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

Abstract

Provided are receptor tyrosine kinase-like orphan receptor 1 (ROR1)-binding molecules, in particular, to human antibodies specific for ROR1, including antibody fragments. The present disclosure further relates to recombinant receptors, including chimeric antigen receptors (CARs) that contain such antibodies or fragments, and polynucleotides that encode the antibodies, antigen-binding fragments or receptors specific for ROR1. The disclosure further relates to genetically engineered cells, containing such ROR1 -binding proteins and receptors, and related methods and uses thereof in adoptive cell therapy.

Description

ANTIBODIES AND CHIMERIC ANTIGEN RECEPTORS SPECIFIC FOR RECEPTOR TYROSINE KINASE LIKE ORPHAN RECEPTOR 1 (ROR1) Cross-Reference to Related Applications

[0001] This application claims priority from U.S. provisional 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. Incorporation by Reference of Sequence Listing

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 735042017740SeqList.txt, created January 28, 2020, which is 225 kilobytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. Field

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

[0004] Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane receptor expressed during embryogenesis, but typically not in normal adult cells. ROR1, however, is expressed in the context of a variety of different cancers, and in some cases, 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. Improved ROR1-binding molecules and engineered ROR1-binding receptor-expressing cells are needed. Provided are embodiments that meet such needs. Summary

[0005] Provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vy) region, and a light chain variable (V1) region, wherein: (i) the Vy region contains a heavy chain complementarity determining region 1 (CDR-H1) containing the sequence set forth in SEQ ID NO: 67, 82 or 52, a heavy chain complementarity determining region 2 (CDR-H2) containing the sequence set forth in SEQ ID NO: 71, 86, 56 or 97, and a heavy chain complementarity determining region 3 (CDR-H3) containing the sequence set forth in SEQ ID NO: 73, 88, 58 or 99, and the V1. region contains a light chain complementarity determining region 1 (CDR-L1) containing the sequence set forth in SEQ ID NO: 75, 90 or 60, a light chain complementarity determining region 2 (CDR-L2) containing the sequence set forth in SEQ ID NO: 77, 92 or 62; and a light chain complementarity determining region 3 (CDR-L3) containing the sequence set forth in SEQ ID NO: 79, 94 or 64; or (ii) the Vy region contains a CDR-H1 containing the sequence set forth in SEQ ID NO: 65, 80 or 50, a CDR-H2 containing the sequence set forth in SEQ ID NO: 69, 84, 54 or 95, and a CDR-H3 containing the sequence set forth in SEQ ID NO: 73, 88, 58 or 99, and the Vy region contains a CDR-L1 containing the sequence set forth in SEQ ID NO: 75, 90 or 60, a CDR-L2 containing the sequence set forth in SEQ ID NO: 77, 92 or 62; and a CDR-L3 containing the sequence set forth in SEQ ID NO: 79, 94 or 64; or (iii) the Vu region contains a CDR-H1 containing the sequence set forth in SEQ ID NO: 66, 81 or 51, a CDR-H2 containing the sequence set forth in SEQ ID NO: 70, 85, 55 or 96, and a CDR-H3 containing the sequence set forth in SEQ ID NO: 73, 88, 58 or 99, and the Vi region contains a CDR-L1 containing the sequence set forth in SEQ ID NO: 75, 90 or 60, a CDR-L2 containing the sequence set forth in SEQ ID NO: 77, 92 or 62; and a CDR-L3 containing the sequence set forth in SEQ ID NO: 79, 94 or 64; or (iv) the Vy region contains a CDR-H1 containing the sequence set forth in SEQ ID NO: 68, 83 or 53, a CDR-H2 containing the sequence set forth in SEQ ID NO: 72, 87, 57 or 98, and a CDR-H3 containing the sequence set forth in SEQ ID NO: 74, 89, 59 or 100, and the Vy region contains a CDR-L1 containing the sequence set forth in SEQ ID NO: 76, 91 or 61, a CDR-L2 containing the sequence set forth in SEQ ID NO: 78, 93 or 63; and a CDR-L3 containing the sequence set forth in SEQ ID NO: 79, 04 or 64.

[0006] Also provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vg) region, and a light chain variable (V1) region, wherein: (i) the Va region contains 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) containing the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the Vi. region contains 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) containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:52, 56 and 58, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vy region contains a CDR-H1, a CDR-H2 and a CDR- H3 containing the sequence set forth in SEQ ID NOS:52, 97 and 99, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; (ii) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:65, 69 and 73, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vy region contains a CDR-HI, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:80, 84 and 88, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vi region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:50, 54 and 58, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vg region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:50, 95 and 99, respectively, and the Vi. region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; (iii) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:66, 70 and 73, respectively, and the Vi. region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:81, 85 and 88, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:51, 55 and 58, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vg region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:51, 96 and 99, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; (iv) the Vy region contains a CDR-H1, a CDR-H2 and a CDR- H3 containing the sequence set forth in SEQ ID NOS:68, 72 and 74, respectively, and the V1 region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:76, 78 and 79, respectively; or the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:83, 87 and 89, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:91, 93 and 94, respectively; the Vy region contains a CDR-HI1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:53, 57 and 59, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 63 and 64, respectively; or the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:53, 98 and 100, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:61, 63 and 64, respectively.

[0007] In some of any such embodiments: (i) the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the VL region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; (ii) the Vi region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:65, 69 and 73, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; (iii) the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:66, 70 and 73, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; or (iv) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:68, 72 and 74, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:76, 78 and 79, respectively.

[0008] In some of any such embodiments: (i) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the Vi. region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; (ii) the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:80, 84 and 88, respectively, and the Vi. region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; (iii) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:81, 85 and 88, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; or (iv) the Vu region contains a CDR-HI1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:83, 87 and 89, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:91, 93 and 94, respectively.

[0009] In some of any embodiments, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR- H3 comprising the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the V1 region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively. In some of any embodiments, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively. In some of any such embodiments, the Vu region comprises a CDR- HI, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 56 and 58, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively. In some of any such embodiments, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 97 and 99, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0010] Also provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vg) region and a light chain variable (V1) region, wherein: the Vu region contains 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 within SEQ ID NO: 112, 121, 103 or 130, and the Vy region contains 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) contained within SEQ ID NO: 115, 124 or 106.

[0011] Also provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vy) region and a light chain variable (V1) region, wherein: the Vu region contains 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 within SEQ ID NO:112, and the Vy region contains 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) contained within SEQ ID NO:115; the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121, and the V1. region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 124; the Vg region contains a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:103, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106; or the Vg region contains a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:130, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106.

[0012] In some of any such embodiments, the Vu region contains a CDR-HI, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112, and the Vy. region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 115. In some of any such embodiments, the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 124. In some of any embodiments, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:103, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106. In some of any embodiments, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:130, and the Vy. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106.

[0013] In some of any such embodiments, the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, 121, 103 or 130, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115, 124 or 106. In some of any such embodiments, the Vu region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the VL region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115; the Vu region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124; the Vg region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98% or 99% identity to SEQ ID NO:106; or the Vi region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the V1 region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106.

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

[0015] Also provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vg) region and a light chain variable (V1) region, wherein: the Vu region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, 121, 103 or 130, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115, 124 or 106.

[0016] Also provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vy) region and a light chain variable (V1) region, wherein: the Vu region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the VL region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115; the Vu region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124; the Vg region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106; or the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106.

[0017] In some of any such embodiments, the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the V1 region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115. In some of any such embodiments, the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124.

[0018] In some of any such embodiments: the Vi region is or contains the sequence set forth in SEQ ID NO: 112, 121, 103 or 130, and the Vy region is or contains the sequence set forth in SEQ ID NO: 115, 124 or 106. In some of any such embodiments: the Vy region and the Vy. region are or contain the sequence set forth in SEQ ID NOS: 112 and 115, respectively; the Vi region and the Vy region are or contain the sequence set forth in SEQ ID NOS: 121 and 124, respectively; the Vy region and the Vi region are or contain the sequence set forth in SEQ ID NOS: 103 and 106, respectively; or the Vu region and the Vi region are or contain the sequence set forth in SEQ ID NOS: 130 and 106, respectively.

[0019] Also provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vy) region and a light chain variable (V1) region, wherein: the Vu region is or contains the sequence set forth in SEQ ID NO: 112, 121, 103 or 130, and the Vy region is or contains the sequence set forth in SEQ ID NO: 115, 124 or 106.

[0020] Also provided herein is an anti-ROR1 antibody or antigen-binding fragment thereof, containing: a heavy chain variable (Vg) region and a light chain variable (V1) region, wherein: the Vy region and the Vy region are or contain the sequence set forth in SEQ ID NOS: 112 and 115, respectively; the Vy region and the Vy region are or contain the sequence set forth in SEQ ID NOS: 121 and 124, respectively; the Vu region and the Vy region are or contain the sequence set forth in SEQ ID NOS: 103 and 106, respectively; or the Vi region and the Vy region are or contain the sequence set forth in SEQ ID NOS: 130 and 106, respectively.

[0021] In some of any such embodiments, the Vy region and the Vy. region are or contain the sequence set forth in SEQ ID NOS: 112 and 115, respectively. In some of any such embodiments, the Vy region and the Vy region are or contain the sequence set forth in SEQ ID NOS:121 and 124, respectively. In some of any embodiments, the Vy region and the V1 region are or comprise the sequence set forth in SEQ ID NOS: 103 and 106, respectively. In some of any embodiments, the Vi region and the Vy region are or comprise the sequence set forth in SEQ ID NOS:130 and 106, respectively.

[0022] In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 110, 119, 101 or 128 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, 119, 101 or 128, and the V1 region is or contains the amino acid sequence encoded by SEQ ID NO: 113, 122 or 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 81%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113, 122 or 104. In some of any such embodiments, the Vu region is or contains the amino acid sequence encoded by SEQ ID NO: 111, 120, 102 or 129, and the V1. region is or contains the amino acid sequence encoded by SEQ ID NO: 114, 123, 105 or 131. In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 110 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, and the Vi, region is or contains the amino acid sequence encoded by SEQ ID NO: 113, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113. In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 111, and the V1. region is or contains the amino acid sequence encoded by SEQ ID NO: 114. In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 119 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 119, and the VL region is or contains the amino acid sequence encoded by SEQ ID NO: 122, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 122. In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 120, and the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 123.

[0023] In some of any embodiments, the antibody is a full length antibody. In some of any embodiments, the antibody is an antigen-binding fragment. In some of any such embodiments, said anti- RORI antibody or antigen-binding fragment thereof is isolated. In some of any such embodiments, said anti-RORI antibody or antigen-binding fragment thereof is recombinant. In some of any such embodiments, at least a portion of the Vy region and the Vy region is human or is from a human protein. In some of any such embodiments, the antigen-binding fragment thereof is or contains a single chain fragment. In some of any such embodiments, the antigen-binding fragment thereof is or contains a single chain Fv (scFv).

[0024] In some of any such embodiments, the Vy region is amino-terminal to the Vi region. In some of any such embodiments, the Vy region is carboxy-terminal to the Vi region. In some of any such embodiments, the Vu region and the V1 region are joined by a flexible linker. In some of any such embodiments, the flexible linker contains the sequence set forth in SEQ ID NO:41.

[0025] In some of any such embodiments, the scFv is or contains the sequence set forth in SEQ ID NO: 118, 127, 109 or 134, or an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 118, 127, 109 or 134. In some of any such embodiments, the scFv is or contains the sequence set forth in SEQ ID NO: 118. In some of any such embodiments, the scFv is or contains 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 or contains the amino acid sequence encoded by SEQ ID NO: 116, 125, 107 or 132 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 116, 125, 107 or 132. In some of any such embodiments, the scFv is or contains the amino acid sequence encoded by SEQ ID NO: 117, 126, 108 or 133. In some of any such embodiments, the scFv is or contains the amino acid sequence encoded by SEQ ID NO: 116 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 116. In some of any such embodiments, the scFv is or contains the amino acid sequence encoded by SEQ ID NO: 117. In some of any such embodiments, the scFv is or contains the amino acid sequence encoded by SEQ ID NO: 125 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 125. In some of any such embodiments, the scFv is or contains the amino acid sequence encoded by SEQ ID NO: 126.

[0027] In some of any such embodiments, the anti-ROR1 antibody or fragment further contains at least a portion of an immunoglobulin constant region or a variant thereof. In some of any such embodiments, the portion of an immunoglobulin constant region contains at least a portion of a hinge region or a variant thereof. In some of any such embodiments, the at least a portion of an immunoglobulin constant region or a variant thereof contains at least a portion of a Cu2 region or a variant thereof. In some of any such embodiments, the at least a portion of an immunoglobulin constant region or a variant thereof contains at least a portion of a Cu3 region or a variant thereof. In some of any such embodiments, the at least a portion of an immunoglobulin constant region or a variant thereof contains at least a portion of a Cu2 region and / or a Cu3 region or a variant thereof. In some of any such embodiments, the at least a portion of an immunoglobulin constant region or a variant thereof is human or from a human protein or a variant thereof.

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

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

[0030] In some of any such embodiments, said anti-ROR1 antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower level or degree or affinity to a Receptor tyrosine kinase-like orphan receptor 2 (ROR2) protein. In some of any such embodiments, said anti-ROR1 antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower level or degree or affinity to a human ROR2 protein. In some of any such embodiments, the extent, level or degree or affinity of binding of said anti-RORI1 antibody or antigen-binding fragment thereof to a human ROR? is at least at or about 75%, 80%, 90%, 95% or 99% less than the extent, level or degree or affinity of binding to a human ROR1 protein.

[0031] In some of any embodiments, the antibody or antigen-binding fragment thereof binds to human ROR! protein with an equilibrium dissociation constant (Kp) of from about 1 x 10"! M to about 1 x 107 M. In some of any embodiments, the antibody or antigen-binding fragment thereof binds to human ROR! protein with an equilibrium dissociation constant (Kp) of from about 1 x 10 M to about 1 x 107 M. In some of any embodiments, the antibody or antigen-binding fragment thereof binds to human ROR protein with an equilibrium dissociation constant (Kp) of from about 5 x 10"! M to about 1 x 101° M.

[0032] In some of any embodiments, the antibody or antigen-binding fragment thereof binds to human ROR1 protein with an dissociation rate constant (ks or kez) of from about 1 x 10” 1 / s to about 1 x 102 1 / s. In some of any embodiments, the antibody or antigen-binding fragment thereof binds to human ROR! protein with an dissociation rate constant (ke or ket) of from about 1 x 10 1 / s to about 1 x 10? 1 / s. In some of any embodiments, the antibody or antigen-binding fragment thereof binds to human ROR1 protein with an dissociation rate constant (ks or keg) of from about 1 x 10° 1 / s to about 1 x 10 1 / s.

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

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

[0035] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing an extracellular antigen-binding domain containing the 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) containing an extracellular antigen-binding domain containing 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] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vg) region, and a light chain variable (V1) region, and an intracellular signaling region, wherein: (i) the Vi region contains a heavy chain complementarity determining region 1 (CDR-H1) containing the sequence set forth in SEQ ID NO: 67, 82 or 52, a heavy chain complementarity determining region 2 (CDR-H2) containing the sequence set forth in SEQ ID NO: 71, 86, 56 or 97, and a heavy chain complementarity determining region 3 (CDR- H3) containing the sequence set forth in SEQ ID NO: 73, 88, 58 or 99, and the Vy, region contains a light chain complementarity determining region 1 (CDR-L1) containing the sequence set forth in SEQ ID NO: 75, 90 or 60, a light chain complementarity determining region 2 (CDR-L2) containing the sequence set forth in SEQ ID NO: 77, 92 or 62; and a light chain complementarity determining region 3 (CDR-L3) containing the sequence set forth in SEQ ID NO: 79, 94 or 64; or (ii) the Vu region contains a CDR-H1 containing the sequence set forth in SEQ ID NO: 65, 80 or 50, a CDR-H2 containing the sequence set forth in SEQ ID NO: 69, 84, 54 or 95, and a CDR-H3 containing the sequence set forth in SEQ ID NO: 73, 88, 58 or 99, and the Vy region contains a CDR-L1 containing the sequence set forth in SEQ ID NO: 75, 90 or 60, a CDR-L2 containing the sequence set forth in SEQ ID NO: 77, 92 or 62; and a CDR-L3 containing the sequence set forth in SEQ ID NO: 79, 94 or 64; or (iii) the Vu region contains a CDR-H1 containing the sequence set forth in SEQ ID NO: 66, 81 or 51, a CDR-H2 containing the sequence set forth in SEQ ID NO: 70, 85, 55 or 96, and a CDR-H3 containing the sequence set forth in SEQ ID NO: 73, 88, 58 or 99, and the Vy. region contains a CDR-L1 containing the sequence set forth in SEQ ID NO: 75, 90 or 60, a CDR-L2 containing the sequence set forth in SEQ ID NO: 77, 92 or 62; and a CDR-L3 containing the sequence set forth in SEQ ID NO: 79, 94 or 64; or (iv) the Vy region contains a CDR-H1 containing the sequence set forth in SEQ ID NO: 68, 83 or 53, a CDR-H2 containing the sequence set forth in SEQ ID NO: 72, 87, 57 or 98, and a CDR-H3 containing the sequence set forth in SEQ ID NO: 74, 89, 59 or 100, and the Vy region contains a CDR-L1 containing the sequence set forth in SEQ ID NO: 76, 91 or 61, a CDR-L2 containing the sequence set forth in SEQ ID NO: 78, 93 or 63; and a CDR-L3 containing the sequence set forth in SEQ ID NO: 79, 94 or 64.

[0038] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vg) region, and a light chain variable (V1) region, and an intracellular signaling region, wherein: (i) the Vu region contains 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) containing the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the Vy region contains 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) containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the VL region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vu region contains a CDR-HI1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:52, 56 and 58, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:52, 97 and 99, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; (ii) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:65, 69 and 73, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vi region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:80, 84 and 88, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vi region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:50, 54 and 58, respectively, and the Vi. region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:50, 95 and 99, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; (iii) the Vi region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:66, 70 and 73, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Va region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:81, 85 and 88, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vi region contains a CDR-HI, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:51, 55 and 58, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:51, 96 and 99, respectively, and the Vi. region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; (iv) the Vg region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:68, 72 and 74, respectively, and the V1 region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:76, 78 and 79, respectively; or the Vi region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:83, 87 and 89, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:91, 93 and 94, respectively; the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:53, 57 and 59, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:60, 63 and 64, respectively; or the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:53, 98 and 100, respectively, and the Vi region contains a CDR-L1I, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:61, 63 and 64, respectively.

[0039] In some of any such embodiments: (i) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the VL region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; (ii) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:65, 69 and 73, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; (iii) the Vg region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:66, 70 and 73, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; or (iv) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:68, 72 and 74, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:76, 78 and 79, respectively.

[0040] In some of any such embodiments: (i) the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the VL region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; (ii) the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:80, 84 and 88, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; (iii) the Vu region contains a CDR-H1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:81, 85 and 88, respectively, and the Vi region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; or (iv) the Vu region contains a CDR-HI1, a CDR-H2 and a CDR-H3 containing the sequence set forth in SEQ ID NOS:83, 87 and 89, respectively, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 containing the sequence set forth in SEQ ID NOS:91, 93 and 94, respectively.

[0041] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vg) region and a light chain variable (V1) region, and an intracellular signaling region, wherein: the Vy region contains 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 within SEQ ID NO: 112, 121, 103 or 130, and the Vy region contains 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) contained within SEQ ID NO: 115, 124 or 106.

[0042] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vg) region and a light chain variable (V1) region, and an intracellular signaling region, wherein: the Vu region contains 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 within SEQ ID NO:112, and the Vy region contains 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) contained within SEQ ID NO:115; the Vy region contains a CDR-HI, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 124; the Vy region contains a CDR-H1, a CDR- H2 and a CDR-H3 contained within SEQ ID NO:103, and the Vy. region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106; or the Vy region contains a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:130, and the Vy region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106.

[0043] In some of any such embodiments, the Vy region contains a CDR-HI1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112, and the Vy. region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 115. In some of any such embodiments, the Vi region contains a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121, and the V1 region contains a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 124.

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

[0045] In some of any such embodiments, the Vu region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the V1 region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115. In some of any such embodiments, the Vi region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124.

[0046] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vy) region and a light chain variable (V1) region, and an intracellular signaling region, wherein: the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, 121, 103 or 130, and the Vy. region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115, 124 or 106.

[0047] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vy) region and a light chain variable (V1) region, and an intracellular signaling region, wherein: the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the V1 region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115; the Vg region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124; the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106; or the Vi region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106.

[0048] In some of any such embodiments, the Vu region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the V1 region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115. In some of any such embodiments, the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98% or 99% identity to SEQ ID NO:124.

