Anti-ROR-2 antibodies and methods of use thereof

Abstract

Provided herein are, inter alia, antibodies (e.g., humanized antibodies, monoclonal antibodies), antibody fragments (e.g., scFvs), and antibody compositions (e.g., chimeric antigen receptors, bispecific antibodies) that bind to human tyrosine kinase-like orphan receptor 2 (ROR2) with high efficiency and specificity and are useful, inter alia, for the diagnosis and treatment of cancer and other ROR2-associated diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 478,067, filed December 30, 2022, the entire contents of which are incorporated herein by reference for all purposes. [Background technology]

[0002] Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a developmentally restricted receptor for certain Wingless-related integration site (Wnt) factors, such as Wnt5a. Human ROR2 is a 943-amino acid, single-pass type I membrane protein with a calculated molecular mass of 104.8 kDa. It is highly conserved across multiple species, with 92% amino acid sequence identity between the mouse and human proteins. ROR2 regulates Wnt signaling by repressing the transcription of Wnt target genes and sequestering canonical Wnt ligands, thereby functioning as a tumor suppressor in various cellular environments. Consistent with its function(s) primarily in embryonic development, ROR2 expression is attenuated during embryonic / fetal development, and most normal postnatal tissues do not express ROR2. However, ROR2 is expressed by a variety of cancers (e.g., breast, ovarian, pancreatic, cervical, gastric, renal, head and neck, bone, skin, soft tissue, or prostate cancer) and may promote tumor progression, metastasis, and / or self-renewal. Thus, there is a need for antibodies, antibody fragments, bispecific antibodies, and chimeric antigen receptors that specifically target human ROR2 and inhibit its function, thereby serving as effective therapeutic and diagnostic agents. The compositions and methods provided herein address these and other needs in the art. Summary of the Invention [Means for solving the problem]

[0003] In one embodiment, a method for identifying an anti-ROR2 antibody is provided, comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising a histidine at a position corresponding to position 349 of SEQ ID NO: 34; (ii) detecting an antibody that binds to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide that does not comprise a histidine at a position corresponding to position 349 of SEQ ID NO: 34; and (iv) detecting an antibody that does not bind to the second ROR2 polypeptide, thereby identifying the anti-ROR2 antibody.

[0004] In one embodiment, a method for identifying an anti-ROR2 antibody is provided, comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising an aspartic acid at position 354 of SEQ ID NO: 34; (ii) detecting an antibody that binds to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide that does not comprise an aspartic acid at position 354 of SEQ ID NO: 34; and (iv) detecting an antibody that does not bind to the second ROR2 polypeptide, thereby identifying the anti-ROR2 antibody.

[0005] In one embodiment, a method for identifying an anti-ROR2 antibody is provided, comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising a methionine at position 386 of SEQ ID NO: 34; (ii) detecting an antibody that binds to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide that does not comprise a methionine at position 386 of SEQ ID NO: 34; and (iv) detecting an antibody that does not bind to the second ROR2 polypeptide, thereby identifying the anti-ROR2 antibody.

[0006] In one aspect, an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody is provided, comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 1, the light chain variable domain comprises the sequence of SEQ ID NO: 2, the heavy chain variable domain comprises the sequence of SEQ ID NO: 3, the light chain variable domain comprises the sequence of SEQ ID NO: 4, the heavy chain variable domain comprises the sequence of SEQ ID NO: 5, the light chain variable domain comprises the sequence of SEQ ID NO: 6, the heavy chain variable domain comprises the sequence of SEQ ID NO: 7, the light chain variable domain comprises the sequence of SEQ ID NO: 8, the heavy chain variable domain comprises the sequence of SEQ ID NO: 9, the light chain variable domain comprises the sequence of SEQ ID NO: 10, the heavy chain variable domain comprises the sequence of SEQ ID NO: 11, the light chain variable domain comprises the sequence of SEQ ID NO: 12, the heavy chain variable domain comprises the sequence of SEQ ID NO: 13, the light chain variable domain comprises the sequence of SEQ ID NO: 14, and the heavy chain variable domain comprises the sequence of SEQ ID NO: 15. wherein the light chain variable domain comprises the sequence of SEQ ID NO: 16, the heavy chain variable domain comprises the sequence of SEQ ID NO: 17, the light chain variable domain comprises the sequence of SEQ ID NO: 18, the heavy chain variable domain comprises the sequence of SEQ ID NO: 19, the light chain variable domain comprises the sequence of SEQ ID NO: 20, the heavy chain variable domain comprises the sequence of SEQ ID NO: 21, the light chain variable domain comprises the sequence of SEQ ID NO: 22, the heavy chain variable domain comprises the sequence of SEQ ID NO: 23, the light chain variable domain comprises the sequence of SEQ ID NO: 24, the heavy chain variable domain comprises the sequence of SEQ ID NO: 25, the light chain variable domain comprises the sequence of SEQ ID NO: 26, the heavy chain variable domain comprises the sequence of SEQ ID NO: 27, the light chain variable domain comprises the sequence of SEQ ID NO: 28, the heavy chain variable domain comprises the sequence of SEQ ID NO: 29, the light chain variable domain comprises the sequence of SEQ ID NO: 30, or the heavy chain variable domain comprises the sequence of SEQ ID NO: 31 and the light chain variable domain comprises the sequence of SEQ ID NO: 32.

