence having at least at or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:119, and L The region is or comprises an amino acid sequence encoded by SEQ ID NO:122 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:122. H The region is or includes the amino acid sequence encoded by SEQ ID NO: 120, L The region is or includes the amino acid sequence encoded by SEQ ID NO:123.

[0055] In some of any such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof is isolated. In some of any such embodiments, the anti-ROR1 antibody or antigen-binding fragment thereof is recombinant. In some of any such embodiments, V H Area and V L At least a portion of the region is human or derived from a human protein.

[0056] In some of any such embodiments, the antigen-binding fragment is or comprises a single-chain fragment. In some of any such embodiments, the antigen-binding fragment is or comprises a single-chain Fv (scFv).

[0057] In some of any such embodiments, V H The area is V L In some of any such embodiments, V H The area is V L In some of any such embodiments, V H Area and V L The regions are connected by a flexible linker. In some of any such embodiments, the flexible linker comprises the sequence shown in SEQ ID NO:41.

[0058] In some of any such embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO:118, 127, 109, or 134, or an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO:118, 127, 109, or 134. In some of any such embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO:118. In some of any such embodiments, the scFv is or comprises the sequence shown in SEQ ID NO: 127. In some of any such embodiments, the scFv is or comprises the sequence shown in SEQ ID NO: 116, 125, 107, or 132, or or about 99% identity to NDC NO:116, 125, 107, or 132. In some of any such embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO:117, 126, 108, or 133.In some of any such embodiments, the scFv is or comprises an amino acid sequence encoded by SEQ ID NO:116 or by a nucleic acid sequence having at least at or about 80%, 81% or about 81%, 82% or about 82%, 83% or about 83%, 84% or about 84%, 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:116. In some of any such embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO:117. In some of any such embodiments, the scFv is or comprises an amino acid sequence encoded by SEQ ID NO:125 or by a nucleic acid sequence having at least at or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:125. In some of any such embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO:126.

[0059] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor further comprises a spacer between the extracellular antigen-binding domain and the transmembrane domain. In some of any such embodiments, the spacer comprises at least a portion of an immunoglobulin or a variant thereof. In some of any such embodiments, the spacer comprises at least a portion of an immunoglobulin hinge region or a variant thereof. In some of any such embodiments, the spacer is less than 15 or about 15 amino acids in length. In some of any such embodiments, the spacer is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:1, 26, 27, 29, 31, 32, 33, or 135.

[0060] In some of any such embodiments, at least a portion of the hinge region comprises all or a portion of an IgG4 hinge region. In some of any such embodiments, at least a portion of the hinge region comprises all or a portion of a human IgG4 hinge region, or a variant thereof. In some of any such embodiments, at least a portion of the hinge region comprises all or a portion of an IgG2 hinge region. In some of any such embodiments, at least a portion of the hinge region comprises all or a portion of a human IgG2 hinge region, or a variant thereof.

[0061] In some of any such embodiments, the spacer is or comprises the sequence shown in SEQ ID NO:1. In some of any such embodiments, the spacer is or comprises an amino acid sequence encoded by SEQ ID NO:2 or 30 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:2 or 30. In some of any such embodiments, the spacer is or includes the amino acid sequence encoded by SEQ ID NO:30.

[0062] In some of any such embodiments, the spacer is or includes the sequence shown in SEQ ID NO:135. In some of any such embodiments, the spacer is or comprises an amino acid sequence encoded by SEQ ID NO:192 or 136, or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:192 or 136. In some of any such embodiments, the spacer is or includes the amino acid sequence encoded by SEQ ID NO:136.

[0063] In some of any such embodiments, the spacer is a C H In some of any such embodiments, the C H At least a portion of the three regions is IgG4 C H In some of any such embodiments, C H At least a portion of the three regions is IgG2 C H In some of any such embodiments, C H At least a portion of the three regions is IgG4 C H 3 and / or IgG2 C H In some of any such embodiments, the IgG4 C H 3 is human IgG4 C H 3 and IgG2 C H 3 is human IgG2 C HIn some of any such embodiments, the spacer comprises at least a portion of an immunoglobulin hinge region and C H The spacer comprises at least a portion of the three regions, or variants thereof. In some of any such embodiments, the spacer is 111 or about 111 amino acids in length, 112 or about 112 amino acids in length, 113 or about 113 amino acids in length, 114 or about 114 amino acids in length, 115 or about 115 amino acids in length, 116 or about 116 amino acids in length, 117 or about 117 amino acids in length, 118 or about 118 amino acids in length, 119 or about 119 amino acids in length, 120 or about 120 amino acids in length, 121 or about 121 amino acids in length, 122 or about 122 amino acids in length, 123 or about 123 amino acids in length, 124 or about 124 amino acids in length, or 125 or about 125 amino acids in length, or a length between any of the foregoing. In some of any such embodiments, the spacer is 120 or about 120 amino acids in length.

[0064] In some of any such embodiments, the spacer is or comprises an amino acid sequence having at least at or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 138. In some of any such embodiments, the spacer is or comprises the sequence set forth in SEQ ID NO: 138. In some of any such embodiments, the spacer is or comprises an amino acid sequence encoded by SEQ ID NO:193 or 139 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:193 or 139. In some of any such embodiments, the spacer is or includes the amino acid sequence encoded by SEQ ID NO:139.

[0065] In some of any such embodiments, the spacer is 120 or about 120 amino acids in length. In some of any such embodiments, the spacer is or comprises an amino acid sequence having at least at or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:3. In some of any such embodiments, the spacer is or comprises the sequence set forth in SEQ ID NO:3. In some of any such embodiments, the spacer is or comprises an amino acid sequence encoded by SEQ ID NO:4 or 137 or by a nucleic acid sequence having at least at or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:4 or 137. In some of any such embodiments, the spacer is or comprises the amino acid sequence encoded by SEQ ID NO:137.

[0066] In some of any such embodiments, the spacer is a C H 2 or a variant thereof. H At least a portion of the 2 regions is IgG4 C HIn some of any such embodiments, C H At least a portion of the 2 region is IgG2 C H In some of any such embodiments, C H At least a portion of the 2 regions is IgG4 C H 2 and / or IgG2 C H In some of any such embodiments, the IgG4 C H 2 is human IgG4 C H 2 and IgG2 C H 2 is human IgG2 C H In some of any such embodiments, the spacer comprises at least a portion of a hinge region, C, of ​​an immunoglobulin. H 2, and at least a portion of C H It comprises at least a portion of the three regions, or variants thereof. In some of any such embodiments, the spacer is 130 or about 130 amino acids in length, 140 or about 140 amino acids in length, 150 or about 150 amino acids in length, 160 or about 160 amino acids in length, 170 or about 170 amino acids in length, 180 or about 180 amino acids in length, 190 or about 190 amino acids in length, 200 or about 200 amino acids in length, 210 or about 210 amino acids in length, 220 or about 220 amino acids in length, 221 or about 221 amino acids in length, 222 or about 222 amino acids in length, 223 or about 223 amino acids in length, 224 or about 224 amino acids in length, 225 or about 225 amino acids in length, 226 or about 226 amino acids in length, 227 or about 227 amino acids in length, 228 or about 228 amino acids in length, 229 or about 229 amino acids in length, or 230 or about 230 amino acids in length, or has a length between any of the foregoing. In some of any such embodiments, the hinge region, C H 2 area, and C H One or more of the three regions are derived from human IgG4, H All or part of the 2nd area and C HIn some of any such embodiments, the hinge region, C H 2 area, and C H One or more of the three regions are chimeric and include a hinge, C ... H 2 area, and C H Includes three areas.

[0067] In some of any such embodiments, the spacer comprises an IgG4 / 2 chimeric hinge region, or a modified IgG4 hinge region comprising at least one amino acid substitution compared to a human IgG4 hinge; an IgG2 / 4 chimeric hinge region; H 2 region; and IgG4 C H Includes three areas.

[0068] In some of any such embodiments, the spacer is or comprises an amino acid sequence having at least at or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 194. In some of any such embodiments, the spacer is or comprises the sequence set forth in SEQ ID NO: 194. In some of any such embodiments, the spacer is or comprises an amino acid sequence encoded by SEQ ID NO:195 or 196, or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:195 or 196. In some of any such embodiments, the spacer is or includes the amino acid sequence encoded by SEQ ID NO:196.

[0069] In some of any such embodiments, the spacer is or comprises an amino acid sequence having at least at or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 37. In some of any such embodiments, the spacer is or comprises the sequence set forth in SEQ ID NO: 37. In some of any such embodiments, the spacer is or comprises an amino acid sequence encoded by SEQ ID NO:38 or 140, or by a nucleic acid sequence having at least at or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:38 or 140. In some of any such embodiments, the spacer is or includes the amino acid sequence encoded by SEQ ID NO:140.

[0070] In some of any such embodiments, the intracellular signaling region comprises an intracellular signaling domain. In some of any such embodiments, the intracellular signaling domain is capable of inducing a primary activation signal in a T cell, is a component of a T cell receptor (TCR), or comprises an immunoreceptor tyrosine-based activation motif (ITAM). In some of any such embodiments, the intracellular signaling domain is or comprises the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain, or a functional variant or signaling portion thereof. In some of any such embodiments, the intracellular signaling domain is human or derived from a human protein. In some of any such embodiments, the intracellular signaling domain is or comprises the sequence set forth in SEQ ID NO:13, 14, or 15, or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO:13, 14, or 15. In some of any such embodiments, the intracellular signaling domain is or comprises the sequence set forth in SEQ ID NO:13.

[0071] In some of any such embodiments, the intracellular signaling region further comprises a costimulatory signaling region. In some of any such embodiments, the costimulatory signaling region comprises the intracellular signaling domain of a T cell costimulatory molecule, or a signaling portion thereof. In some of any such embodiments, the costimulatory signaling region comprises the intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof. In some of any such embodiments, the costimulatory signaling region is human or derived from a human protein. In some of any such embodiments, the costimulatory signaling region comprises the intracellular signaling domain of CD28. In some of any such embodiments, the costimulatory signaling region is or comprises the sequence set forth in SEQ ID NO: 10, or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO: 10. In some of any such embodiments, the costimulatory signaling region comprises the intracellular signaling domain of 4-1BB. In some of any such embodiments, the costimulatory signaling region is or comprises the sequence set forth in SEQ ID NO:12, or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO:12.

[0072] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor further comprises a transmembrane region. In some of any such embodiments, a costimulatory signaling region is between the transmembrane region and the intracellular signaling domain. In some of any such embodiments, the transmembrane region is or comprises a transmembrane domain derived from CD4, CD28, or CD8. In some of any such embodiments, the transmembrane region is or comprises a transmembrane domain derived from CD28. In some of any such embodiments, the transmembrane region is human or derived from a human protein.

[0073] In some of any such embodiments, the transmembrane domain is or comprises SEQ ID NO:8 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO:8. In some of any such embodiments, the transmembrane domain is or comprises the sequence set forth in SEQ ID NO:8. In some of any such embodiments, the transmembrane domain is or comprises an amino acid sequence encoded by SEQ ID NO:197 or 198, or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:197 or 198. In some of any such embodiments, the transmembrane domain is or comprises the amino acid sequence encoded by SEQ ID NO:198.

[0074] In some of any such embodiments, the transmembrane domain is or comprises SEQ ID NO: 149 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO: 149. In some of any such embodiments, the transmembrane domain is or comprises the sequence set forth in SEQ ID NO: 149. In some of any such embodiments, the transmembrane domain is or comprises an amino acid sequence encoded by SEQ ID NO:147 or 148, or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:147 or 148. In some of any such embodiments, the transmembrane domain is or comprises the amino acid sequence encoded by SEQ ID NO:148.

[0075] In some of any such embodiments, the encoded chimeric antigen receptor comprises, from its N-terminus to its C-terminus, an extracellular antigen-binding domain, a spacer, a transmembrane region, and an intracellular signaling region. In some of any such embodiments, the encoded chimeric antigen receptor comprises, from its N-terminus to its C-terminus, the following: an extracellular antigen-binding domain comprising an scFv, a spacer comprising a modified IgG4 hinge, a transmembrane domain, and an intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and the intracellular signaling domain of a costimulatory signaling region. In some of any such embodiments, the encoded chimeric antigen receptor comprises, from its N-terminus to its C-terminus, an extracellular antigen-binding domain comprising an scFv, a spacer comprising a modified IgG4 hinge comprising the sequence set forth in SEQ ID NO:135, a transmembrane domain derived from human CD28, and an intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and the intracellular signaling domain of a costimulatory signaling region comprising the intracellular signaling domain of 4-1BB. In some of any such embodiments, the encoded chimeric antigen receptor comprises, from its N-terminus to its C-terminus: an extracellular antigen-binding domain comprising an scFv, a modified IgG4 hinge-C, and a chimeric antigen receptor comprising an extracellular antigen-binding domain comprising an scFv. H a spacer comprising 3; a transmembrane domain; and an intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and the intracellular signaling domain of a costimulatory signaling region. In some of any such embodiments, the encoded chimeric antigen receptor comprises, in order from its N-terminus to its C-terminus: an extracellular antigen-binding domain comprising an scFv; a modified IgG4 hinge-C comprising the sequence set forth in SEQ ID NO: 138; Ha spacer comprising 3; a transmembrane domain derived from human CD28; and an intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and an intracellular signaling domain of a costimulatory signaling region comprising the intracellular signaling domain of 4-1BB. In some of any such embodiments, the extracellular antigen-binding domain is an scFv.

[0076] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO:184, 185, 186, 187, 188, or 189, or a sequence exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:184, 185, 186, 187, 188, or 189.

[0077] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 184 or a sequence exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 184. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 184. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 185 or a sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 185. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 185. In some of either embodiment, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 186 or a sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 186. In some of either embodiment, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 186. In some of either embodiment, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 187 or a sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 187. In some of either embodiment, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 187.In some of any of the embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 188 or a sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 188. In some of any of the embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 188. In some of either embodiment, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 189 or a sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 189. In some of either embodiment, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 189.

[0078] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is encoded by a sequence set forth in SEQ ID NO:156, 157, 158, 159, 160, or 161, or by a sequence exhibiting at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:156, 157, 158, 159, 160, or 161. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is encoded by the sequence set forth in SEQ ID NO: 156, or by a sequence exhibiting at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 156. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is encoded by the sequence set forth in SEQ ID NO: 156. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is encoded by the sequence set forth in SEQ ID NO: 157, or by a sequence exhibiting at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 157. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is encoded by the sequence set forth in SEQ ID NO: 157.

[0079] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor specifically binds to receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor specifically binds to human ROR1 protein. In some of any such embodiments, the human ROR1 protein comprises the amino acid sequence set forth in SEQ ID NO: 144, 145, or 146. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor does not bind, does not cross-react, or binds at a lower level, degree, or affinity to receptor tyrosine kinase-like orphan receptor 2 (ROR2) protein. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor does not bind, does not cross-react, or binds at a lower level, degree, or affinity to human ROR2.

[0080] In some of any such embodiments, the degree, level, or degree of binding or affinity of the anti-ROR1 chimeric antigen receptor to human ROR2 is at least 75% or about 75%, 80% or about 80%, 90% or about 90%, 95% or about 95%, or 99% or about 99% lower than the degree, level, or degree of binding or affinity to human ROR1. In some of any such embodiments, binding is compared under the same or substantially the same conditions or assays. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or a lower level or degree of signaling or activity in the presence of ROR2 protein compared to the level or degree of signaling or activity in the presence of ROR1 protein. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or a lower level or degree of signaling or activity in the presence of human ROR2 protein compared to the level or degree of signaling or activity in the presence of human ROR1 protein. In some of any such embodiments, the activity is compared under the same or substantially the same conditions or assay. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits a level or degree of signaling or activity in the presence of human ROR2 that is at least 75% or about 75%, 80% or about 80%, 90% or about 90%, 95% or about 95%, or 99% or about 99% lower than the level or degree of signaling or activity in the presence of human ROR1. In some of any such embodiments, the activity is compared under the same or substantially the same conditions or assay.

[0081] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or a lower level or degree of signaling or activity in the presence of a ROR2 protein compared to a reference ROR1-specific chimeric antigen receptor. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or a lower level or degree of signaling or activity in the presence of human ROR2 compared to a reference ROR1-specific chimeric antigen receptor. In some of any embodiments, the activities are compared under the same or substantially the same conditions or assays.

[0082] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or a lower level or degree of signaling or activity in the presence of a ROR2 protein compared to a reference ROR1-specific chimeric antigen receptor. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or a lower level or degree of signaling or activity in the presence of a human ROR2 protein compared to a reference ROR1-specific chimeric antigen receptor. In some of any such embodiments, the activity is compared under the same or substantially the same conditions or assays. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or higher antigen-specific or antigen-dependent activity or signaling compared to a reference ROR1-specific chimeric antigen receptor. In some of any such embodiments, the activity is compared under the same or substantially the same conditions or assays. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same, or lower tonic signaling or antigen-independent activity or signaling compared to a reference ROR1-specific chimeric antigen receptor. In some of any such embodiments, the activity is compared under the same or substantially the same conditions or assay. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor exhibits a level or degree of tonic signaling or antigen-independent activity or signaling that is at least 75% or about 75%, 80% or about 80%, 90% or about 90%, 95% or about 95%, or 99% or about 99% lower than the level or degree of tonic signaling or antigen-independent activity of the reference ROR1-specific chimeric antigen receptor. In some of any such embodiments, the activity is compared under the same or substantially the same conditions or assay.