[0049] In some of any such embodiments: the Vy region is or contains the sequence set forth in SEQ ID NO: 112, 121, 103 or 130, and the Vy region is or contains the sequence set forth in SEQ ID NO: 115, 124 or 106.

[0050] In some of any such embodiments: the Vu region and the Vi region are or contain the sequence set forth in SEQ ID NOS: 112 and 115, respectively; the Vi region and the Vi. region are or contain the sequence set forth in SEQ ID NOS: 121 and 124, respectively; the Vy region and the Vi region are or contain the sequence set forth in SEQ ID NOS: 103 and 106, respectively; or the Vu region and the Vi region are or contain the sequence set forth in SEQ ID NOS: 130 and 106, respectively.

[0051] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vg) region and a light chain variable (V1) region, and an intracellular signaling region, wherein: the Vy region is or contains the sequence set forth in SEQ ID NO: 112, 121, 103 or 130, and the Vy region is or contains the sequence set forth in SEQ ID NO: 115, 124 or 106.

[0052] Also provided herein is an anti-ROR1 chimeric antigen receptor (CAR) containing: an extracellular antigen-binding domain containing a heavy chain variable (Vg) region and a light chain variable (V1) region, and an intracellular signaling region, wherein: the Vy region and the Vi. region are or contain the sequence set forth in SEQ ID NOS: 112 and 115, respectively; the Vy region and the Vi region are or contain the sequence set forth in SEQ ID NOS: 121 and 124, respectively; the Vu region and the Vi region are or contain the sequence set forth in SEQ ID NOS: 103 and 106, respectively; or the Vx region and the V1. region are or contain the sequence set forth in SEQ ID NOS: 130 and 106, respectively.

[0053] In some of any such embodiments, the Vy region and the Vy. region are or contain the sequence set forth in SEQ ID NOS: 112 and 115, respectively. In some of any such embodiments, the Va region and the V1. region are or contain the sequence set forth in SEQ ID NOS:121 and 124, respectively.

[0054] In some of any such embodiments, the Vu region is or contains the amino acid sequence encoded by SEQ ID NO: 110, 119, 101 or 128 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, 119, 101 or 128, and the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 113, 122 or 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113, 122 or 104. In some of any such embodiments, the Vu region is or contains the amino acid sequence encoded by SEQ ID NO: 111, 120, 102 or 129, and the Vi region is or contains the amino acid sequence encoded by SEQ ID NO: 114, 123, 105 or 131. In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 110 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, and the V1 region is or contains the amino acid sequence encoded by SEQ ID NO: 113, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113. In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 111, and the V1 region is or contains the amino acid sequence encoded by SEQ ID NO: 114. In some of any such embodiments, the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 119 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 119, and the V1. region is or contains the amino acid sequence encoded by SEQ ID NO: 122, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 122. In some of any such embodiments, the Vg region is or contains the amino acid sequence encoded by SEQ ID NO: 120, and the Vy region is or contains the amino acid sequence encoded by SEQ ID NO: 123.

[0055] In some of any such embodiments, said anti-ROR1 antibody or antigen-binding fragment thereof is isolated. In some of any such embodiments, said anti-ROR1 antibody or antigen-binding fragment thereof is recombinant. In some of any such embodiments, at least a portion of the Vy region and the Vy region is human or is from a human protein.

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

[0057] In some of any such embodiments, the Vy region is amino-terminal to the Vy region. In some of any such embodiments, the Vy region is carboxy-terminal to the Vy region. In some of any such embodiments, the Vy region and the Vy region are joined by a flexible linker. In some of any such embodiments, the flexible linker contains the sequence set forth in SEQ ID NO:41.

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

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

[0060] In some of any such embodiments, the at least a portion of a hinge region contains all or a portion of an IgG4 hinge region. In some of any such embodiments, the at least a portion of a hinge region contains all or a portion of a human IgG4 hinge region, or a variant thereof. In some of any such embodiments, the at least a portion of a hinge region contains all or a portion of an IgG2 hinge region. In some of any such embodiments, the at least a portion of a hinge region contains 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 contains the sequence set forth in SEQ ID NO:1. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 2 or 30 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2 or 30. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 30.

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

[0063] In some of any such embodiments, the spacer contains at least a portion of a Cu3 region of an immunoglobulin or a variant thereof. In some of any such embodiments, the at least a portion of a Cu3 region contains all or a portion of an IgG4 C3. In some of any such embodiments, the at least a portion of a Cu3 region contains all or a portion of an IgG2 Cx3. In some of any such embodiments, the at least a portion of a Cu3 region contains all or a portion of an IgG4 Cu3 and / or an IgG2 Cu3. In some of any such embodiments, the IgG4 Cy3 is a human IgG4 Cy3 and the IgG2 C3 is a human IgG2 Cy3. In some of any such embodiments, the spacer contains at least a portion of a hinge region and at least a portion of a Cy3 region of an immunoglobulin or a variant thereof. In some of any such embodiments, the spacer is ator about 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 or 125 amino acids in length, or has a length between any of the foregoing. In some of any such embodiments, the spacer is at or about 120 amino acids in length.

[0064] In some of any such embodiments, the spacer is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 138. In some of any such embodiments, the spacer is or contains the sequence set forth in SEQ ID NO:138. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 193 or 139 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 871%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 193 or 139. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 139.

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

[0066] In some of any such embodiments, the spacer contains at least a portion of a Cu2 of an immunoglobulin or a variant thereof. In some of any such embodiments, the at least a portion of a Cs2 region contains all or a portion of an IgG4 Cu2. In some of any such embodiments, the at least a portion of a Cu2 region contains all or a portion of an IgG2 Cy2. In some of any such embodiments, the at least a portion of a Cu2 region contains all or a portion of an IgG4 Cu2 and / or an IgG2 Cu2. In some of any such embodiments, the IgG4 Cu2 is a human IgG4 Cu2 and the IgG2 Cu2 is a human IgG2 Cy2. In some of any such embodiments, the spacer contains at least a portion of a hinge region, at least a portion of a Cu2 and at least a portion of a Cy3 region of an immunoglobulin or a variant thereof. In some of any such embodiments, the spacer is at or about 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 221, 222, 223, 224,225, 226, 227, 228, 229 or 230 amino acids in length, or has a length between any of the foregoing. In some of any such embodiments, one or more of the hinge region, the Cu2 region and the Cu3 region contains all or a portion of a Cx2 region and all or a portion of a Cx3 region from human IgG4. In some of any such embodiments, one or more of the hinge region, the Cu2 region and the Cy3 region is chimeric and contains a hinge, a Cg2 region and a Cg3 region from human IgG4 and human IgG2.

[0067] In some of any such embodiments, the spacer contains a IgG4 / 2 chimeric hinge region or a modified IgG4 hinge region containing at least one amino acid replacement compared to a human IgG4 hinge; an IgG2 / 4 chimeric C2 region; and an IgG4 Cu3 region.

[0068] In some of any such embodiments, the spacer is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:194. In some of any such embodiments, the spacer is or contains the sequence set forth in SEQ ID NO: 194. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 195 or 196 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 871%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 195 or 196. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 196.

[0069] In some of any such embodiments, the spacer is or contains an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:37. In some of any such embodiments, the spacer is or contains the sequence set forth in SEQ ID NO: 37. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 38 or 140 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 871%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38 or 140. In some of any such embodiments, the spacer is or contains the amino acid sequence encoded by SEQ ID NO: 140.

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

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

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

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

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

[0075] In some of any such embodiments, the encoded chimeric antigen receptor contains from its N to C terminus in order: the extracellular antigen-binding domain, the spacer, the transmembrane region and the intracellular signaling region. In some of any such embodiments, the encoded chimeric antigen receptor contains, from its N to C terminus in order: an extracellular antigen-binding domain containing an scFv, a spacer containing a modified IgG4 hinge; a transmembrane domain; and an intracellular signaling region containing a cytoplasmic signaling domain of a CD3-zeta (CD3() chain and an intracellular signaling domain of a costimulatory signaling region. In some of any such embodiments, the encoded chimeric antigen receptor contains, from its N to C terminus in order: an extracellular antigen- binding domain containing an scFv, a spacer containing a modified IgG4 hinge containing the sequence set forth in SEQ ID NO:135; a transmembrane domain from a human CD28; and an intracellular signaling region containing a cytoplasmic signaling domain of a CD3-zeta (CD3() chain and an intracellular signaling domain of a costimulatory signaling region containing an intracellular signaling domain of 4-1BB. In some of any such embodiments, the encoded chimeric antigen receptor contains, from its N to C terminus in order: an extracellular antigen-binding domain containing an scFv, a spacer containing a modified IgG4 hinge-Cu3; a transmembrane domain; and an intracellular signaling region containing a cytoplasmic signaling domain of a CD3-zeta (CD3{) chain and an intracellular signaling domain of a costimulatory signaling region. In some of any such embodiments, the encoded chimeric antigen receptor contains, from its N to C terminus in order: an extracellular antigen-binding domain containing an scFv, a spacer containing a modified IgG4 hinge-Cy3 containing the sequence set forth in SEQ ID NO: 138; a transmembrane domain from a human CD28; and an intracellular signaling region containing a cytoplasmic signaling domain of a CD3-zeta (CD3() chain and an intracellular signaling domain of a costimulatory signaling region containing an 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 contains the sequence set forth in SEQ ID NO: 184, 185, 186, 187, 188 or 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: 184, 185, 186, 187, 188 or 189.

[0077] In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or contains the sequence set forth in SEQ ID NO: 184 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: 184. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or contains the sequence set forth in SEQ ID NO: 184. In some of any such embodiments, the anti-ROR1 chimeric antigen receptor is or contains 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 contains the sequence set forth in SEQ ID NO: 185. In some of any embodiments, 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 any embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 186. In some of any embodiments, 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 any embodiments, the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 187. In some of any 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 embodiments, the anti- RORI chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 188. In some of any embodiments, 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 any embodiments, 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 the sequence set forth in SEQ ID NO: 156, 157, 158, 159, 160 or 161 or a sequence that exhibits at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 81%, 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 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 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 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 anti-ROR1 chimeric antigen receptor is encoded by the sequence set forth in SEQ ID NO: 157.

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

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

[0081] In some of any such embodiments, said anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same or lower level or degree of signaling or activity in the presence of a ROR2 protein compared to a reference ROR 1-specific chimeric antigen receptor. In some of any such embodiments, said anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same or lower level or degree of signaling or activity in the presence of a human ROR2, compared to a reference ROR 1-specific chimeric antigen receptor. In some of any embodiments, activity is compared under the same or substantially the same conditions or assay.

[0082] In some of any such embodiments, said anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same or 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, said anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same or 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, activity is compared under the same or substantially the same conditions or assay. In some of any such embodiments, said anti-ROR1 chimeric antigen receptor exhibits the same, substantially the same or higher antigen-specific signaling or antigen dependent activity or signaling compared to a reference ROR 1-specific chimeric antigen receptor. In some of any such embodiments, activity is compared under the same or substantially the same conditions or assay. In some of any such embodiments, said anti- RORI 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, activity is compared under the same or substantially the same conditions or assay. In some of any such embodiments, said anti-ROR1 chimeric antigen receptor exhibits a level or degree of tonic signaling or antigen independent activity or signaling that is at least at or about 75%, 80%, 90%, 95% or 99% less than the level or degree of tonic signaling or antigen independent activity of a reference ROR1-specific chimeric antigen receptor. In some of any such embodiments, activity is compared under the same or substantially the same conditions or assay.

[0083] In some of any such embodiments, the reference ROR 1-specific chimeric antigen receptor contains 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 ROR 1-specific chimeric antigen receptor contains an scFv from R12 or 2A2. In some of any such embodiments, the reference ROR1-specific chimeric antigen receptor contains the anti-ROR1 antibody R12 or an scFv from R12 or 2A2.

[0084] Also provided herein is a polynucleotide containing 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, said polynucleotide contains a nucleic acid encoding the Vi containing the sequence set forth in SEQ ID NO: 110, 119, 101 or 128 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, 119, 101 or 128, and a nucleic acid encoding the V1 containing the sequence set forth in SEQ ID NO: 113, 122 or 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113, 122 or 104. In some of any such embodiments, said polynucleotide contains a nucleic acid encoding the Vy containing the sequence set forth in SEQ ID NO: 110 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, and a nucleic acid encoding the Vy. containing the sequence set forth in SEQ ID NO: 113, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113. In some of any such embodiments, said polynucleotide contains a nucleic acid encoding the Vu containing the sequence set forth in SEQ ID NO: 119 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 119, and a nucleic acid encoding the V1. containing the sequence set forth in SEQ ID NO: 122, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 122.

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

[0087] In some of any such embodiments, said polynucleotide contains a nucleic acid encoding the spacer containing the sequence set forth in SEQ ID NO: 192 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 192. In some of any such embodiments, said polynucleotide contains a nucleic acid encoding the spacer containing the sequence set forth in SEQ ID NO: 193 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 193. In some of any such embodiments, said polynucleotide contains a nucleic acid encoding the spacer containing the sequence set forth in SEQ ID NO: 195 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 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, the single chain cell surface protein, the conjugate or the anti-ROR1 chimeric antigen receptor contains at least one modified splice donor or splice acceptor site or both, said modified splice donor and / or acceptor site containing one or more nucleotide modifications corresponding to a reference splice donor site and / or reference splice acceptor site. In some of any such embodiments, the one or more nucleotide modifications contain a nucleic acid substitution. In some of any such embodiments, the reference splice donor and / or reference splice acceptor sites are canonical, non-canonical, or cryptic splice sites. In some of any embodiments, the polynucleotide is optimized by splice site elimination.

[0089] In some of any such embodiments: the reference splice donor or reference splice acceptor site(s) or both has a splice site prediction score of at least at or about 0.4, 0.5, 0.6, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 0.99 or 1.0; or the reference splice donor or reference splice acceptor site(s) or both is / are predicted to be involved in a splice event with a probability of at least at or about 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%.

[0090] In some of any such embodiments: the reference splice donor or reference splice acceptor site(s) or both has a splice site prediction score of at least at or about 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 0.99 or 1.0; and / or the reference splice donor or reference splice acceptor site(s) or both is / are predicted to be involved in a splice event with a probability of at least at or about 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%.

[0091] In some of any such embodiments, at least one of the one or more nucleotide modifications are 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 is silent or results in a degenerate codon or does not change the amino acid sequence of the encoded protein, or one or more or all of the foregoing.

[0092] In some of any such embodiments, upon expression of the polynucleotide in a cell, the transcribed RNA from the polynucleotide, exhibits at least at or about 70%, at or about 75%, at or about 80%, at or about 85%, at or about 90%, or at or about 95% RNA homogeneity. In some of any such embodiments, upon expression in a cell, the transcribed RNA from the polynucleotide exhibits reduced heterogeneity compared to the heterogeneity of the mRNA transcribed from a reference polynucleotide, said reference polynucleotide encoding the same amino acid sequence as the polynucleotide, wherein the reference polynucleotide differs by the presence of one or more splice donor site or one or more splice acceptor site or both, in the nucleic acid encoding the spacer or contains one or more nucleotide modifications compared to the polynucleotide. In some of any such embodiments, the RNA heterogeneity is reduced by greater than at or about 10%, 15%, 20%, 25%, 30%, 40% or 50% or more. In some of any such embodiments, the transcribed RNA from the reference polynucleotide exhibits greater than at or about 10%, 15%, 20%, 25%, 30%, 40% or 50% or more RNA heterogeneity. In some of any such embodiments, the transcribed RNA messenger RNA (mRNA). In some of any such embodiments, the RNA homogeneity or heterogeneity or both is determined 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, said polynucleotide contains a nucleic acid encoding the Vi containing the sequence set forth in SEQ ID NO: 111, 120, 102 or 129, and a nucleic acid encoding the V1. containing the sequence set forth in SEQ ID NO: 114, 123, 105 or 131. In some of any such embodiments, said polynucleotide contains a nucleic acid encoding the Vy containing the sequence set forth in SEQ ID NO: 111, and a nucleic acid encoding the V1. containing the sequence set forth in SEQ ID NO: 114. In some of any such embodiments, said polynucleotide contains a nucleic acid encoding the Vu containing the sequence set forth in SEQ ID NO: 120, and a nucleic acid encoding the Vy. containing the sequence set forth in SEQ ID NO: 123.

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

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

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

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

[0099] Also provided herein is a vector, containing the polynucleotide of any 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 containing the anti-ROR1 chimeric antigen receptor of any of the embodiments provided herein. Also provided herein is a cell containing 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 containing the anti-ROR1 antibody or antigen-binding fragment thereof 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 cell is a lymphocyte. In some embodiments, the cell is an NK cell oraT cell. In some of any such embodiments, the cell is a T cell and the T cell is a CD4+ or a CD8+ T cell. In some of any such embodiments, the cell is a primary cell obtained from a subject.

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

[0103] Also provided herein is a composition containing 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 or the anti-ROR1 chimeric antigen receptor of any of the embodiments provided herein.

[0104] Also provided herein is a composition containing the cell of any of the embodiments provided herein. In some of any such embodiments, the composition further contains a pharmaceutically acceptable excipient. In some of any such embodiments, the composition contains CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is from at or about 1:3 to 3:1. In some of any such embodiments, the composition contains CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is at or about 1:2 to 2:1. In some of any such embodiments, the composition contains CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is at or about 1:1.

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

[0106] Also provided herein is a method of treatment, containing administering the 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 method of treatment, containing administering 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, the vector of any of the embodiments provided herein, or the cell of any of the embodiments provided herein to a subject having a disease or disorder associated with ROR1. Also provided herein is a composition of 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 of 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 of any of the embodiments provided herein for the treatment of a disease or disorder associated with ROR1. Also provided herein is a method of treatment, containing administering the cells of any of the embodiments provided herein to a subject having a disease or disorder associated with ROR.

[0108] Also provided herein is a method of treatment, containing administering 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, the vector of any of the embodiments provided herein, or the cell of any of the embodiments provided herein to a subject having a disease or disorder associated with ROR1. Also provided herein is a cell of 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 of 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 of any of the embodiments provided herein for the treatment of a disease or disorder associated with ROR1.

[0109] In some of any of the provided embodiments, the disease or disorder associated with ROR1 is a cancer. In some of any of the provided embodiments, the cancer is a ROR1-expressing cancer. In some of any of the provided embodiments, the cancer is associated with a ROR 1-expressing solid tumor or a ROR1-expressing hematologic malignancy.

[0110] In some of any of the provided embodiments, the cancer is associated with a ROR1- expressing solid tumor. In some of any 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, epithelial squamous cell cancer, melanoma, myeloma, stomach 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 any of the provided embodiments, the lung cancer is a non-small cell lung cancer (NSCLC), lung adenocarcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and atypical carcinoid. In some of any of the provided embodiments, the lung cancer is a non-small cell lung cancer (NSCLC). In some of any of the provided embodiments, the breast cancer is a triple negative breast cancer (TNBC).

[0111] In some of any of the provided embodiments, the cancer is associated with a ROR1- expressing hematologic malignancy. In some of any of the provided embodiments, the hematologic 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 ROR is a 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 ROR 1-expressing hematologic malignancy.

[0113] In some embodiments of the methods provided herein, the cancer is associated with a ROR1- expressing solid tumor. 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, epithelial squamous cell cancer, melanoma, myeloma, stomach 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 a 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 a non-small cell lung cancer (NSCLC). In some embodiments of the methods provided herein, the breast cancer is a triple negative breast cancer (TNBC).

[0114] In some embodiments of the methods provided herein, the cancer is associated with a ROR1- expressing hematologic malignancy. In some embodiments of the methods provided herein, the hematologic 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 ROR is a cancer. In some embodiments of the cells or compositions for use provided herein, the cancer is a ROR 1-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 RORI1- expressing hematologic malignancy.

[0116] In some embodiments of the cells or compositions for use provided herein, the cancer is associated with a ROR 1-expressing solid tumor. 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, epithelial squamous cell cancer, melanoma, myeloma, stomach 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 a 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 a non-small cell lung cancer (NSCLC). In some embodiments of the cells or compositions for use provided herein, the breast cancer is a triple negative breast cancer (TNBC).

[0117] In some embodiments of the cells or compositions for use provided herein, the cancer is associated with a ROR 1-expressing hematologic malignancy. In some embodiments of the cells or compositions for use provided herein, the hematologic 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 RORI is a 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 hematologic malignancy.

[0119] In some embodiments of the uses provided herein, the cancer is associated with a ROR1- expressing solid tumor. In some embodiments of the uses 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, epithelial squamous cell cancer, melanoma, myeloma, stomach 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 uses provided herein, the lung cancer is a non-small cell lung cancer (NSCLC). In some embodiments of the uses provided herein, the breast cancer is a triple negative breast cancer (TNBC).