[0007] In one aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof).

[0008] In one aspect, a method of inhibiting metastasis of a ROR2-expressing cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof).

[0009] In one aspect, there is provided a chimeric antigen receptor comprising: (i) an antibody region comprising any one of the light chain variable domain and heavy chain variable domain pairs provided herein (including embodiments thereof); and (ii) a transmembrane domain.

[0010] In one aspect, an anti-ROR2 antibody is provided that is capable of binding to the same epitope as the antibodies provided herein (including embodiments thereof).

[0011] In another aspect, a CDR H1 is provided which comprises: (i) a CDR H1 comprising an amino acid sequence of the formula GFTFS-X1-YG-X2-X3 (I), wherein X1 is A, D, E, F, G, H, K, N, P, Q, R, S, T, or V; X2 is A, H, I, L, M, Q, S, T, or V; and X3 is S or N; provided that when X2 is M and X3 is S, X1 is not N; (ii) a CDR H2 is provided which comprises an amino acid sequence of the formula X4-ISSGGGYT-X5-Y-X6 (II), wherein X4 is T or S; X5 is H or Y; and X6 is V or A; (iii) a CDR H3 is provided which comprises an amino acid sequence of the formula ARHPRDFSYA-X7-DY (III). H3, (wherein X7 is A, F, H, I, K, L, M, N, Q, S, T, or V), (iv) CDR L1 comprising the amino acid sequence of the formula QDVGHY(IV), (v) CDR L2 comprising the amino acid sequence of the formula WAS(V), and (vi) CDR L3 comprising the sequence of SEQ ID NO: 53.

[0012] In another embodiment, a CDR H1 comprises an amino acid sequence of the formula GFTFS-X1-YG-X2-X3 (I), wherein X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y; X2 is A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; and X3 is S or N; provided that when X2 is M and X3 is S, X1 is not N. (iii) CDR H3 comprising an amino acid sequence of the formula DFSYA-X7-DYWG(III), wherein X7 is A, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; (iv) CDR L1 comprising an amino acid sequence of the formula X8-ASQDVGHY-X9-A(IV), wherein X8 is K or R, X9 is V or L, and when X8 is K, X9 is not V; (v) CDR L2 comprising an amino acid sequence of the formula WASTR-X10-T(V), wherein X8 is K or R, X9 is V or L, and when X8 is K, X9 is not V; and (vi) CDR L3 comprising the sequence of SEQ ID NO: 53.

[0013] In another aspect, a CDR H1 is provided comprising: (i) a CDR H1 comprising an amino acid sequence of the formula GFTFS-X1-YG-X2-X3 (I), wherein X1 is A, D, E, F, G, H, K, N, P, Q, R, S, T, or V; X2 is A, , H, I, , L, M, , Q, S, T, or V; and X3 is S or N, provided that when X2 is M and X3 is S, X1 is not N; (ii) a CDR H2 is provided comprising an amino acid sequence of the formula X4-ISSGGGYT-X5-Y-X6 (II), and (iii) a CDR H2 is provided comprising an amino acid sequence of the formula ARHPRDFSYA-X7-DY (III). H3, (wherein X7 is A, F, H, I, K, L, M, N, P, Q, S, T, or V), (iv) CDR L1 comprising an amino acid sequence of the formula QDVGHY, (v) CDR L2 comprising an amino acid sequence of the formula WAS, and (vi) CDR L3 comprising the sequence of SEQ ID NO: 53.

[0014] In another aspect, there is provided a method of treating cancer in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof).

[0015] In another aspect, a method for detecting a ROR2-expressing cell is provided, the method comprising: (i) contacting a ROR2-expressing cell with an antibody provided herein (including embodiments thereof); and (ii) detecting binding of the antibody to ROR2 protein expressed by the cell.

[0016] In another aspect, a method of delivering a therapeutic agent to a ROR2-expressing cell is provided, the method comprising contacting the ROR2-expressing cell with an antibody provided herein (including embodiments thereof), wherein the antibody binds to the therapeutic agent.

[0017] In another aspect, a method of inhibiting metastasis of ROR2-expressing cells is provided, said method comprising contacting ROR2-expressing cells with an antibody provided herein (including embodiments thereof).

[0018] In another aspect, an anti-ROR2 antibody is provided, which binds to the same epitope as the anti-ROR2 antibody provided herein (including embodiments thereof).

[0019] In another aspect, there is provided a chimeric antigen receptor comprising: (i) an anti-ROR2 antibody provided herein (including embodiments thereof); and (ii) a transmembrane domain.