[0083] In some of any such embodiments, the reference ROR1-specific chimeric antigen receptor comprises the anti-ROR1 antibody R12 or the anti-ROR1 antibody 2A2, or an antigen-binding fragment thereof. In some of any such embodiments, the reference ROR1-specific chimeric antigen receptor comprises an scFv derived from R12 or 2A2. In some of any such embodiments, the reference ROR1-specific chimeric antigen receptor comprises the anti-ROR1 antibody R12 or an scFv derived from R12 or 2A2.

[0084] Also provided herein is a polynucleotide comprising a nucleic acid encoding all or a portion of the anti-ROR1 antibody or antigen-binding domain thereof of any of the embodiments provided herein, the single-chain cell surface protein of any of the embodiments provided herein, the conjugate of any of the embodiments provided herein, or the anti-ROR1 chimeric antigen receptor of any of the embodiments provided herein.

[0085] In some of any such embodiments, the polynucleotide has a sequence set forth in SEQ ID NO:110, 119, 101, or 128, or a sequence similar to SEQ ID NO:110, 119, 101, or 128. V includes a nucleic acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 96%, 97%, 97%, 98%, 98%, or 99% identity to SEQ ID NO:110, 119, 101, or 128. Hand a nucleic acid encoding a sequence set forth in SEQ ID NO:113, 122, or 104, or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:113, 122, or 104. L In some of any such embodiments, the polynucleotide comprises a sequence set forth in SEQ ID NO:110, or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:110. Hand a nucleic acid encoding the sequence set forth in SEQ ID NO:113, or a nucleic acid sequence having at least or about 80%, 81% or about 81%, 82% or about 82%, 83% or about 83%, 84% or about 84%, 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:113. L In some of any such embodiments, the polynucleotide comprises a sequence set forth in SEQ ID NO:119 or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:119. Hand a nucleic acid encoding the sequence set forth in SEQ ID NO:122, or a nucleic acid sequence having at least or about 80%, 81% or about 81%, 82% or about 82%, 83% or about 83%, 84% or about 84%, 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:122. L and a nucleic acid encoding the

[0086] In some of any such embodiments, the polynucleotide has a sequence set forth in SEQ ID NO:116, 125, 107, or 132, or a sequence similar to SEQ ID NO:116, 125, 107, or 132. and nucleic acids encoding scFvs comprising a nucleic acid sequence having at least or about 80%, 81% or about 81%, 82% or about 82%, 83% or about 83%, 84% or about 84%, 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to NO:116, 125, 107, or 132. In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding an scFv comprising a sequence set forth in SEQ ID NO:116, or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:116.In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding an scFv comprising a sequence set forth in SEQ ID NO:125 or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:125.

[0087] In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding a spacer comprising a sequence set forth in SEQ ID NO:192 or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:192. In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding a spacer comprising a sequence set forth in SEQ ID NO:193, or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:193.In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding a spacer comprising a sequence set forth in SEQ ID NO:195 or a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:195.

[0088] In some of any such embodiments, the nucleic acid encoding the anti-ROR1 antibody or antigen-binding domain thereof, single-chain cell surface protein, conjugate, or anti-ROR1 chimeric antigen receptor comprises at least one modified splice donor site or modified splice acceptor site, or both, wherein the modified splice donor site and / or modified acceptor site comprising one or more nucleotide modifications corresponds to a reference splice donor site and / or reference splice acceptor site. In some of any such embodiments, the one or more nucleotide modifications comprise a nucleic acid substitution. In some of any such embodiments, the reference splice donor site and / or reference splice acceptor site is a canonical splice site, a non-canonical splice site, or a cryptic splice site. In some of any embodiments, the polynucleotide is optimized by elimination of a splice site.

[0089] In some of any such embodiments, the reference splice donor or reference splice acceptor site, or both, has a splice site prediction sequence of at least or about 0.4, 0.5 or about 0.5, 0.6 or about 0.6, 0.7 or about 0.7, 0.75 or about 0.75, 0.8 or about 0.8, 0.85 or about 0.85, 0.9 or about 0.9, 0.95 or about 0.95, 0.99 or about 0.99, or 1.0 or about 1.0. or the reference splice donor or reference splice acceptor site or both are predicted to be involved in splice events at least at or about 40%, 50% or about 50%, 60% or about 60%, 70% or about 70%, 75% or about 75%, 80% or about 80%, 85% or about 85%, 90% or about 90%, 95% or about 95%, 99% or about 99%, or 100% or about 100% of the time.

[0090] In some of any such embodiments, the reference splice donor or reference splice acceptor site, or both, has a splice site prediction score of at least at or about 0.7, 0.75 or about 0.75, 0.8 or about 0.8, 0.85 or about 0.85, 0.9 or about 0.9, 0.95 or about 0.95, 0.99 or about 0.99, or 1.0; and / or the reference splice donor or reference splice acceptor site, or both, is predicted to be involved in a splice event at least at or about 70%, 75% or about 75%, 80% or about 80%, 85% or about 85%, 90% or about 90%, 95% or about 95%, 99% or about 99%, or 100% or about 100% of the time.

[0091] In some of any such embodiments, at least one of the one or more nucleotide modifications is within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues of the splice site junction of the reference splice acceptor and / or reference splice donor site, In some of any such embodiments, the one or more nucleotide modifications are silent, result in a degenerate codon, do not change the amino acid sequence of the encoded protein, or are one or more or all of the above.

[0092] In some of any such embodiments, when the polynucleotide is expressed in a cell, RNA transcribed from the polynucleotide exhibits at least 70% or about 70%, 75% or about 75%, 80% or about 80%, 85% or about 85%, 90% or about 90%, or 95% or about 95% RNA homogeneity. In some of any such embodiments, when the RNA transcribed from the polynucleotide is expressed in a cell, it exhibits reduced heterogeneity compared to the heterogeneity of mRNA transcribed from a reference polynucleotide that encodes the same amino acid sequence as the polynucleotide, where the reference polynucleotide differs in the presence of one or more splice donor sites or one or more splice acceptor sites, or both, in a nucleic acid encoding a spacer, or contains one or more nucleotide alterations compared to the polynucleotide. In some of such embodiments, RNA heterogeneity is reduced by more than 10% or about 10%, more than 15% or about 15%, more than 20% or about 20%, more than 25% or about 25%, more than 30% or about 30%, more than 40% or about 40%, or more than 50% or about 50%, or more. In some of such embodiments, the RNA transcribed from the reference polynucleotide exhibits RNA heterogeneity of more than 10% or about 10%, more than 15% or about 15%, more than 20% or about 20%, more than 25% or about 25%, more than 30% or about 30%, more than 40% or about 40%, or more than 50% or about 50%, or more. In some of such embodiments, the transcribed RNA is messenger RNA (mRNA). In some of any such embodiments, RNA homogeneity or RNA heterogeneity or both are examined by agarose gel electrophoresis, chip-based capillary electrophoresis, analytical ultracentrifugation, field-flow fractionation or liquid chromatography.

[0093] In some of any such embodiments, the polynucleotide is codon-optimized for expression in a human cell.

[0094] In some of any such embodiments, the polynucleotide comprises a V sequence comprising the sequence set forth in SEQ ID NO: 111, 120, 102, or 129. H and a nucleic acid encoding the V L In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding V comprising the sequence set forth in SEQ ID NO:111. H and a nucleic acid encoding V comprising the sequence shown in SEQ ID NO:114. L In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding V comprising the sequence set forth in SEQ ID NO:120. H and a nucleic acid encoding the sequence shown in SEQ ID NO: 123, L and a nucleic acid encoding the

[0095] In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding an scFv comprising the sequence set forth in SEQ ID NO: 117, 126, 108, or 133. In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding an scFv comprising the sequence set forth in SEQ ID NO: 117. In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding an scFv comprising the sequence set forth in SEQ ID NO: 126.

[0096] In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding a spacer comprising the sequence set forth in SEQ ID NO: 136. In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding a spacer comprising the sequence set forth in SEQ ID NO: 139. In some of any such embodiments, the polynucleotide comprises a nucleic acid encoding a spacer comprising the sequence set forth in SEQ ID NO: 196.

[0097] In some of any such embodiments, the polynucleotide comprises a sequence set forth in SEQ ID NO:156, 157, 158, 159, 160, or 161, or a sequence exhibiting at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:156, 157, 158, 159, 160, or 161. In some of any such embodiments, the polynucleotide comprises the sequence set forth in SEQ ID NO: 156, or a sequence that exhibits at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 156. In some of any such embodiments, the polynucleotide comprises the sequence set forth in SEQ ID NO: 156. In some of any such embodiments, the polynucleotide comprises the sequence set forth in SEQ ID NO: 157 or a sequence that exhibits at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 157. In some of any such embodiments, the polynucleotide comprises the sequence set forth in SEQ ID NO: 157.

[0098] In some of any such embodiments, the polynucleotide further comprises a CD33 signal sequence, a GM-CSF signal sequence, a CD8 signal sequence, or an Igκ signal sequence. In some of any such embodiments, the polynucleotide further comprises a CD33 signal sequence. In some of any such embodiments, the CD33 signal sequence is set forth in SEQ ID NO:190 or is a nucleic acid sequence having at least or about 80%, 81% or about 81%, 82% or about 82%, 83% or about 83%, 84% or about 84%, 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:190.

[0099] Also provided herein is a vector comprising any of the polynucleotides of the embodiments provided herein. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector or a lentiviral vector.

[0100] Also provided herein is a cell comprising the anti-ROR1 chimeric antigen receptor of any of the embodiments provided herein. Also provided herein is a cell comprising the polynucleotide of any of the embodiments provided herein or the vector of any of the embodiments provided herein. Also provided herein is a cell comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any of the embodiments provided herein, the conjugate of any of the embodiments provided herein, the single-chain cell surface protein of any of the embodiments provided herein, the anti-ROR1 chimeric antigen receptor of any of the embodiments provided herein, the polynucleotide of any of the embodiments provided herein, or the vector of any of the embodiments provided herein.

[0101] In some embodiments, the cells are lymphocytes. In some embodiments, the cells are NK cells or T cells. In some of any such embodiments, the cells are T cells, and the T cells are CD4+ T cells or CD8+ T cells. In some of any such embodiments, the cells are primary cells obtained from a subject.

[0102] In some of any such embodiments, of the plurality of cells, less than or about 10%, less than or about 9%, less than or about 8%, less than or about 7%, less than or about 7%, less than or about 5%, less than or about 4%, less than or about 4%, less than or about 3%, less than or about 2%, or less than or about 1% of the cells of the plurality comprise an anti-ROR1 chimeric antigen receptor that exhibits tonic or antigen-independent activity or signaling.

[0103] Also provided herein is a composition comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any of the embodiments provided herein, a conjugate according to any of the embodiments provided herein, a single-chain cell surface protein according to any of the embodiments provided herein, or an anti-ROR1 chimeric antigen receptor according to any of the embodiments provided herein.

[0104] Also provided herein are compositions comprising the cells of any of the embodiments provided herein. In some of any such embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some of any such embodiments, the composition comprises CD4+ T cells and CD8+ T cells, wherein the ratio of CD4+ T cells to CD8+ T cells is 1:3 or about 1:3 to 3:1. In some of any such embodiments, the composition comprises CD4+ T cells and CD8+ T cells, wherein the ratio of CD4+ T cells to CD8+ T cells is 1:2 or about 1:2 to 2:1 or about 2:1. In some of any such embodiments, the composition comprises CD4+ T cells and CD8+ T cells, wherein the ratio of CD4+ T cells to CD8+ T cells is 1:1 or about 1:1.

[0105] In some of any such embodiments, of a plurality of cells in the composition, less than or about 10%, less than or about 9%, less than or about 8%, less than or about 7%, less than or about 7%, less than or about 5%, less than or about 4%, less than or about 3%, less than or about 2%, or less than or about 1% of the cells of the plurality comprise an anti-ROR1 chimeric antigen receptor that exhibits tonic or antigen-independent activity or signaling.

[0106] Also provided herein are methods of treatment that include administering a composition of any of the embodiments provided herein to a subject having a disease or disorder associated with ROR1.

[0107] Also provided herein is a therapeutic method comprising administering to a subject having a disease or disorder associated with ROR1 an anti-ROR1 antibody or antigen-binding fragment thereof according to any of the embodiments provided herein, a conjugate according to any of the embodiments provided herein, a single-chain cell surface protein according to any of the embodiments provided herein, an anti-ROR1 chimeric antigen receptor according to any of the embodiments provided herein, a polynucleotide according to any of the embodiments provided herein, a vector according to any of the embodiments provided herein, or a cell according to any of the embodiments provided herein. Also provided herein is a composition according to any of the embodiments provided herein for use in treating a disease or disorder associated with ROR1. Also provided herein is a use of a composition according to any of the embodiments provided herein for the manufacture of a medicament for treating a disease or disorder associated with ROR1. Also provided herein is a use of a composition according to any of the embodiments provided herein for treating a disease or disorder associated with ROR1. Also provided herein is a therapeutic method comprising administering to a subject having a disease or disorder associated with ROR1 a cell according to any of the embodiments provided herein.

[0108] Also provided herein is a therapeutic method comprising administering to a subject having a disease or disorder associated with ROR1 an anti-ROR1 antibody or antigen-binding fragment thereof according to any of the embodiments provided herein, a conjugate according to any of the embodiments provided herein, a single-chain cell surface protein according to any of the embodiments provided herein, an anti-ROR1 chimeric antigen receptor according to any of the embodiments provided herein, a polynucleotide according to any of the embodiments provided herein, a vector according to any of the embodiments provided herein, or a cell according to any of the embodiments provided herein. Also provided herein is a cell according to any of the embodiments provided herein for use in treating a disease or disorder associated with ROR1. Also provided herein is a use of a cell according to any of the embodiments provided herein for the manufacture of a medicament for treating a disease or disorder associated with ROR1. Also provided herein is a use of a cell according to any of the embodiments provided herein for the treatment of a disease or disorder associated with ROR1.

[0109] In some of the provided embodiments, the disease or disorder associated with ROR1 is cancer. In some of the provided embodiments, the cancer is a ROR1-expressing cancer. In some of the provided embodiments, the cancer is associated with a ROR1-expressing solid tumor or a ROR1-expressing hematological malignancy.

[0110] In some of the provided embodiments, the cancer is associated with a solid tumor that expresses ROR1. In some of the provided embodiments, the cancer associated with a solid tumor is selected from the group consisting of neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, myeloma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer. In some of the provided embodiments, the lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and atypical carcinoid. In some of the provided embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some of the provided embodiments, the breast cancer is triple-negative breast cancer (TNBC).

[0111] In some of the provided embodiments, the cancer is associated with a hematological malignancy that expresses ROR1. In some of the provided embodiments, the hematological malignancy is selected from the group consisting of B-cell leukemia, lymphoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's lymphoma, or mantle cell lymphoma (MCL).

[0112] In some embodiments of the methods provided herein, the disease or disorder associated with ROR1 is cancer. In some embodiments of the methods provided herein, the cancer is a ROR1-expressing cancer. In some embodiments of the methods provided herein, the cancer is associated with a ROR1-expressing solid tumor or a ROR1-expressing hematological malignancy.

[0113] In some embodiments of the methods provided herein, the cancer is associated with a solid tumor that expresses ROR1. In some embodiments of the methods provided herein, the cancer associated with a solid tumor is selected from the group consisting of neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, myeloma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer. In some embodiments of the methods provided herein, the lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and atypical carcinoid. In some embodiments of the methods provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments of the methods provided herein, the breast cancer is triple-negative breast cancer (TNBC).

[0114] In some embodiments of the methods provided herein, the cancer is associated with a hematological malignancy that expresses ROR1. In some embodiments of the methods provided herein, the hematological malignancy is selected from the group consisting of B-cell leukemia, lymphoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's lymphoma, or mantle cell lymphoma (MCL).

[0115] In some embodiments of the cells or compositions for use provided herein, the disease or disorder associated with ROR1 is cancer. In some embodiments of the cells or compositions for use provided herein, the cancer is a ROR1-expressing cancer. In some embodiments of the cells or compositions for use provided herein, the cancer is associated with a ROR1-expressing solid tumor or a ROR1-expressing hematological malignancy.

[0116] In some embodiments of the cells or compositions for use provided herein, the cancer is associated with a solid tumor that expresses ROR1. In some embodiments of the cells or compositions for use provided herein, the cancer associated with a solid tumor is selected from the group consisting of neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, myeloma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer. In some embodiments of the cells or compositions for use provided herein, the lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and atypical carcinoid. In some embodiments of the cells or compositions for use provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments of the cells or compositions for use provided herein, the breast cancer is triple-negative breast cancer (TNBC).

[0117] In some embodiments of the cells or compositions for use provided herein, the cancer is associated with a hematological malignancy that expresses ROR1. In some embodiments of the cells or compositions for use provided herein, the hematological malignancy is selected from the group consisting of B-cell leukemia, lymphoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's lymphoma, or mantle cell lymphoma (MCL).

[0118] In some embodiments of the uses provided herein, the disease or disorder associated with ROR1 is cancer. In some embodiments of the uses provided herein, the cancer is a ROR1-expressing cancer. In some embodiments of the uses provided herein, the cancer is associated with a ROR1-expressing solid tumor or a ROR1-expressing hematological malignancy.

[0119] In some embodiments of the use provided herein, the cancer is associated with a solid tumor that expresses ROR1. In some embodiments of the use provided herein, the cancer associated with a solid tumor is selected from the group consisting of neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, myeloma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer. In some embodiments of the use provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments of the use provided herein, the breast cancer is triple-negative breast cancer (TNBC).