[0120] In some embodiments of the uses provided herein, the cancer is associated with a ROR1- expressing hematologic malignancy. In some embodiments of the uses provided herein, the hematologic 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 ROR1 expression. In some of any such embodiments, the disease or disorder associated with RORI is a B cell-related disorder. In some of any such embodiments, the disease or disorder associated with ROR1 is a cancer. In some of any such embodiments, the cancer is a ROR1-expressing cancer. In some of any such embodiments, the ROR 1-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, epithelial squamous cell cancer, melanoma, myeloma, stomach 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 containing 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, or the 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, the single chain cell surface protein, the conjugate, the anti-ROR1 chimeric antigen receptor, the cell or the composition. In some of any such embodiments, the instructions are in accord with the method, the composition for use or the use of any of the embodiments provided herein.

[0123] Also provided herein is an article of manufacture containing 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. Brief Description of the Drawings

[0124] FIG. 1 depicts the relative intracellular IFN-y, TNF-a or IL-2 expression levels by ICS in GFP+ CD4+ T cells compared to the levels of each cytokine in cells expressing the reference anti-ROR1 (R12) CAR, after 24 hours stimulation with plate-bound recombinant ROR1-Fc, in primary T cells expressing select candidate anti-ROR1 CAR-expressing T cells from a screen as described in Example 1.

[0125] FIG. 2 shows the relative intracellular IFN-y, TNF-a or IL-2 expression levels by ICS in primary T cells expressing select candidate anti-ROR1 CAR-expressing T cells from a screen as described in Example 1, compared to the levels of each cytokine in cells expressing the reference anti- RORI1 (R12) CAR, after 24-70 hour co-culture with MDA-MB-231 target cells expressing ROR1.

[0126] FIGS. 3A-3B depict the results from an in vitro cytotoxicity assay, after co-culture of NucLight Red (NLR)-labeled H1975 target cells and primary T cells expressing one of 6 selected candidate anti-ROR1 CARs, as assessed by measuring the loss of red fluorescent signal over a period of between 0 and 70 hours. As controls, cultures of target cells only and co-cultures of mock cells (not expressing a CAR) with the target cells were assessed.

[0127] FIGS. 4A-4C show the production of IFN-y, TNF-a or IL-2 after 70 hours of co-culture of primary T cells expressing one of 6 selected candidate anti-ROR1 CARs from two separate donors, with H1975 (FIGS. 4A and 4B), or the production of IL-2 after co-culture with MDA-MB-231, A549 or BT- 549 (FIG. 4C) target cells. As controls, cultures of target cells only and co-cultures of mock cells (not expressing a CAR) with the target cells were assessed.

[0128] FIGS. 5A-5D show the anti-tumor activity, as assessed by the changes in mean or individual tumor volume after administration of cells expressing one of 6 selected candidate anti-ROR1 CARs or the reference anti-ROR1 (R12) CAR, in a H1975 non-small cell lung cancer (NSCLC) mouse model. FIG. 5A (low dose) and FIG. 5B (high dose) depict mean tumor volume of all treated mice; in this depiction, tumor curves were terminated after the first mouse of a group succumbed to disease. Results from all individual mice are shown in FIG. 5C (low dose) or FIG. 5D (high dose). As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0129] FIGS. 6A-6B depict the Kaplan-Meier survival curves after administration of a low dose (FIG. 6A) or a high dose (FIG. 6B) of cells expressing one of 6 selected candidate anti-ROR1 CARs or the reference anti-ROR1 (R12) CAR, in a H1975 non-small cell lung cancer (NSCLC) mouse model.

[0130] FIGS. 7A-7D show the average number of CD4+ and CD8+ CAR-expressing cells in the blood of each mouse determined at day 10 and day 24 after administration of cells expressing one of 6 selected candidate anti-ROR1 CARs or the reference anti-ROR1 (R12) CAR, at the low dose (FIGS. 7A and 7B) or high dose (FIGS. 7C and 7D). FIGS. 7E-7F show the average number of CD3+ CAR- expressing cells in the blood of each mouse determined at day 10 and day 24 after administration of cells expressing one of 6 selected candidate anti-ROR1 CARs or the reference anti-ROR1 (R12) CAR, at the low dose (FIG. 7E) or high dose (FIG. 7F). Data are shown as individual values along with group means + standard deviation.

[0131] FIGS. 8A-8C depict the changes in the mean and individual tumor volume in H1975 non- small cell lung cancer (NSCLC) mice administered cells expressing anti-ROR1 CAR-F, CAR-A or the R12 reference CAR, at the low dose (mean: FIG. 8A; individual: FIG. 8C) or the high dose (mean: FIG. 8B; individual: FIG. 8C). As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0132] FIGS. 9A-9B depict the Kaplan-Meier survival curves after administration of a low dose (FIG. 9A) or a high dose (FIG. 9B) of mice administered cells expressing anti-ROR1 CAR-F, CAR-A or the R12 reference CAR. As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0133] FIGS. 10A-10D depict the average CD4+ (FIG. 10A and 10C) and CD8+ (FIG. 10B and 10D) CAR+ T cell count per microliter of blood at days 7, 14 and 21 after administration of a low dose (FIG. 10A and 10B) or a high dose (FIG. 10C and 10D) cells expressing anti-ROR1 CAR-F, CAR-A or the R12 reference CAR.

[0134] FIGS. 11A-11B depict the number of CD4+ (FIG. 11A) and CD8+ (FIG. 11B) CAR+ T cells present in the tumor at 14 days after administration of cells expressing anti-ROR1 CAR-F, CAR-A or the R12 reference CAR.

[0135] FIGS. 12A-12C depict bioluminescence images assessed up to approximately day 49 post administration of a low dose (FIG. 12B) or a high dose (FIG. 12C) of cells expressing anti-ROR1 CAR- F, CAR-A or the R12 reference CAR in MDA-MB-231 triple negative breast cancer mouse model. As a control, mice were administered cells not expressing a CAR (mock) or were untreated (FIG. 12A).

[0136] FIGS. 13A-13C depict the mean measured total flux (p / s) from the bioluminescence imaging, assessed up to approximately day 49 post administration of a low dose (FIG. 13A) or a high dose (FIG. 13B) of cells expressing anti-ROR1 CAR-F, CAR-A or the R12 reference CAR in MDA- MB-231 triple negative breast cancer mouse model, shown as group means + standard error. FIG. 13C depicts the measured total flux (p / s) of individual mice. As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0137] FIGS. 14A-14E depict the changes in the mean and individual tumor volume in MDA-MB- 231 triple negative breast cancer model mice administered cells expressing anti-ROR1 CAR-F, CAR-A or the R12 reference CAR, at the low dose (mean: FIG. 14A) or the high dose (mean: FIG. 14B). The changes in the mean tumor volume following administration of T cells expressinganti-ROR1 CAR F and reference CAR R12, up to a further time point in the same study are depicted for the high dose (FIG. 14C) and low dose (FIG. 14D). Results of tumor volume for individual treated mice at the high dose or low dose for each treated condition are shown in FIG. 14E. Mean tumor volume is depicted as group means + standard error up to the last day that all mice in treatment groups survived. As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0138] FIGS. 15A and 15B depict the Kaplan-Meier survival curve in MDA-MB-231 triple negative breast cancer model mice administered cells expressing anti-ROR1 CAR-F or the R12 reference CAR, at the low dose (FIG. 15B) or the high dose (FIG. 15A). As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0139] FIGS. 16A-16D show the average number of CD4+ (FIG. 16A and 16C) and CD8+ (FIG. 16B and 16D) CAR-expressing cells in the blood of the animal were determined at days 7, 14, 21 and 30 after administration after administration of cells expressing anti-ROR1 CAR-F, CAR-A or the R12 reference CAR, at the low dose (FIG. 16A and 16B) or a high dose (FIG. 16C and 16D). The average 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 also was determined at days 7, 14, 21 and 30 are shown in FIG. 16E. As shown, cells expressing anti-ROR1 CAR-F exhibited high expansion in the MDA-MB-231 mouse model, when administered at both high and low doses.

[0140] FIG. 17 depicts the loss of Rapid Red labeled target cells (CD4 / CD8 T cell depleted leukapheresis samples) co-cultured for approximately 6 days with engineered cells expressing anti-ROR1 CAR-F, anti-CD19 CAR or the R12 reference CAR generated from with from two primary CLL donors, at two E:T ratios.

[0141] FIG. 18A shows the results of a cytotoxicity assay by flow cytometry, showing the loss of CD19+ target cells or CD19+ ROR1+ target cells (CD4 / CD8 T cell depleted leukapheresis samples) co- cultured for approximately 4 days with engineered cells expressing anti-ROR1 CAR-F, anti-CD19 CAR or the R12 reference CAR generated from two primary CLL donors, at two E:T ratios. FIG. 18B depicts the proliferation of CAR-expressing cells (anti-ROR1 CAR-F, anti-CD19 CAR or the R12 reference CAR) labeled with CellTrace™ Violet (CTV) cell proliferation reagent, and co-cultured with target cells from the subjects with CLL at an E:T ratio of 2.5:1 and 0.25:1. FIG. 18C shows the production of IFN-Y, TNF-a and IL-2, as assessed from the supernatant of the co-culture on day 4. Mock treated cells or target cells only were compared as controls.

[0142] FIGS. 19A-19D depict the changes in the mean and individual tumor volume in a mouse model of mantel cell lymphoma (MCL), implanted with firefly luciferase and green fluorescent protein (FfLuc-GFP)-expressing human mantel cell lymphoma (MCL) JeKo-1 cells administered cells expressing anti-ROR1 CAR-F, anti-CD19 or the R12 reference CAR, at the high dose (mean: FIG. 19A; individual: FIG. 19C) or the low dose (mean: FIG. 19B; individual: FIG. 19D) or. As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0143] FIGS. 20A-20B depict the Kaplan-Meier survival curve in a mouse model of MCL administered cells expressing anti-ROR1 CAR-F, anti-CD19 or the R12 reference CAR, at the high dose (FIG. 20A) or the low dose (FIG. 20B). As a control, mice were administered cells not expressing a CAR (mock) or were untreated.

[0144] FIG. 21 shows the average number of average number of CD3+ CAR-expressing cells in the blood of a mouse model of MCL, determined at days 7, 14, 21 and 28 after administration of engineered cells expressing anti-ROR1 CAR-F, anti-CD19 or the R12 reference CAR, at the low dose or a high dose.

[0145] FIGS. 22A-22E depict binding of various recombinantly produced anti-ROR1 scFv-mFcs, including anti-ROR1 scFv ROR1-1 (SEQ ID NO: 118; FIG. 22A), ROR1-2 (SEQ ID NO: 127; FIG. 22B), ROR1-3 (SEQ ID NO: 109; FIG. 22C) and ROR1-4 (SEQ ID NO: 134; FIG. 22D), the scFv binding domains of CAR-A, CAR-F, CAR-G, CAR-I, CAR-R and CAR-BI, and the scFv antigen binding domain of the reference CAR R12 (SEQ ID NO: 142; FIG. 22E), to with a C-terminal 6xHis tag (RORI ECD 6xHis), assessed by surface plasmon resonance (SPR) using multi-cycle kinetics implemented by subsequent injections of recombinant human ROR1 at concentrations of 183, 61.0, 20.33, 6.78, and 2.26 nM.

[0146] FIG. 23 depicts ROR1 expression in response to a 2-fold increasing dilution series of doxycycline from 512 ng / mL to 0 ng / mL in a K562-ROR1-TetOn cell line. The 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.

[0147] FIG. 24 depicts a dose response curve for production of IFNy, IL-2 and TNFa assessed from supernatants of a 72 hour co-culture of engineered cells expressing anti-ROR1 CAR-F or the reference CAR R12, with K562-ROR1-TetOn at a 4:1 E:T ratio with the addition of increasing concentrations of doxycycline. Cells not expressing a CAR (mock) were used as a control.

[0148] FIGS. 25A-25B depict results of a cytotoxicity assay, as determined by loss of red fluorescent signal from NucLight Red-labeled K562-ROR1-TetOn cells cultured in the presence of various concentrations (2 ng / mL — 512 ng / mL) of doxycycline and of engineered cells expressing anti- ROR1 CAR-F or the reference CAR R12, at a 4:1 E:T ratio, for approximately 72 hours. DMSO, no doxycycline and untreated cells were used as controls.

[0149] FIG. 26 shows assessment of ROR1 species cross reactivity in Jurkat Nur77 reporter cells expressing either the ROR1 CAR-F or the ROR1 R12 CAR co-cultured with CT26 cells engineered to express human ROR1 (hROR1) or murine ROR1 (mRORI). K562 cells and unmodified CT26 cells were used as non-specific controls. Detailed Description

[0150] Provided are receptor tyrosine kinase-like orphan receptor 1 (ROR1)-binding molecules, such as antibodies (including antigen-binding antibody fragments, such as single chain fragments, including single chain Fv fragments (scFvs)) and recombinant receptors, including chimeric receptors containing such antibodies or fragments and nucleic acids encoding such antibodies, fragments or recombinant receptors. In some aspects, provided are antibodies, fragments and chimeric antigen receptors (CARs) targeting or directed to ROR1 and ROR 1-expressing cells and disease. It is observed that ROR1 is expressed in cells or tissues associated with certain diseases and conditions such as malignancies, e.g., on malignant plasma cells such as from relapsed or newly diagnosed myeloma patients, for example, with little expression on normal tissues. Among the provided embodiments are approaches useful in the treatment of diseases and conditions and / or for targeting such cell types, including nucleic acid molecules that encode 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 receptors generally can contain antibodies (including antigen-binding antibody fragments, such as heavy chain variable (Vg) regions, single domain antibody fragments and single chain fragments, including scFvs) specific for ROR1, for example as the antigen- binding domain. Also provided are cells, such as engineered or recombinant cells, expressing such ROR 1-binding receptors, e.g., anti-ROR1 CARs and / or containing nucleic acids encoding such receptors, and compositions and articles of manufacture and therapeutic doses containing such cells. Also provided are methods of making and using the antibodies and fragments as well as cells expressing or containing the antibodies and fragments, such as for production of the antibodies or fragments thereof. Also provided are compositions, including pharmaceutical compositions, containing 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 a therapy or a method of treatment.

[0151] Therapies targeting ROR1, such as with anti-ROR1 antibodies or adoptive cell therapies (including those involving the administration of cells expressing chimeric receptors such as chimeric antigen receptors (CARs) and / or other recombinant antigen receptors, specific for RORI, as well as other adoptive immune cell and adoptive T cell therapies) can be effective in the treatment of cancer and other diseases and disorders, for example, ROR1. In certain contexts, available approaches to adoptive cell therapy may not always be entirely satisfactory. In some aspects, the ability of the administered cells to recognize and bind to a target, e.g., target antigen such as ROR, to traffic, localize to and successfully enter appropriate sites within the subject, tumors, and environments thereof, to become activated, expand, to exert various effector functions, including cytotoxic killing and secretion of various factors such as cytokines, to persist, including long-term, to differentiate, transition or engage in reprogramming into certain phenotypic states to provide effective and robust recall responses following clearance and re- exposure to target ligand or antigen, and avoid or reduce exhaustion, anergy, terminal differentiation, and / or differentiation into a suppressive state.

[0152] In some contexts, properties of particular target antigens that the antibodies or recombinant receptors containing antigen-binding domains specifically bind, recognize or target, can that affect the activity of the receptor. In some contexts, ROR is expressed by certain cancers and is an attractive therapeutic target for cell therapy. Improved strategies are needed for optimal responses to antibody or cell therapies, in particular, for recombinant receptors that specifically bind, recognize or target ROR1. Provided are embodiments that meet such needs.

[0153] In some aspects, the provided embodiments are based on observations that administration of engineered cells expressing the provided ROR1 binding molecules, such as chimeric antigen receptors (CARs), exhibit an improved antigen-specific activity, signaling and function, high anti-tumor activity, consistent antigen-dependent activity or signaling, greater or prolonged in vivo expansion, and improved persistence when administered, while exhibiting minimal antigen-independent activity or signaling or cross-reactivity to a different antigen. Such antibodies and recombinant receptors can be used to facilitate safe and effective treatment of particular diseases and disorders, such as those associated with expression of RORI.

[0154] In some contexts, optimal response to therapy can depend on the ability of the antibody or antigen-binding fragment, or recombinant receptors that contain such antibody or antigen-binding fragment as antigen-binding domains, to recognize the target antigen. In some aspects, it is observed herein that the binding affinity, specificity or kinetics of binding to ROR1 of certain provided antibody or antigen-binding fragments, such as when present as the antigen-binding domain of a recombinant receptor (e.g. CAR), can be associated with an improved or greater response to the therapy. In some aspects, the provided embodiments are based on observations that provided binding molecules exhibit a lower binding affinity and / or a faster dissociation rate constant (kes or ka; fast off-rate) to ROR1 compared to available antibodies, and also exhibit improved anti-tumor activity, greater or prolonged in vivo expansion, improved persistence, and / or reduced antigen-independent activity or signaling. In some aspects, engineered cells (e.g. T cells) expressing a recombinant receptor containing an antigen-binding domain (e.g., antibody or antigen-binding fragment thereof) with a lower binding affinity (e.g. higher equilibrium dissociation constant) may exhibit substantially improved in vivo expansion, increased persistence, greater or improved antigen-specific anti-tumor activity and prolonged survival, including against various different types of tumors.

[0155] In some aspects, engineered cells (e.g. T cells) expressing a recombinant receptor containing an antigen-binding domain (e.g., antibody or antigen-binding fragment thereof) with a faster dissociation rate constant (Kefr or Kg; fast off-rate) may exhibit substantially improved in vivo expansion, increased persistence, greater or improved antigen-specific anti-tumor activity and prolonged survival, including against various different types of tumors. In some aspects, engineered cells (e.g. T cells) expressing a recombinant receptor containing an antigen-binding domain (e.g., antibody or antigen-binding fragment thereof) with a lower binding affinity (e.g. higher equilibrium dissociation constant) and a faster dissociation rate constant (ket or kg; fast off-rate) may exhibit substantially improved in vivo expansion, increased persistence, greater or improved antigen-specific anti-tumor activity and prolonged survival, including against various different types of tumors. Without wishing to be bound by theory, in some aspects, it is observed herein that the increased antigen-binding off-rate of the binding domain of an exemplary anti-ROR1 CAR for ROR1 binding potentially contributes to increased sensitivity of the CAR to low antigen levels.

[0156] In some contexts, optimal response to therapy such as cell therapy can depend on the ability of the engineered recombinant receptors such as CARs, to be consistently and reliably expressed on the surface of the cells and / or bind the target antigen. For example, in some cases, heterogeneity of the transcribed RNA from an introduced transgene (e.g., encoding the recombinant receptor) can affect the expression and / or activity of the recombinant receptor, in some cases when expressed in a cell, such as a human T cell, used in cell therapy.

[0157] In some contexts, the length and type of spacer in the recombinant receptor, such as a CAR, can affect the expression, activity and / or function of the receptor.

[0158] Also, in some contexts, certain recombinant receptors can exhibit antigen-independent activity or signaling (also known as “tonic signaling”), which could lead to undesirable effects, such as due to increased differentiation and / or exhaustion of T cells that express the recombinant receptor. In some aspects, such activities may limit the T cell's activity, effect or potency. In some cases, during engineering and ex vivo expansion of the cells for recombinant receptor expression, the cells may exhibit phenotypes indicative of exhaustion, due to tonic signaling through the recombinant receptor.

[0159] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0160] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. 1. RORI1-BINDING MOLECULES

[0161] Provided in some aspects are ROR1-binding molecules, such as ROR1-binding polypeptides. Such binding molecules include antibodies (including antigen-binding fragments) that specifically bind to RORI proteins, such as a human ROR1 protein. Also among the binding molecules are polypeptides containing such antibodies, including single chain cell surface proteins, e.g., recombinant receptors such as chimeric antigen receptors (CARs), containing such antibodies. Provided in some aspects are ROR1- binding cell surface proteins, such as recombinant receptors or chimeric antigen receptors (CARs) that bind RORI molecules and polynucleotides encoding ROR1 binding cell surface proteins, such as recombinant receptors (e.g., CARs), and cells expressing such receptors. Also provided are polynucleotides containing nucleic acids sequences encoding all or a portion of such antibodies, antigen- binding fragments and binding molecules, such as those described in Section L.A or L.D. Exemplary of such polynucleotides include those described in Section LE. In some aspects the polynucleotides can be introduced into a cell to generate an engineered cell that contains or expresses the provided binding molecules, e.g., ROR 1-binding antibodies, antigen-binding domains and receptors, such as CARs. A. RORI1-Targeting Antibodies

[0162] Provided are anti-ROR1 polypeptides, including antibodies and functional antigen-binding fragments. Among the ROR1-binding polypeptides are antibodies, such as single-chain antibodies (e.g., antigen binding antibody fragments), such as those containing a heavy chain variable (Vg) region and / or a light chain variable (VL) region, or a portion thereof. In some embodiments, the antibodies or antigen- binding fragments include a Vy and a Vy, such as single chain Fv fragments (scFvs). The antibodies include antibodies that specifically bind to ROR1, e.g., human ROR1. Among the provided anti-ROR1 antibodies are human antibodies, or antibodies that are modified from or variant of human antibodies. The antibodies include isolated antibodies. Also provided are ROR 1-binding molecules containing such antibodies, such as single-chain proteins, fusion proteins, conjugates and / or recombinant receptors such as chimeric receptors, including antigen receptors. In some aspects, the ROR1-binding molecules include isolated molecules.