[0020] In one aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a chimeric antigen receptor provided herein (including embodiments thereof). [Brief explanation of the drawings]

[0021] [Figure 1] Figure 1 shows a comparison of the extracellular domains of human and mouse receptor tyrosine kinase-like orphan receptor 2 (ROR2). Alignment of the amino acid sequences of the extracellular domains of human (upper sequence) and mouse (lower sequence) ROR2 is shown. Dots indicate homology at that position, while differences are designated by single-letter amino acid codons. The Ig-like, cysteine-rich domain (CRD), and kringle domain are labeled and indicated by lines above the sequences. [Figure 2A]Figure 1 shows the identification of the binding region of anti-human ROR2 mAb by assessing binding to chimeric human / mouse recombinant ROR2 protein. A schematic diagram of the chimeric constructs of the extracellular portion of ROR2 used to map the binding region of each ROR2 mAb is shown. The dark area of ​​each construct represents human ROR2, and the shaded area represents the region of mouse ROR2. h1-111 and h1-160 refer to the first 111 and 160 amino acids of human ROR2, respectively. hCRD and hKringle contain the cysteine-rich domain and Kringle domain of human ROR2, respectively. [Figure 2B] Figure 1 shows the identification of the binding region of anti-human ROR2 mAb by assessing binding to chimeric human / mouse recombinant ROR2 protein. Protein sequence alignment of the Kringle domains of human ROR2 and mouse ROR2 is shown. Numbers above the sequences indicate the positions of the amino acid residues below. Dots in the mROR2 sequence indicate sequence homology with hROR2 at that position. Letters in the mROR2 sequence indicate amino acids that differ from hROR2 at that position. Recombinant human ROR2 proteins in which one amino acid that differs in the Kringle domain between human ROR2 and mouse ROR2 has been replaced with the corresponding amino acid in mouse ROR2 are boxed and the amino acid, amino acid position, and the amino acid (T327M) present in hROR2 and the replaced amino acid in mROR2 are shown in the key. [Figure 2C] Figure 1 shows the identification of the binding region of anti-human ROR2 mAb by assessing binding to chimeric human / mouse recombinant ROR2 protein. Each recombinant protein was transferred to a nylon membrane, probed with c6E6 mAb, and detected with an anti-human IgG antibody conjugated to horseradish peroxidase. c6E6 mAb binds to ROR2 recombinant protein containing the human Kringle domain. c6E6 binding is abolished by amino acid substitutions at positions 349 and 354. [Figure 3]Figure 2 shows the identification of the binding region of humanized anti-human ROR2 mAbs by assessing binding to chimeric human / mouse recombinant ROR2 proteins. The recombinant human / mouse ROR2 proteins shown in Figure 2A were transferred to nylon membranes, probed with h6E6 mAb, and detected with an anti-human IgG antibody conjugated to horseradish peroxidase. The key on the right indicates the position of each recombinant protein, arranged in two rows of six. The underlined numbers above each paired row indicate the name of the h6E6 mAb used on that membrane. Each membrane was incubated separately with the primary and secondary antibodies and developed and imaged together. Each of the 16 h6E6 mAbs exhibited the same binding pattern as the chimeric 6E6 mAb, which is the parent mouse variable region fused to human IgG1. Each mAb bound to ROR2 recombinant proteins containing the human Kringle domain, and binding was inhibited by amino acid substitutions at positions 349 and 354, indicating that specific binding to human ROR2 was not altered by humanization. [Figure 4] 1 shows the identification of the binding region of anti-human ROR2 mAb by assessing binding to chimeric human / mouse recombinant ROR2 protein. [Figure 5A] Alignment of immunoglobulin heavy chain variable region gene (IGHV) amino acid sequences of 16 humanized anti-human ROR2 hybridomas is shown. For each alignment, the top sequence represents the amino acid sequence of the heavy chain variable region, starting with the first codon of the first framework region and ending with the last codon of the fourth framework region. Amino acids that differ from the other 15 sequences are recorded within each aligned sequence and designated as single-letter amino acid codons. Framework (FR) and complementarity-determining (CDR) regions are marked above the sequences, and amino acid positions are marked. The name of each mAb sequence is listed to the left of each sequence. [Figure 5B]Figure 1 shows an alignment of immunoglobulin kappa variable cluster (IGKV) amino acid sequences of 16 humanized anti-human ROR2 hybridomas. For each alignment, the top sequence represents the amino acid sequence of the light chain variable region, starting with the first codon of the first framework region and ending with the last codon of the fourth framework region. Amino acids that differ from the other 15 sequences are recorded within each aligned sequence and designated as single-letter amino acid codons. Framework (FR) and complementarity-determining (CDR) regions are marked above the sequences, and amino acid positions are marked. The name of each mAb sequence is listed to the left of each sequence. [Figure 6A] Figure 1 shows that the h6E6-116 and h6E6-070 humanized anti-human ROR2 mAbs specifically bind to human ROR2. The binding of h6E6-116 and h6E6-070 mAbs to human ROR2 was assessed by flow cytometry staining and analysis of several human cell lines known to express ROR2. Cells were stained with 5 μg / ml of h6E6-116 or h6E6-070 anti-human ROR2-Alexa647 conjugated mAb (shaded histograms) or an equivalent amount of isotype-matched control mAb (open histograms) for 20 minutes on ice, washed, and analyzed. Histograms show the relative fluorescence intensity (x-axis) of live cells as determined by light scattering properties. [Figure 6B] These results show that the h6E6-116 and h6E6-070 humanized anti-human ROR2 mAbs specifically bind to human ROR2. Specificity was verified by the lack of binding to HCT116 colorectal cancer cells in which ROR2 expression had been ablated using CRISPR-cas9, compared to the parental ROR2-expressing cell line or MEC1 leukemia cells transfected to express human ROR2. [Figure 7]This figure shows that the h6E6-116 humanized anti-human ROR2 mAb does not bind to lymphocytes (Lymphs) or peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. Blood cells were isolated from consenting healthy donors by Ficoll density centrifugation. Cells were stained with 5 μg / ml of the h6E6-116 anti-human ROR2-Alexa647 conjugated mAb (shaded histogram) or an equivalent amount of an isotype-matched control mAb (open histogram) for 20 minutes on ice, washed, and analyzed by flow cytometry. Histograms show staining of live mononuclear cells (PMBCs) or lymphocytes (Lymphs) as determined by light scatter characteristics. Staining of K562 cells was performed as a positive control. [Figure 8] This figure shows that the h6E6-116 humanized anti-human ROR2 chimeric antigen receptor (CAR) specifically binds to recombinant human ROR2 protein. Jurkat cells were transfected with the h6E6-116 anti-human ROR2 chimeric antigen receptor construct or the anti-human ROR1 CAR construct. All cells were evaluated for binding of recombinant human ROR2-Ig protein, which consists of the ROR2 extracellular domain and the CH2-CH3 constant region domains of human IgG1, by flow cytometry 48 hours later. Cells were stained with 1 μg / ml recombinant ROR2-Ig (top panel) or 1 μg / ml control ROR1-Ig (bottom panel) for 20 minutes on ice, washed, and stained with phycoerythrin (PE)-conjugated anti-human IgG1 antibody for an additional 20 minutes on ice, washed, and analyzed by flow cytometry. Shaded histograms show the relative fluorescence intensity (x-axis) of live cells stained with either ROR2-Ig or ROR1-Ig, as determined based on light scatter characteristics, compared to cells stained with anti-human IgG1-PE antibody alone (open histogram). Jurkat cells transfected with the CAR construct h6E6-116a bind to ROR2-Ig (top panel) but not to ROR1-Ig, which consists of the same human IgG domain fused to the extracellular region of human ROR1. In contrast, cells transfected with the ROR1 CAR bind only to ROR1-Ig. DETAILED DESCRIPTION OF THE INVENTION