[0120] In some embodiments of the uses provided herein, the cancer is associated with a hematological malignancy that expresses ROR1. In some embodiments of the uses provided herein, the hematological malignancy is selected from the group consisting of B-cell leukemia, lymphoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's lymphoma, or mantle cell lymphoma (MCL).

[0121] In some of any such embodiments, the disease or disorder associated with ROR1 is associated with expression of ROR1. In some of any such embodiments, the disease or disorder associated with ROR1 is a B-cell related disorder. In some of any such embodiments, the disease or disorder associated with ROR1 is cancer. In some of any such embodiments, the cancer is a ROR1-expressing cancer. In some of any such embodiments, the ROR1-expressing cancer is selected from the group consisting of B-cell leukemia, lymphoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's lymphoma, mantle cell lymphoma (MCL), non-small cell lung cancer (NSCLC), neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, myeloma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0122] Also provided herein is a kit comprising an anti-ROR1 antibody or antigen-binding fragment thereof of any of the embodiments provided herein, a single-chain cell surface protein of any of the embodiments provided herein, a conjugate of any of the embodiments provided herein, an anti-ROR1 chimeric antigen receptor of any of the embodiments provided herein, a cell of any of the embodiments provided herein, or a composition of any of the embodiments provided herein, and instructions for use. In some of any such embodiments, the instructions are for administering the anti-ROR1 antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, anti-ROR1 chimeric antigen receptor, cell, or composition. In some of any such embodiments, the instructions are for following the method, composition for use, or use of any of the embodiments provided herein.