[0163] Also provided are ROR1-binding cell surface proteins, such as ROR1-binding recombinant receptors. The ROR1-binding cell surface proteins can contain the provided antibodies (e.g., antigen- binding antibody fragments) that specifically bind to RORI, such as to ROR1 proteins, such as human RORI protein. In some aspects, the provided binding molecules bind to an extracellular portion of RORI. In some examples, the recombinant receptors are chimeric antigen receptors, such as those containing anti-ROR1 antibodies or antigen-binding fragments thereof.

[0164] Also provided are polynucleotides containing nucleic acids 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) or RNA constructs, such as those that can be introduced into cells for expression of the encoded ROR1-binding antibodies, antigen-binding fragments, conjugates or receptors, e.g., anti-ROR1 CARs. In some aspects, the encoded antibodies, antigen-binding fragments, conjugates and receptors, such as those containing ROR1-binding polypeptides, and compositions and articles of manufacture and uses of the same, also are provided.

[0165] The term “antibody” herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab"), fragments, Fab’ fragments, Fv fragments, recombinant IgG (rIgG) fragments, heavy chain variable (Vg) regions capable of specifically binding the antigen, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (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, and heteroconjugate antibodies, multispecific, e.g., bispecific or trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di- scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof also referred to herein as “antigen-binding fragments.” The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.

[0166] The terms “complementarity determining region,” and “CDR,” synonymous with “hypervariable region” or “HVR,” are known to refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). “Framework regions” and “FR” are known to refer to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4).

[0167] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by 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 er 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 Pliickthun 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).

[0168] 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 alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. The AbM scheme is a compromise between Kabat and Chothia definitions based on that used by Oxford Molecular’s AbM antibody modeling software. The IgBLAST scheme is based on matching to germline V, D and J genes, and can be determined using National Center for Biotechnology Information (NCBI)'s IgBLAST tool.

[0169] Table 1, below, lists exemplary position boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-HI, CDR-H2, CDR-H3 as identified by 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 CDRs, for example, with FR-L1 located before CDR-L1, FR-L2 located between CDR- L1 and CDR-L2, FR-L3 located between CDR-L2 and CDR-L3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loon when numbered using the shown Kabat numberine convention varies hetween H3? and H34.

[0170] Thus, unless otherwise specified, a “CDR” or “complementary determining region,” or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the aforementioned schemes, or other known schemes. For example, where it is stated that a particular CDR (e.g., a CDR-H3) contains the amino acid sequence of a corresponding CDR in a given Vy or Vi region amino acid sequence, it is understood that such a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the variable region, as defined by any of the aforementioned schemes, or other known schemes. In some embodiments, specific CDR sequences are specified. Exemplary CDR sequences of provided antibodies are described using various numbering schemes (see e.g. Table 2), although it is understood that a provided antibody can include CDRs as described according to any of the other aforementioned numbering schemes or other known numbering schemes.

[0171] Likewise, unless otherwise specified, a FR or individual specified FR(s) (e.g., FR-H1, FR- H2, FR-H3, FR-H4), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR, FR, or FRs or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In other cases, the particular amino acid sequence of a CDR or FR is given.

[0172] 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 antigen. The variable regions of the heavy chain and light chain (Vu and V1, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs. (See, e.g., Kindt er al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007). A single Vg or Vi. domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a Vi or V1. domain from an antibody that binds the antigen to screen a library of complementary Vi or Vy domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0173] Among the provided antibodies are antibody fragments. An “antibody fragment” or “antigen-binding fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds 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’); diabodies; linear antibodies; heavy chain variable (Vg) regions, single-chain antibody molecules such as scFvs and single-domain antibodies comprising only the Vy region; and multispecific antibodies formed from antibody fragments. In some embodiments, the antibody is or comprises an antibody fragment comprising a variable heavy chain (Vg) and a variable light chain (V1) region. In particular embodiments, the antibodies are single- chain antibody fragments comprising a heavy chain variable (Vg) region and / or a light chain variable (VL) region, such as scFvs.

[0174] Single-domain antibodies (sdAbs) are antibody fragments comprising 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, a single-domain antibody is a human single-domain antibody.

[0175] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. In some embodiments, the antibodies are recombinantly-produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and / or that are may not be produced by enzyme digestion of a naturally-occurring intact antibody. In some aspects, the antibody fragments are scFvs.

[0176] 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 optionally may include 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 the non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human 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 antibody specificity or affinity.

[0177] Among the provided anti-RORI1 antibodies are human antibodies. A “human antibody” is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or non-human source that utilizes human antibody repertoires or other human antibody- encoding sequences, including human antibody libraries. The term excludes humanized forms of non- human antibodies comprising non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human. The term includes antigen-binding fragments of human antibodies.

[0178] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal's chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have generally been inactivated. Human antibodies also may be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody-encoding sequences derived from a human repertoire.

[0179] Among the provided antibodies are monoclonal antibodies, including monoclonal antibody fragments. The term “monoclonal antibody” as used herein refers to an antibody obtained from or within a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical, except for possible variants containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. The term is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be made by a variety of techniques, including but not limited to generation from a hybridoma, recombinant DNA methods, phage-display and other antibody display methods.

[0180] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains and other peptides, e.g., linkers and ROR 1-binding peptides, may include amino acid residues including natural and / or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification. 1. Exemplary Antibodies

[0181] In some embodiments, the antibody, e.g., the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a heavy and / or light chain variable (Vy or V1) region sequence as described, or a sufficient antigen-binding portion thereof. In some embodiments, the antibody, e.g., the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a heavy chain variable region (Vy) sequence and / or a light chain variable region (V1) sequence as described, or a sufficient antigen-binding portion thereof. In some embodiments, the antibody, e.g., the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, is a single chain fragment, such as a single chain Fv (scFv) fragment. In some aspects, the scFv comprises a Vy region and a Vy region. In some embodiments, the antibody, e.g., the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, is a single domain antibody (sdAb), such as an antibody that contains a Vy region only.

[0182] In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a Vg region sequence or sufficient antigen-binding portion thereof that contains a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and / or a heavy chain complementarity determining region 3 (CDR-H3) as described. In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a Vy region sequence or sufficient antigen-binding portion thereof that contains a CDR-H1, a CDR-H2 and a CDR- H3 as described. In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a Vy region sequence or sufficient antigen-binding portion that contains a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), and / or a light chain complementarity determining region 3 (CDR-L3) as described. In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a Vy region sequence or sufficient antigen-binding portion that contains a CDR-L1, a CDR-L2 and a CDR-L3 as described.

[0183] In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a Vy region sequence that contains a CDR-H1, a CDR-H2 and / or a CDR-H3 as described and contains a Vy region sequence that contains a CDR-L1, a CDR-L2 and / or a CDR-L3 as described. In some embodiments, the anti-ROR1 antibody, e.g., antigen-binding antibody fragment, contains a Vi region sequence that contains a CDR-H1, a CDR-H2 and a CDR-H3 as described and contains a Vi region sequence that contains a CDR-L1, a CDR-L2 and a CDR-L3 as described. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3, Vg, V1, scFv sequences or other sequences of the antibodies of fragment thereof described herein. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 85% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 86% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 87% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 88% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 89% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 90% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 91% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 92% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 93% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 94% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 95% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 96% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 97% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 98% sequence identity to any such sequences. In some aspects, among the provided antibodies and fragment thereof are those having sequences at least at or about 99% sequence identity to any such sequences.

[0184] In some embodiments, the antibody is an sdAb comprising only a Vu region sequence or a sufficient antigen-binding portion thereof, such as any of the Vu sequences described herein (e.g., a CDR-H1, a CDR-H2, a CDR-H3 and / or a CDR-H4). In some embodiments, the antibodies or antigen- binding fragments include those that are single domain antibodies, containing a Vy region that, without pairing with a V1 region) and / or without any additional antibody domain or binding site, are capable of specifically binding to ROR1.

[0185] In some embodiments, the Vu region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and / or a CDR-H3 according to Kabat numbering. In some embodiments, the Vg region of an antibody or antigen-binding fragment thereof comprises a CDR-HI, a CDR-H2 and / or a CDR-H3 according to Chothia numbering. In some embodiments, the Vu region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and / or a CDR-H3 according to AbM numbering. In some embodiments, the Vu region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and / or a CDR-H3 according to [gBLAST numbering. In some embodiments, the Vy region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and / or a CDR-H3 according to Kabat, Chothia, AbM, IMGT or IgBLAST numbering, or other numbering schemes.

[0186] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, has a heavy chain variable (Vg) region having the amino acid sequence set forth in SEQ ID NO: 112, 121, 103 or 130, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vu region amino acid sequence set forth in SEQ ID NO: 112, 121, 103 or 130, or contains a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2) and / or a heavy chain complementarity determining region 3 (CDR-H3) present in such a Vy sequence, such as one that contains a CDR-HI1, a CDR-H2, and a CDR-H3 present in such a Vu sequence. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, has a Vy region having the amino acid sequence set forth in SEQ ID NO: 112 or 121, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vu region amino acid sequence set forth in SEQ ID NO: 112 or 121, or contains a CDR-H1, a CDR-H2 and / or a CDR-H3 present in such a Vy sequence, such as one that contains a CDR-H1, a CDR-H2, and a CDR-H3 present in such a Vg sequence.

[0187] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, has a Vi region having the amino acid sequence set forth in SEQ ID NO: 112, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in SEQ ID NO: 112, or contains a CDR-H1, a CDR-H2 and / or a CDR-H3 present in such a Vg sequence, such as one that contains a CDR-HI, a CDR-H2, and a CDR-H3 present in such a Vu sequence. In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a Vy region having the amino acid sequence set forth in SEQ ID NO: 121, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in SEQ ID NO: 121, or contains a CDR-H1, a CDR-H2 and / or a CDR-H3 present in such a Vu sequence, such as one that contains a CDR-H1, a CDR-H2, and a CDR-H3 present in such a Vy sequence. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, has a Vy region having the amino acid sequence set forth in SEQ ID NO: 103, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vu region amino acid sequence set forth in SEQ ID NO: 103, or contains a CDR-H1, a CDR-H2 and / or a CDR-H3 present in such a Vi sequence, such as one that contains a CDR-H1, a CDR-H2, and a CDR-H3 present in such a Vu sequence. In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a Vi region having the amino acid sequence set forth in SEQ ID NO: 130, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vi region amino acid sequence set forth in SEQ ID NO: 130, or contains a CDR-H1, a CDR-H2 and / or a CDR-H3 present in such a Vi sequence, such as one that contains a CDR-H1, a CDR-H2, and a CDR-H3 present in such a Vy sequence.

[0188] In some of any of the provided embodiments, the Vy 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, the Vy 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, the Vy region comprises a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58 or 99.

[0189] In some of any of the provided embodiments, the Vy 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, the Vy 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, the Vy region comprises a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58 or 99.

[0190] In some of any of the provided embodiments, the Vu 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, the Vy 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, the Vg region comprises a CDR-H3 comprising the sequence set forth in SEQ ID NO: 73, 88, 58 or 99.

[0191] In some of any of the provided embodiments, the Vx 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, the Vy 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, the Vy region comprises a CDR-H3 comprising the sequence set forth in SEQ ID NO: 74, 89, 59 or 100.

[0192] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1comprising 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 antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu 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. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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.

[0193] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu 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. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi 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. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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.

[0194] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively; SEQ ID NOS:82, 86 and 88; SEQ ID NOS:52, 56 and 58, respectively; or SEQ ID NOS:52, 97 and 99, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence 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 antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence 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 antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth 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.

[0195] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 69 and 73, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:66, 70 and 73, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:68, 72 and 74, respectively.

[0196] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-HI1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:80, 84 and 88, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:81, 85 and 88, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:83, 87 and 89, respectively.

[0197] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3, respectively, comprising the amino acid sequence of a CDR-H1, a CDR-H2 and a CDR-H3 contained within the Vy region amino acid sequence set forth in any one of SEQ ID NOs: 112, 121, 103 or 130. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112 or 121.

[0198] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:103. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:130.

[0199] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises any of the CDR-H1, the CDR- H2 and the CDR-H3 as described and comprises a framework region 1 (FR1), a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vy region amino acid sequence set forth in any one of SEQ ID NOs: 112, 121, 103 or 130. In some of any embodiments, the Vi region comprises a FR1, a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 112. In some of any embodiments, the Vi region comprises a FR1, a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vg region amino acid sequence set forth in SEQ ID NO: 121. In some of any embodiments, the Vu region comprises a FR1, a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 103. In some of any embodiments, the Vi region comprises a FR1, a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vg region amino acid sequence set forth in SEQ ID NO: 130.

[0200] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises the amino acid sequence set forth in SEQ ID NO:112. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence set forth in SEQ ID NO:121. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region is or comprises the amino acid sequence set forth in SEQ ID NO:103. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region is or comprises the amino acid sequence set forth in SEQ ID NO:130.

[0201] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region is or comprises the amino acid sequence encoded by SEQ ID NO: 110, 119, 101 or 128 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, 119, 101 or 128. In some embodiments of the antibody, antigen- binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 111, 120, 102 or 129.

[0202] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 110 or 119 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110 or 119. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises the amino acid sequence encoded by SEQ ID NO: 111 or 120.

[0203] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 110 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 111.

[0204] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region is or comprises the amino acid sequence encoded by SEQ ID NO: 119 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 119. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises the amino acid sequence encoded by SEQ ID NO: 120.

[0205] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region is or comprises the amino acid sequence encoded by SEQ ID NO: 101 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 101. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises the amino acid sequence encoded by SEQ ID NO: 102.

[0206] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region is or comprises the amino acid sequence encoded by SEQ ID NO: 128 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 128. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 129. Also provided are polynucleotides that contain any of the nucleotide sequences described herein, e.g., encoding all of a portion of the provided binding molecules.

[0207] In some embodiments, the antibody or antibody fragment, in the provided CAR (e.g., an 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 contains a variable light chain (V1) region, or a sufficient antigen-binding portion of a Vi region. In some embodiments, the antibody or antigen-binding fragment thereof contains a Vy region and a variable light chain (V1) region, or a sufficient antigen-binding portion of a Vy and Vy region. In any such embodiments, a Vu region sequence can be any of the Vu region sequence described herein. In any such embodiments, a Vy region sequence can be any of the Vy region sequence described herein. In any such embodiments, any of the Vy region sequence and any of the Vy region sequence described herein can be used in combination. In some of any such embodiments, any one or more of the CDR-H1, the CDR-H2 and / or the CDR-H3 sequences described herein, and any one or more of the CDR-L1, the CDR-L2 and / or the CDR-L3 sequences described herein can be used in combination. In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or an 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 contains a constant region.

[0208] In some embodiments, a binding molecule, such as a receptor, e.g., a CAR provided herein, contains an antibody such as an anti-ROR1 antibody, or antigen-binding fragment thereof that contains any of contains a V1 region or a sufficient antigen binding portion thereof. For example, in some embodiments, the CAR contains an antibody or antigen-binding fragment thereof that contains a Vu region and a Vi region, or a sufficient antigen-binding portion of a Vi and Vy region. In any such embodiments, a Vy region sequence can be any of the Vy region sequence described herein. In any such embodiments, a Vi region sequence can be any of the V1 region sequence described herein. In any such embodiments, any of the Vu region sequence and any of the Vy. region sequence described herein can be used in combination. In some of any such embodiments, any one or more of the CDR-H1, the CDR-H2 and / or the CDR-H3 sequences described herein, and any one or more of the CDR-L1, the CDR-L2 and / or the CDR-L3 sequences described herein can be used in combination. In some such embodiments, the antibody contained in the provided recombinant receptor is an antigen-binding fragment, such as a Fab or an scFv. In some such embodiments, the receptor, e.g., CAR, further contains a spacer, such as a portion of an immunoglobulin constant region or a variant thereof, for example, as described below in Section 1B.

[0209] In some embodiments, the Vu region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and / or a CDR-L3 according to Kabat numbering. In some embodiments, the Vi region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and / or a CDR-L3 according to Chothia numbering. In some embodiments, the Vy region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and / or a CDR-L3 according to AbM numbering. In some embodiments, the Vy region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and / or a CDR-L3 according to IMGT numbering. In some embodiments, the Vy region of an antibody or antigen-binding fragment thereof comprises a CDR- L1, a CDR-L2 and / or a CDR-L3 according to IgBLAST numbering. In some embodiments, the Vi region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and / or a CDR-L3 according to Kabat, Chothia, AbM, IMGT or IgBLAST numbering, or other numbering schemes.

[0210] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, has a light chain variable (V1) region having the amino acid sequence set forth in SEQ ID NO: 115, 124 or 106, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in SEQ ID NO: 115, 124 or 106, or contains a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2) and / or a light chain complementarity determining region 3 (CDR-L3) present in such a V1 sequence, such as one that contains a CDR-L1, a CDR-L2, and a CDR-L3 present in such a Vi. sequence. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, has a V1 region having the amino acid sequence set forth in SEQ ID NO:115 or 124, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 115 or 124, or contains a CDR-L1, a CDR-L2 and / or a CDR-L3 present in such a Vi sequence, such as one that contains a CDR-L1, a CDR-L2, and a CDR-L3 present in such a Vy sequence.

[0211] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, has a Vi region having the amino acid sequence set forth in SEQ ID NO: 115, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vi region amino acid sequence set forth in SEQ ID NO: 115, or contains a CDR-L1, a CDR-L2 and / or a CDR-L3 present in such a Vy sequence, such as one that contains a CDR-L1, a CDR-L2, and a CDR-L3 present in such a Vy sequence. In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a Vi, region having the amino acid sequence set forth in SEQ ID NO: 124, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the V1. region amino acid sequence set forth in SEQ ID NO: 124, or contains a CDR-L1, a CDR-L2 and / or a CDR-L3 present in such a Vy sequence, such as one that contains a CDR- L1, a CDR-L2, and a CDR-L3 present in such a Vy. sequence. In some embodiments, the antibody, e.g., antigen-binding fragment thereof, has a Vy region having the amino acid sequence set forth in SEQ ID NO: 106, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vi. region amino acid sequence set forth in SEQ ID NO: 106, or contains a CDR-L1, a CDR-L2 and / or a CDR-L3 present in such a Vp. sequence, such as one that contains a CDR-L1, a CDR-L2, and a CDR-L3 present in such a Vi sequence.

[0212] In some of any of the provided embodiments, the V1 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, the Vi 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, the Vy region comprises a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94 or 64.

[0213] In some of any of the provided embodiments, the V1 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, the Vi 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, the Vy region comprises a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79, 94 or 64.

[0214] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the V1 region comprises 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.

[0215] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises 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 antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 76 or 91, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 78 or 93; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79 or 94.

[0216] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence 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 antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth 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.

[0217] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the V1 region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:76, 78 and 79, respectively.

[0218] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the V1 region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:91, 93 and 94, respectively.

[0219] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3, respectively, comprising the amino acid sequence of a CDR-L1, a CDR-L2 and a CDR-L3 contained within the Vy region amino acid sequence set forth in any one of SEQ ID NOs: 115, 124 or 106. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO: 115 or 124.

[0220] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO: 115. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO: 124. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the V1 region comprises CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO: 106.

[0221] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the V1 region comprises any of the CDR-L1, the CDR- L2 and the CDR-L3 as described and comprises a framework region 1 (FR1), a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vy region amino acid sequence set forth in any one of SEQ ID NOs: 115, 124 or 106. In some of any embodiments, the Vi. region comprises a FR1, a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 115. In some of any embodiments, the Vy region comprises a FR1, a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the V1 region amino acid sequence set forth in SEQ ID NO: 124. In some of any embodiments, the Vy. region comprises a FR1, a FR2, a FR3 and / or a FR4 having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 106.