[0022] While various embodiments and aspects of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0023] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are expressly incorporated herein by reference in their entirety for any purpose.

[0024] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0025] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not intended to limit the scope of the present disclosure.

[0026] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof or their complements, or nucleosides (e.g., deoxyribonucleosides or ribonucleosides) in either single-, double-, or multi-stranded form. In embodiments, "nucleic acid" does not include nucleosides. The terms "polynucleotide," "oligonucleotide," "oligo," and the like refer, in their usual and customary sense, to a linear sequence of nucleotides. The term "nucleoside" refers, in their usual and customary sense, to a glycosylamine comprising a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non-limiting examples of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine, and inosine. The term "nucleotide" refers, in their usual and customary sense, to a single polynucleotide unit (i.e., monomer). A nucleotide can be a ribonucleotide, a deoxyribonucleotide, or a modified version thereof. Examples of polynucleotides contemplated herein include single- and double-stranded DNA, single- and double-stranded RNA, and hybrid molecules comprising a mixture of single- and double-stranded DNA and RNA. Examples of nucleic acids (e.g., polynucleotides) contemplated herein include all types of RNA (e.g., mRNA, siRNA, miRNA, and guide RNA), and all types of DNA (genomic DNA, plasmid DNA, and minicircle DNA), and any fragments thereof. The term "duplex" in the context of a polynucleotide refers to double-strandedness in the usual and customary sense. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides, or nucleic acids can be branched, e.g., such that the nucleic acid comprises one or more arms or branches of nucleotides. Optionally, branched nucleic acids are repeatedly branched to form higher-order structures such as dendrimers.

[0027] For example, a nucleic acid, including a nucleic acid having a phosphothioate backbone, may contain one or more reactive moieties. As used herein, the term reactive moiety includes any group that can react with another molecule (e.g., a nucleic acid or polypeptide) through a covalent bond, a non-covalent bond, or other interaction. For example, a nucleic acid may contain an amino acid reactive moiety that reacts with an amino acid on a protein or polypeptide through a covalent bond, a non-covalent bond, or other interaction.