[0123] Also provided herein is an article of manufacture comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any of the embodiments provided herein, the single-chain cell surface protein of any of the embodiments provided herein, the conjugate of any of the embodiments provided herein, the anti-ROR1 chimeric antigen receptor of any of the embodiments provided herein, the cell of any of the embodiments provided herein, the composition of any of the embodiments provided herein, or the kit of any of the embodiments provided herein. [The present invention 1001] Heavy chain variable (V H ) region and the light chain variable (V L ) region, Applicable V H The region comprises heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2) and heavy chain complementarity determining region 3 (CDR-H3) contained in SEQ ID NO: 112, and L whether the region comprises light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3) contained in SEQ ID NO: 115; Applicable V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121, and L whether the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 124; Applicable V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 103, and L the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106; or Applicable V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 130, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106; An anti-ROR1 antibody or an antigen-binding fragment thereof. [The present invention 1002] The above V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 112, and L 1001. The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention, wherein the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 115. [The present invention 1003] The above V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121, and L 1001. The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention, wherein the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 124. [The present invention 1004] The above V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 103, and L 1001. The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention, wherein the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106. [The present invention 1005] The above V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 130, and L 1001. The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention, wherein the region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106. [The present invention 1006] Heavy chain variable (V H ) region and the light chain variable (V L ) region, Applicable V H The V region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequences set forth in SEQ ID NOs: 67, 71 and 73, respectively; L whether the region comprises light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3), which comprise the sequences set forth in SEQ ID NOs: 75, 77 and 79, respectively; Applicable V H The V region comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence shown in SEQ ID NO: 82, 86, and 88, respectively; L the region comprises CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively; Applicable V H The V region comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence shown in SEQ ID NO: 52, 56, and 58, respectively; L the region comprises CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; or Applicable V H The V region comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence shown in SEQ ID NO: 52, 97, and 99, respectively; L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively; An anti-ROR1 antibody or an antigen-binding fragment thereof. [The present invention 1007] The above V H The V region comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence shown in SEQ ID NO: 67, 71, and 73, respectively; L An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1002 and 1006 of the present invention, comprising CDR-L1, CDR-L2, and CDR-L3, the regions of which comprise the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively. [The present invention 1008] The above V H The V region comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence shown in SEQ ID NO: 82, 86, and 88, respectively; L The anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1003 and 1006 of the present invention, wherein the regions comprise CDR-L1, CDR-L2, and CDR-L3, which regions comprise the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively. [The present invention 1009] The above V H The V region comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence shown in SEQ ID NO: 52, 56, and 58, respectively; L An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1004 and 1006 of the present invention, comprising CDR-L1, CDR-L2, and CDR-L3, the regions of which comprise the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively. [The present invention 1010] The above V H The V region comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence shown in SEQ ID NO: 52, 97, and 99, respectively; L An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1005 and 1006 of the present invention, comprising CDR-L1, CDR-L2, and CDR-L3, the regions of which comprise the sequences set forth in SEQ ID NOs: 60, 62, and 64, respectively. [The present invention 1011] The above V H wherein the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115; The above V H wherein the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:124; The above V H wherein the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:106; or The above V H wherein the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and L the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106, The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention 1001 or 1006. [The present invention 1012] Heavy chain variable (V H ) region and the light chain variable (V L ) region, Applicable V H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115; Applicable V H wherein the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:124; Applicable V H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:106; or Applicable V H the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and L the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106, An anti-ROR1 antibody or an antigen-binding fragment thereof. [The present invention 1013] The above V H wherein the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115; Any of the anti-ROR1 antibodies 1001, 1002, 1006, 1007, 1011 and 1012 or antigen-binding fragments thereof of the present invention. [The present invention 1014] The above V H wherein the region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:124, Any of the anti-ROR1 antibodies or antigen-binding fragments thereof of the present invention 1001, 1003, 1006, 1008, 1011 and 1012. [The present invention 1015] The above V H wherein the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106, Any of the anti-ROR1 antibodies or antigen-binding fragments thereof of the present invention 1001, 1004, 1006, 1009, 1011 and 1012. [The present invention 1016] The above V H wherein the region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and L the region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106, Any of the anti-ROR1 antibodies or antigen-binding fragments thereof of the present invention 1001, 1005, 1006, 1010, 1011 and 1012. [The present invention 1017] The above V H Region and V L the regions are or include the sequences set forth in SEQ ID NOs: 112 and 115, respectively; The above V H Region and V L the regions are or include the sequences set forth in SEQ ID NOs: 121 and 124, respectively; The above V H Region and V L the regions are or comprise the sequences set forth in SEQ ID NOs: 103 and 106, respectively; or The above V H Region and V L The regions are or include the sequences set forth in SEQ ID NOs: 130 and 106, respectively; Any of the anti-ROR1 antibodies 1001, 1006, 1011 and 1012 or antigen-binding fragments thereof of the present invention. [The present invention 1018] Heavy chain variable (V H ) region and the light chain variable (V L ) region, Applicable V H Region and the V L the regions are or include the sequences set forth in SEQ ID NOs: 112 and 115, respectively; Applicable V H Region and the V L the regions are or include the sequences set forth in SEQ ID NOs: 121 and 124, respectively; Applicable V H Region and the V L the regions are or comprise the sequences set forth in SEQ ID NOs: 103 and 106, respectively; or Applicable V H Region and the V L The regions are or include the sequences set forth in SEQ ID NOs: 130 and 106, respectively; An anti-ROR1 antibody or an antigen-binding fragment thereof. [The present invention 1019] The above V H Region and V L An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1002, 1006, 1007, 1011, 1012, 1013, 1017 and 1018, wherein the region is or comprises the sequence set forth in SEQ ID NOs: 112 and 115, respectively. [The present invention 1020] The above V H Region and V L An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1003, 1006, 1008, 1011, 1012, 1014, 1017 and 1018, wherein the region is or comprises the sequence shown in SEQ ID NOs: 121 and 124, respectively. [The present invention 1021] The above V H Region and V L An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1004, 1006, 1009, 1011, 1012, 1015, 1017 and 1018, wherein the region is or comprises the sequence shown in SEQ ID NOs: 103 and 106, respectively. [The present invention 1022] The above V H Region and V L An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001, 1005, 1006, 1010, 1011, 1012, 1016, 1017 and 1018, wherein the region is or comprises the sequence shown in SEQ ID NOs: 130 and 106, respectively. [The present invention 1023] The anti-ROR1 antibody or antigen-binding fragment thereof of any one of claims 1001 to 1022 of the present invention, wherein the antibody is a full-length antibody. [The present invention 1024] The anti-ROR1 antibody or antigen-binding fragment thereof of any one of claims 1001 to 1022 of the present invention, wherein the antibody is an antigen-binding fragment. [The present invention 1025] Any one of the anti-ROR1 antibodies or antigen-binding fragments thereof according to the present invention 1001 to 1024, which is a recombinant antibody. [The present invention 1026] The above V H Region and V L An anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1001 to 1025 of the present invention, wherein the region is human or derived from a human protein. [The present invention 1027] The anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1001 to 1022 and 1024 to 1026 of the present invention, wherein the antigen-binding fragment comprises a single-chain Fv (scFv). [The present invention 1028] The above V H The region is V L The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention 1027, which is amino-terminal to the region. [The present invention 1029] The above V H The region is VL The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention 1027, which is carboxy-terminal to the region. [The present invention 1030] The above V H Region and V L An anti-ROR1 antibody or an antigen-binding fragment thereof according to any one of 1027 to 1029 of the present invention, wherein the regions are linked by a flexible linker. [The present invention 1031] The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention 1030, wherein the flexible linker comprises the sequence shown in SEQ ID NO:41. [The present invention 1032] 1027, 1028, 1030, and 1031, or an antigen-binding fragment thereof, of the anti-ROR1 antibody of the present invention, wherein the scFv is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO: 118, 127, 109, or 134. [The present invention 1033] The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1027, 1028 and 1030 to 1032 of the present invention, wherein the scFv is the sequence shown in SEQ ID NO:118 or comprises the sequence. [The present invention 1034] The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1027, 1028, and 1030 to 1032 of the present invention, wherein the scFv has the sequence shown in SEQ ID NO: 127 or comprises the sequence. [This invention 1035] The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1027, 1028 and 1030 to 1032 of the present invention, wherein the scFv is the sequence shown in SEQ ID NO: 109 or comprises the sequence. [The present invention 1036] The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1027, 1028 and 1030 to 1032 of the present invention, wherein the scFv has the sequence shown in SEQ ID NO: 134 or comprises the sequence. [This invention 1037] An anti-ROR1 antibody or an antigen-binding fragment thereof according to any one of claims 1001 to 1036 of the present invention, which specifically binds to human receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein. [The present invention 1038] The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention 1037, wherein the human ROR1 protein comprises the amino acid sequence shown in SEQ ID NO: 144, 145, or 146. [This invention 1039] The anti-ROR1 antibody or antigen-binding fragment thereof of the present invention 1037 or 1038, which specifically binds to an epitope consisting of the sequence shown in SEQ ID NO:199 or an epitope present within the sequence shown in SEQ ID NO:199. [The present invention 1040] An anti-ROR1 antibody or antigen-binding fragment thereof of any of 1037 to 1039 of the present invention, which further binds to one or more epitopes consisting of a sequence selected from any one of SEQ ID NOs: 200 to 214, or an epitope present within a sequence selected from any one of SEQ ID NOs: 200 to 214. [The present invention 1041] An anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1001 to 1040 of the present invention, which does not bind to, does not cross-react with, or binds to, receptor tyrosine kinase-like orphan receptor 2 (ROR2) protein, optionally human ROR2 protein, at a lower level, degree, or affinity. [The present invention 1042] An anti-ROR1 antibody or antigen-binding fragment thereof of any of the present inventions 1001 to 1041, wherein the degree, level, degree, or affinity of the anti-ROR1 antibody or antigen-binding fragment thereof to human ROR2 is at least 75% or about 75%, 80% or about 80%, 90% or about 90%, 95% or about 95%, or 99% or about 99% lower than the degree, level, degree, or affinity of the binding to human ROR1 protein. [This invention 1043] Approximately 1×10 -11 M ~ approx. 1×10 -7 The equilibrium dissociation constant (K D The anti-ROR1 antibody or antigen-binding fragment thereof of any one of claims 1001 to 1042 of the present invention, which binds to human ROR1 protein at the 5'-terminal end of the ROR1 domain. [This invention 1044] Approximately 1×10 -8 M ~ approx. 1×10 -7 The equilibrium dissociation constant (K D ) The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1001 to 1043 of the present invention, which binds to human ROR1 protein at the 5'-terminal end. [This invention 1045] Approximately 5×10 -11 M ~ approx. 1×10 -10 The equilibrium dissociation constant (K D ) The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1001 to 1043 of the present invention, which binds to human ROR1 protein at the 5'-terminal end. [The present invention 1046] Approximately 1×10 -5 1 / s~approx. 1×10 -2 Dissociation rate constant (k d or k off ) The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1001 to 1045 of the present invention, which binds to human ROR1 protein at the . [This invention 1047] Approximately 1×10 -3 1 / s~approx. 1×10 -2 Dissociation rate constant (k d or k off ) The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1001 to 1046 of the present invention, which binds to human ROR1 protein at the . [This invention 1048] Approximately 1×10 -5 1 / s~approx. 1×10 -4 Dissociation rate constant (k d or k off ) The anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1001 to 1046 of the present invention, which binds to human ROR1 protein at the . [This invention 1049] A single-chain cell surface protein comprising any one of the anti-ROR1 antibodies of the present invention 1001 to 1048 or an antigen-binding fragment thereof. [The present invention 1050] A conjugate comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of 1001 to 1048 of the present invention and a heterologous molecule or heterologous moiety. [This invention 1051] The conjugate of the present invention 1050, wherein said heterologous molecule or heterologous moiety is a therapeutic moiety. [This invention 1052] An anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain containing any of the anti-ROR1 antibodies or antigen-binding fragments thereof of the present invention as set forth in any one of 1001 to 1048, a transmembrane region, and an intracellular signal transduction region. [This invention 1053] 1052. The anti-ROR1 chimeric antigen receptor of the present invention, further comprising a spacer between the extracellular antigen-binding domain and the transmembrane domain. [This invention 1054] The anti-ROR1 chimeric antigen receptor of the present invention 1053, wherein the spacer comprises at least a portion of an immunoglobulin or a variant thereof. [This invention 1055] The anti-ROR1 chimeric antigen receptor of the present invention 1053 or 1054, wherein the spacer comprises at least a portion of an immunoglobulin hinge region or a variant thereof. [The present invention 1056] 1056. The anti-ROR1 chimeric antigen receptor of any one of 1053 to 1055, wherein the spacer is less than 15 or about 15 amino acids in length. [This invention 1057] The anti-ROR1 chimeric antigen receptor of any of the present inventions 1053 to 1056, wherein the spacer is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 1, 26, 27, 29, 31, 32, 33, or 135. [This invention 1058] The anti-ROR1 chimeric antigen receptor of any of 1053 to 1057, wherein at least a portion of the hinge region comprises all or a portion of an IgG4 hinge region, optionally a human IgG4 hinge region, or a variant thereof. [This invention 1059] The anti-ROR1 chimeric antigen receptor of any of 1053 to 1057, wherein at least a portion of the hinge region comprises all or a portion of an IgG2 hinge region, optionally a human IgG2 hinge region, or a variant thereof. [The present invention 1060] The anti-ROR1 chimeric antigen receptor of any one of claims 1053 to 1058, wherein the spacer is or comprises the sequence shown in SEQ ID NO:1. [The present invention 1061] The anti-ROR1 chimeric antigen receptor of any one of 1053 to 1058, wherein the spacer is or comprises the sequence shown in SEQ ID NO: 135. [This invention 1062] The anti-ROR1 chimeric antigen receptor of any of 1053 to 1055, wherein the spacer comprises at least a portion of the hinge region and at least a portion of the CH3 region of an immunoglobulin, or a variant thereof. [The present invention 1063] The anti-ROR1 chimeric antigen receptor of any of claims 1053 to 1055 and 1062, wherein at least a portion of the CH3 region comprises all or a portion of an IgG4 CH3 and / or an IgG2 CH3, and the IgG4 CH3 is optionally a human IgG4 CH3, and the IgG2 CH3 is optionally a human IgG2 CH3. [This invention 1064] The anti-ROR1 chimeric antigen receptor of any of the present inventions 1053 to 1055, 1062, and 1063, wherein the spacer is 111 or about 111 amino acids in length, 112 or about 112 amino acids in length, 113 or about 113 amino acids in length, 114 or about 114 amino acids in length, 115 or about 115 amino acids in length, 116 or about 116 amino acids in length, 117 or about 117 amino acids in length, 118 or about 118 amino acids in length, 119 or about 119 amino acids in length, 120 or about 120 amino acids in length, 121 or about 121 amino acids in length, 122 or about 122 amino acids in length, 123 or about 123 amino acids in length, 124 or about 124 amino acids in length, or 125 or about 125 amino acids in length, or has a length between any of the above. [This invention 1065] The anti-ROR1 chimeric antigen receptor of any one of 1053 to 1055 and 1062 to 1064 of the present invention, wherein the spacer is 120 or about 120 amino acids in length. [The present invention 1066] The anti-ROR1 chimeric antigen receptor of any of the present inventions 1053 to 1055 and 1062 to 1065, wherein the spacer is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 3 or 138. [This invention 1067] The anti-ROR1 chimeric antigen receptor of any one of claims 1053 to 1055 and 1062 to 1066, wherein the spacer is the sequence shown in SEQ ID NO: 3 or 138 or comprises the sequence. [The present invention 1068] An anti-ROR1 chimeric antigen receptor of any of 1053 to 1055, wherein the spacer comprises at least a portion of the hinge region, at least a portion of the CH2, and at least a portion of the CH3 region of an immunoglobulin, or variants thereof. [The present invention 1069] The anti-ROR1 chimeric antigen receptor of any of claims 1053 to 1055 and 1068, wherein at least a portion of the CH2 region comprises all or a portion of an IgG4 CH2 and / or an IgG2 CH2, and the IgG4 CH2 is optionally a human IgG4 CH2, and the IgG2 CH2 is optionally a human IgG2 CH2. [The present invention 1070] The spacer may be 130 or about 130 amino acids in length, 140 or about 140 amino acids in length, 150 or about 150 amino acids in length, 160 or about 160 amino acids in length, 170 or about 170 amino acids in length, 180 or about 180 amino acids in length, 190 or about 190 amino acids in length, 200 or about 200 amino acids in length, 210 or about 210 amino acids in length, 220 or about 220 amino acids in length, 221 or about 221 amino acids in length, or 222 or about 222 amino acids in length. 223 or about 223 amino acids in length, 224 or about 224 amino acids in length, 225 or about 225 amino acids in length, 226 or about 226 amino acids in length, 227 or about 227 amino acids in length, 228 or about 228 amino acids in length, 229 or about 229 amino acids in length, or 230 or about 230 amino acids in length, or having a length between any of the foregoing. [This invention 1071] one or more of the hinge region, the CH2 region, and the CH3 region comprise all or a portion of a CH2 region and all or a portion of a CH3 region derived from human IgG4; or one or more of the hinge region, the CH2 region, and the CH3 region are chimeric and comprise hinges, CH2 regions, and CH3 regions derived from human IgG4 and human IgG2; or the spacer comprises an IgG4 / 2 chimeric hinge region, or a modified IgG4 hinge region comprising at least one amino acid substitution compared to a human IgG4 hinge; an IgG2 / 4 chimeric CH2 region; and an IgG4 CH3 region. An anti-ROR1 chimeric antigen receptor according to any one of 1053 to 1055 and 1068 to 1070 of the present invention. [This invention 1072] The anti-ROR1 chimeric antigen receptor of any of the present inventions 1053 to 1055 and 1068 to 1071, wherein the spacer is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 37 or 194. [This invention 1073] The anti-ROR1 chimeric antigen receptor of any one of claims 1053 to 1055 and 1068 to 1072, wherein the spacer is the sequence shown in SEQ ID NO: 37 or 194 or comprises the same. [This invention 1074] The anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1073, wherein the transmembrane region is or comprises a transmembrane domain derived from CD4, CD28, or CD8. [This invention 1075] The anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1074, wherein the transmembrane region is or comprises a transmembrane domain derived from CD28, optionally human CD28. [This invention 1076] The anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1075, wherein the transmembrane domain is or comprises an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO: 8 or 149. [This invention 1077] The anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1076, wherein the intracellular signaling region comprises an intracellular signaling domain capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component, and / or comprises an immunoreceptor tyrosine-based activation motif (ITAM). [This invention 1078] The anti-ROR1 chimeric antigen receptor of any one of 1052 to 1077, wherein the intracellular signaling domain is or comprises the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain, optionally the human CD3ζ chain. [This invention 1079] The anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1078, wherein the intracellular signaling domain is or comprises an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the sequence set forth in SEQ ID NO: 13, 14, or 15, or to SEQ ID NO: 13, 14, or 15. [The present invention 1080] The anti-ROR1 chimeric antigen receptor of any one of 1052 to 1079, wherein the intracellular signaling domain is or comprises the sequence shown in SEQ ID NO:13. [This invention 1081] The anti-ROR1 chimeric antigen receptor of any one of 1052 to 1080, wherein the intracellular signaling region further comprises a costimulatory signaling region. [This invention 1082] 1081. The anti-ROR1 chimeric antigen receptor of the present invention, wherein the costimulatory signaling region is located between the transmembrane region and the intracellular signaling domain. [This invention 1083] The anti-ROR1 chimeric antigen receptor of the present invention 1081 or 1082, wherein the costimulatory signaling region comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. [This invention 1084] The anti-ROR1 chimeric antigen receptor of any one of 1081 to 1083, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS. [This invention 1085] The anti-ROR1 chimeric antigen receptor of any one of 1081 to 1084, wherein the costimulatory signaling region comprises the intracellular signaling domain of CD28, optionally human CD28. [The present invention 1086] The anti-ROR1 chimeric antigen receptor of any of the present inventions 1081 to 1085, wherein the costimulatory signaling region is or comprises the sequence set forth in SEQ ID NO: 10, or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO: 10. [This invention 1087] The anti-ROR1 chimeric antigen receptor of any one of 1081 to 1084, wherein the costimulatory signaling region comprises the intracellular signaling domain of 4-1BB, optionally human 4-1BB. [This invention 1088] The anti-ROR1 chimeric antigen receptor of any of the present inventions 1081 to 1084 and 1087, wherein the costimulatory signaling region is or comprises the sequence set forth in SEQ ID NO: 12, or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO: 12. [This invention 1089] The anti-ROR1 chimeric antigen receptor of any of claims 1081 to 1088, wherein the encoded chimeric antigen receptor comprises, in order from its N-terminus to its C-terminus, the extracellular antigen-binding domain, the spacer, the transmembrane region, and the intracellular signaling region. [The present invention 1090] The anti-ROR1 chimeric antigen receptor of any of claims 1081 to 1089, wherein the antigen-binding domain is an scFv, and the encoded chimeric antigen receptor comprises, in order from the N-terminus to the C-terminus, an extracellular antigen-binding domain comprising the scFv; a spacer optionally comprising a modified IgG4 hinge comprising the sequence set forth in SEQ ID NO: 135; a transmembrane domain, optionally a transmembrane domain derived from human CD28; and an intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and an intracellular signaling domain of a costimulatory signaling region optionally comprising the intracellular signaling domain of 4-1BB. [This invention 1091] The anti-ROR1 chimeric antigen receptor of any of claims 1081 to 1089, wherein the antigen-binding domain is an scFv, and the encoded chimeric antigen receptor comprises, in order from the N-terminus to the C-terminus, an extracellular antigen-binding domain comprising the scFv; a spacer optionally comprising a modified IgG4 hinge-CH3 comprising the sequence set forth in SEQ ID NO: 138; a transmembrane domain, optionally a transmembrane domain derived from human CD28; and an intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and an intracellular signaling domain of a costimulatory signaling region optionally comprising the intracellular signaling domain of 4-1BB. [This invention 1092] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1091 of the present invention, which is or comprises a sequence set forth in SEQ ID NO: 184, 185, 186, 187, 188, or 189, or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 184, 185, 186, 187, 188, or 189. [This invention 1093] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 of the present invention, which is or comprises the sequence shown in SEQ ID NO: 184 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence shown in SEQ ID NO: 184. [This invention 1094] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1093, which has or comprises the sequence shown in SEQ ID NO:184. [This invention 1095] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 of the present invention, which is or comprises the sequence set forth in SEQ ID NO: 185 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 185. [This invention 1096] An anti-ROR1 chimeric antigen receptor of any one of 1052 to 1092 and 1095 of the present invention, which is or comprises the sequence shown in SEQ ID NO:185. [This invention 1097] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 of the present invention, which is or comprises the sequence set forth in SEQ ID NO: 186 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 186. [This invention 1098] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 and 1097, which is or comprises the sequence shown in SEQ ID NO:186. [This invention 1099] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 of the present invention, which is or comprises the sequence set forth in SEQ ID NO: 187 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 187. [The present invention 1100] An anti-ROR1 chimeric antigen receptor of any of the present inventions 1052 to 1092 and 1099, which is or comprises the sequence shown in SEQ ID NO:187. [The present invention 1101] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 of the present invention, which is or comprises the sequence set forth in SEQ ID NO: 188 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 188. [The present invention 1102] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 and 1101, which is or comprises the sequence set forth in SEQ ID NO:188. [The present invention 1103] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 of the present invention, which is or comprises the sequence set forth in SEQ ID NO: 189 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 189. [The present invention 1104] An anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1092 and 1103, which is or comprises the sequence shown in SEQ ID NO:189. [This invention 1105] A polynucleotide comprising a nucleic acid encoding any one of the anti-ROR1 antibodies of the present invention 1001 to 1048 or an antigen-binding domain thereof. [The present invention 1106] A polynucleotide comprising a nucleic acid encoding a single-chain cell surface protein of the present invention. [This invention 1107] A polynucleotide comprising a nucleic acid encoding a conjugate of the present invention 1050 or the present invention 1051. [This invention 1108] A polynucleotide comprising a nucleic acid encoding an anti-ROR1 chimeric antigen receptor of any one of 1052 to 1104 of the present invention. [This invention 1109] The polynucleotide of any one of 1105 to 1108 of the present invention, which is optimized by splice site elimination. [The present invention 1110] The polynucleotide of any one of 1105 to 1109 of the present invention, wherein the codons are optimized for expression in human cells. [The present invention 1111] A vector comprising any one of the polynucleotides of the present invention 1105 to 1110. [The present invention 1112] The vector of the present invention 1111, which is a viral vector. [The present invention 1113] The vector of the present invention 1112, wherein the viral vector is a retroviral vector or a lentiviral vector. [This invention 1114] A cell comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any one of 1001 to 1048 of the present invention, the single-chain cell surface protein of 1049 of the present invention, or a conjugate of 1050 of the present invention or 1051 of the present invention. [This invention 1115] A cell comprising an anti-ROR1 chimeric antigen receptor according to any one of 1052 to 1104 of the present invention. [The present invention 1116] A cell comprising any one of the polynucleotides of the present inventions 1105 to 1110 or any one of the vectors of the present inventions 1111 to 1113. [This invention 1117] The cell of any one of 1114 to 1116 of the present invention, which is a lymphocyte. [This invention 1118] The cell of any one of 1114 to 1116 of the present invention, which is an NK cell or a T cell. [This invention 1119] The cell of any one of 1114 to 1118 of the present invention, wherein the cell is a T cell, and the T cell is a CD4+ T cell or a CD8+ T cell. [The present invention 1120] The cell of any one of 1114 to 1119 of the present invention, which is a primary cell obtained from a subject. [This invention 1121] The cell of any of claims 1114 to 1120, wherein, among a plurality of said cells, less than 10% or less than about 10%, less than 9% or less than about 9%, less than 8% or less than about 8%, less than 7% or less than about 7%, less than 5% or less than about 5%, less than 4% or less than about 4%, less than 3% or less than about 3%, less than 2% or less than about 2%, or less than 1% or less than about 1% of said plurality of cells comprise an anti-ROR1 chimeric antigen receptor that exhibits tonic signaling and / or antigen-independent activity or signaling. [This invention 1122] A composition comprising any one of the cells of the present inventions 1114 to 1121. [This invention 1123] A composition comprising an anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001 to 1048 of the present invention, a single-chain cell surface protein of 1049 of the present invention, a conjugate of 1050 of the present invention or 1051 of the present invention, or an anti-ROR1 chimeric antigen receptor of any of 1052 to 1104 of the present invention. [This invention 1124] The composition of invention 1122 or invention 1123, further comprising a pharmaceutically acceptable excipient. [This invention 1125] The composition of invention 1122 or invention 1124, wherein the composition comprises CD4+ T cells and CD8+ T cells, and the ratio of the CD4+ T cells to the CD8+ T cells is 1:3 or about 1:3 to 3:1 or about 3:1, optionally 1:2 or about 1:2 to 2:1 or about 2:1, optionally 1:1 or about 1:1. [Invention 1126] Any of the compositions of 1122, 1124 and 1125, wherein of a plurality of said cells in said composition, less than or about 10%, less than or about 9%, less than or about 8%, less than or about 7%, less than or about 7%, less than or about 5%, less than or about 4%, less than or about 3%, less than or about 2%, or less than or about 1% of said plurality of cells comprise an anti-ROR1 chimeric antigen receptor that exhibits tonic signaling and / or antigen-independent activity or signaling. [This invention 1127] A therapeutic method comprising administering any one of the cells of the present inventions 1114 to 1121 or any one of the compositions of the present inventions 1122 to 1126 to a subject having a disease or disorder associated with ROR1. [This invention 1128] A cell according to any one of claims 1114 to 1121 or a composition according to any one of claims 1122 to 1126 for use in treating a disease or disorder associated with ROR1. [This invention 1129] Use of a cell according to any one of claims 1114 to 1121 or a composition according to any one of claims 1122 to 1126 for the manufacture of a medicament for the treatment of a disease or disorder associated with ROR1. [The present invention 1130] Use of a cell according to any one of claims 1114 to 1121 or a composition according to any one of claims 1122 to 1126 for the treatment of a disease or disorder associated with ROR1. [This invention 1131] A therapeutic method comprising administering to a subject having a disease or disorder associated with ROR1 any of the anti-ROR1 antibodies or antigen-binding fragments thereof of the present inventions 1001 to 1048, the single-chain cell surface protein of the present invention 1049, the conjugate of the present invention 1050 or 1051, the anti-ROR1 chimeric antigen receptor of the present inventions 1052 to 1104, the polynucleotide of the present inventions 1105 to 1110, or the vector of the present inventions 1111 to 1113. [This invention 1132] An anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1001 to 1048, a single-chain cell surface protein of claim 1049, a conjugate of claim 1050 or claim 1051, an anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1104, a polynucleotide of any of claims 1105 to 1110, or a vector of any of claims 1111 to 1113, for use in treating a disease or disorder associated with ROR1. [This invention 1133] Use of an anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1001 to 1048, a single-chain cell surface protein of claim 1049, a conjugate of claim 1050 or claim 1051, an anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1104, a polynucleotide of any of claims 1105 to 1110, or a vector of any of claims 1111 to 1113, for the manufacture of a pharmaceutical for the treatment of a disease or disorder associated with ROR1. [This invention 1134] Use of an anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1001 to 1048, a single-chain cell surface protein of claim 1049, a conjugate of claim 1050 or claim 1051, an anti-ROR1 chimeric antigen receptor of any of claims 1052 to 1104, a polynucleotide of any of claims 1105 to 1110, or a vector of any of claims 1111 to 1113, for the treatment of a disease or disorder associated with ROR1. [This invention 1135] A cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for use, or use, of any of the methods of inventions 1127 to 1134, wherein the disease or disorder associated with ROR1 is cancer. [This invention 1136] The method, or cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector, or use of the present invention 1135, wherein the cancer is a ROR1-expressing cancer. [This invention 1137] A cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for use, or use, of any of the methods of inventions 1127 to 1136, wherein the cancer is associated with a ROR1-expressing solid tumor or a ROR1-expressing hematologic malignancy. [This invention 1138] A cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for use, or use, of any of the methods of inventions 1127 to 1137, wherein the cancer is associated with a solid tumor that expresses ROR1. [This invention 1139] The cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for the method or use of invention 1137 or invention 1138, or the use, wherein the cancer associated with a solid tumor is selected from the group consisting of neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, myeloma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer. [The present invention 1140] The cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for the method or use of the present invention 1139, wherein the lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and atypical carcinoid. [This invention 1141] 1140. The cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for the method or use of the present invention, wherein said lung cancer is NSCLC. [This invention 1142] The cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for the method or use of the present invention 1139, wherein the breast cancer is triple-negative breast cancer (TNBC). [This invention 1143] A cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for use, or use, of any of the methods of inventions 1127 to 1137, wherein the cancer is associated with a hematological malignancy that expresses ROR1. [This invention 1144] 1143. The cell, composition, antibody or antigen-binding fragment thereof, single-chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide, or vector for the method or use of the present invention, wherein said hematological malignancy is selected from the group consisting of B-cell leukemia, lymphoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's lymphoma, or mantle cell lymphoma (MCL). [Invention 1145] The present invention comprises an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1001 to 1048, a single-chain cell surface protein according to claim 1049, a conjugate according to claim 1050 or claim 1051, an anti-ROR1 chimeric antigen receptor according to any one of claims 1052 to 1104, a polynucleotide according to any one of claims 1105 to 1110, a vector according to any one of claims 1111 to 1113, a cell according to any one of claims 1114 to 1121, or a composition according to any one of claims 1122 to 1126, together with an instruction for use. A kit, optionally wherein the instructions are for administering the anti-ROR1 antibody or antigen-binding fragment thereof, the single-chain cell surface protein, the conjugate, the anti-ROR1 chimeric antigen receptor, the cell, or the composition, optionally in accordance with any of the methods, or cells, compositions, antibodies or antigen-binding fragments thereof, single-chain cell surface proteins, conjugates, chimeric antigen receptors, polynucleotides, or vectors for use, or uses, of inventions 1127 to 1144. [Invention 1146] An article of manufacture comprising an anti-ROR1 antibody or antigen-binding fragment thereof of any of 1001 to 1048 of the present invention, a single-chain cell surface protein of 1049 of the present invention, a conjugate of 1050 or 1051 of the present invention, an anti-ROR1 chimeric antigen receptor of any of 1052 to 1104 of the present invention, a polynucleotide of any of 1105 to 1110 of the present invention, a vector of any of 1111 to 1113 of the present invention, a cell of any of 1114 to 1121 of the present invention, or a composition of any of 1122 to 1126 of the present invention, or a kit of 1145 of the present invention. [Brief explanation of the drawings]