[0222] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 antibody, antigen- binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence set forth in SEQ ID NO: 124. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the V1 region is or comprises the amino acid sequence set forth in SEQ ID NO: 106.

[0223] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 113, 122 or 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113, 122 or 104. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises the amino acid sequence encoded by SEQ ID NO: 114, 123, 105 or 131.

[0224] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 113 or 122, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113 or 122. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 114 or 123.

[0225] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 113, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy. region is or comprises the amino acid sequence encoded by SEQ ID NO: 114.

[0226] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 122, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 122. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy. region is or comprises the amino acid sequence encoded by SEQ ID NO: 123.

[0227] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 104. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 105. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises the amino acid sequence encoded by SEQ ID NO: 131.

[0228] In some embodiments, the antibody or antigen binding fragment is an scFv comprising a heavy chain variable (Vg) region and a light chain variable (V1) region. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, 121, 103 or 130, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115, 124 or 106. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises an amino acid sequence having at least at or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:112 or 121, and the Vy region is or comprises an amino acid sequence having at least at or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:115 or 124.

[0229] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the Vy. region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115; the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy. region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124; the Vu region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the V1 region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106; or the Vi region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the V1 region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106.

[0230] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the Vy. region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the Vy. region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106.

[0231] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region of the antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2, a CDR-H3, respectively, comprising the amino acid sequences of CDR-HI1, a CDR-H2 and a CDR-H3 contained within the Vy region amino acid sequence selected from any one of SEQ ID NOs: 112, 121, 103 or 130; and comprises a CDR-L1, a CDR-L2, a CDR-L3, respectively, comprising the amino acid sequences of CDR-L1, a CDR-L2 and a CDR-L3, respectively contained within the V1 region amino acid sequence selected from any one of SEQ ID NOs: 115, 124 or 106. In some of any such embodiments, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112 or 121, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO:115 or 124.

[0232] In some of any such embodiments, the Vy region comprises a CDR-HI1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112, and the Vy. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID NO:115. In some of any such embodiments, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121, and the Vy. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 124. In some of any such embodiments, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:103, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106. In some of any such embodiments, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR- H3 contained within SEQ ID NO:130, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106.

[0233] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 Vy 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.

[0234] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 the Vi 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

[0235] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 the Vi 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

[0236] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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, and the Vy region comprises 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.

[0237] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg 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 the Vy region comprises 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.

[0238] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi 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 the Vy region comprises 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.

[0239] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 the Vy region comprises 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.

[0240] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 the Vy region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 76 or 91, a CDR-L2 comprising the sequence set forth in SEQ ID NO: 78 or 93; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 79 or 94.

[0241] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy 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 sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the Vi. 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 sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 56 and 58, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 97 and 99, respectively, and the V1 region comprises a CDR- L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0242] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 69 and 73, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:80, 84 and 88, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:50, 54 and 58, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:50, 95 and 99, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively;

[0243] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:66, 70 and 73, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:81, 85 and 88, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vu region comprises a CDR-HI1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:51, 55 and 58, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:51, 96 and 99, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively;

[0244] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:68, 72 and 74, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:76, 78 and 79, respectively; or the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:83, 87 and 89, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:91, 93 and 94, respectively; the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:53, 57 and 59, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 63 and 64, respectively; or the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:53, 98 and 100, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:61, 63 and 64, respectively.

[0245] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively.

[0246] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:65, 69 and 73, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively.

[0247] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:66, 70 and 73, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively.

[0248] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:68, 72 and 74, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:76, 78 and 79, respectively.

[0249] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively.

[0250] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:80, 84 and 88, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively.

[0251] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:81, 85 and 88, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively.

[0252] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:83, 87 and 89, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:91, 93 and 94, respectively.

[0253] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 56 and 58, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0254] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:50, 54 and 58, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0255] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:51, 55 and 58, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0256] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:53, 57 and 59, respectively, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 63 and 64, respectively.

[0257] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 97 and 99, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0258] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:50, 95 and 99, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0259] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:51, 96 and 99, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

[0260] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:53, 98 and 100, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:61, 63 and 64, respectively.

[0261] In some embodiments, the Vi region of the antibody or antigen-binding fragment thereof, receptor, e.g., CAR, conjugates or binding molecules comprise the amino acid sequence of SEQ ID NOs: 112, 121, 103 or 130 and the Vy regions of the antibody or antigen-binding fragment comprises the amino acid sequence 115, 124 or 106. In some embodiments, the Vy and V1 regions of the antibody or antigen-binding fragment thereof, receptor, e.g., CAR, conjugates or binding molecules comprise the amino acid sequences of SEQ ID NOs: 112 and 115, respectively; SEQ ID NOs: 121 and 124, respectively; SEQ ID NOs: 103 and 106, respectively; or SEQ ID NOs: 130 and 106, respectively, or any antibody or antigen-binding fragment thereof that has at least at or about 90% sequence identity to any of the above Vu and V1, such as at least at or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. For example, the Vi and Vy regions of the antibody or antigen-binding fragment thereof provided therein comprise the amino acid sequences selected from: SEQ ID NOs: 112 and 115; SEQ ID NOs: 121 and 124; SEQ ID NOs: 103 and 106; or SEQ ID NOs: 130 and 106, respectively.

[0262] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 112 and 115, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 121 and 124, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region and the V1 region are or comprise the sequence set forth in SEQ ID NOS: 103 and 106, respectively. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 130 and 106, respectively.

[0263] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region is or comprises the amino acid sequence encoded by SEQ ID NO: 110, 119, 101 or 128 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, 119, 101 or 128, and the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 113, 122 or 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 81%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 91%, 98% or 99% identity to SEQ ID NO: 113, 122 or 104. In some embodiments of the antibody, antigen- binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 111, 120, 102 or 129, and the Vi region is or comprises the amino acid sequence encoded by SEQ ID NO: 114, 123, 105 or 131.

[0264] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region is or comprises the amino acid sequence encoded by SEQ ID NO: 110 or 119 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110 or 119, and the Vy. region is or comprises the amino acid sequence encoded by SEQ ID NO: 113 or 122, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113 or 122. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vi region is or comprises the amino acid sequence encoded by SEQ ID NO: 111 or 120, and the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 114 or 123.

[0265] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region is or comprises the amino acid sequence encoded by SEQ ID NO: 110 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 871%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 110, and the V1 region is or comprises the amino acid sequence encoded by SEQ ID NO: 113, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 113. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vu region is or comprises the amino acid sequence encoded by SEQ ID NO: 111, and the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 114.

[0266] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 119 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 119, and the V1 region is or comprises the amino acid sequence encoded by SEQ ID NO: 122, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 122. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 120, and the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 123.

[0267] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 101 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 101, and the Vy. region is or comprises the amino acid sequence encoded by SEQ ID NO: 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 104. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 102 and the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 105.

[0268] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 128 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 128 and the Vy region is or comprises the amino acid sequence encoded by SEQ ID NO: 104, or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 104. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the Vg region is or comprises the amino acid sequence encoded by SEQ ID NO: 129, and the V1 region is or comprises the amino acid sequence encoded by SEQ ID NO: 131.

[0269] In some embodiments, the antibody or antigen-binding fragment thereof, in the provided CAR, is a single-chain antibody fragment, such as a single chain variable fragment (scFv) or a diabody or a single domain antibody (sdAb). In some embodiments, the antibody or antigen binding fragment is a multi-domain antibody, such as an scFv comprising a heavy chain variable (Vg) region and a light chain variable (V1) region. In some embodiments, the single-chain antibody fragment (e.g., scFv) includes one or more linkers joining two antibody domains or regions, such as a heavy chain variable (Vy) region and a light chain variable (V1) region. The linker typically is a peptide linker, e.g., a flexible and / or soluble peptide linker. Among the linkers are those rich in glycine and serine and / or in some cases threonine. In some embodiments, the linkers further include charged residues such as lysine and / or glutamate, which can improve solubility. In some embodiments, the linkers further include one or more proline.

[0270] Accordingly, the provided CARs contain anti-ROR1 antibodies that include single-chain antibody fragments, such as scFvs and diabodies, particularly human single-chain antibody fragments, typically comprising linker(s) joining two antibody domains or regions, such Vy and Vi regions. The linker typically is a peptide linker, e.g., a flexible and / or soluble peptide linker, such as one rich in glycine and serine.

[0271] In some aspects, the linkers rich in glycine and serine (and / or threonine) include at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% such amino acid(s). In some embodiments, they include at least at or about 50%, 55%, 60%, 70%, or 75%, glycine, serine, and / or threonine. In some embodiments, the linker is comprised substantially entirely of glycine, serine, and / or threonine. The linkers generally are between about 5 and about 50 amino acids in length, typically between at or about 10 and at or about 30, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some examples between 10 and 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS; SEQ ID NO: 39) or GGGS (3GS; SEQ ID NO: 40), such as between 2, 3, 4 and 5 repeats of such a sequence. Exemplary linkers include those having or consisting of an sequence set forth in SEQ ID NO: 41 (GGGGSGGGGSGGGGS). Exemplary linkers further include those having or consisting of the sequence set forth in SEQ ID NO: 24 (GSTSGSGKPGSGEGSTKG). Exemplary linkers further include those having or consisting of the sequence set forth in SEQ ID NO: 162 (SRGGGGSGGGGSGGGGSLEMA). An exemplary linker includes those having or consisting of the sequence set forth in SEQ ID NO; 163 (GSRGGGGSGGGGSGGGGSLEMA).

[0272] Accordingly, in some embodiments, the provided embodiments include single-chain antibody fragments, e.g., scFvs, comprising one or more of the aforementioned linkers, such as glycine / serine rich linkers, including linkers having repeats of GGGS (SEQ ID NO: 40) or GGGGS (SEQ ID NO: 39), such as the linker set forth in SEQ ID NO: 41, 162 or 163.

[0273] In some embodiments, the Vy region may be amino terminal to the Vi region. In some embodiments, the Vy region may be carboxy terminal to the Vy region. In particular embodiments, the fragment, e.g., scFv, may include a Vy region or portion thereof, followed by the linker, followed by a Vi region or portion thereof. In other embodiments, the fragment, e.g., the scFv, may include the Vy region or portion thereof, followed by the linker, followed by the Vg region or portion thereof.

[0274] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, 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 at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 118, 127, 109 or 134. In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the scFv is or comprises the sequence set forth in SEQ ID NO: 118 or 127 or an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 118 or 127. In some of any of the provided embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO: 118. In some of any of the provided embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO: 127. In some of any of the provided embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO: 109. In some of any of the provided embodiments, the scFv is or comprises the sequence set forth in SEQ ID NO: 134.

[0275] In some embodiments of the antibody, antigen-binding fragment, receptor, e.g., CAR, conjugates or binding molecules provided herein, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 116, 125, 107 or 132 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 91%, 98% or 99% identity to SEQ ID NO: 116, 125, 107 or 132. In some of any of the provided embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 117, 126, 108 or 133.

[0276] In some of any of the provided embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 116 or 125 or a nucleic acid sequence having at least at or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 116 or 125. In some embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 117 or 126. In some embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 117. In some embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 126. In some embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 108. In some embodiments, the scFv is or comprises the amino acid sequence encoded by SEQ ID NO: 133

[0277] Table 2 provides the SEQ ID NOS: of exemplary provided antibody fragments, such as scFvs. In some aspects, the exemplary provided antibody fragments can be comprised in the provided ROR1-binding receptors, such as anti-ROR1 chimeric antigen receptors (CARs). In some embodiments, the ROR 1-binding antibody or fragment thereof, such as an scFv, comprises a Vu region that comprises the CDR-H1, the CDR-H2 and the CDR-H3 sequence and a Vy region that comprises the CDR-L1, the CDR-L2 and the CDR-L3 sequence set forth in the SEQ ID NOS: listed in each row of Table 2 below (by Kabat, Chothia, AbM and IgBLAST numbering schemes). In some embodiments, the ROR1-binding antibody or fragment thereof, such as an scFv, comprises a Vu region sequence and a Vy region sequence set forth in the SEQ ID NOS: listed in each row of Table 2 below, or an antibody comprising a Vu region and a V1 region amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vi region sequence and the Vy. region sequence set forth in the SEQ ID NOS: listed in each row of Table 2 below. In some embodiments, the ROR1-binding antibody or fragment thereof, such as an scFv, comprises a Vy region sequence and a Vy region sequence set forth in the SEQ ID NOS: listed in each row of Table 2 below. In some embodiments, the ROR1-binding antibody or fragment thereof comprises an scFv sequence set forth in the SEQ ID NOS: listed in each row of Table 2 below, or an antibody comprising an scFv amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the scFv sequence set forth in the SEQ ID NOS: listed in each row of Table 2 below. In some embodiments, the ROR 1-binding antibody or fragment thereof comprises an scFv sequence set forth in the SEQ ID NOS: listed in each row of Table 2 below. In some embodiments, any of the antibody or antigen-binding fragment thereof, such as scFv, listed in each row of Table 2 can be comprised in a receptor, such as a chimeric antigen receptor (CAR), for example, as the extracellular antigen-binding domain.

[0278] In some embodiments, the provided antibody or antigen-binding fragment thereof comprises a Vgregion and a Vi region, wherein the Vy region of the antibody or antigen-binding fragment thereof can contain a combination of any of the CDR-H1, the CDR-H2 and the CDR-H3 amino acid sequences set forth in Table 2, and the V1 region of the antibody or antigen-binding fragment thereof can contain a combination of any of the CDR-L1, the CDR-L2 and the CDR-L3 amino acid sequences set forth in Table 2. In some embodiments, the provided antibody or antigen-binding fragment thereof comprises a Vu region and / or a Vy region set forth in Table 2, in any combination, orientation or containing a different linker. In some aspects, the antibody or antigen-binding fragment thereof comprises a Vu region described in Table 2. In some aspects, the antibody or antigen-binding fragment thereof comprises a Vi region described in Table 2. In some embodiments, the provided antibody or antigen-binding fragment thereof is a single-domain antibody (sdAb), comprising a Vg region set forth in Table 2, or a Vy region set forth in Table 2. In some embodiments, the provided antibody or antigen-binding fragment thereof is a single-domain antibody (sdAb), comprising a Vg region containing a CDR-H1, a CDR-H2 and / or a CDR-H3 set forth in Table 2, or a Vi region containing a CDR-L1, a CDR-L2 and / or a CDR-L3 set forth in Table 2. some embodiments of a provided human anti-ROR1 antibody, e.g., antigen-binding fragments, the human antibody contains a Vg region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and / or contains a Vy region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment.

[0280] Among the provided antibodies, e.g., antigen-binding fragments, are human antibodies. In some embodiments of a provided human anti-RORI antibody, e.g., antigen-binding fragments, the human antibody contains a Vu region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and contains a Vy region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment. In some embodiments, the portion of the Vi region corresponds to the CDR-H1, the CDR-H2 and / or the CDR- H3. In some embodiments, the portion of the Vi region corresponds to the CDR-H1, the CDR-H2 and the CDR-H3. In some embodiments, the portion of the Vy region corresponds to the framework region 1 (FRI), FR2, FR2 and / or FR4. In some embodiments, the portion of the V1 region corresponds to the CDR-L1, the CDR-L2 and / or the CDR-L3. In some embodiments, the portion of the Vy region corresponds to the CDR-L1, the CDR-L2 and the CDR-L3. In some embodiments, the portion of the Vi. region corresponds to the FR1, FR2, FR2 and / or FR4.

[0281] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-H1 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H1 region within a sequence encoded by a germline nucleotide human heavy chain V segment. For example, the human antibody in some embodiments contains a CDR-H1 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-H1 region within a sequence encoded by a germline nucleotide human heavy chain V segment.

[0282] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-H2 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H2 region within a sequence encoded by a germline nucleotide human heavy chain V segment. For example, the human antibody in some embodiments contains a CDR-H2 having a sequence that is 100% identical or with no more than one, two or three amino acid difference as compared to the corresponding CDR-H2 region within a sequence encoded by a germline nucleotide human heavy chain V segment.

[0283] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-H3 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H3 region within a sequence encoded by a germline nucleotide human heavy chain V segment, D segment and J segment. For example, the human antibody in some embodiments contains a CDR-H3 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-H3 region within a sequence encoded by a germline nucleotide human heavy chain V segment, D segment and J segment.

[0284] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-L1 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L1 region within a sequence encoded by a germline nucleotide human light chain V segment. For example, the human antibody in some embodiments contains a CDR- L1 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-L1 region within a sequence encoded by a germline nucleotide human light chain V segment.

[0285] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-L2 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L2 region within a sequence encoded by a germline nucleotide human light chain V segment. For example, the human antibody in some embodiments contains a CDR- L2 having a sequence that is 100% identical or with no more than one, two or three amino acid difference as compared to the corresponding CDR-L2 region within a sequence encoded by a germline nucleotide human light chain V segment.

[0286] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a CDR-L3 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L3 region within a sequence encoded by a germline nucleotide human light chain V segment and J segment. For example, the human antibody in some embodiments contains a CDR-L3 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-L3 region within a sequence encoded by a germline nucleotide human light chain V segment and J segment.

[0287] In some embodiments, the human antibody or antigen-binding fragment thereof, contains a framework region that contains human germline gene segment sequences. For example, in some embodiments, the human antibody contains a Vu region in which the framework region, e.g. FR1, FR2, FR3 and FR4, has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a framework region encoded by a human germline antibody segment, such as a V segment and / or J segment. In some embodiments, the human antibody contains a V1. region in which the framework region e.g. FR1, FR2, FR3 and FR4, has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a framework region encoded by a human germline antibody segment, such as a V segment and / or J segment. For example, in some such embodiments, the framework region sequence contained within the Vy region and / or Vi region differs by no more than 10 amino acids, such as no more than 9, 8,7, 6, 5, 4, 3, 2 or 1 amino acid, compared to the framework region sequence encoded by a human germline antibody segment.

[0288] The antibody or antigen-binding fragment thereof, may contain at least a portion of an immunoglobulin constant region, such as one or more constant region domain. In some embodiments, the constant regions include a light chain constant region and / or a heavy chain constant region 1 (Cgl). In some embodiments, the antibody includes at least a portion of a hinge region or a variant thereof. In some embodiments, the antibody includes a Cs2 and / or Cx3 domain, such as an Fc region. In some embodiments, the Fc region is an Fc region of a human IgG, such as an IgG1 or IgG4. 2. Exemplary Features

[0289] In some aspects, the provided antibodies have one or more specified functional features, such as binding properties, including binding to particular epitopes or exhibiting lower or reduced binding to a related but non-specific antigen. In some aspects, the provided antibodies can bind to an epitope that is similar to or overlaps with epitopes of other antibodies, such as reference antibodies, and / or exhibit particular binding affinities. In some aspects, the provided antibodies can bind to an epitope that is different from epitopes of other antibodies, e.g., binding a conformational epitope.

[0290] In some embodiments, the provided antibodies or antigen-binding fragment thereof specifically bind to a receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein. In some of any of the embodiments provided herein, RORI refers to human ROR1. The observation that an antibody or other binding molecule binds to ROR1 or specifically binds to ROR1 does not necessarily mean that it binds to ROR1 from every species. For example, in some embodiments, features of binding to ROR1, such as the ability to specifically bind thereto and / or to compete for binding thereto with a reference antibody, and / or to bind with a particular affinity or compete to a particular degree, in some embodiments, refers to the ability with respect to a human ROR protein and the antibody may not have this feature with respect to a ROR1 of another species such as mouse. In some embodiments, the antibody binds to human ROR1 and binds to ROR1 of another species, such as Rhesus macaque or cynomolgus macaque. In some embodiments, the antibody or an antigen-binding fragment thereof binds to human ROR1 and does not bind to ROR1 of another species, such as mouse. In some embodiments, the antibody binds to human ROR1 and binds to ROR1 of another species, such as mouse.

[0291] In some embodiments, the antibodies, such as the anti-ROR1 antibodies, e.g., the human antibodies, specifically bind to a particular epitope or region of ROR1, such as generally an extracellular epitope or region. ROR1 is a type I membrane protein that contains an extracellular region containing an immunoglobulin (Ig) domain, a frizzled (Fz) domain and a kringle (Kr) domain followed by a transmembrane domain. With reference to human ROR1 set forth in SEQ ID NO:144 (GenBank No. AAA60275.1; sequence including the signal peptide set forth in SEQ ID NO:215, Uniprot No. Q01973), the extracellular region corresponds to amino acids 1-377, amino acids 13-118 correspond to the Ig domain, amino acids 136-270 correspond to the Fz domain and amino acids 283-362 correspond to the Kr domain (corresponding to amino acids 42-147 for the Ig domain, amino acids 165-299 for the Fz domain and amino acids 312-391 for the Kr domain with reference to amino acid sequence set forth in SEQ ID NO:215). In some embodiments, the antibodies, such as human antibodies, bind to an epitope comprising residues within the Ig domain, the Fz domain and / or the Kr domain. In some embodiments, the antibodies, such as human antibodies, bind to an epitope comprising residues with the Ig domain and / or Fz domain. In some embodiments, the antibodies, such as human antibodies, bind to an epitope comprising residues within both the Ig and Fz domains.