[0028] This term also encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, including synthetic, naturally occurring, and non-naturally occurring nucleic acids that have similar binding properties to the reference nucleic acid and are metabolized in the same manner as the reference nucleotide. Examples of such analogs include, but are not limited to, phosphoramidates, phosphorodiamidates, phosphorothioates (also known as phosphothioates, where the oxygen in the phosphate is replaced with a double-bonded sulfur), phosphorodithioates, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acids, phosphonoformic acids, methylphosphonates, boronphosphonates, or phosphodiester derivatives containing O-methylphosphoramidite linkages (Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press), as well as modifications of nucleotide bases such as 5-methylcytidine or pseudouridine, and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with cationic backbones, non-ionic backbones, modified sugars, and non-ribose backbones (e.g., phosphorodiamidate morpholino oligos or locked nucleic acids (LNAs) known in the art), including those described in U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7 of ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acid. Modifications to the ribose-phosphate backbone can be made for a variety of reasons, including increasing the stability and half-life of such molecules in physiological environments or as probes on biochips. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs and mixtures of naturally occurring nucleic acids and analogs can be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0029] Nucleic acids may contain non-specific sequences. As used herein, the term "non-specific sequence" refers to a nucleic acid sequence containing a series of residues that are not designed to be complementary or only partially complementary to any other nucleic acid sequence. For example, a non-specific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[0030] A polynucleotide is typically composed of a specific sequence of the four nucleotide bases adenine (A), cytosine (C), guanine (G), and thymine (T) (uracil (U) is substituted for thymine (T) when the polynucleotide is RNA). Thus, the term "polynucleotide sequence" refers to an alphabetical representation of a polynucleotide molecule; alternatively, the term may apply to the polynucleotide molecule itself. This alphabetical representation can be input into a database on a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. A polynucleotide may optionally contain one or more non-standard nucleotide(s), nucleotide analog(s), and / or modified nucleotides.

[0031] As used herein, the term "complement" refers to a nucleotide (e.g., RNA or DNA) or sequence of nucleotides that can base-pair with a complementary nucleotide or sequence of nucleotides. As described herein and generally known in the art, the complementary (matching) nucleotide of adenosine is thymidine, and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement can include a sequence of nucleotides that base-pair with the corresponding complementary nucleotides of a second nucleic acid sequence. The complementary nucleotides can partially or completely match the nucleotides of the second nucleic acid sequence. When the complementary nucleotides completely match each nucleotide of the second nucleic acid sequence, the complement will base-pair with each nucleotide of the second nucleic acid sequence. When the complementary nucleotides partially match the nucleotides of the second nucleic acid sequence, only a portion of the complementary nucleotides will base-pair with the nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding sequences and non-coding sequences, where the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. Further examples of complementary sequences include sense and antisense sequences, where the sense sequence comprises complementary nucleotides to the antisense sequence, thus forming the complement of the antisense sequence.

[0032] As described herein, sequence complementarity can be partial, where only some nucleic acids match through base pairing, or all nucleic acids match completely through base pairing. Thus, two sequences that are complementary to each other can have a certain percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity over a specified region).

[0033] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. An amino acid analog refers to a compound that has the same basic chemical structure as a naturally occurring amino acid (i.e., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium). Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. An amino acid mimetic refers to a chemical compound that has a structure that differs from the general chemical structure of an amino acid, but functions in a manner similar to a naturally occurring amino acid. The terms "non-naturally occurring amino acid" and "unnatural amino acid" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

[0034] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0035] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which, in embodiments, may be conjugated to a moiety that is not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of corresponding naturally occurring amino acids, as well as to naturally occurring and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0036] The "position" of an amino acid or nucleotide base is indicated by a number sequentially identifying each amino acid (or nucleotide base) in a reference sequence based on its position relative to the N-terminus (or 5'-terminus). Due to deletions, insertions, truncations, fusions, etc., which must be considered when determining optimal alignment, the number of amino acid residues in a test sequence, as determined by simple counting from the N-terminus, is generally not necessarily the same as the number at that corresponding position in the reference sequence. For example, if a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant corresponding to the reference sequence position at the site of the deletion. If there is an insertion in an aligned reference sequence, the insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there may be a stretch of amino acids in the reference or aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0037] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refer to the numbering of residues in a particular reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue of a protein "corresponds" to a given residue if it occupies the same essential structural position within the protein as the given residue. Those skilled in the art will readily recognize the identity and position of a residue that corresponds to a particular position in a protein (e.g., ROR2) in other proteins with different numbering systems. For example, by performing a simple sequence alignment with a protein (e.g., ROR2), the identity and position of a residue that corresponds to a particular position in the protein can be identified in other protein sequences that align to the protein. For example, if the selected residue occupies the same essential spatial or other structural relationship as the aspartic acid at position 354, then the selected residue in the selected protein corresponds to the aspartic acid at position 354. In some embodiments, when a selected protein is aligned for maximum homology with a protein, the position in the aligned selected protein that aligns with aspartic acid 354 is the position corresponding to aspartic acid 354. Also, instead of a primary sequence alignment, a three-dimensional structural alignment can be used, for example, in which the structures of the selected proteins are aligned to maximize correspondence with aspartic acid at position 354, and the overall structures are compared. In this case, the amino acid occupying the same essential position as aspartic acid 354 in the structural model is the amino acid corresponding to the aspartic acid 354 residue.