[0124] [Figure 1]Figure 1 shows the relative intracellular expression levels of IFN-γ, TNF-α, or IL-2 by ICS in GFP+CD4+ T cells after 24 hours of stimulation with plate-bound recombinant ROR1-Fc in primary T cells expressing candidate anti-ROR1 CARs selected from the screening described in Example 1, compared to the levels of each cytokine in cells expressing the anti-ROR1 (R12) reference CAR. [Figure 2] Figure 2 shows the relative intracellular expression levels of IFN-γ, TNF-α, or IL-2 by ICS in primary T cells expressing candidate anti-ROR1 CARs selected from the screening described in Example 1, compared to the levels of each cytokine in cells expressing the anti-ROR1 (R12) reference CAR, after 24 to 70 hours of coculture with ROR1-expressing MDA-MB-231 target cells. [Figure 3] Figures 3A-3B show the results of an in vitro cytotoxicity assay following co-culture of NucLight Red (NLR)-labeled H1975 target cells with primary T cells expressing one of six selected candidate anti-ROR1 CARs, assessed by measuring the decrease in red fluorescent signal over a period of 0-70 h. As controls, cultures of target cells alone and co-cultures of mock cells (not expressing a CAR) with target cells were evaluated. [Figure 4A] Figures 4A-4C show the production of IFN-γ, TNF-α, or IL-2 by primary T cells expressing one of six selected candidate anti-ROR1 CARs from two separate donors after 70 hours of coculture with H1975 (Figures 4A and 4B) or MDA-MB-231, A549, or BT-549 target cells (Figure 4C). As controls, cultures of target cells alone and cocultures of mock cells (not expressing a CAR) with target cells were evaluated. [Figure 4B] See legend to Figure 4A. [Figure 4C] See legend to Figure 4A. [Figure 5A]Figures 5A-5D show antitumor activity, assessed by the change in mean or individual tumor volume, following administration of cells expressing one of six selected candidate anti-ROR1 CARs or the anti-ROR1 (R12) reference CAR in the H1975 non-small cell lung cancer (NSCLC) mouse model. Figure 5A (low dose) and Figure 5B (high dose) show the mean tumor volume for all treated mice; in this figure, the tumor curve was terminated after the first mouse in the group died of disease. Results for all individual mice are shown in Figure 5C (low dose) or Figure 5D (high dose). As controls, mice were administered cells not expressing a CAR (mock) or left untreated. [Figure 5B] See legend to Figure 5A. [Figure 5C] See legend to Figure 5A. [Figure 5D] See legend to Figure 5A. [Figure 6] Figures 6A-6B show Kaplan-Meier survival curves for the H1975 non-small cell lung cancer (NSCLC) mouse model after administration of cells expressing one of the six selected candidate anti-ROR1 CARs or the anti-ROR1 (R12) reference CAR at low (Figure 6A) or high (Figure 6B) doses. [Figure 7-1] Figures 7A-7D show the average number of CD4+ and CD8+ CAR-expressing cells in the blood of each mouse measured on days 10 and 24 after administration of cells expressing one of the six selected candidate anti-ROR1 CARs or the anti-ROR1(R12) reference CAR at low (Figures 7A and 7B) or high (Figures 7C and 7D) doses. Figures 7E-7F show the average number of CD3+ CAR-expressing cells in the blood of each mouse measured on days 10 and 24 after administration of cells expressing one of the six selected candidate anti-ROR1 CARs or the anti-ROR1(R12) reference CAR at low (Figure 7E) or high (Figure 7F) doses. Data are shown as individual values ​​with group means ± standard deviations. [Figure 7-2] See description of Figure 7-1. [Figure 7-3] See description of Figure 7-1. [Figure 8-1]Figures 8A-8C show the changes in mean and individual tumor volumes in H1975 non-small cell lung cancer (NSCLC) mice administered low (mean: Figure 8A; individual: Figure 8C) or high (mean: Figure 8B; individual: Figure 8C) doses of cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR. As controls, mice were administered cells not expressing CAR (mock) or left untreated. [Figure 8-2] See description of Figure 8-1. [Figure 9] Figures 9A-9B show Kaplan-Meier survival curves following administration of cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR at low (Figure 9A) or high (Figure 9B) doses to mice. As controls, mice were administered cells not expressing CAR (mock) or left untreated. [Figure 10-1] Figures 10A-10D show the mean counts of CD4+ (Figures 10A and 10C) and CD8+ (Figures 10B and 10D) CAR+ T cells per microliter of blood on days 7, 14, and 21 after administration of low (Figures 10A and 10B) or high (Figures 10C and 10D) doses of cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR. [Figure 10-2] See description of Figure 10-1. [Figure 11] Figures 11A-11B show the numbers of CD4+ (Figure 11A) and CD8+ (Figure 11B) CAR+ T cells present within tumors 14 days after administration of cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR. [Figure 12A] Figures 12A-12C show bioluminescence images assessed up to approximately day 49 after administration of low (Figure 12B) or high (Figure 12C) doses of cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR in an MDA-MB-231 triple-negative breast cancer mouse model. As controls, mice were administered cells not expressing CAR (mock) or left untreated (Figure 12A). [Figure 12B] See legend to Figure 12A. [Figure 12C] See legend to Figure 12A. [Figure 13-1] Figures 13A-13C show the average total flux measurements (p / s) by bioluminescence imaging assessed up to approximately 49 days after administration of low (Figure 13A) or high (Figure 13B) doses of cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR in the MDA-MB-231 triple-negative breast cancer mouse model, and are shown as group means ± standard errors. Figure 13C shows the total flux measurements (p / s) for individual mice. As controls, mice were administered cells not expressing CAR (mock) or left untreated. [Figure 13-2] See description of Figure 13-1. [Figure 14A-B] Figures 14A-14E show the changes in mean and individual tumor volumes in MDA-MB-231 triple-negative breast cancer model mice administered with cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR at low (mean: Figure 14A) or high (mean: Figure 14B) doses. The changes in mean tumor volume at additional time points in the same study after administration of T cells expressing anti-ROR1 CAR F and the reference CAR R12 are shown for the high dose (Figure 14C) and low dose (Figure 14D). The results of tumor volume for individual treated mice under each treatment condition at high or low doses are shown in Figure 14E. The mean tumor volume is shown as the group mean ± standard error until the last day that all mice in the treatment group survived. As a control, mice were administered with cells not expressing a CAR (mock) or left untreated. [Figure 14C] See legend to Figures 14A-B. [Figure 14D] See legend to Figures 14A-B. [Figure 14E] See legend to Figures 14A-B. [Figure 15]Figures 15A and 15B show Kaplan-Meier survival curves in MDA-MB-231 triple-negative breast cancer model mice treated with low (Figure 15B) or high (Figure 15A) doses of cells expressing anti-ROR1 CAR-F or the R12 reference CAR. As controls, mice were treated with non-CAR-expressing cells (mock) or left untreated. [Figure 16-1] Figures 16A-16D show the mean numbers of CD4+ (Figures 16A and 16C) and CD8+ (Figures 16B and 16D) CAR-expressing cells in the blood of animals measured at days 7, 14, 21, and 30 after administration of low (Figures 16A and 16B) or high (Figures 16C and 16D) doses of cells expressing anti-ROR1 CAR-F, CAR-A, or the R12 reference CAR. Also shown in Figure 16E is the mean number of CD3+ CAR-expressing cells (CD45+CD3+CAR+) in the blood of each mouse administered cells expressing anti-ROR1 CAR-F or the R12 reference CAR, measured at days 7, 14, 21, and 30. As shown, cells expressing anti-ROR1 CAR-F showed high expansion in the MDA-MB-231 mouse model when administered at both high and low doses. [Figure 16-2] See description of Figure 16-1. [Figure 16-3] See description of Figure 16-1. [Figure 17] Figure 17 shows the reduction of Rapid Red-labeled target cells (CD4 / CD8 T cell-depleted leukapheresis samples) from two primary CLL donors after approximately 6 days of co-culture with engineered cells expressing anti-ROR1 CAR-F, anti-CD19 CAR, or R12 reference CAR at two E:T ratios. [Figure 18A] Figure 18A shows the results of a flow cytometry cytotoxicity assay demonstrating the reduction of CD19+ or CD19+ROR1+ target cells (CD4 / CD8 T cell-depleted leukapheresis samples) generated from two primary CLL donors after approximately four days of co-culture at two E:T ratios with engineered cells expressing anti-ROR1 CAR-F, anti-CD19 CAR, or R12 reference CAR. [Figure 18B] Figure 18B shows the proliferation of CAR-expressing cells (anti-ROR1 CAR-F, anti-CD19 CAR, or R12 reference CAR) labeled with CellTrace™ Violet (CTV) cell proliferation reagent and co-cultured with target cells derived from a subject with CLL at E:T ratios of 2.5:1 and 0.25:1. [Figure 18C] Figure 18C shows the production of IFN-γ, TNF-α, and IL-2 assessed by the supernatants of co-cultures on day 4. Mock-treated cells or target cells alone were compared as controls. [Figure 19] Figures 19A-19D show the change in mean and individual tumor volume in a mouse model of mantle cell lymphoma (MCL) implanted with human mantle cell lymphoma (MCL) JeKo-1 cells expressing firefly luciferase and green fluorescent protein (FfLuc-GFP) and treated with high (average: Figure 19A; individual: Figure 19C) or low (average: Figure 19B; individual: Figure 19D) doses of cells expressing anti-ROR1 CAR-F, anti-CD19, or the R12 reference CAR. As a control, mice were administered with cells not expressing a CAR (mock) or left untreated. [Figure 20] Figures 20A-20B show Kaplan-Meier survival curves in a mouse model of MCL treated with high (Figure 20A) or low (Figure 20B) doses of cells expressing anti-ROR1 CAR-F, anti-CD19, or the R12 reference CAR. As controls, mice were administered with cells not expressing CAR (mock) or left untreated. [Figure 21] Figure 21 shows the mean number of CD3+ CAR-expressing cells in the blood of a mouse model of MCL measured at days 7, 14, 21, and 28 after administration of low or high doses of cells expressing the modified anti-ROR1 CAR-F, anti-CD19, or R12 reference CAR. [Figure 22A]Figures 22A-22E show the scFv binding domains of anti-ROR1 scFv ROR1-1 (SEQ ID NO:118; Figure 22A), ROR1-2 (SEQ ID NO:127; Figure 22B), ROR1-3 (SEQ ID NO:109; Figure 22C) and ROR1-4 (SEQ ID NO:134; Figure 22D), CAR-A, CAR-F, CAR-G, CAR-I, CAR-R, and CAR-B1, as well as the scFv antigen-binding domain of reference CAR R12 (SEQ ID NO:140; Figure 22E), against a C-terminal 6xHis tag (ROR1 ECD 6xHis), as assessed by surface plasmon resonance (SPR) with multi-cycle kinetics performed with subsequent injections of recombinant human ROR1 at concentrations of 183, 61.0, 20.33, 6.78, and 2.26 nM. Figure 22B shows the binding of various recombinantly produced anti-ROR1 scFv-mFc, including NO:142; Figure 22E. [Figure 22B] See legend to Figure 22A. [Figure 22C] See legend to Figure 22A. [Figure 22D] See legend to Figure 22A. [Figure 22E] See legend to Figure 22A. [Figure 23] Figure 23 shows the expression of ROR1 in the K562-ROR1-TetOn cell line in response to a serial two-fold dilution series of doxycycline from 512 ng / mL to 0 ng / mL. ROR1- parental K562 cells, two endogenously expressing ROR1+ cell lines, the MCL cell line JeKo-1, and the TNBC cell line MDA-MB-231 were used as controls. [Figure 24] Figure 24 shows dose-response curves for the production of IFNγ, IL-2, and TNFα assessed in the supernatant of a 72-hour coculture of engineered cells expressing anti-ROR1 CAR-F or the reference CAR R12 with K562-ROR1-TetOn at an E:T ratio of 4:1 with the addition of increasing concentrations of doxycycline. Cells not expressing CAR (mock) were used as a control. [Figure 25A]Figures 25A-25B show the results of a cytotoxicity assay, measured by the reduction in red fluorescent signal from NucLight Red-labeled K562-ROR1-TetOn cells cultured for approximately 72 hours at an E:T ratio of 4:1 in the presence of various concentrations (2 ng / mL to 512 ng / mL) of doxycycline and engineered cells expressing anti-ROR1 CAR-F or reference CAR R12. DMSO, no doxycycline, and untreated cells were used as controls. [Figure 25B] See legend to Figure 25A. [Figure 26] Figure 26 shows the evaluation of ROR1 cross-species reactivity in Jurkat Nur77 reporter cells expressing either ROR1 CAR-F or ROR1 R12 CAR co-cultured with CT26 cells modified to express human ROR1 (hROR1) or mouse ROR1 (mROR1). K562 cells and unmodified CT26 cells were used as non-specific controls. DETAILED DESCRIPTION OF THE INVENTION

[0125] Detailed Description Receptor tyrosine kinase-like orphan receptor 1 (ROR1)-binding molecules, e.g., antibodies (e.g., antigen-binding antibody fragments, e.g., single-chain fragments, e.g., single-chain Fv fragments (scFv)), and recombinant receptors comprising such antibodies or fragments, e.g., chimeric receptors, and nucleic acids encoding such antibodies, fragments, or recombinant receptors are provided. In some aspects, antibodies, fragments, and chimeric antigen receptors (CARs) are provided that target or are directed against ROR1 and cells and diseases expressing ROR1. ROR1 has been observed to be expressed in cells or tissues associated with certain diseases and conditions, such as malignant tumors, e.g., on malignant plasma cells from patients with relapsed or newly diagnosed myeloma, and is rarely expressed in normal tissues. Among the embodiments provided are approaches useful for treating diseases and conditions and / or for targeting such cell types, e.g., nucleic acid molecules encoding ROR1-binding antibodies, fragments, or receptors, and the encoded antibodies or antigen-binding fragments and receptors. Also provided are compositions and articles of manufacture comprising the same. The receptor is generally an antibody (antigen-binding antibody fragment, e.g., heavy chain variable (V) H ) regions, single-domain antibody fragments, and single-chain fragments, e.g., scFvs), e.g., as antigen-binding domains. Also provided are cells, e.g., engineered or recombinant cells, expressing such ROR1-binding receptors, e.g., anti-ROR1 CARs, and / or containing nucleic acids encoding such receptors, as well as compositions, articles of manufacture, and therapeutic doses comprising such cells. Also provided are methods of making and using the antibodies and fragments, and cells expressing or containing the antibodies and fragments, e.g., for producing the antibodies or fragments. Also provided are compositions, e.g., pharmaceutical compositions, comprising such antibodies, antigen-binding fragments, receptors, or cells, and conjugates comprising such antibodies or fragments. In some aspects, the provided compositions, antibodies, antigen-binding fragments, receptors, or cells can be used in connection with therapeutic methods or methods.

[0126] Therapies or adoptive cell therapies that target ROR1, such as with anti-ROR1 antibodies (e.g., those involving the administration of cells expressing chimeric receptors, such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors specific for ROR1, as well as other adoptive immune cell and adoptive T cell therapies), can be effective in treating cancer and other diseases and disorders, such as ROR1. In some specific situations, available approaches to adoptive cell therapy may not always be completely satisfactory. In some aspects, the administered cells have the ability to recognize and bind to a target, e.g., a target antigen, e.g., ROR1; to transport, localize and successfully invade appropriate sites within the subject, tumor and its environment; to become activated and proliferate; to exert various effector functions such as cytotoxic killing and secretion of various factors, e.g., cytokines; to persist for long periods of time; to participate in differentiation, migration or clearance and reprogramming to a particular phenotypic state that results in an effective and robust recall response after re-exposure to the target ligand or antigen, and to avoid or reduce differentiation into exhaustion, anergy, terminal differentiation and / or suppression.

[0127] In some situations, the properties of a particular target antigen that an antibody or recombinant receptor containing an antigen-binding domain specifically binds to, recognizes, or targets may affect the activity of the receptor. In some situations, ROR1 is expressed by certain cancers, making it an attractive therapeutic target for cell therapy. There is a need for improved strategies for optimal response to antibody or cell therapy, particularly for recombinant receptors that specifically bind to, recognize, or target ROR1. Embodiments that meet this need are provided.

[0128] In some aspects, provided embodiments are based on the observation that administration of modified cells expressing provided ROR1-binding molecules, e.g., chimeric antigen receptors (CARs), exhibits improved antigen-specific activity, signaling and function, increased anti-tumor activity, consistent antigen-dependent activity or signaling, greater or longer in vivo expansion, and improved persistence upon administration, while exhibiting minimal antigen-independent activity or signaling or cross-reactivity with different antigens. Such antibodies and recombinant receptors can be used to promote safe and effective treatment of certain diseases and disorders (e.g., those associated with ROR1 expression).

[0129] In some situations, optimal response to therapy may depend on the ability of the antibody or antigen-binding fragment, or a recombinant receptor comprising such an antibody or antigen-binding fragment as an antigen-binding domain, to recognize the target antigen. In some aspects, it has been observed herein that the binding affinity, specificity, or binding kinetics of some particular provided antibodies or antigen-binding fragments to ROR1, for example, when present as an antigen-binding domain of a recombinant receptor (e.g., CAR), may be associated with improved or greater response to therapy. In some aspects, provided embodiments provide binding molecules that have a lower binding affinity and / or a faster dissociation rate constant (k off or k d This is based on the observation that engineered cells (e.g., T cells) expressing recombinant receptors comprising antigen-binding domains (e.g., antibodies or antigen-binding fragments thereof) with lower binding affinity (e.g., higher equilibrium dissociation constants) may exhibit significantly improved in vivo expansion, increased persistence, greater or improved antigen-specific anti-tumor activity, and prolonged survival, for example, against a variety of tumor types.