[0292] In some embodiments, the antibodies or antigen-binding fragment thereof bind, such as specifically bind, to human ROR, such as to one or more epitopes or region of human ROR1, such as the human ROR1 set forth in SEQ ID NO:144 (GenBank No. AAA60275.1; sequence including the signal peptide set forth in SEQ ID NO:215, Uniprot No. Q01973), or an allelic variant or splice variant thereof. In some embodiments, the antibodies or antigen-binding fragment thereof specifically binds to one or more epitopes within a human ROR protein. In one embodiment, human ROR1 is a transcript variant or isoform that has the sequence of amino acids forth in SEQ ID NO:145 or 146. In some embodiments, human ROR1 protein comprises an amino acid sequence set forth in SEQ ID NO: 144, 145, 146 or 215. In some embodiments, the antibodies or antigen-binding fragment thereof bind to the extracellular region ROR1, such as to one or more extracellular epitopes present within the extracellular region of human ROR, e.g., corresponding to residues 1-377 of the human ROR1 sequence set forth in SEQ ID NO:144 (corresponding to residues 30-406 of the human RORI sequence set forth in SEQ ID NO:215 that includes the signal peptide).

[0293] In some embodiments, the antibodies or antigen-binding fragment thereof bind one or more epitope of ROR1, such as a human ROR1. In some embodiments, the antibodies or antigen-binding fragment thereof bind a linear epitope of ROR1, such as a human ROR1. In some embodiments, the antibodies or antigen-binding fragment thereof bind one or more conformational epitopes of ROR1, such as a human ROR 1.

[0294] In some embodiments, the antibodies or antigen-binding fragment thereof bind one or more epitopes of human ROR1, such as one or more epitopes comprising or consisting of an amino acid sequence selected from among any one of SEQ ID NOS: 199-214, or one or more epitopes present within an amino acid sequence selected from among any one of SEQ ID NOS: 199-214. In some embodiments, the antibodies or antigen-binding fragment thereof bind one or more epitopes of human RORI, such as one or more epitopes that include the sequence FRSTTYGSRLRIRNL (set forth in SEQ ID NO:199). In some embedment'’s, the anti-ROR1 antibody or antigen-binding fragment thereof specifically binds to an epitope consisting of the sequence set forth in SEQ ID NO:199 or an epitope present within the sequence set forth in SEQ ID NO:199. In some embodiments, the antibodies or antigen-binding fragment thereof bind additional epitopes, such as one or more conformational epitopes. In some embodiments, the antibodies or antigen-binding fragment thereof bind additional epitopes, in addition to the sequence FRSTIYGSRLRIRNL (set forth in SEQ ID NO:199). Exemplary of one or more additional epitopes include, but are not limited to, one or more of the sequences set forth in SEQ ID NO:200-214 or one or more epitopes present within an amino acid sequence selected from among any one of SEQ ID NOS: 200-214.

[0295] In some embodiments, the antibody binds to non-human ROR, such as Rhesus macaques (Macaca mulatta) ROR1 (set forth in SEQ ID NO:216, Uniprot No. FSRUP2) or cynomolgus macaques (Macaca fasicularis) ROR1 (set forth in SEQ ID NO:217, Uniprot No. AOA2KSWTX7; or SEQ ID NO:218, Uniprot No. AOA2K5SWTX4). In some aspects, the extracellular domain of the non-human RORI is at least 99% identical to the human ROR1 sequence.

[0296] In some embodiments, the antibody binds to non-human ROR, such as monkey, rabbit, rat, mouse, or other species of ROR1. In some embodiments, the antibody binds to mouse (Mus musculus) ROR, such as to an epitope or region of mouse ROR, such as the mouse ROR1 set forth in SEQ ID NO: 171 (GenBank No. NP_038873; sequence including the signal peptide set forth in SEQ ID NO:219, Uniprot No. Q9Z139). In some embodiments, the antibody binds to human ROR1 and binds to mouse RORI1. In some embodiments, the extent of binding of some of the provided anti-ROR1 antibodies or fragments thereof to a non-human ROR, such as mouse ROR1, is at least at or about 75%, 80%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150% or more of the binding of the antibody to human ROR1.

[0297] In some of any of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower extent, level or degree or affinity to a non-human ROR, optionally a mouse ROR1. In some embodiments, the extent of binding of an anti- RORI1 antibody to an unrelated, non-ROR1 protein or to a non-human ROR protein, such as a mouse RORI protein, or other non-ROR1 protein, is less than at or about 50%, 40%, 30%, 20% or 10% of the binding of the antibody to human RORI as measured. In some embodiments, the antibodies or antigen- binding fragments thereof do not bind to mouse ROR, such as the mouse ROR1 set forth in SEQ ID NO:171 or 219. In some embodiments, the antibodies or antigen-binding fragments do not bind to, is not cross-reactive to, or binds at a lower level or degree or affinity to a mouse RORI. In some embodiments, the extent, level or degree or affinity of binding of the provided anti-ROR1 antibody or antigen-binding fragment thereof to a mouse ROR is at least at or about 75%, 80%, 90%, 95% or 99% less than the extent, level or degree or affinity of binding to a human ROR1.

[0298] In some of any of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower extent, level or degree or affinity to a receptor tyrosine kinase-like orphan receptor 2 (ROR2) protein, optionally a human ROR2 protein. In some embodiments, the extent of binding of some of the provided anti-ROR1 antibodies or fragments thereof to a non-ROR1 protein, such as a ROR2 protein, is at least at or about 75%, 80%, 90%, 95% or 99% less than the binding of the antibody to human ROR1. In some embodiments, the provided antibody or antigen-binding fragment thereof does not bind to, is not cross-reactive to, or binds at a lower level or degree or affinity to a ROR2 protein, optionally a human ROR2 protein. In some embodiments, among provided antibodies are antibodies in which binding to mouse ROR1 is less than or at or about 30%, 20% or 10%, such as less than at or about 10%, of the binding of the antibody to human ROR1. In some embodiments, among provided antibodies are antibodies in which binding to a ROR2, such as a human ROR?2, is less than or at or about 30%, 20% or 10%, such as less than at or about 10%, of the binding of the antibody to human ROR1.

[0299] In some embodiments, the provided antibodies are capable of binding ROR1, such as human ROR, with at least a certain affinity, as measured by any of a number of known methods. In some embodiments, the affinity is represented by an equilibrium dissociation constant (Kp). In some embodiments, the affinity is represented by ECso.

[0300] A variety of assays are known for assessing binding affinity, equilibrium dissociation constant (Kp), equilibrium association constant (Ka), ECso, on-rate (association rate constant; Kon or Ka; units of 1 / Ms or M's!) and the off-rate (dissociation rate constant; kor or ka; units of 1 / s or s™") and / or determining whether a binding molecule (e.g., an antibody or fragment thereof) specifically binds to a particular ligand (e.g., an antigen, such as a RORI1 protein). One can determine the binding affinity of a binding molecule, e.g., an antibody or an antigen-binding fragment thereof, for an antigen, e.g., ROR1, such as human ROR1 or cynomolgus ROR1 or mouse ROR1, such as by using any of a number of binding assays that are well known. For example, in some embodiments, a BIAcore® instrument can be used to determine the binding kinetics and constants of a complex between two proteins (e.g., an antibody or fragment thereof, and an antigen, such as a ROR1 protein), using surface plasmon resonance (SPR) analysis (see, e.g., Scatchard et al., Ann. N.Y. Acad. Sci. 51:660, 1949; Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 53:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent).

[0301] SPR measures changes in the concentration of molecules at a sensor surface as molecules bind to or dissociate from the surface. The change in the SPR signal is directly proportional to the change in mass concentration close to the surface, thereby allowing measurement of binding kinetics between two molecules. The dissociation rate constant (kerr or ka), the association rate constant (Kor or ka) and / or equilibrium dissociation constant (Kp) and / or equilibrium association constant (Ka) for the complex can be determined by monitoring changes in the refractive index with respect to time as buffer is passed over the chip. Other suitable assays for measuring the binding of one protein to another include, for example, immunoassays such as enzyme linked immunosorbent assays (ELISA) and radioimmunoassays (RIA), or determination of binding by monitoring the change in the spectroscopic or optical properties of the proteins through fluorescence, UV absorption, circular dichroism, or nuclear magnetic resonance (NMR). Other exemplary assays include, but are not limited to, Western blot, ELISA, analytical ultracentrifugation, spectroscopy, flow cytometry, sequencing, genetic reporter assays, flow cytometry, and other methods for detection of expressed nucleic acids or binding of proteins.

[0302] In some embodiments, the binding molecule, e.g., antibody or fragment thereof, binds, such as specifically binds, to an antigen, e.g., a ROR1 protein or an epitope therein, with an affinity or Ka (i.e., an equilibrium association constant of a particular binding interaction with units of 1 / M or M™!; equal to the ratio of the on-rate [Ken Or ks] to the off-rate [kos or ka] for this association reaction, assuming bimolecular interaction) equal to or greater than 10° M™!. In some embodiments, the peptide binding molecule binds, such as specifically binds, to an epitope of an antigen, e.g., human ROR1, with an affinity or Ka (i.e., an equilibrium association constant of a particular binding interaction with units of 1 / M or M!) equal to or greater than 10° M! (which equals the ratio of the on-rate [kon] to the off-rate [kot] for this association reaction). In some embodiments, the binding molecule, e.g., antibody or antigen-binding fragment thereof, exhibits a binding affinity for a T cell epitope of the target polypeptide with an affinity or Ka ranging from at or about 106 M! to at or about 10'® M'!, such as from at or about 10° M! to at or about 10° M', or from at or about 10° M™! to at or about 10® M!. In some embodiments, binding affinity may be classified as high affinity or as low affinity. For example, in some cases, a binding molecule, e.g., antibody or antigen-binding fragment thereof, that exhibits high affinity binding to a particular epitope interacts with such epitope with a Ka of at least at or about 10’ M!, at least at or about 10° M, at least at or about 10° M™, at least at or about 10'® M, at least at or about 10" M*, at least at or about 10'> M'!, or at least at or about 10" M. In some cases, a binding molecule, e.g., antibody or antigen-binding fragment thereof, that exhibits low affinity binding exhibits a Ka of up to 107 M*, up to 105M, up to 10° ML,

[0303] Alternatively, affinity can be defined as an equilibrium dissociation constant (Kp) of a particular binding interaction with units of M (e.g., 10° M to 10"> M). In some embodiments, the antibody or fragment thereof exhibits a binding affinity for the epitope with a Kp (i.e., an equilibrium dissociation constant of a particular binding interaction with units of M; equal to the ratio of the off-rate [Koss or ka] to the on-rate [Ken or ka] for this association reaction, assuming bimolecular interaction) of equal to or less than 10° M. For example, the equilibrium dissociation constant Kp can range from 10° Mto 102 M, such as 107M to 10' M, 107 M to 10° M, 107 M to 10° M, 10% M to 10° M, or 10° M to 101° M.

[0304] The on-rate (association rate constant; Ko, or Ka; units of 1 / Ms or M's) and the off-rate (dissociation rate constant; Keer or ka; units of 1 / s or s™) can be determined using any of the known assay methods, for example, surface plasmon resonance (SPR), or other methods described herein for measuring the binding of one protein to another.

[0305] In some embodiments, the binding affinity (ECso) and / or the equilibrium dissociation constant (Kp) of the antibody to ROR1, such as human ROR1, is from at or about 0.1 nM to at or about 500 nM, from at or about 0.1 nM to at or about 100 nM, from at or about 0.1 nM to at or about 50 nM, from at or about 0.1 nM to at or about 10 nM, from at or about 0.1 nM to at or about 1 nM, from at or about 1 nM to at or about 500 nM, from at or about 1 nM to at or about 100 nM, from at or about 1 nM to at or about 50 nM, from at or about 1 nM to at or about 10 nM, from at or about 10 nM to at or about 500 nM, from at or about 10 nM to at or about 100 nM, from at or about 10 nM to at or about 50 nM, from at or about 50 nM to at or about 500 nM, from at or about 50 nM to at or about 100 nM or from at or about 100 nM to at or about 500 nM. In certain embodiments, the binding affinity (ECso) and / or the equilibrium dissociation constant (Kp) of the antibody to ROR1, such as human ROR1, is at or about or less than at or about 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM, or arange defined by any of the foregoing. In some embodiments, the antibodies bind to ROR, such as human ROR1, with a sub-nanomolar binding affinity, for example, with a binding affinity less than at or about 1 nM, such as less than at or about 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM or 0.1 nM. In some embodiments, the binding affinity (ECso) and / or the equilibrium dissociation constant, Kp, of the binding molecule, e.g., anti-ROR1 antibody or fragment thereof, to a ROR1 protein, such as a human ROR1 protein, is from at or about 0.01 nM to about 1 uM, 0.1 nM to 1 uM, 1 nM to 1 uM, 1 nM to 500 nM, 1 nM to 100 nM, 1 nM to 50 nM, 1 nM to 10 nM, 10 nM to 500 nM, 10 nM to 100 nM, 10 nM to 50 nM, 50 nM to 500 nM, 50 nM to 100 nM or 100 nM to 500 nM. In certain embodiments, the binding affinity (ECso) and / or the equilibrium dissociation constant, Kp, of the binding molecule, e.g., anti-ROR1 antibody or fragment thereof, to a ROR1 protein, such as a human ROR1 protein, is at or about or less than at or about 1 uM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less, or a range defined by any of the foregoing.

[0306] In some embodiments, the ECso and / or the Kp of the binding molecule, e.g., anti-ROR1 antibody or fragment thereof, to a RORI protein, is between at or about 10 nM and at or about 90 nM, between at or about 20 nM and at or about 80 nM, between at or about 30 nM and at or about 70 nM, between at or about 40 nM and at or about 60 nM, or between at or about 40 nM and at or about 50 nM. In certain embodiments, the ECso and / or the Kp of the binding molecule, e.g., anti-ROR1 antibody or fragment thereof, to a ROR1 protein, such as a human ROR1 protein, is at or about 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM or 100 nM, or a range defined by any of the foregoing. In certain embodiments, the ECso and / or the Kp of the binding molecule, e.g., anti-ROR1 antibody or fragment thereof, to a ROR1 protein, such as a human ROR1 protein, is at or about 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM or 100 nM, or a range defined by any of the foregoing. In certain embodiments, the ECso and / or the Kp of the binding molecule, e.g., anti-ROR1 antibody or fragment thereof, to a ROR1 protein, such as a human ROR1 protein, is at or about 40 nM, 41 nM, 42 nM, 43 nM, 44 nM, or 45 nM, or a range defined by any of the foregoing.

[0307] In some embodiments, the Vu region of the provided binding molecules comprises a CDR- HI, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112, and the Vy region of the provided binding molecules comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 115 and the equilibrium dissociation constant (Kp) for human ROR1 is between at or about 30 nM and at or about 50 nM. In some embodiments, the Vu region and the V1 region of the provided binding molecules are or comprise the sequence set forth in SEQ ID NOS: 112 and 115, respectively, and the off-rate (kos or ks) for human RORI is at or about 40 nM.

[0308] In some embodiments, the provided binding molecule, e.g., anti-ROR1 antibody or antigen- binding fragment thereof or receptors containing such antibody or antigen-binding fragments, has a fast off-rate (dissociation rate constant; Kes or kg; units of 1 / s or s™'). In some embodiments, the off-rate (kos or ka) of the provided binding molecules is between at or about 1 x 10° s™ and at or about 1 x 102s, such as at or about 5 x 10s”! and at or about 9 x 10” 5, at or about 1 x 10* 5”! and at or about 8 x 10” 5 1 at or about 5 x 10s! and at or about 7 x 10” s’!, at or about 1 x 10? s! and at or about 6 x 10? s!, and at or about 4 x 10” s! and at or about 6 x 10? s'. In some embodiments, the off-rate (ko or ke) of the provided binding molecules is at least at or about 1 x 10° 51, 5x 10% s™, 1 x 104s, 5x 10*s7, 1 x 10? s1,5%x 10% s%, or 1 x 10% 5". In some embodiments, the off-rate (kos or ke) of the provided binding molecules is at least at or about 6 x 10% s™, 7x 10s”, 8x 10*s*,9x 10*s?, 1x 10%s?, 2x 10%s7,3 x 10°51, 4x 10%, 5x 107s, 6x 107s), 7x 10% s1,8x 10% s7,9x 103s! or 1 x 10? s’'. In some embodiments, the off-rate (kos or ka) of the provided binding molecules is at least at or about 4 x 10? s™!, 5x 10? 5! or 6 x 10? sor a range defined by any of the foregoing. In some embodiments, the provided binding molecule, e.g., anti-ROR1 antibody or antigen-binding fragment thereof or receptors containing such antibody or antigen-binding fragments, has an off-rate that is at least at or about 2-fold, 3-fold, 4- fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold or 10-fold faster than the off-rate of a reference anti-ROR1 antibody or an antigen-binding fragment thereof, or receptors containing such antibody or antigen- binding fragments, for example, anti-ROR1 antibody R12.

[0309] In some embodiments, the Vu region of the provided binding molecules comprises a CDR- H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112, and the Vy region of the provided binding molecules comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 115 and the off-rate (Kos or ko) for human ROR1 is between at or about 4 x 10° s! and at or about 6 x 107s”. In some embodiments, the Vy region and the Vy region of the provided binding molecules are or comprise the sequence set forth in SEQ ID NOS: 112 and 115, respectively, and the off-rate (kotor ka) for human ROR] is at or about 5 x 102 s°!.

[0310] In some embodiments, the binding affinity of a binding molecule, such as an anti-ROR1 antibody, for different antigens, e.g., ROR1 proteins from different species can be compared to determine the species cross-reactivity. For example, species cross-reactivity can be classified as high cross reactivity or low cross reactivity. In some embodiments, the equilibrium dissociation constant, Kp, for different antigens, e.g., ROR1 proteins from different species such as human, cynomolgus monkey or mouse, can be compared to determine species cross-reactivity. In some embodiments, the species cross- reactivity of an anti-ROR1 antibody can be high, e.g., the anti-ROR1 antibody binds to human ROR1 and a species variant RORI to a similar degree, e.g., the ratio of Kp for human ROR1 and Kp for the species variant ROR1 is or is about 1. In some embodiments, the species cross-reactivity of an anti-ROR1 antibody can be low, e.g., the anti-ROR1 antibody has a high affinity for human ROR1 but a low affinity for a species variant ROR1, or vice versa. For example, the ratio of Kp for the species variant ROR1 and Kp for the human ROR1 is more than 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, 1000, 2000 or more, and the anti-ROR1 antibody has low species cross-reactivity. The degree of species cross- reactivity can be compared with the species cross-reactivity of a known antibody, such as a reference antibody.

[0311] In some embodiments, the provided antibodies or antigen binding fragments thereof bind to a similar degree to a human ROR1 protein and a non-human ROR1 protein. For example, in some embodiments, the provided antibodies or antigen binding fragments thereof bind to a human ROR1 protein, or an allelic variant or splice variant thereof, with a specific an equilibrium dissociation constant (Kp), and to a non-human ROR, such as a cynomolgus monkey ROR 1, with a Kp that is similar, or about the same, or less than 2-fold different, or less than 5-fold different.

[0312] For example, in some embodiments, the provided antibodies or antigen binding fragments thereof bind to a human ROR1 with a Kp of about or less than at or about 1 uM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less, and binds to a cynomolgus monkey ROR1 with a Kp of about or less than at or about 1 uM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less. In some embodiments, the provided antibodies or antigen binding fragments thereof bind to a mouse ROR1 protein with a Kp of about or less than at or about 1 uM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less. In some embodiments, the provided antibodies or antigen binding fragments thereof bind to a human ROR1, a cynomolgus monkey ROR1 and a mouse ROR1 with high affinity. In some embodiments, the provided antibodies or antigen binding fragments thereof bind to a human ROR1 and cynomolgus monkey ROR1 with a high affinity, and to a mouse ROR1 with low affinity. In some embodiments, the provided antibodies or antigen binding fragments thereof bind to a human ROR1 and RORI1 from other species, or other variants of the ROR1 protein, with high affinity.