[0038] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to a particular nucleic acid sequence, "conservatively modified variants" refers to nucleic acids that encode identical or essentially identical amino acid sequences. Due to the degeneracy of the genetic code, several nucleic acid sequences will encode any given protein. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Thus, at every position where alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one type of conservatively modified variation. Every nucleic acid sequence herein that encodes a polypeptide also describes every possible silent variation of the nucleic acid. Those of skill in the art will recognize that each codon in a nucleic acid (except AUG, which is usually the only codon for methionine, and TGG, which is usually the only codon for tryptophan) can be modified to produce a functionally identical molecule. Thus, each silent variation of a nucleic acid that encodes a polypeptide is implicit in each described sequence.

[0039] With respect to amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions, or additions to a nucleic acid, peptide, polypeptide, or protein sequence that alter, add, or delete a single amino acid or a small percentage of amino acids in the encoded sequence are "conservatively modified variants" in that the changes result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables that result in functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to, and do not exclude, polymorphic variants, interspecies homologs, and alleles of the present disclosure.

[0040] The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) aspartic acid (D), glutamic acid (E); 3) asparagine (N), glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); 6) phenylalanine (F), tyrosine (Y), tryptophan (W); 7) serine (S), threonine (T); and 8) Cysteine ​​(C), Methionine (M) (See, e.g., Creighton, Proteins (1984)).

[0041] The terms "identical" or "percent identity," in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that contain the same or a specified percentage of identical amino acid residues or nucleotides (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region when compared and aligned for closest correspondence over a comparison window or designated region), as determined using the BLAST or BLAST 2.0 sequence comparison algorithm with default parameters described below, or by manual alignment and visual inspection (see, e.g., the NCBI website http: / / www.ncbi.nlm.nih.gov / BLAST / ). Such sequences are then said to be "substantially identical." This definition also refers to or can be applied to the complement of a test sequence. This definition also includes sequences that have deletions and / or additions, as well as sequences that have substitutions. As explained below, preferred algorithms can account for gaps, etc. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

[0042] "Percent sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, where the portion of the polynucleotide or polypeptide sequence in the comparison window may contain additions or deletions (i.e., gaps) compared to a reference sequence (which does not contain additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions where the identical nucleic acid base or amino acid residue occurs in both sequences to obtain the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percent sequence identity.

[0043] "Comparison window," as used herein, refers to a sequence that can be compared to a reference sequence for the same number of contiguous positions after the two sequences are optimally aligned, including reference to the full-length sequence or any segment of the sequence for a number of contiguous positions selected from the group consisting of 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides. Methods for aligning sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be achieved, for example, by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, the search for similarity method of Pearson and Lipman (1988) Proc. Nat'l. Acad. Sci. USA 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0044] Examples of algorithms suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves identifying high-scoring sequence pairs (HSPs) by first identifying short words of length W in the query sequence that, when aligned with words of the same length in a database sequence, either match or meet some positive threshold score T. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. Word hits are extended in both directions along each sequence for as far as possible to increase the cumulative alignment score. Cumulative scores are calculated using the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0) for nucleotide sequences. For amino acid sequences, a scoring matrix is ​​used to calculate the cumulative score. Extension of word hits in each direction is stopped when the cumulative alignment score drops by an amount X from its maximum achieved value, when the cumulative score falls below 0 due to the accumulation of one or more negative-scoring residue alignments, or when the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. For example, the BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands.For amino acid sequences, the BLASTP program uses as default a word length of 3, an expectation (E) of 10, an alignment (B) of 50, an expectation (E) of 10, M=5, N=-4 in the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915), and a comparison of both strands.

[0045] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability that a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid with the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0046] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the sequences can be amplified using the same primers.

[0047] Antibodies are large, complex molecules (molecular weight of about 150,000 or about 1320 amino acids) with complex internal structures. Natural antibody molecules contain two identical pairs of polypeptide chains, each pair having one light chain and one heavy chain. Each light and heavy chain in turn consists of two regions: a variable ("V") region, which is responsible for binding the target antigen, and a constant ("C") region, which interacts with other components of the immune system. The light and heavy chain variable regions (also referred to herein as light chain variable (VL) domains and heavy chain variable (VH) domains, respectively) combine in three-dimensional space to form a variable region that binds to antigens (e.g., receptors on cell surfaces). Within each light or heavy chain variable region, there are three short segments (averaging 10 amino acids in length) called complementarity-determining regions ("CDRs"). The six CDRs in an antibody variable domain (three from the light chain and three from the heavy chain) fold together in three-dimensional space to form the actual antibody binding site that docks to the target antigen. The position and length of the CDRs are precisely defined by Kabat, E. et al., Sequences of Proteins of Immunological Interest, USDapartment of Health and Human Services, 1983, 1987. The parts of the variable region not included in the CDRs are called the framework ("FR"), which forms the environment for the CDRs.