[0130] In some aspects, the faster dissociation rate constant (k off or k d Engineered cells (e.g., T cells) expressing recombinant receptors comprising antigen-binding domains (e.g., antibodies or antigen-binding fragments thereof) with a lower binding affinity (e.g., a higher equilibrium dissociation constant) and a faster dissociation rate constant (k ) can exhibit, for example, significantly improved in vivo expansion, increased persistence, greater or improved antigen-specific anti-tumor activity, and prolonged survival against a variety of tumor types. In some aspects, engineered cells expressing recombinant receptors with a lower binding affinity (e.g., a higher equilibrium dissociation constant) and a faster dissociation rate constant (k ). off or k d Engineered cells (e.g., T cells) expressing recombinant receptors comprising antigen-binding domains (e.g., antibodies or antigen-binding fragments thereof) with a fast off-rate (high antigen binding activity; high ...

[0131] In some situations, optimal response to treatment, e.g., cell therapy, may depend on the ability of the modified recombinant receptor (e.g., CAR) to be consistently and reliably expressed on the cell surface and / or to bind to the target antigen. For example, in some cases, heterogeneity of the transcribed RNA from the introduced transgene (e.g., encoding the recombinant receptor) may affect the expression and / or activity of the recombinant receptor when expressed in cells used in cell therapy, e.g., human T cells.

[0132] In some situations, the length and type of spacer in a recombinant receptor (e.g., a CAR) can affect the expression, activity, and / or function of the receptor.

[0133] Additionally, in some circumstances, certain recombinant receptors may exhibit antigen-independent activity or signaling (also known as "tonic signaling"), which may result in undesirable effects, for example, due to increased differentiation and / or exhaustion of T cells expressing the recombinant receptor. In some aspects, such activity may limit the activity, efficacy, or effectiveness of the T cells. In some cases, upon engineering and ex vivo expansion of cells to express a recombinant receptor, the cells may exhibit an exhaustive phenotype due to tonic signaling through the recombinant receptor.

[0134] All publications referenced in this application, including patent documents, scientific papers, and databases, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. To the extent that a definition set forth herein conflicts or is otherwise inconsistent with a definition set forth in a patent, patent application, published patent application, or other publication incorporated herein by reference, the definition set forth herein shall take precedence over the definition incorporated herein by reference.

[0135] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0136] I. ROR1 binding molecules In some aspects, ROR1-binding molecules, e.g., ROR1-binding polypeptides, are provided. Such binding molecules include antibodies (including antigen-binding fragments) that specifically bind to ROR1 proteins, e.g., human ROR1 proteins. Also included among the binding molecules are polypeptides comprising such antibodies, e.g., single-chain cell surface proteins comprising such antibodies, e.g., recombinant receptors, e.g., chimeric antigen receptors (CARs). In some aspects, polynucleotides encoding ROR1-binding cell surface proteins, e.g., recombinant receptors or chimeric antigen receptors (CARs), that bind to ROR1 molecules and cell surface proteins, e.g., recombinant receptors (e.g., CARs), that bind to ROR1, and cells expressing such receptors are provided. Also provided are polynucleotides comprising nucleic acid sequences encoding all or a portion of such antibodies, antigen-binding fragments, and binding molecules, e.g., those described in Sections IA or ID. Examples of such polynucleotides include those described in Section IE. In some aspects, the polynucleotides can be introduced into cells to generate engineered cells containing or expressing the provided binding molecules (e.g., antibodies, antigen-binding domains, and receptors, e.g., CARs, that bind to ROR1).

[0137] A. Antibodies targeting ROR1 Anti-ROR1 polypeptides, e.g., antibodies and functional antigen-binding fragments, are provided. Among the ROR1-binding polypeptides are antibodies, e.g., single-chain antibodies (e.g., antigen-binding antibody fragments), e.g., heavy chain variable (V H ) region and / or light chain variable (V L In some embodiments, the antibody or antigen-binding fragment comprises a V H and V LThe ROR1-binding molecule may be an antibody comprising a single-chain Fv fragment (scFv), for example. Antibodies include antibodies that specifically bind to ROR1, for example, human ROR1. Among the anti-ROR1 antibodies provided are antibodies that are human antibodies or modified or variants of human antibodies. Antibodies include isolated antibodies. Also provided are ROR1-binding molecules comprising such antibodies, for example, single-chain proteins, fusion proteins, conjugates and / or recombinant receptors, for example, chimeric receptors, e.g., antigen receptors. In some aspects, the ROR1-binding molecule includes an isolated molecule.

[0138] Also provided are ROR1-binding cell surface proteins, e.g., ROR1-binding recombinant receptors. ROR1-binding cell surface proteins can include provided antibodies (e.g., antigen-binding antibody fragments) that specifically bind to ROR1, e.g., ROR1 proteins, e.g., human ROR1 proteins. In some aspects, provided binding molecules bind to the extracellular portion of ROR1. In some examples, the recombinant receptor comprises a chimeric antigen receptor, e.g., an anti-ROR1 antibody or an antigen-binding fragment thereof.

[0139] Also provided are polynucleotides comprising nucleic acid sequences encoding all or a portion of such antibodies, antigen-binding fragments, and binding molecules. The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) constructs or RNA constructs, for example, that can be introduced into cells for expression of the encoded ROR1-binding antibodies, antigen-binding fragments, conjugates, or receptors, such as anti-ROR1 CARs. In some aspects, the encoded antibodies, antigen-binding fragments, conjugates, and receptors, such as those comprising ROR1-binding polypeptides, as well as compositions, articles of manufacture, and uses thereof, are also provided.

[0140] The term "antibody" is used herein in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments, such as fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, heavy chain variable (V) fragments capable of specifically binding to an antigen, and H ) regions, single-chain antibody fragments, such as single-chain variable fragments (scFvs), and single-domain antibody (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, as well as heteroconjugate antibodies, multispecific, e.g., bispecific or trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFvs, and tandem tri-scFvs. Unless otherwise specified, the term "antibody" is understood to encompass functional antibody fragments thereof, also referred to herein as "antigen-binding fragments." The term also encompasses intact or full-length antibodies, e.g., antibodies of any class or subclass, such as IgG and its subclasses, IgM, IgE, IgA, and IgD.

[0141] The terms "complementarity-determining region" and "CDR," synonymous with "hypervariable region" or "HVR," are known to refer to non-contiguous amino acid sequences within an antibody variable region that confer antigen specificity and / or binding affinity. Generally, there are three CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region and three CDRs (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region. The terms "framework region" and "FR" are known to refer to the non-CDR portions of the heavy and light chain variable regions. Generally, there are four FRs (FR-H1, FR-H2, FR-H3, and FR-H4) in each full-length heavy chain variable region and four FRs (FR-L1, FR-L2, FR-L3, and FR-L4) in each full-length light chain variable region.

[0142] The exact amino acid sequence boundaries of a given CDR or FR can be determined according to any of several well-known schemes, e.g., Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732-745 ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains," Dev Comp Immunol, 2003 Jan; 27 (1): 55-77 ("IMGT" numbering scheme); Honegger A and Plueckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J Mol Biol, 2001 Jun 8; 309 (3): 657-70, ("Aho" numbering scheme); Martin et al., "Modeling antibody hypervariable loops: a combined algorithm," PNAS, 1989, 86 (23): 9268-9272 ("AbM" numbering scheme); and Ye et al., "IgBLAST: an immunoglobulin variable domain sequence analysis tool," Nucleic Acids Res. 2013 Jul; 41 (Web Server issue): W34-40 ("IgBLAST" numbering scheme).

[0143] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignment, while the Chothia scheme is based on structural information. The numbering in both the Kabat and Chothia schemes is based on the length of the most common antibody region sequences, and some antibodies have insertions and deletions that are addressed by an insertion letter, e.g., "30a." Certain insertions and deletions ("indels") are located at different positions in the two schemes, resulting in different numbering. The Contact scheme is based on the analysis of complex crystal structures and is similar in many ways to the Chothia numbering scheme. The AbM scheme is a compromise between the Kabat and Chothia definitions, based on those used by Oxford Molecular's AbM antibody modeling software. The IgBLAST scheme is based on matching V, D, and J genes from germline sequences and can be determined using the IgBLAST tool from the National Center for Biotechnology Information (NCBI).

[0144] Table 1 below lists exemplary boundary locations for CDR-L1, CDR-L2, CDR-L3, and CDR-H1, CDR-H2, and CDR-H3, as identified by the Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-H1, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between the CDRs; e.g., FR-L1 precedes CDR-L1, FR-L2 is located between CDR-L1 and CDR-L2, FR-L3 is located between CDR-L2 and CDR-L3, etc. Note that because the Kabat numbering scheme shown places the insertion at H35A and H35B, the endpoint of the Chothia CDR-H1 loop when numbered using the Kabat numbering designation shown varies between H32 and H34 depending on the length of this loop.

[0145] Table 1. CDR boundaries according to various numbering schemes TIFF0007678753000001.tif59163

[0146] Thus, unless otherwise specified, the "CDRs" or "complementarity determining regions" of a given antibody or regions thereof, such as the variable regions thereof, or the individual CDRs designated (e.g., CDR-H1, CDR-H2, CDR-H3), should be understood to encompass the complementarity determining regions (or particular regions) defined by any of the foregoing schemes or other known schemes. For example, if a particular CDR (e.g., CDR-H3) is present in a given V H Area or V LWhen a variable region is described as comprising the amino acid sequence of a corresponding CDR in the amino acid sequence of a variable region, it is understood that such CDR has the sequence of the corresponding CDR (e.g., CDR-H3) in the variable region defined by any of the above-mentioned schemes or other known schemes. In some embodiments, specific CDR sequences are specified. While exemplary CDR sequences of the provided antibodies are described using various numbering schemes (see, e.g., Table 2), it is understood that the provided antibodies may also comprise CDRs described according to any of the other numbering schemes above or other known numbering schemes.

[0147] Similarly, unless otherwise specified, a given antibody or region thereof, such as the FRs of its variable region or designated individual FRs (e.g., FR-H1, FR-H2, FR-H3, FR-H4), is understood to encompass framework regions (or specific framework regions) defined by any known scheme. In some cases, a scheme for identifying a specific CDR, FR, or multiple FRs or CDRs is specified, such as CDRs defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method or other known schemes. In other cases, the specific amino acid sequence of the CDR or FR is provided.

[0148] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable regions of the heavy and light chains of a native antibody (V H and V L ) have a generally similar structure, with each domain containing four conserved framework regions (FR) and three CDRs. (See, for example, Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007). A single V H Domain or V LA V domain may be sufficient to confer antigen-binding specificity. Furthermore, an antibody that binds to a particular antigen may have a V domain derived from the antibody that binds to that antigen. H Domain or V L The V domains are isolated and each has a complementary V L Domain or V H Libraries of domains can be screened. See, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991).

[0149] Among the antibodies provided are antibody fragments. An "antibody fragment" or "antigen-binding fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; heavy chain variable (V) antibodies; H ) regions, single chain antibody molecules, such as scFv and V H In some embodiments, the antibody comprises a heavy chain variable (V H ) and light chain variable (V L In certain embodiments, the antibody is an antibody fragment comprising a heavy chain variable (V H ) region and / or light chain variable (V L ) region, such as a single-chain antibody fragment, e.g., scFv.

[0150] A single domain antibody (sdAb) is an antibody fragment that contains all or a portion of the heavy chain variable region or all or a portion of the light chain variable region of an antibody. In certain embodiments, the single domain antibody is a human single domain antibody.

[0151] Antibody fragments can be produced by various techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells. In some embodiments, the antibody is a recombinantly produced fragment, e.g., a fragment containing a non-naturally occurring structure, e.g., two or more antibody regions or antibody chains linked by a synthetic linker, e.g., a peptide linker, and / or a fragment containing a structure that cannot be produced by enzymatic digestion of a naturally occurring intact antibody. In some aspects, the antibody fragment is an scFv.

[0152] A "humanized" antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody may optionally contain at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of a non-human antibody refers to a variant of a non-human antibody that has been humanized, typically to reduce immunogenicity to humans, but that retains the specificity and affinity of the non-human parent antibody. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to restore or improve the specificity or affinity of the antibody.

[0153] Among the anti-ROR1 antibodies provided are human antibodies. A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by a human or human cell, or by a non-human source, e.g., a human antibody library, in which a human antibody repertoire or other human antibody coding sequence is utilized. The term excludes humanized forms of non-human antibodies containing non-human antigen-binding regions, e.g., those in which all or substantially all CDRs are non-human. The term encompasses antigen-binding fragments of human antibodies.

[0154] Human antibodies can be prepared by administering immunogens to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or part of a human immunoglobulin locus that replaces the endogenous immunoglobulin locus or is present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic animals, the endogenous immunoglobulin loci are generally inactivated. Human antibodies can also be derived from human antibody libraries, such as phage display and cell-free libraries, that contain antibody coding sequences derived from the human repertoire.

[0155] Among the antibodies provided are monoclonal antibodies, including monoclonal antibody fragments. As used herein, the term "monoclonal antibody" refers to an antibody obtained from or within a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical except for possible variants that contain naturally occurring mutations or that arise during the production of the monoclonal antibody preparation, and such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically contain various antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. This term should not be construed as requiring that the antibody be produced by any particular method. Monoclonal antibodies can be produced by a variety of techniques, including, but not limited to, generation from hybridomas, recombinant DNA techniques, phage display, and other antibody display methods.

[0156] The terms "polypeptide" and "protein" are used interchangeably to refer to polymers of amino acid residues, with no minimum length restriction. Polypeptides, such as the provided antibodies and antibody chains, as well as other peptides, such as linkers and ROR1-binding peptides, can contain amino acid residues, including natural and / or unnatural amino acid residues. The term also encompasses post-expression modifications of polypeptides, such as glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, polypeptides may contain modifications to the native or native sequence, so long as the protein maintains the desired activity. Such modifications may be intentional, such as by site-directed mutagenesis, or may be accidental, for example, due to mutations in the host producing the protein or errors during PCR amplification.

[0157] 1. Exemplary Antibodies In some embodiments, the antibody, e.g., anti-ROR1 antibody, e.g., antigen-binding antibody fragment, comprises a heavy and / or light chain variable (V H Or V L In some embodiments, the antibody, e.g., the anti-ROR1 antibody, e.g., the antigen-binding antibody fragment, comprises a heavy chain variable region (V) sequence as described. H ) sequence and / or light chain variable region (V L ) sequence, or a sufficient antigen-binding portion thereof. In some embodiments, the antibody, e.g., anti-ROR1 antibody, e.g., antigen-binding antibody fragment, is a single-chain fragment, e.g., a single-chain Fv (scFv) fragment. In some aspects, the scFv comprises a V H Area and V L In some embodiments, the antibody, e.g., an anti-ROR1 antibody, e.g., an antigen-binding antibody fragment, is a single domain antibody (sdAb), e.g., a V H It is an antibody containing only the region.

[0158] In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, comprises a V domain comprising heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2), and / or heavy chain complementarity determining region 3 (CDR-H3), as described. H In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, comprises a V domain sequence comprising CDR-H1, CDR-H2, and CDR-H3 as described above. H In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, comprises a V domain sequence comprising light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2), and / or light chain complementarity determining region 3 (CDR-L3), as described. L In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, comprises a V domain sequence comprising CDR-L1, CDR-L2, and CDR-L3 as described above. L It includes the domain sequence, or a sufficient antigen-binding portion.

[0159] In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, comprises a V domain comprising CDR-H1, CDR-H2, and / or CDR-H3 as described. H V comprising the region sequence and including CDR-L1, CDR-L2, and / or CDR-L3 as described L In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, comprises a V region sequence comprising CDR-H1, CDR-H2, and CDR-H3 as described. H V comprising the region sequence and including CDR-L1, CDR-L2, and CDR-L3 as described L Also provided are antibodies and fragments thereof that contain such sequences, e.g., CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3, V ... H , V L, scFv sequences, or other sequences. In some aspects, some of the provided antibodies and fragments thereof have sequences that are at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identical to any of these sequences. In some aspects, some of the provided antibodies and fragments thereof have sequences that are at least 85% or about 85% identical to any of these sequences. In some aspects, some of the provided antibodies and fragments thereof have sequences that are at least 86% or about 86% identical to any of these sequences. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 87% or about 87% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 88% or about 88% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 89% or about 89% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 90% or about 90% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 91% or about 91% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 92% or about 92% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 93% or about 93% sequence identity to any such sequence. In some aspects, among the antibodies and fragments thereof provided are those having sequences with at least 94% or about 94% sequence identity to any such sequence.In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 95% or about 95% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 96% or about 96% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 97% or about 97% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 98% or about 98% sequence identity to any such sequence. In some aspects, some of the provided antibodies and fragments thereof have sequences with at least 99% or about 99% sequence identity to any such sequence.

[0160] In some embodiments, the antibody is H A domain sequence or a sufficient antigen-binding portion thereof, such as a V H In some embodiments, the antibody or antigen-binding fragment is an sdAb that contains only one of the sequences (e.g., CDR-H1, CDR-H2, CDR-H3, and / or CDR-H4). L (unpaired with region)V H The present invention also includes single domain antibodies that contain regions and / or no additional antibody domains or binding sites and that are capable of specifically binding to ROR1.