[0313] In some embodiments, the total binding capacity (Rmax), as measured using particular surface plasmon resonance (SPR) conditions, is used to determine the ability or capacity of binding of the provided antibody or antigen binding fragment thereof, to the antigen, e.g., a ROR1 protein, such as a human ROR1 protein. For SPR analysis, the “ligand” is the immobilized target molecule on the surface of the sensor, for example, a ROR1 protein, and the “analyte” is the tested molecule, e.g., antibody, for binding to the “ligand”. For example, the “analyte” can be any of the provided antibodies or antigen binding fragments thereof, that binds to a ROR1 protein. For a particular ligand and analyte pair in SPR, the Rmax can be determined assuming a 1:1 binding stoichiometry model, for a particular condition. In some embodiments, binding capacity (Rmax) can be determined using the following formula: Ruex (RU) = (analyte molecular weight) / (ligand molecular weight) x immobilized ligand level (RU). In particular aspects of SPR conditions, the Ruax of binding between any of the provided antibody or antigen binding fragment thereof and a ROR protein, such as a human ROR1 or a cynomolgus ROR, is at least or at least about 50 resonance units (RU), such as about 25 RU, 20 RU, 15RU, 10 RU, 5 RU or 1 RU.

[0314] In some embodiments, properties or features of the provided antibodies are described in relation to properties observed for another antibody, e.g., a reference antibody. In some embodiments, the reference antibody is a non-human anti-ROR1 antibody, such as a rabbit or chimeric or humanized anti-ROR1 antibody. In some aspects, the reference antibody is the chimeric rabbit / human IgG1 antibody designated R12 (see, e.g., Yang er al. (2011) PloS ONE, 6:¢21018; U.S. Patent Application No. US 2013 / 0251642), and / or a fragment derived therefrom such as an scFv fragment thereof, and / or an antibody containing the Vy and Vy sequences of such an antibody and / or the heavy and light chain CDRs of such an antibody. A chimeric antigen receptor (CAR) containing an antigen-binding scFv fragment of R12 has been demonstrated to effectively promote antitumor reactivity in a CAR therapy (Hudecek et al. (2013) Clin. Cancer Res., 19:3153; International published PCT Appl. No. W02014031687). In some embodiments, the reference antibody is an scFv that comprises the sequence of amino acids set forth in SEQ ID NO:142.

[0315] In some embodiments, the reference antibody is the mouse anti-human ROR1 antibody designated 2A2, and / or a fragment derived therefrom such as an scFv fragment thereof, and / or an antibody containing the Vi and V1 sequences of such an antibody and / or the heavy and light chain CDRs of such an antibody (see, e.g., Baskar er al. (2012) MAbs, 4:349-361; published U.S. Patent Appl. No. US2012 / 20058051). For example, in some embodiments, the reference antibody has a Vu region containing the sequence set forth in SEQ ID NO: 172 and a V. containing the sequence set forth in SEQ ID NO: 173. In some embodiments, the reference antibody is an scFv form of antibody 2A2.

[0316] In some embodiments, the reference antibody is a human or humanized anti-ROR1 antibody. Exemplary humanized anti-ROR1 antibodies are described in International PCT Appl. No. ‘W02014 / 031174. In some embodiments, the reference antibody is a humanized variant of an antibody designated 99961. In some embodiments, the reference antibody has a Vu region containing the sequence set forth in SEQ ID NO: 174, 175, 176 or 177 and a Vy. containing the sequence set forth in SEQ ID NO: 178, 179, 180 or 181.

[0317] In some embodiments, the provided antibody contains heavy and light chain CDRs that are distinct from the CDRs present in the reference antibody or antibodies. Among the provided antibodies are those that compete for binding with and / or bind to the same or overlapping epitopes of ROR1 as those bound by a reference antibody or antibody, such as R12, but nonetheless contain distinct CDRs, e.g., distinct heavy and / or light chain CDR1, CDR2, and CDR3.

[0318] In some embodiments, the antibody has an affinity that is about the same as or lower than that of the corresponding form of the reference antibody, e.g., ECso or Kp that is no more than at or about 1.5-fold or no more than at or about 2-fold greater, no more than at or about 3-fold greater, and / or no more than at or about 10-fold greater, than the ECso or Kp of the corresponding form of the reference antibody. In some embodiments, the antibody has an affinity that is about the same as or lower than that of the corresponding form of the reference antibody, e.g., ECso or Kp that is at least at or about 1.5-fold greater, at least at or about 2-fold greater, at least at or about 3-fold greater, at least at or about 5-fold greater, at least at or about 10-fold greater, at least at or about 20-fold greater, at least at or about 25-fold greater, at least at or about 30-fold greater, at least at or about 40-fold greater, at least at or about 50-fold greater, or at least at or about 100-fold greater, than the ECso or Kp of the corresponding form of the reference antibody. In some embodiments, the antibody has an affinity that is about the same as or lower than that of the corresponding form of the reference antibody, an affinity that is at or about 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50- fold or 100-fold lower than the affinity of the reference antibody.

[0319] In some embodiments, the antibody has an affinity that is greater than that of the corresponding form of the reference antibody, e.g., ECso or Kp that is lower than or lower than at or about 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold or lower than the ECsp or Kp of the corresponding form of the reference antibody.

[0320] In some embodiments, the antibodies display a binding preference for ROR1-expressing cells as compared to ROR 1-negative cells, such as particular cells known and / or described herein to express ROR1 and known not to express ROR, or expressing a related but different antigen, e.g., ROR2. In some embodiments, the binding preference is observed where a significantly greater degree of binding is measured to the ROR 1-expressing, as compared to the non-expressing, cells or cells expressing a related but different antigen. In some embodiments, the fold change in degree of binding detected, for example, as measured by mean fluorescence intensity in a flow cytometry-based assay and / or dissociation constant or ECso, to the ROR 1-expressing cells as compared to the non-ROR1-expressing cells or cells expressing a related but different antigen, is at least at or about 1.5, 2, 3, 4, 5, 6, or more, and / or is about as great, about the same, at least as great or at least about as great, or greater, than the fold change observed for the corresponding form of the reference antibody. In some cases, the total degree of observed binding to ROR1 or to the ROR 1-expressing cells is approximately the same, at least as great, or greater than that observed for the corresponding form of the reference antibody.

[0321] In some aspects, the affinity is at or about the same degree or substantially the same degree of affinity compared to the corresponding form of the reference antibody, such as rabbit ROR1 antibody. In some aspects, the affinity is at least at or about 80, 85, 90, 95, or 99% of or the same as that of the corresponding form of the reference antibody.

[0322] In some embodiments, the antibody specifically binds to an epitope that overlaps with the epitope of ROR1 bound by a reference antibody. In some aspects, among such antibodies are antibodies that bind to the same or a similar epitope as the reference antibody. In some embodiments, the antibodies bind to the same or a similar epitope or an epitope within the same region or containing residues within the same region of ROR1 as a reference antibody, such as anti-ROR1 antibody R12 or scFv fragment thereof (set forth in SEQ ID NO: 142; see e.g. Yang et al. (2011) PloS ONE, 6:¢21018). In some embodiments, the antibody inhibits binding to and / or competes for binding to ROR1, such as human RORI1, with the reference antibody.

[0323] Competitive inhibition assays are known and include ELISA-based, flow cytometry-based assays, and RIA-based assays. In some aspects, competitive inhibition assays are carried out by incorporating an excess of an unlabeled form of one of the antibodies and assessing its ability to block binding of the other antibody, which is labeled with a detectable marker, such that degree of binding and reduction thereof can be assessed by detection of the label or marker. In some embodiments, addition of the provided antibody in excess, e.g., 1-, 2-, 5-, 10-, 50- or 100-fold excess, as compared to the amount or concentration of the reference antibody, inhibits binding to the antigen by the reference antibody (or vice versa). In some embodiments, the inhibition of binding is by at least 50%, and in some embodiments by at least 75%, 90% or 99%. In some aspects, the competitive inhibition is as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 1990:50:1495-1502). Competition assays may be used to identify an antibody that competes with any of the antibodies described herein. Assays for mapping epitopes bound by the antibodies and reference antibodies also may be used and are known.

[0324] In some embodiments, where the reference antibody is present at a concentration of or of about 2 nM, the provided antibody inhibits binding of the reference antibody with an ICs of less than at or about 200 nM, 150 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, or 10 nM, or less than at or about 9 nM, 8 nM, 7 nM, 6 nM, or 5 nM. In some embodiments, where the provided antibody is present at a concentration of or about 2 nM, the reference antibody inhibits binding of the provided antibody with an ICs of less than at or about 200 nM, 150 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, or 10 nM, or less than at or about 9 nM, 8 nM, 7 nM, 6 nM, or 5 nM. In some embodiments, competitive inhibition of the reference antibody’s binding by the provided antibody (or vice versa) is at or about or least at or about the same degree as the degree of competitive inhibition of the reference antibody’s binding by the reference antibody itself, e.g., unlabeled reference antibody. In some embodiments, the provided antibody inhibits binding of the reference antibody, such as binding of R12 scFv, to human ROR1 by at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%, or 99%.

[0325] Anti-RORI1 antibodies provided herein may be identified, screened for, or characterized for their physical / chemical properties and / or biological activities by various known assays. In one aspect, the antibody is tested for its antigen binding activity, e.g., by known methods such as ELISA, Western blotting, and / or flow cytometric assays, including cell-based binding assays, for example, assessing binding of the antibody (e.g., conjugated to a fluorescent marker or tagged) to a cell expressing the target antigen, e.g., ROR1, in some cases compared to results using cells that do not express the target antigen, e.g., ROR, or cells that express a different antigen, e.g., ROR2. Binding affinity may be measured as Kp, Ka or ECsp. 3. Variants

[0326] In certain embodiments, the antibodies include one or more amino acid variations, e.g., substitutions, deletions, insertions, and / or mutations, compared to the sequence of an antibody described herein. Exemplary variants include those designed to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.

[0327] In certain embodiments, the antibodies include one or more amino acid substitutions, e.g., as compared to an antibody sequence described herein and / or compared to a sequence of a natural repertoire, e.g., human repertoire. Sites of interest for substitutional mutagenesis include the CDRs and FRs. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained / improved antigen binding, decreased immunogenicity, improved half- life, and / or improved effector function, such as the ability to promote antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

[0328] In some embodiments, one or more residues within a CDR of a parent antibody (e.g. a humanized or human antibody) is / are substituted. In some embodiments, the substitution is made to revert a sequence or position in the sequence to a germline sequence, such as an antibody sequence found in the germline (e.g., human germline), for example, to reduce the likelihood of immunogenicity, e.g., upon administration to a human subject.

[0329] In some embodiments, alterations are made in CDR “hotspots,” residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or residues that contact antigen, with the resulting variant Vu or Vy being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves CDR-directed approaches, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

[0330] In certain embodiments, substitutions, insertions, or deletions may occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in CDRs. Such alterations may, for example, be outside of antigen contacting residues in the CDRs. In certain embodiments of the variant Vi and Vi. sequences provided above, each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions.

[0331] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme or a polypeptide which increases the serum half-life of the antibody. 4. Modifications

[0332] In certain embodiments, the antibody is altered to increase or decrease the extent to which the antibody is glycosylated, for example, by removing or inserting one or more glycosylation sites by altering the amino acid sequence and / or by modifying the oligosaccharide(s) attached to the glycosylation sites, e.g., using certain cell lines.

[0333] In some embodiments, an N-linked glycosylation, which is a glycosylation site that occurs at asparagines in the consensus sequence -Asn-Xaa-Ser / Thr is removed or inserted. In some embodiments, one or more re replaced with another amino acid to remove the glycosylation site.

[0334] Exemplary modifications, variants, and cell lines are described, e.g., in Patent Publication Nos. US 2003 / 0157108, US 2004 / 0093621, US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; W02005 / 053742; W02002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Ripka et al. Arch. Biochem. Biophys. 249:533- 545 (1986); US Pat Appl No US 2003 / 0157108 Al, Presta, L; and WO 2004 / 056312 Al, Yamane- Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003 / 085107); WO 2003 / 011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005 / 0123546 (Umana et al.); WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).

[0335] Among the modified antibodies are those having one or more amino acid modifications in the Fc region, such as those having a human Fc region sequence or other portion of a constant region (e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions.

[0336] Such modifications can be made, e.g., to improve half-life, alter binding to one or more types of Fc receptors, and / or alter effector functions.

[0337] Also among the variants are cysteine engineered antibodies such as “thioMAbs” and other cysteine engineered variants, in which one or more residues of an antibody are substituted with cysteine residues, in order to generate reactive thiol groups at accessible sites, e.g., for use in conjugation of agents and linker-agents, to produce immunoconjugates. Cysteine engineered antibodies are described, e.g., in U.S. Patent Nos. 7,855,275 and 7,521,541.

[0338] In some embodiments, the antibodies are modified to contain additional nonproteinaceous moieties, including water soluble polymers. Exemplary polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide / ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc. B. Immunoconjugates

[0339] In some embodiments, the antibody is or is part of an immunoconjugate, in which the antibody is conjugated to one or more heterologous molecule(s), such as, but not limited to, a cytotoxic or an imaging agent. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At?! 121 1'%, Y®, Re'®, Re'®, Sm'*?, Bi?!?, P*2, Pb?!? and radioactive isotopes of Lu); chemotherapeutic agents (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins. In some embodiments, the antibody is conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

[0340] Among the immunoconjugates are antibody-drug conjugates (ADCs), in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman er al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz er al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

[0341] Also among the immunoconjugates are those in which the antibody is conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

[0342] Also among the immunoconjugates are those in which the antibody is conjugated to a radioactive atom to form a radioconjugate. Exemplary radioactive isotopes include At"! I, 1'%%, Y%, Re!®¢, Re!®, Sm!®, Bi?!2, P32, Pb2!2 and radioactive isotopes of Lu.

[0343] Conjugates of an antibody and cytotoxic agent may be made using any of a number of known protein coupling agents, e.g., linkers, (see Vitetta et al., Science 238:1098 (1987)), W094 / 11026. The linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell, such as acid- labile linkers, peptidase-sensitive linkers, photolabile linkers, dimethyl linkers, and disulfide-containing linkers (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020). C. Multispecific Antibodies

[0344] In certain embodiments, the ROR1-binding molecules, e.g., antibodies or polypeptides such as chimeric receptors containing the same, are multispecific. Among the multispecific binding molecules are multispecific antibodies, including, e.g. bispecific. Multispecific binding partners, e.g., antibodies, have binding specificities for at least two different sites, which may be in the same or different antigens. In certain embodiments, one of the binding specificities is for ROR1 and the other is for another antigen. In certain embodiments, bispecific antibodies may bind to two different epitopes of ROR1. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express ROR1. Bispecific antibodies can be prepared as full length antibodies or antibody fragments. Among the multispecific antibodies are multispecific single-chain antibodies, e.g., diabodies, triabodies, and tetrabodies, tandem di-scFvs, and tandem tri-scFvs. Also provided are multispecific chimeric receptors, such as multispecific CARs, containing the antibodies. Also provided are multispecific cells containing the antibodies or polypeptides including the same, such as cells containing a cell surface protein including the anti-ROR1 antibody and an additional cell surface protein, such as an additional chimeric receptor, which binds to a different antigen or a different epitope on ROR1.

[0345] Exemplary additional antigens include B cell specific antigens, other tumor-specific antigens, such as antigens expressed specifically on or associated with 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, epithelial squamous cell cancer, melanoma, myeloma, stomach 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 / or head and neck cancer, and antigens expressed on T cells. Exemplary antigens include CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74, CD80, CD126, CD138, B7, MUC-1, Ta, HM1.24, HLA-DR, tenascin, an angiogenesis factor, VEGF, PIGF, ED-B fibronectin, an oncogene, an oncogene product, CD66a-d, necrosis antigens, Ii, IL-2, T101, TAC, IL-6, TRAIL-R1 (DR4) and TRAIL-R2 (DRS). D. Recombinant Receptors

[0346] Among the provided binding molecules, e.g., ROR1 binding molecules, are cell surface proteins, such as recombinant receptors, such as those that include one of the provided antibodies or antigen-binding fragments. Also provided are polynucleotides that encode all or a portion of such cell surface proteins, e.g., receptors. The receptors include antigen receptors and other chimeric receptors that specifically bind to ROR1, such as receptors containing the provided anti-RORI1 antibodies, e.g., antigen-binding fragments. Among the antigen receptors are functional non-TCR antigen r...

Claims

Claims 1. An anti-receptor tyrosine kinase-like orphan receptor 1 (ROR1) antibody or antigen- binding fragment thereof, comprising: a heavy chain variable (Vi) region and a light chain variable (V1) region, wherein: the Vu 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 within SEQ ID NO:112, and the Vy 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) contained within SEQ ID NO:115; the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 124; the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:103, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106; or the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:130, and the V1 region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106.

2. The anti-ROR1 antibody or antigen-binding fragment thereof of claim 1, wherein the Vi region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:112, and the Vi. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 115. 3 The anti-ROR1 antibody or antigen-binding fragment thereof of claim 1, wherein the Vi region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:121, and the V1 region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 124.

4. The anti-ROR1 antibody or antigen-binding fragment thereof of claim 1, wherein the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:103, and the V1 region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106. 5 The anti-ROR1 antibody or antigen-binding fragment thereof of claim 1, wherein the Vu region comprises a CDR-H1, a CDR-H2 and a CDR-H3 contained within SEQ ID NO:130, and the Vi, region comprises a CDR-L1, a CDR-L2 and a CDR-L3 contained within SEQ ID: NO 106.

6. An anti-ROR1 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable (Vu) region, and a light chain variable (V1) region, wherein the Vy 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 sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the Vi 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 sequence set forth in SEQ ID NOS:75, 77 and 79, respectively; the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the Vy. region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively; the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 56 and 58, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively; or the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 97 and 99, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively. 7 The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 2 and 6, wherein the Vi region comprises a CDR-HI1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:67, 71 and 73, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:75, 77 and 79, respectively.

8. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 3 and 6, wherein the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:82, 86 and 88, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:90, 92 and 94, respectively.

9. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 4 and 6, wherein the Vy region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 56 and 58, respectively, and the Vy region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

10. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 5 and 6, wherein the Vg region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS:52, 97 and 99, respectively, and the Vi region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS:60, 62 and 64, respectively.

11. The anti-RORI1 antibody or antigen-binding fragment thereof of claim 1 or claim 6: the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115; the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124; the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106; or the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

106.

12. An anti-ROR1 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable (Vg) region and a light chain variable (V1) region, wherein: the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115; the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:124; the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:106; or the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

106.

13. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 2, 6, 7, 11 and 12, wherein the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:112, and the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

115.

14. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 3, 6, 8, 11 and 12, wherein the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:121, and the V1 region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

124.

15. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 4, 6, 9, 11 and 12, wherein the Vi region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:103, and the V1 region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

106.

16. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 5, 6, 10, 11 and 12, wherein the Vy region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:130, and the V1 region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

106.

17. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 6, 11 and 12, wherein: the Vi region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 112 and 115, respectively; the Vi region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 121 and 124, respectively; the Vy region and the V1. region are or comprise the sequence set forth in SEQ ID NOS: 103 and 106, respectively; or the Vy region and the V1. region are or comprise the sequence set forth in SEQ ID NOS: 130 and 106, respectively.

18. An anti-ROR1 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable (Vg) region and a light chain variable (Vy) region, wherein: the Vy region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 112 and 115, respectively; the Vy region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 121 and 124, respectively; the Vy region and the Vi region are or comprise the sequence set forth in SEQ ID NOS: 103 and 106, respectively; or the Vy region and the Vi region are or comprise the sequence set forth in SEQ ID NOS: 130 and 106, respectively.

19. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 2, 6, 7, 11, 12, 13, 17 and 18, wherein the Vy region and the Vi region are or comprise the sequence set forth in SEQ ID NOS: 112 and 115, respectively.

20. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 3, 6, 8, 11, 12, 14, 17 and 18, wherein the Vy region and the V1 region are or comprise the sequence set forth in SEQ ID NOS:121 and 124, respectively.

21. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 4, 6, 9, 11, 12, 15, 17 and 18, wherein the Vg region and the Vy region are or comprise the sequence set forth in SEQ ID NOS: 103 and 106, respectively.

22. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1, 5, 6, 10, 11, 12, 16, 17 and 18, wherein the Vy region and the Vy. region are or comprise the sequence set forth in SEQ ID NOS:130 and 106, respectively. 23 The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-22, wherein the antibody is a full length antibody.

24. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-22, wherein the antibody is an antigen-binding fragment. 2s. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-24, wherein said anti-ROR1 antibody or antigen-binding fragment thereof is recombinant.

26. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-25, wherein the Vy region and the Vy region is human or is from a human protein.

27. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-22 and 24-26, wherein the antigen-binding fragment thereof comprises a single chain Fv (scFv).

28. The anti-ROR1 antibody or antigen-binding fragment thereof of claim 27, wherein the Vy region is amino-terminal to the Vi region.

29. The anti-ROR1 antibody or antigen-binding fragment thereof of claim 27, wherein the Vy region is carboxy-terminal to the Vy region.

30. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 27-29, when the Vg region and the Vy region are joined by a flexible linker. 31 The anti-ROR1 antibody or antigen-binding fragment thereof of claim 30, wherein the flexible linker comprises the sequence set forth in SEQ ID NO:

41.

32. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 27, 28, 30 and 31, wherein 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 at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 118, 127, 109 or 134.

33. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 27, 28 and 30-32, wherein the scFv is or comprises the sequence set forth in SEQ ID NO:

118.

34. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 27, 28 and 30-32, wherein the scFv is or comprises the sequence set forth in SEQ ID NO:

127. 3s. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 27, 28 and 30-32, wherein the scFv is or comprises the sequence set forth in SEQ ID NO:

109.

36. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 27, 28 and 30-32, wherein the scFv is or comprises the sequence set forth in SEQ ID NO:

134.

37. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-36, wherein said anti-ROR1 antibody or antigen-binding fragment thereof specifically binds to a human Receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein.

38. The anti-ROR1 antibody or antigen-binding fragment thereof of claim 37, wherein the human RORI1 protein comprises an amino acid sequence set forth in SEQ ID NO: 144, 145 or 146.

39. The anti-ROR1 antibody or antigen-binding fragment thereof of claim 37 or claim 38, wherein said anti-ROR1 antibody or antigen-binding fragment thereof specifically binds to an epitope consisting of the sequence set forth in SEQ ID NO:199 or an epitope present within the sequence set forth in SEQ ID NO:

199.

40. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 37-39, wherein the antibody or antigen-binding fragment thereof further binds to one or more epitopes consisting of a sequence selected from among any one of SEQ ID NOS: 200-214 or an epitope present within a sequence selected from among any one of SEQ ID NOS: 200-214.

41. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-40, wherein said anti-ROR1 antibody or antigen-binding fragment thereof does not bind to, is not cross- reactive to, or binds at a lower level or degree or affinity to a Receptor tyrosine kinase-like orphan receptor 2 (ROR2) protein, optionally a human ROR2 protein.

42. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-41, wherein the extent, level or degree or affinity of binding of said anti-ROR1 antibody or antigen-binding fragment thereof to a human ROR2 is at least at or about 75%, 80%, 90%, 95% or 99% less than the extent, level or degree or affinity of binding to a human RORI1 protein.

43. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-42, wherein the antibody or antigen-binding fragment thereof binds to human ROR1 protein with an equilibrium dissociation constant (Kp) of from about 1 x 10"! M to about 1 x 107 M.

44. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-43, wherein the antibody or antigen-binding fragment thereof binds to human ROR1 protein with an equilibrium dissociation constant (Kp) of from about 1 x 10% M to about 1 x 107 M.

45. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-43, wherein the antibody or antigen-binding fragment thereof binds to human ROR1 protein with an equilibrium dissociation constant (Kp) of from about 5 x 10"! M to about 1 x 10° M.

46. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-45, wherein the antibody or antigen-binding fragment thereof binds to human ROR1 protein with a dissociation rate constant (ka or Kor) of from about 1 x 10 1 / s to about 1 x 102 1 / s.

47. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-46, wherein the antibody or antigen-binding fragment thereof binds to human ROR protein with a dissociation rate constant (kg or Kor) of from about 1 x 103 1 / s to about 1 x 102 1 / s.

48. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-46, wherein the antibody or antigen-binding fragment thereof binds to human RORI protein with a dissociation rate constant (kq or Kor) of from about 1 x 10 1 / s to about 1 x 10 1 / s.

49. A single chain cell-surface protein, comprising the anti-ROR1 antibody or antigen- binding fragment thereof of any of claims 1-48.

50. A conjugate, comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-48 and a heterologous molecule or moiety. SL The conjugate of claim 50, wherein the heterologous molecule or moiety is a therapeutic moiety.

52. 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 claims 1-48, a transmembrane region and an intracellular signaling region.

53. The anti-ROR1 chimeric antigen receptor of claim 52, further comprising a spacer between the extracellular antigen-binding domain and the transmembrane domain.

54. The anti-ROR1 chimeric antigen receptor of claim 53, wherein the spacer comprises at least a portion of an immunoglobulin or a variant thereof.

54. The anti-ROR1 chimeric antigen receptor of claim 53 or claim 54, wherein the spacer comprises at least a portion of a hinge region of an immunoglobulin or a variant thereof.

56. The anti-ROR1 chimeric antigen receptor of any of claims 53-55, wherein the spacer is less than at or about 15 amino acids in length.

57. The anti-ROR1 chimeric antigen receptor of any of claims 53-56, wherein the spacer is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1, 26, 27, 29, 31, 32, 33 or 135.

58. The anti-ROR1 chimeric antigen receptor of any of claims 53-57, wherein the at least a portion of a hinge region comprises all or a portion of an IgG4 hinge region, optionally a human IgG4 hinge region, or a variant thereof.

59. The anti-ROR1 chimeric antigen receptor of any of claims 53-57, wherein the at least a portion of a hinge region comprises all or a portion of an IgG2 hinge region, optionally a human IgG2 hinge region, or a variant thereof.

60. The anti-ROR1 chimeric antigen receptor of any of claims 53-58, wherein the spacer is or comprises the sequence set forth in SEQ ID NO:

1.

61. The anti-ROR1 chimeric antigen receptor of any of claims 53-58, wherein the spacer is or comprises the sequence set forth in SEQ ID NO:

135.

62. The anti-ROR1 chimeric antigen receptor of any of claims 53-55, wherein the spacer comprises at least a portion of a hinge region and at least a portion of a CH3 region of an immunoglobulin or a variant thereof.

63. The anti-ROR1 chimeric antigen receptor of any of claims 53-55 and 62, wherein the at least a portion of a CH3 region comprises all or a portion of an IgG4 CH3 and / or an IgG2 CH3, wherein the IgG4 CH3 is optionally a human IgG4 CH3 and the IgG2 CH3 is optionally a human IgG2 CH3.

64. The anti-ROR1 chimeric antigen receptor of any of claims 53-55, 62 and 63, wherein the spacer is at or about 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124 or 125 amino acids in length, or has a length between any of the foregoing.

65. The anti-ROR1 chimeric antigen receptor of any of claims 53-55 and 62-64, wherein the spacer is at or about 120 amino acids in length.

66. The anti-ROR1 chimeric antigen receptor of any of claims 53-55 and 62-65, wherein the spacer is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3 or 138.

67. The anti-ROR1 chimeric antigen receptor of any of claims 53-55 and 62-66, wherein the spacer is or comprises the sequence set forth in SEQ ID NO: 3 or 138.

68. The anti-ROR1 chimeric antigen receptor of any of claims 53-55, wherein the spacer comprises at least a portion of a hinge region, at least a portion of a CH2 and at least a portion of a CH3 region of an immunoglobulin or a variant thereof.

69. The anti-ROR1 chimeric antigen receptor of any of claims 53-55 and 68, wherein the at least a portion of a CH2 region comprises all or a portion of an IgG4 CH2 and / or an IgG2 CH2, wherein the IgG4 CH?2 is optionally a human IgG4 CH2 and the IgG2 CH2 is optionally a human IgG2 CH2.

70. The anti-ROR1 chimeric antigen receptor of any of claims 53-55, 68 and 69, wherein the spacer is at or about 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229 or 230 amino acids in length, or has a length between any of the foregoing.

71. The anti-RORI1 chimeric antigen receptor of any of claims 53-55 and 68-70, wherein: one or more of the hinge region, the CH2 region and the CH3 region comprises all or a portion of a CH2 region and all or a portion of a CH3 region from human IgG4; or one or more of the hinge region, the CH2 region and the CH3 region is chimeric and comprises a hinge, a CH2 region and a CH3 region from human IgG4 and human IgG2; or the spacer comprises a 1gG4 / 2 chimeric hinge region or a modified IgG4 hinge region comprising at least one amino acid replacement compared to a human IgG4 hinge; an IgG2 / 4 chimeric CH2 region; and an IgG4 CH3 region.

72. The anti-ROR1 chimeric antigen receptor of any of claims 53-55 and 68-71, wherein the spacer is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:37 or 194.

73. The anti-ROR1 chimeric antigen receptor of any of claims 53-55 and 68-72, wherein the spacer is or comprises the sequence set forth in SEQ ID NO: 37 or 194.

74. The anti-ROR1 chimeric antigen receptor of any of claims 52-73, wherein the transmembrane region is or comprises a transmembrane domain from CD4, CD28, or CDS.

75. The anti-ROR1 chimeric antigen receptor of any of claims 52-74, wherein the transmembrane region is or comprises a transmembrane domain from CD28, optionally a human CD28.

76. The anti-ROR1 chimeric antigen receptor of any of claims 52-75, wherein the transmembrane domain is or comprises SEQ ID NO: 8 or 149 or an amino acid sequence having at least at or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 8 or 149.

717. The anti-ROR1 chimeric antigen receptor of any of claims 52-76, wherein 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).

78. The anti-ROR1 chimeric antigen receptor of any of claims 52-77, wherein the intracellular signaling domain is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3() chain, optionally a human CD3{ chain.

79. The anti-ROR1 chimeric antigen receptor of any of claims 52-78, wherein 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 at or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:13, 14 or 15.

80. The anti-ROR1 chimeric antigen receptor of any of claims 52-79, wherein the intracellular signaling domain is or comprises the sequence set forth in SEQ ID NO:

13.

81. The anti-ROR1 chimeric antigen receptor of any of claims 52-80, wherein the intracellular signaling region further comprises a costimulatory signaling region.

82. The anti-ROR1 chimeric antigen receptor of claim 81, wherein the costimulatory signaling region is between the transmembrane region and the intracellular signaling domain.

83. The anti-ROR1 chimeric antigen receptor of claim 81 or claim 82, wherein the costimulatory signaling region comprises an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

84. The anti-ROR1 chimeric antigen receptor of any of claims 81-83, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS.

85. The anti-ROR1 chimeric antigen receptor of any of claims 81-84, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, optionally a human CD28.

86. The anti-ROR1 chimeric antigen receptor of any of claims 81-85, 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 at or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:

10.

87. The anti-ROR1 chimeric antigen receptor of any of claims 81-84, wherein the costimulatory signaling region comprises an intracellular signaling domain of 4-1BB, optionally a human 4-1BB.

88. The anti-ROR1 chimeric antigen receptor of any of claims 81-84 and 87, 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 at or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:

12.

89. The anti-ROR1 chimeric antigen receptor of any of claims 81-88, wherein the encoded chimeric antigen receptor comprises from its N to C terminus in order: the extracellular antigen-binding domain, the spacer, the transmembrane region and the intracellular signaling region.

90. The anti-ROR1 chimeric antigen receptor of any of claims 81-89, wherein the antigen- binding domain is an scFv and the encoded chimeric antigen receptor comprises, from its N to C terminus in order: an extracellular antigen-binding domain comprising the scFv, a spacer comprising a modified IgG4 hinge, optionally comprising the sequence set forth in SEQ ID NO:135; a transmembrane domain, optionally a transmembrane domain from a human CD28; and an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3-zeta (CD3() chain and an intracellular signaling domain of a costimulatory signaling region, optionally comprising an intracellular signaling domain of 4- 1BB. a. The anti-ROR1 chimeric antigen receptor of any of claims 81-89, wherein the antigen- binding domain is an scFv and the encoded chimeric antigen receptor comprises, from its N to C terminus in order: an extracellular antigen-binding domain comprising the scFv, a spacer comprising a modified IgG4 hinge-CH3, optionally comprising the sequence set forth in SEQ ID NO: 138; a transmembrane domain, optionally a transmembrane domain from a human CD28; and an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3-zeta (CD3() chain and an intracellular signaling domain of a costimulatory signaling region, optionally comprising an intracellular signaling domain of 4-1BB.

92. The anti-ROR1 chimeric antigen receptor of any of claims 52-91, wherein the anti- RORI chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 184, 185, 186, 187, 188 or 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: 184, 185, 186, 187, 188 or 189.

93. The anti-ROR1 chimeric antigen receptor of any of claims 52-92, wherein the anti- RORI chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO: 184 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:

184.

94. The anti-ROR1 chimeric antigen receptor of any of claims 52-93, wherein the anti- RORI1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO:

184.

95. The anti-ROR1 chimeric antigen receptor of any of claims 52-92, wherein the anti- RORI 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.

96. The anti-ROR1 chimeric antigen receptor of any of claims 52-92 and 95, wherein the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO:

185.

97. The anti-ROR1 chimeric antigen receptor of any of claims 52-92, wherein the anti- RORI 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.

98. The anti-ROR1 chimeric antigen receptor of any of claims 52-92 and 97, wherein the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO:

186.

99. The anti-ROR1 chimeric antigen receptor of any of claims 52-92, wherein the anti- RORI 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.

100. The anti-ROR1 chimeric antigen receptor of any of claims 52-92 and 99, wherein the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO:

187.

101. The anti-ROR1 chimeric antigen receptor of any of claims 52-92, wherein the anti- RORI 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.

102. The anti-ROR1 chimeric antigen receptor of any of claims 52-92 and 101, wherein the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO:

188.

103. The anti-ROR1 chimeric antigen receptor of any of claims 52-92, wherein the anti- RORI 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.

104. The anti-ROR1 chimeric antigen receptor of any of claims 52-92 and 103, wherein the anti-ROR1 chimeric antigen receptor is or comprises the sequence set forth in SEQ ID NO:

189.

105. A polynucleotide comprising a nucleic acid encoding the anti-ROR1 antibody or antigen-binding domain thereof of any of claims 1-48.

106. A polynucleotide comprising a nucleic acid encoding the single chain cell surface protein of claim 49.

107. A polynucleotide comprising a nucleic acid encoding the conjugate of claim 50 or claim 51.

108. A polynucleotide comprising a nucleic acid encoding the anti-ROR1 chimeric antigen receptor of any of claims 52-104.

109. The polynucleotide of any of claims 105-108, wherein the polynucleotide is optimized by splice site elimination.

110. The polynucleotide of any of claims 105-109, wherein the polynucleotide is codon- optimized for expression in a human cell.

111. A vector, comprising the polynucleotide of any of claims 105-110.

112. The vector of claim 111, wherein the vector is a viral vector.

113. The vector of claim 112, wherein the viral vector is a retroviral vector or a lentiviral vector.

114. A cell comprising the anti-RORI antibody or antigen-binding fragment thereof of any of claims 1-48, the single chain cell surface protein of claim 49 or the conjugate of claim 50 or claim 51.

115. A cell comprising the anti-ROR1 chimeric antigen receptor of any of claims 52-104.

116. A cell comprising the polynucleotide of any of claims 105-110, or the vector of any of 111-113.

117. The cell of any of claims 114-116, that is a lymphocyte.

118. The cell of any of claims 114-116, that is an NK cell or a T cell.

119. The cell of any of claims 114-118, wherein the cell is a T cell and the T cell is a CD4+ T cell or a CD8&+ T cell.

120. The cell of any of claims 114-119, wherein the cell is a primary cell obtained from a subject.

121. The cell of any of claims 114-120, wherein, among a plurality of the cells, less than at or about 10%, at or about 9%, at or about 8%, at or about 7%, at or about 5%, at or about 4%, at or about 3%, at or about 2% or at or about 1% of the cells in the plurality comprise an anti-ROR1 chimeric antigen receptor that exhibits tonic signaling and / or antigen independent activity or signaling.

122. A composition comprising the cell of any of claims 114-121.

123. A composition comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-48, the single chain cell surface protein of claim 49, the conjugate of claim 50 or claim 51 or the anti-ROR1 chimeric antigen receptor of any of claims 52-104.

124. The composition of claim 122 or claim 123, further comprising a pharmaceutically acceptable excipient.

125. The composition of claim 122 or claim 124, wherein the composition comprises CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is from at or about 1:3 to 3:1, optionally at or about 1:2 to 2:1, optionally at or about 1:

1.

126. The composition of any of claims 122, 124 and 125, wherein, among a plurality of the cells in the composition, less than at or about 10%, at or about 9%, at or about 8%, at or about 7%, at or about 5%, at or about 4%, at or about 3%, at or about 2% or at or about 1% of the cells in the plurality comprise an anti-ROR1 chimeric antigen receptor that exhibits tonic signaling and / or antigen independent activity or signaling.

127. A method of treatment, comprising administering the cell of any of claims 114-121 or the composition of any of claims 122-126 to a subject having a disease or disorder associated with ROR1.

128. The cell of any of claims 114-121 or the composition of any of claims 122-126 for use in treating a disease or disorder associated with ROR1.

129. Use of the cell of any of claims 114-121 or the composition of any of claims 122-126 for the manufacture of a medicament for treating a disease or disorder associated with ROR1.

130. Use of the cell of any of claims 114-121 or the composition of any of claims 122-126 for the treatment of a disease or disorder associated with ROR1.

131. A method of treatment, comprising administering the anti-RORI antibody or antigen- binding fragment thereof of any of claims 1-48, the single chain cell surface protein of claim 49, the conjugate of claim 50 or claim 51, the anti-ROR1 chimeric antigen receptor of any of claims 52-104, the polynucleotide of any of claims 105-110, or the vector of any of 111-113 to a subject having a disease or disorder associated with ROR1.

132. The anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-48, the single chain cell surface protein of claim 49, the conjugate of claim 50 or claim 51, the anti-ROR1 chimeric antigen receptor of any of claims 52-104, the polynucleotide of any of claims 105-110, or the vector of any of 111-113 for use in treating a disease or disorder associated with ROR1.

133. Use of the anti-RORI antibody or antigen-binding fragment thereof of any of claims 1- 48, the single chain cell surface protein of claim 49, the conjugate of claim 50 or claim 51, the anti-ROR1 chimeric antigen receptor of any of claims 52-104, the polynucleotide of any of claims 105-110, or the vector of any of 111-113 for the manufacture of a medicament for treating a disease or disorder associated with ROR1.

134. Use of the anti-RORI antibody or antigen-binding fragment thereof of any of claims 1- 48, the single chain cell surface protein of claim 49, the conjugate of claim 50 or claim 51, the anti-ROR1 chimeric antigen receptor of any of claims 52-104, the polynucleotide of any of claims 105-110, or the vector of any of 111-113 for the treatment of a disease or disorder associated with RORI.

135. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of any of claims 127-134, wherein the disease or disorder associated with ROR1 is a cancer.

136. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of claim 135, wherein the cancer is a ROR 1-expressing cancer.

137. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of any of claims 127-136, wherein the cancer is associated with a ROR 1-expressing solid tumor or a RORI1-expressing hematologic malignancy.

138. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of any of claims 127-137, wherein the cancer is associated with a ROR 1-expressing solid tumor.

139. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of claim 137 or claim 138, 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, epithelial squamous cell cancer, melanoma, myeloma, stomach 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.

140. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of claim 139, wherein the lung cancer is a non-small cell lung cancer (NSCLC), lung adenocarcinoma, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and atypical carcinoid.

141. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of claim 140, wherein the lung cancer is a NSCLC.

142. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of claim 139, wherein the breast cancer is a triple negative breast cancer (TNBC).

143. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of any of claims 127-137, wherein the cancer is associated with a ROR1-expressing hematologic malignancy.

144. The method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of claim 143, wherein the hematologic 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).

145. A kit comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-48, the single chain cell surface protein of claim 49, the conjugate of claim 50 or claim 51, the anti-RORI1 chimeric antigen receptor of any of claims 52-104, the polynucleotide of any of claims 105- 110, the vector of any of 111-113, the cell of any of claims 114-121 or the composition of any of claims 122-126, and instructions for use, optionally wherein the instructions are for administering the anti- RORI 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 accord with the method, the cell, composition, antibody or antigen-binding fragment thereof, single chain cell surface protein, conjugate, chimeric antigen receptor, polynucleotide or vector for use or the use of any of claims 127-144.

146. An article of manufacture comprising the anti-ROR1 antibody or antigen-binding fragment thereof of any of claims 1-48, the single chain cell surface protein of claim 49, the conjugate of claim 50 or claim 51, the anti-ROR1 chimeric antigen receptor of any of claims 52-104, the polynucleotide of any of claims 105-110, the vector of any of 111-113, the cell of any of claims 114-121 or the composition of any of claims 122-126 or the kit of claim 145.

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