[0048] As provided herein, an "antibody variant" refers to a polypeptide capable of binding to an antigen and comprising one or more structural domains of an antibody or fragment thereof (e.g., a light chain variable domain, a heavy chain variable domain). Non-limiting examples of antibody variants include single-domain antibodies or nanobodies, monospecific Fab2s, bispecific Fab2s, trispecific Fab3s, monovalent IgGs, scFvs, diabodies, bispecific diabodies, trispecific triabodies, scFv-Fc, minibodies, IgNARs, V-NARs, hcIgGs, VhHs, or peptibodies. As provided herein, a "peptibody" refers to a peptide moiety attached (via a covalent or non-covalent linker) to the Fc domain of an antibody. Further non-limiting examples of antibody variants known in the art include antibodies produced by cartilaginous fish or camelids. A general description of camelid-derived antibodies and their variable regions, and methods for producing, isolating, and using them, can be found in references WO97 / 49805 and WO97 / 49805, which are incorporated herein by reference in their entirety for all purposes. Similarly, cartilaginous fish-derived antibodies and their variable regions, and methods for producing, isolating, and using them, can be found in WO2005 / 118629, which is incorporated herein by reference in its entirety for all purposes.

[0049] The terms "CDR L1," "CDR L2," and "CDR L3" provided herein refer to complementarity determining regions (CDRs) 1, 2, and 3 of the variable light (L) chain of an antibody. In embodiments, a variable light chain provided herein comprises, from N-terminal to C-terminal, CDR L1, CDR L2, and CDR L3. Similarly, the terms "CDR H1," "CDR H2," and "CDR H3" provided herein refer to complementarity determining regions (CDRs) 1, 2, and 3 of the variable heavy (H) chain of an antibody. In embodiments, a variable heavy chain provided herein comprises, from N-terminal to C-terminal, CDR H1, CDR H2, and CDR H3.

[0050] The terms "FR L1," "FR L2," "FR L3," and "FR L4" provided herein are used according to their common meaning in the art and refer to framework regions (FR) 1, 2, 3, and 4 of the variable light (L) chain of an antibody. In embodiments, a variable light chain provided herein comprises, from N-terminal to C-terminal, FR L1, FR L2, FR L3, and FR L4. Similarly, the terms "FR H1," "FR H2," "FR H3," and "FR H4" provided herein are used according to their common meaning in the art and refer to framework regions (FR) 1, 2, 3, and 4 of the variable heavy (H) chain of an antibody. In embodiments, a variable heavy chain provided herein comprises, from N-terminal to C-terminal, FR H1, FR H2, FR H3, and FR H4.

[0051] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" chain (approximately 25 kD) and one "heavy" chain (approximately 50-70 kD). The N-terminus of each chain defines a variable region of approximately 100-110 amino acids primarily responsible for antigen recognition. The terms variable light chain (VL), variable light chain (VL) domain, or light chain variable region, and variable heavy chain (VH), variable heavy chain (VH) domain, or heavy chain variable region refer to these light chain and heavy chain regions, respectively. As used herein, the terms variable light chain (VL), variable light chain (VL) domain, and light chain variable region may be used interchangeably. As used herein, the terms variable heavy chain (VH), variable heavy chain (VH) domain, and heavy chain variable region may be used interchangeably. The Fc (i.e., fragment crystallizable region) is the "base" or "tail" of an immunoglobulin and is typically composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. The Fc region binds to specific proteins, ensuring that each antibody generates an appropriate immune response to a given antigen. The Fc region also binds to various cellular receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[0052] The term "antibody" is used according to its commonly known meaning in the art. Antibodies exist, for example, as intact immunoglobulins or as several well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests antibodies below the disulfide bond in the hinge region to generate F(ab)'2, a dimer of Fab, a light chain linked to VH-CH1 by a disulfide bond. F(ab)'2 can be reduced under mild conditions to cleave the disulfide bond in the hinge region, thereby converting the F(ab)'2 dimer into a Fab' monomer. A Fab' monomer is essentially a Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3rd ed. 1993)). While various antibody fragments are defined in terms of digestion of an intact antibody, those skilled in the art will understand that such fragments can be synthesized de novo, either chemically or using recombinant DNA methodologies. Thus, as used herein, the term antibody also includes antibody fragments either produced by the modification of whole antibodies, synthesized de novo using recombinant DNA methodologies (e.g., single-chain Fvs), or identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)). The term "antibody" as referred to herein further includes antibody variants such as single-domain antibodies. Thus, in embodiments, an antibody comprises a single monomeric variable antibody domain. Thus, in embodiments, an antibody comprises a variable light chain (VL) domain or a variable heavy chain (VH) domain. In embodiments, an antibody is a variable light chain (VL) domain or a variable heavy chain (VH) domain.