[0161] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises CDR-H1, CDR-H2, and / or CDR-H3 according to the Kabat numbering. H The region comprises CDR-H1, CDR-H2, and / or CDR-H3 according to Chothia numbering. HThe regions include CDR-H1, CDR-H2, and / or CDR-H3 according to AbM numbering. H The region comprises CDR-H1, CDR-H2, and / or CDR-H3 according to IgBLAST numbering. H The regions include CDR-H1, CDR-H2, and / or CDR-H3 according to Kabat, Chothia, AbM, IMGT, or IgBLAST numbering, or other numbering schemes.

[0162] In some embodiments, the antibody, antigen-binding fragment, receptor (e.g., CAR), conjugate, or binding molecule provided herein comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO:112, 121, 103, or 130. H ) region or V as set forth in SEQ ID NO: 112, 121, 103, or 130 H and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. H V having or having a region H The heavy chain complementarity determining region 1 (CDR-H1), the heavy chain complementarity determining region 2 (CDR-H2), and / or the heavy chain complementarity determining region 3 (CDR-H3) present in the sequence, e.g., H V containing CDR-H1, CDR-H2, and CDR-H3 present in the sequence HIn some embodiments, the antibody, antigen-binding fragment, receptor (e.g., CAR), conjugate, or binding molecule provided herein has a V region having the amino acid sequence set forth in SEQ ID NO: 112 or 121. H region or as set forth in SEQ ID NO: 112 or 121 H and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. H V having or having a region H and / or CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence, e.g., H V containing CDR-H1, CDR-H2, and CDR-H3 present in the sequence H It has an area.

[0163] In some embodiments, the antibody, antigen-binding fragment, receptor (e.g., CAR), conjugate, or binding molecule provided herein comprises a V having the amino acid sequence set forth in SEQ ID NO:112. H region or V as shown in SEQ ID NO:112 H and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. H V having or having a regionH and / or CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence, e.g., H V containing CDR-H1, CDR-H2, and CDR-H3 present in the sequence H In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a V region having the amino acid sequence set forth in SEQ ID NO:121. H region or V as shown in SEQ ID NO:121 H and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. H V having or having a region H and / or CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence, e.g., H V containing CDR-H1, CDR-H2, and CDR-H3 present in the sequence H In some embodiments, the antibody, antigen-binding fragment, receptor (e.g., CAR), conjugate, or binding molecule provided herein has a V region having the amino acid sequence set forth in SEQ ID NO:103. H region or V as shown in SEQ ID NO: 103 H and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence.H V having or having a region H and / or CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence, e.g., H V containing CDR-H1, CDR-H2, and CDR-H3 present in the sequence H In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a V region having the amino acid sequence set forth in SEQ ID NO:130. H region or V as shown in SEQ ID NO:130 H and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. H V having or having a region H and / or CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence, e.g., H V containing CDR-H1, CDR-H2, and CDR-H3 present in the sequence H It has an area.

[0164] In some of the embodiments provided, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 67, 82, or 52. In some of any of the provided embodiments, V H The region comprises a CDR-H2 comprising the sequence set forth in SEQ ID NO: 71, 86, 56, or 97. In some of any of the provided embodiments, V H The region includes a CDR-H3 comprising the sequence shown in SEQ ID NO:73, 88, 58, or 99.

[0165] In some of the embodiments provided, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 65, 80, or 50. In some of any of the provided embodiments, V H The region comprises a CDR-H2 comprising the sequence set forth in SEQ ID NO: 69, 84, 54, or 95. In some of any of the provided embodiments, V H The region includes a CDR-H3 comprising the sequence shown in SEQ ID NO:73, 88, 58, or 99.

[0166] In some of the embodiments provided, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 66, 81, or 51. In some of any of the provided embodiments, V H The region comprises a CDR-H2 comprising the sequence set forth in SEQ ID NO: 70, 85, 55, or 96. In some of any of the provided embodiments, V H The region includes a CDR-H3 comprising the sequence shown in SEQ ID NO:73, 88, 58, or 99.

[0167] In some of the embodiments provided, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 68, 83, or 53. In some of any of the provided embodiments, V H The region comprises a CDR-H2 comprising the sequence set forth in SEQ ID NO: 72, 87, 57, or 98. In some of any of the provided embodiments, V H The region includes a CDR-H3 comprising the sequence shown in SEQ ID NO:74, 89, 59, or 100.

[0168] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V HThe regions include a CDR-H1 comprising the sequence set forth in SEQ ID NO: 67, 82, or 52, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 71, 86, 56, or 97, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include a CDR-H1 comprising the sequence set forth in SEQ ID NO: 65, 80, or 50, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 69, 84, 54, or 95, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include a CDR-H1 comprising the sequence set forth in SEQ ID NO: 66, 81, or 51, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 70, 85, 55, or 96, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include CDR-H1 comprising the sequence set forth in SEQ ID NO: 68, 83, or 53, CDR-H2 comprising the sequence set forth in SEQ ID NO: 72, 87, 57, or 98, and CDR-H3 comprising the sequence set forth in SEQ ID NO: 74, 89, 59, or 100.

[0169] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V HThe regions include a CDR-H1 comprising the sequence set forth in SEQ ID NO: 67 or 82, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 71 or 86, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73 or 88. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include a CDR-H1 comprising the sequence set forth in SEQ ID NO: 65 or 80, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 69 or 84, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73 or 88. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include a CDR-H1 comprising the sequence set forth in SEQ ID NO: 66 or 81, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 70 or 85, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73 or 88. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include CDR-H1 comprising the sequence set forth in SEQ ID NO:68 or 83, CDR-H2 comprising the sequence set forth in SEQ ID NO:72 or 87, and CDR-H3 comprising the sequence set forth in SEQ ID NO:74 or 89.

[0170] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The regions include CDR-H1, CDR-H2, and CDR-H3, comprising the sequences set forth in SEQ ID NOs: 67, 71, and 73, respectively; SEQ ID NOs: 82, 86, and 88, respectively; SEQ ID NOs: 52, 56, and 58, respectively; or SEQ ID NOs: 52, 97, and 99, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, VH The regions include CDR-H1, CDR-H2, and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 65, 69, and 73, respectively; SEQ ID NOs: 80, 84, and 88, respectively; SEQ ID NOs: 50, 54, and 58, respectively; or SEQ ID NOs: 50, 95, and 99, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The regions include CDR-H1, CDR-H2, and CDR-H3, comprising the sequences set forth in SEQ ID NOs: 66, 70, and 73, respectively; SEQ ID NOs: 81, 85, and 88, respectively; SEQ ID NOs: 51, 55, and 58, respectively; or SEQ ID NOs: 51, 96, and 99. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences shown in SEQ ID NOs: 68, 72, and 74, respectively; SEQ ID NOs: 83, 87, and 89, respectively; SEQ ID NOs: 53, 57, and 59, respectively; or SEQ ID NOs: 53, 98, and 100, respectively.

[0171] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences set forth in SEQ ID NOs: 67, 71, and 73, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences set forth in SEQ ID NOs: 65, 69, and 73, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V HThe regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences set forth in SEQ ID NOs: 66, 70, and 73, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 68, 72, and 74, respectively.

[0172] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences set forth in SEQ ID NOs: 82, 86, and 88, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences set forth in SEQ ID NOs: 80, 84, and 88, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences set forth in SEQ ID NOs: 81, 85, and 88, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The regions include CDR-H1, CDR-H2, and CDR-H3, which contain the sequences shown in SEQ ID NOs: 83, 87, and 89, respectively.

[0173] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region may be any one of the V sequences set forth in any one of SEQ ID NOs: 112, 121, 103, or 130. HIn some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region comprises a CDR-H1, a CDR-H2, and a CDR-H3, each of which comprises the amino acid sequence of the CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence. H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO:112 or 121.

[0174] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 112. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 103. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO:130.

[0175] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region includes any of CDR-H1, CDR-H2, and CDR-H3 as described, and is selected from the group consisting of V and VL sequences shown in any one of SEQ ID NOs: 112, 121, 103, or 130. HIn some embodiments, the V region comprises framework region 1 (FR1), FR2, FR3, and / or FR4, each having at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 94%, 95%, 95%, 96%, 96%, 97%, 97%, 98%, 98%, or 99% of the amino acid sequence of FR1, FR2, FR3, and / or FR4 contained within the region. H The region is V as shown in SEQ ID NO:112. H FR1, FR2, FR3, and / or FR4 that have at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 94%, 95%, 95%, 96%, 96%, 97%, 97%, 98%, 98%, or 99% of the amino acid sequence of FR1, FR2, FR3, and / or FR4 contained within the region. H The region is V as shown in SEQ ID NO:121. H FR1, FR2, FR3, and / or FR4 that have at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 94%, 95%, 95%, 96%, 96%, 97%, 97%, 98%, 98%, or 99% of the amino acid sequence of FR1, FR2, FR3, and / or FR4 contained within the region. H The region is V as shown in SEQ ID NO:103.H FR1, FR2, FR3, and / or FR4 that have at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 94%, 95%, 95%, 96%, 96%, 97%, 97%, 98%, 98%, or 99% of the amino acid sequence of FR1, FR2, FR3, and / or FR4 contained within the region. H The region is V as shown in SEQ ID NO:130. H The region includes FR1, FR2, FR3, and / or FR4 that have at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% of the FR1, FR2, FR3, and / or FR4 contained within the amino acid sequence.

[0176] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or comprises the amino acid sequence set forth in any one of SEQ ID NOs: 112, 121, 103, or 130. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The V region is or comprises the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region is HThe V region is or comprises the amino acid sequence set forth in SEQ ID NO: 121. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region is H The V region is or comprises the amino acid sequence set forth in SEQ ID NO: 103. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region is H The region is or includes the amino acid sequence shown in SEQ ID NO:130.

[0177] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region may be identified by SEQ ID NO: 110, 119, 101, or 128, or by SEQ ID or about 99% identity to NDC NO:110, 119, 101, or 128. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or includes the amino acid sequence encoded by SEQ ID NO:111, 120, 102, or 129.

[0178] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or comprises an amino acid sequence encoded by SEQ ID NO:110 or 119 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:110 or 119. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or includes the amino acid sequence encoded by SEQ ID NO:111 or 120.

[0179] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V HThe region is or comprises an amino acid sequence encoded by SEQ ID NO:110 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:110. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or includes the amino acid sequence encoded by SEQ ID NO:111.

[0180] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or includes an amino acid sequence encoded by SEQ ID NO:119 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:119. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V HThe region is or includes the amino acid sequence encoded by SEQ ID NO:120.

[0181] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H A region is or comprises an amino acid sequence encoded by SEQ ID NO:101 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:101. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or includes the amino acid sequence encoded by SEQ ID NO:102.

[0182] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V HThe region is or comprises an amino acid sequence encoded by SEQ ID NO:128 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:128. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or includes the amino acid sequence encoded by SEQ ID NO: 129. Also provided are polynucleotides containing any of the nucleotide sequences described herein (e.g., those encoding all of a portion of the provided binding molecules).

[0183] In some embodiments, the antibody or antibody fragment in the provided CAR (e.g., anti-ROR1 CAR) comprises a light chain or a sufficient antigen-binding portion thereof. For example, in some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain variable (V L ) area or V L In some embodiments, the antibody or antigen-binding fragment thereof comprises a sufficient antigen-binding portion of the V H Region and light chain variable (V L ) area, or V H Area and V L In any such embodiment, the V H The domain sequences are V H In any such embodiment, the V L The domain sequences are V LIn any such embodiment, the V H Any of the region arrays and V L Any combination of region sequences may be used. In some of any such embodiments, a combination of any one or more of the CDR-H1, CDR-H2, and / or CDR-H3 sequences described herein with any one or more of the CDR-L1, CDR-L2, and / or CDR-L3 sequences described herein may be used. In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or scFv. In some embodiments, the antibody or antigen-binding fragment further comprises at least a portion of an immunoglobulin constant region or a variant thereof. In some such embodiments, the antibody is a full-length antibody that also comprises a constant region.

[0184] In some embodiments, the binding molecules provided herein, e.g., receptors, e.g., CARs, are selected from the group consisting of any V L The CAR may comprise an antibody comprising the V region or a sufficient antigen-binding portion thereof, e.g., an anti-ROR1 antibody or antigen-binding fragment thereof. For example, in some embodiments, the CAR may comprise a V H Area and V L Area, or V H Area and V L In any such embodiment, the V H The domain sequences are V H In any such embodiment, the V L The domain sequences are V L In any such embodiment, the V H Any of the region arrays and V LIn some of these embodiments, a combination of any one or more of the CDR-H1, CDR-H2, and / or CDR-H3 sequences described herein with any one or more of the CDR-L1, CDR-L2, and / or CDR-L3 sequences described herein may be used. ... the antibody included in the provided recombinant receptor is an antigen-binding fragment, e.g., a Fab or scFv. In some of these embodiments, the receptor (e.g., a CAR) further comprises a spacer, e.g., a portion of an immunoglobulin constant region or a variant thereof, as described below, e.g., in Section IB.

[0185] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises CDR-L1, CDR-L2, and / or CDR-L3 according to the Kabat numbering system. H The region comprises CDR-L1, CDR-L2, and / or CDR-L3 according to Chothia numbering. H The region comprises CDR-L1, CDR-L2, and / or CDR-L3 according to AbM numbering. H The region comprises CDR-L1, CDR-L2, and / or CDR-L3 according to the IMGT numbering system. H The region comprises CDR-L1, CDR-L2, and / or CDR-L3 according to IgBLAST numbering. H The region includes CDR-L1, CDR-L2, and / or CDR-L3 according to Kabat, Chothia, AbM, IMGT, or IgBLAST numbering, or other numbering schemes.

[0186] In some embodiments, the antibody, antigen-binding fragment, receptor (e.g., CAR), conjugate, or binding molecule provided herein comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO:115, 124, or 106. L ) region or V as set forth in SEQ ID NO: 115, 124, or 106 L and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. L V having or having a region L The V L V containing CDR-L1, CDR-L2, and CDR-L3 present in the sequence L In some embodiments, the antibody, antigen-binding fragment, receptor (e.g., CAR), conjugate, or binding molecule provided herein has a V having the amino acid sequence set forth in SEQ ID NO: 115 or 124. L region or V as set forth in SEQ ID NO: 115 or 124 L and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. LV having or having a region L and / or CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence, e.g., L V containing CDR-L1, CDR-L2, and CDR-L3 present in the sequence L It has an array.

[0187] In some embodiments, the antibody, antigen-binding fragment, receptor (e.g., CAR), conjugate, or binding molecule provided herein comprises a V having the amino acid sequence set forth in SEQ ID NO:115. L region or V as shown in SEQ ID NO:115 L and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. L V having or having a region L and / or CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence, e.g., L V containing CDR-L1, CDR-L2, and CDR-L3 present in the sequence L In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a VV having the amino acid sequence set forth in SEQ ID NO:124. L region or V as shown in SEQ ID NO:124 Land V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. L V having or having a region L and / or CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence, e.g., L V containing CDR-L1, CDR-L2, and CDR-L3 present in the sequence L In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a V having the amino acid sequence set forth in SEQ ID NO:106. L region or V as shown in SEQ ID NO:106 L and V having an amino acid sequence having at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the region amino acid sequence. L V having or having a region L and / or CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence, e.g., L V containing CDR-L1, CDR-L2, and CDR-L3 present in the sequence L It has an array.

[0188] In some of the embodiments provided, V LThe region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60. In some of any of the provided embodiments, V L The region comprises a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62. In some of any of the provided embodiments, V L The region includes a CDR-L3 comprising the sequence shown in SEQ ID NO:79, 94, or 64.

[0189] In some of the embodiments provided, V L The region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 76, 91, or 61. In some of any of the provided embodiments, V L The region comprises a CDR-L2 comprising the sequence set forth in SEQ ID NO: 78, 93, or 63. In some of any of the provided embodiments, V L The region includes a CDR-L3 comprising the sequence shown in SEQ ID NO:79, 94, or 64.

[0190] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The regions include a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V L The regions include CDR-L1 comprising the sequence set forth in SEQ ID NO:76, 91, or 61, CDR-L2 comprising the sequence set forth in SEQ ID NO:78, 93, or 63, and CDR-L3 comprising the sequence set forth in SEQ ID NO:79, 94, or 64.

[0191] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The regions include a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75 or 90, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77 or 92, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79 or 94. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V L The regions include CDR-L1 comprising the sequence set forth in SEQ ID NO:76 or 91, CDR-L2 comprising the sequence set forth in SEQ ID NO:78 or 93, and CDR-L3 comprising the sequence set forth in SEQ ID NO:79 or 94.

[0192] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The regions comprise CDR-L1, CDR-L2, and CDR-L3, comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively; SEQ ID NOs: 90, 92, and 94; SEQ ID NOs: 60, 62, and 64, respectively; or SEQ ID NOs: 60, 62, and 64, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences shown in SEQ ID NOs: 76, 78, and 79, respectively; SEQ ID NOs: 91, 93, and 94, respectively; SEQ ID NOs: 60, 63, and 64, respectively; or SEQ ID NOs: 61, 63, and 64, respectively.

[0193] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V LThe regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences shown in SEQ ID NOs: 76, 78, and 79, respectively.

[0194] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 90, 92, and 94, respectively. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences shown in SEQ ID NOs: 91, 93, and 94, respectively.

[0195] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region is a V region as set forth in any one of SEQ ID NOs: 115, 124, or 106. L In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region comprises a CDR-L1, a CDR-L2, and a CDR-L3, each of which comprises the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within the V region amino acid sequence. L The region includes CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO:115 or 124.

[0196] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 115. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 124. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V L The region includes CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO:106.

[0197] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region includes any of CDR-L1, CDR-L2, and CDR-L3 as described, and is selected from the group consisting of V and VL2, as set forth in any one of SEQ ID NOs: 115, 124, or 106. L 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% of the amino acid sequence of framework region 1 (FR1), FR2, FR3, and / or FR4, respectively, contained within the region. L The region is V as shown in SEQ ID NO:115. LFR1, FR2, FR3, and / or FR4 that have at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% of the amino acid sequence of FR1, FR2, FR3, and / or FR4, respectively, contained within the region. L The region is V as shown in SEQ ID NO:124. L FR1, FR2, FR3, and / or FR4 that have at least 85% or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% of the amino acid sequence of FR1, FR2, FR3, and / or FR4, respectively, contained within the region. L The region is V shown in SEQ ID NO:106. L The region includes FR1, FR2, FR3, and / or FR4 that have at least 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 96%, 97%, 97%, 98%, or 98%, or 99% of the amino acid sequence of each of FR1, FR2, FR3, and / or FR4 contained within the region.

[0198] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region is or comprises the amino acid sequence set forth in any one of SEQ ID NOs: 115, 124, or 106. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V L The V region is or comprises the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region is L The V region is or comprises the amino acid sequence set forth in SEQ ID NO: 124. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region is L The region is or includes the amino acid sequence set forth in SEQ ID NO:106.

[0199] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V LThe region is or comprises an amino acid sequence encoded by SEQ ID NO:113, 122, or 104, or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:113, 122, or 104. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region is or includes the amino acid sequence encoded by SEQ ID NO:114, 123, 105, or 131.

[0200] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V LThe region is or comprises an amino acid sequence encoded by SEQ ID NO:113 or 122 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:113 or 122. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region is or includes the amino acid sequence encoded by SEQ ID NO:114 or 123.

[0201] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region is or comprises an amino acid sequence encoded by SEQ ID NO:113 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:113. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, VL The region is or includes the amino acid sequence encoded by SEQ ID NO:114.

[0202] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region is or comprises an amino acid sequence encoded by SEQ ID NO:122 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:122. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The region is or includes the amino acid sequence encoded by SEQ ID NO:123.

[0203] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V LThe region is or comprises an amino acid sequence encoded by SEQ ID NO:104 or by a nucleic acid sequence having at least or about 80%, 81%, or about 81%, 82%, or about 82%, 83%, or about 83%, 84%, or about 84%, 85%, or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95% or about 95%, 96%, or about 96%, 97%, or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:104. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V L The V region is or comprises the amino acid sequence encoded by SEQ ID NO: 105. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V region is L The region is or includes the amino acid sequence encoded by SEQ ID NO:131.

[0204] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable (V H ) region and the light chain variable (V L In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V HThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 112, 121, 103, or 130, and L The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:115, 124, or 106. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or comprises an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO: 112 or 121, L The region is or comprises an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to SEQ ID NO:115 or 124.

[0205] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 115; H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO: 124; H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:106; or HThe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and L The region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106.

[0206] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:112, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 115. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:121, and L The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 124. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V HThe region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:103, and L The region is or comprises an amino acid sequence having at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 106. In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region is or comprises an amino acid sequence having at least at or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:130, and LThe region is or comprises an amino acid sequence having at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:106.

[0207] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, the V H The region is selected from any one of SEQ ID NOs: 112, 121, 103, or 130. H a CDR-H1, CDR-H2, or CDR-H3 region selected from any one of SEQ ID NOs: 115, 124, or 106, each of which contains an amino acid sequence of CDR-H1, CDR-H2, or CDR-H3, respectively; L In some of any such embodiments, the V region includes CDR-L1, CDR-L2, and CDR-L3, each of which includes the amino acid sequence of CDR-L1, CDR-L2, and CDR-L3 contained within the V region amino acid sequence. H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 112 or 121, and L The region includes CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO:115 or 124.

[0208] In some of any such embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 112, and LThe region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 115. In some of any such embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 121, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 124. In some of any such embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 103, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO: 106. In some of any such embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained in SEQ ID NO: 130, and L The region includes CDR-L1, CDR-L2, and CDR-L3 contained in SEQ ID NO:106.

[0209] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in SEQ ID NO: 67, 82, or 52, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in SEQ ID NO: 71, 86, 56, or 97, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99, and L The regions include light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in SEQ ID NO: 79, 94, or 64.

[0210] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 65, 80, or 50, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 69, 84, 54, or 95, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99, and V L the region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or

[0211] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 66, 81, or 51, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 70, 85, 55, or 96, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58, or 99, and V L the region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 75, 90, or 60, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 77, 92, or 62, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94, or 64; or

[0212] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 68, 83, or 53, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 72, 87, 57, or 98, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 74, 89, 59, or 100, andL The regions include CDR-L1 comprising the sequence set forth in SEQ ID NO:76, 91, or 61, CDR-L2 comprising the sequence set forth in SEQ ID NO:78, 93, or 63, and CDR-L3 comprising the sequence set forth in SEQ ID NO:79, 94, or 64.

[0213] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 67 or 82, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 71 or 86, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73 or 88, and L The regions include CDR-L1 comprising the sequence shown in SEQ ID NO:75 or 90, CDR-L2 comprising the sequence shown in SEQ ID NO:77 or 92, and CDR-L3 comprising the sequence shown in SEQ ID NO:79 or 94.

[0214] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 65 or 80, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 69 or 84, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73 or 88, and L The regions include CDR-L1 comprising the sequence shown in SEQ ID NO:75 or 90, CDR-L2 comprising the sequence shown in SEQ ID NO:77 or 92, and CDR-L3 comprising the sequence shown in SEQ ID NO:79 or 94.

[0215] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V HThe region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 66 or 81, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 70 or 85, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73 or 88, and L The regions include CDR-L1 comprising the sequence shown in SEQ ID NO:75 or 90, CDR-L2 comprising the sequence shown in SEQ ID NO:77 or 92, and CDR-L3 comprising the sequence shown in SEQ ID NO:79 or 94.

[0216] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 68 or 83, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 72 or 87, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 74 or 89, and L The regions include CDR-L1 comprising the sequence set forth in SEQ ID NO:76 or 91, CDR-L2 comprising the sequence set forth in SEQ ID NO:78 or 93, and CDR-L3 comprising the sequence set forth in SEQ ID NO:79 or 94.

[0217] In some embodiments of the antibodies, antigen-binding fragments, receptors (e.g., CARs), conjugates, or binding molecules provided herein, V H The regions comprise heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2), and heavy chain complementarity determining region 3 (CDR-H3), each comprising the sequences set forth in SEQ ID NOs: 67, 71, and 73, respectively; and V L whether the region comprises light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2), and light chain complementarity determining region 3 (CDR-L3), each comprising the sequences set forth in SEQ ID NOs: 75, 77, and 79; V HThe regions include CDR-H1, CDR-H2, and CDR-H3, which comprise the sequences set forth in SEQ ID NOs: 82, 86, a...

Claims

1. Heavy chain variable (V H ) region and the light chain variable (V L ) region, Applicable V H The V region comprises heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2) and heavy chain complementarity determining region 3 (CDR-H3) consisting of the sequences shown in SEQ ID NOs: 67, 71 and 73, respectively, according to the Kabat numbering scheme; L the regions comprising light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3) consisting of the sequences set forth in SEQ ID NOs: 75, 77 and 79, respectively, according to the Kabat numbering scheme; An anti-ROR1 antibody or an antigen-binding fragment thereof.

2. The above V H The region is or comprises an amino acid sequence having at least 90% identity to SEQ ID NO:112, and L The anti-ROR1 antibody or antigen-binding fragment thereof of claim 1, wherein the region is or comprises an amino acid sequence having at least 90% identity to SEQ ID NO:

115.

3. Heavy chain variable (V H ) region and the light chain variable (V L ) region, Applicable V H The region is or comprises the amino acid sequence shown in SEQ ID NO: 112, and L The region is or comprises the amino acid sequence set forth in SEQ ID NO: 115, An anti-ROR1 antibody or an antigen-binding fragment thereof.

4. The anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, wherein the antibody is a full-length antibody or an antigen-binding fragment.

5. The anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein the antigen-binding fragment comprises a single-chain Fv (scFv).

6. The anti-ROR1 antibody or antigen-binding fragment thereof of claim 5, wherein the scFv comprises an amino acid sequence shown in SEQ ID NO:118 or having at least 90% sequence identity to SEQ ID NO:

118.

7. A single-chain cell surface protein comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6.

8. A conjugate comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, or a single-chain cell surface protein according to claim 7, and a heterologous molecule or moiety.

9. An anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, or a single-chain cell surface protein according to claim 7, a transmembrane region, and an intracellular signaling region.

10. The anti-ROR1 chimeric antigen receptor of claim 9, further comprising a spacer between the extracellular antigen binding domain and the transmembrane region.

11. The anti-ROR1 chimeric antigen receptor of claim 10, wherein the spacer comprises at least a portion of an immunoglobulin hinge region or a variant thereof.

12. The anti-ROR1 chimeric antigen receptor of claim 10 or 11, wherein the spacer comprises an amino acid sequence having at least 90% identity to SEQ ID NO:1, 26, 27, 29, 31, 32, 33 or 135.

13. The anti-ROR1 chimeric antigen receptor of claim 11 or 12, wherein the hinge region comprises all or a portion of an IgG4 hinge region, or a variant thereof.

14. The anti-ROR1 chimeric antigen receptor of any one of claims 10 to 13, wherein the spacer comprises the sequence shown in SEQ ID NO:

135.

15. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 14, wherein the transmembrane region is or comprises a transmembrane domain derived from CD28.

16. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 15, wherein the transmembrane region comprises a transmembrane domain derived from human CD28.

17. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 16, wherein the transmembrane region is or comprises SEQ ID NO:8 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:

8.

18. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 17, wherein the transmembrane region comprises SEQ ID NO:

8.

19. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 18, wherein the intracellular signaling region is or comprises the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain.

20. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 19, wherein the intracellular signaling region is or comprises an amino acid sequence set forth in SEQ ID NO: 13, 14, or 15, or an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 13, 14, or 15.

21. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 20, wherein the intracellular signaling region is or comprises the sequence shown in SEQ ID NO:

13.

22. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 21, wherein the intracellular signaling region further comprises a costimulatory signaling region.

23. The anti-ROR1 chimeric antigen receptor of claim 22, wherein the costimulatory signaling region is between the transmembrane region and the intracellular signaling region.

24. The anti-ROR1 chimeric antigen receptor of claim 22 or 23, wherein the costimulatory signaling region comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

25. The anti-ROR1 chimeric antigen receptor of any one of claims 22 to 24, wherein the costimulatory signaling region comprises the intracellular signaling domain of CD28, 4-1BB, or ICOS.

26. The anti-ROR1 chimeric antigen receptor of any one of claims 22 to 25, wherein the costimulatory signaling region comprises the intracellular signaling domain of CD28.

27. The anti-ROR1 chimeric antigen receptor of any one of claims 22 to 25, wherein the costimulatory signaling region comprises the intracellular signaling domain of 4-1BB.

28. The anti-ROR1 chimeric antigen receptor of any one of claims 22 to 25 and 27, wherein the costimulatory signaling region is or comprises the sequence shown in SEQ ID NO:12 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:

12.

29. The anti-ROR1 chimeric antigen receptor of any one of claims 10 to 28, wherein the chimeric antigen receptor comprises, in order from its N-terminus to its C-terminus, the extracellular antigen-binding domain, the spacer, the transmembrane region, and the intracellular signaling region.

30. An anti-ROR1 chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising an anti-ROR1 antibody or an antigen-binding fragment thereof, a spacer, a transmembrane region, and an intracellular signaling region, the anti-ROR1 antibody or antigen-binding fragment thereof comprises CDR-H1, CDR-H2, and CDR-H3 consisting of the sequences set forth in SEQ ID NOs: 67, 71, and 73, respectively, according to the Kabat numbering scheme, and CDR-L1, CDR-L2, and CDR-L3 consisting of the sequences set forth in SEQ ID NOs: 75, 77, and 79, respectively, according to the Kabat numbering scheme; the spacer comprises the amino acid sequence shown in SEQ ID NO: 135; the transmembrane domain comprises the amino acid sequence shown in SEQ ID NO:8; The intracellular signaling region comprises the amino acid sequence shown in SEQ ID NO:

13. Anti-ROR1 chimeric antigen receptor (CAR).

31. The anti-ROR1 chimeric antigen receptor of any one of claims 10 to 29, wherein the antigen-binding domain is an scFv, and the encoded chimeric antigen receptor comprises, in order from its N-terminus to its C-terminus, an extracellular antigen-binding domain comprising the scFv; a spacer comprising a modified IgG4 hinge-CH3; a transmembrane domain; and an intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and the intracellular signaling domain of a costimulatory signaling region.

32. The anti-ROR1 chimeric antigen receptor of any one of claims 9 to 31, which is or comprises the sequence shown in SEQ ID NO: 184 or a sequence exhibiting at least 90% sequence identity to the sequence shown in SEQ ID NO:

184.

33. A polynucleotide comprising a nucleic acid encoding the anti-ROR1 antibody or its antigen-binding domain according to any one of claims 1 to 6.

34. A polynucleotide comprising a nucleic acid encoding the anti-ROR1 chimeric antigen receptor of any one of claims 9 to 32.

35. A vector comprising the polynucleotide of claim 33 or 34.

36. 36. The vector of claim 35, which is a viral vector.

37. A cell comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, a chimeric antigen receptor according to any one of claims 9 to 32, a polynucleotide according to claim 33 or 34, or a vector according to claim 35 or 36.

38. 38. The cell of claim 37, which is a lymphocyte.

39. 39. The cell of claim 37 or 38, which is a NK cell or a T cell.

40. 37. A T cell comprising a chimeric antigen receptor according to any one of claims 9 to 32, or a polynucleotide according to claim 33 or 34, or a vector according to claim 35 or 36.

41. 41. The cell of claim 39 or 40, wherein the cell is a T cell, and the T cell is a CD4+ T cell or a CD8+ T cell.

42. The cell of any one of claims 37 to 41, which is a primary cell obtained from a subject.

43. A composition comprising a cell according to any one of claims 37 to 42.

44. A composition comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, a chimeric antigen receptor according to any one of claims 9 to 32, a polynucleotide according to claim 33 or 34, or a vector according to claim 35 or 36.

45. 45. The composition of claim 43 or 44, further comprising a pharma- ceutically acceptable excipient.

46. The composition of claim 43 or 45, wherein the composition comprises CD4+ T cells and CD8+ T cells, and the ratio of the CD4+ T cells to the CD8+ T cells is 1:3 to 3:

1.

47. The composition of any one of claims 43, 45, and 46, wherein among the plurality of cells in the composition, less than 10% of the cells comprise an anti-ROR1 chimeric antigen receptor that exhibits tonic signaling and / or antigen-independent activity or signaling.

48. A cell according to any one of claims 37 to 42 or a composition according to any one of claims 43 to 47 for use in the treatment of a disease or disorder associated with ROR1.

49. Use of a cell according to any one of claims 37 to 42 or a composition according to any one of claims 43 to 47 for the manufacture of a medicament for the treatment of a disease or disorder associated with ROR1.

50. An anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, a single chain cell surface protein according to claim 7, a conjugate according to claim 8, an anti-ROR1 chimeric antigen receptor according to any one of claims 9 to 32, a polynucleotide according to claim 33 or 34, a vector according to claim 35 or 36, a cell according to any one of claims 37 to 42, or a composition according to any one of claims 43 to 47 for use in the treatment of a disease or disorder associated with ROR1.

51. 50. The use of claim 49, wherein the disease or disorder associated with ROR1 is cancer.

52. 52. The use of claim 51, wherein the cancer is a ROR1-expressing cancer.

53. 53. The use of claim 51 or 52, wherein the cancer is associated with a ROR1-expressing solid tumor or a ROR1-expressing hematological malignancy.

54. The use of any one of claims 51 to 53, wherein the cancer is associated with a solid tumor that expresses ROR1.

55. 55. The use according to claim 53 or 54, wherein the cancer associated with a solid tumor is selected from the group consisting of neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, myeloma, gastric cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

56. 56. The use of claim 55, wherein the cancer associated with a solid tumor is lung cancer, and the lung cancer is NSCLC.

57. 56. The use of claim 55, wherein the cancer associated with a solid tumor is breast cancer, and the breast cancer is triple-negative breast cancer (TNBC).

58. 54. The use of any one of claims 51 to 53, wherein the cancer is associated with a hematological malignancy that expresses ROR1.

59. 59. The use of claim 58, wherein the hematological malignancy is selected from the group consisting of B-cell leukemia, lymphoma, B-cell chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), Burkitt's lymphoma or mantle cell lymphoma (MCL).

60. A kit comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, a single-chain cell surface protein according to claim 7, a conjugate according to claim 8, an anti-ROR1 chimeric antigen receptor according to any one of claims 9 to 32, a polynucleotide according to claim 33 or 34, a vector according to claim 35 or 36, a cell according to any one of claims 37 to 42, or a composition according to any one of claims 43 to 47.

61. 61. The kit of claim 60 for use in treating a subject with cancer.

62. 13. An article of manufacture comprising an anti-ROR1 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, a single chain cell surface protein according to claim 7, a conjugate according to claim 8, an anti-ROR1 chimeric antigen receptor according to any one of claims 9 to 32, a polynucleotide according to claim 33 or 34, a vector according to claim 35 or 36, a cell according to any one of claims 37 to 42, or a composition according to any one of claims 43 to 47.

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