[0053] Any technique known in the art can be used to prepare monoclonal or polyclonal antibodies (see, for example, Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). A "monoclonal" antibody (mAb) refers to an antibody derived from a single clone. Techniques for producing single-chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to generate antibodies against polypeptides of the present invention. Alternatively, transgenic mice or other organisms, such as other mammals, can be used to express humanized antibodies. Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to a selected antigen (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).

[0054] Single-chain variable fragments (scFv) are typically fusion proteins of the variable regions of immunoglobulin heavy (VH) and light (VL) chains, connected with a short linker peptide of 10 to about 25 amino acids. The linker is usually glycine-rich for flexibility and may be serine- or threonine-rich for solubility. The linker can connect the N-terminus of VH to the C-terminus of VL, or vice versa.

[0055] The epitope of a mAb is the region of its antigen to which the mAb binds. Two antibodies bind to the same or overlapping epitopes if each competitively inhibits (blocks) the binding of the other to the antigen. That is, a 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess of one antibody inhibits binding of the other by at least 30%, but preferably 50%, 75%, 90%, or even 99%, as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 50:1495, 1990). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

[0056] Many techniques known in the art can be used to prepare suitable antibodies of the invention (e.g., recombinant, monoclonal, or polyclonal antibodies) and use them in accordance with the present invention (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2nd ed. 1986)). Genes encoding the heavy and light chains of an antibody of interest can be cloned from cells; for example, genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce recombinant monoclonal antibodies. Gene libraries encoding the heavy and light chains of monoclonal antibodies can also be generated from hybridoma cells or plasma cells. Random combination of heavy and light chain gene products generates a large pool of antibodies with different antigen specificities (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for producing single-chain antibodies or recombinant antibodies (U.S. Pat. No. 4,946,778, U.S. Pat. No. 4,816,567) can be adapted to produce antibodies against the polypeptides of the present invention.Also, transgenic mice or other organisms, such as other mammals, can be used to express humanized or human antibodies (see, e.g., U.S. Pat. Nos. 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Co., J. Med. Chem. Soc. 1999, 11:1011-1013). (See Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to a selected antigen (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., capable of recognizing two different antigens (see, e.g., WO 93 / 08829; Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). The antibody may also be a heteroconjugate, such as two covalently joined antibodies, or an immunotoxin (see, for example, U.S. Pat. No. 4,676,980, WO 91 / 00360, WO 92 / 200373, and EP 03089).

[0057] Methods for humanizing or primatizing non-human antibodies are well known in the art (see, e.g., U.S. Pat. Nos. 4,816,567, 5,530,101, 5,859,205, 5,585,089, 5,693,761, 5,693,762, 5,777,085, 6,180,370, 6,210,671, and 6,329,511, WO 87 / 02671, EP Patent Application No. 0173494, Jones et al. (1986) Nature 321:522, and Verhoyen et al. (1988) Science 239:1534). Humanized antibodies are further described, for example, in Winter and Milstein (1991) Nature 349:293. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues, often referred to as introduced residues, are usually taken from an imported variable domain. Humanization was essentially performed according to the method of Winter et al. (e.g., Morrison et al., PNAS USA, 81:6851-6855 (1984); Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988); Verhoeyen et al., Science 239:1534-1536 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Padlan, Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3):169-217 (1994)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Such humanized antibodies are thus chimeric antibodies (U.S. Pat. No. 4,816,567), in which substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, a polynucleotide comprising a first set of sequences encoding humanized immunoglobulin framework regions and a second set of sequences encoding the desired immunoglobulin complementarity-determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated from a variety of human cells according to well-known procedures.

[0058] A "chimeric antibody" is (a) an antibody molecule in which the constant region or a portion thereof has been altered, substituted, or replaced so that the antigen-binding site (variable region) is linked to a constant region of a different or altered class, effector function, and / or species, or to an entirely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody, or (b) an antibody molecule in which the variable region or a portion thereof has been altered, substituted, or replaced with a variable region having a different or altered antigen specificity. Preferred antibodies of the invention and for use in accordance with the invention include humanized and / or chimeric monoclonal antibodies.

[0059] When referring to a protein or peptide, the phrases "specifically (or selectively) bind to an antibody" or "specifically (or selectively) immunoreactive with" often refer to a binding reaction that determines the presence of a protein in a heterogeneous population of proteins and other biologics. Thus, under specified immunoassay conditions, a specified antibody binds to a particular protein at least twice as much as background, more typically more than 10-100 times as much as background. Specific binding to an antibody under such conditions requires that the antibody be selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies specifically immunoreactive with a selected antigen and not with other proteins. This selection can be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats can be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase enzyme-linked immunosorbent assays (ELISAs) are routinely used to select antibodies specifically immunoreactive with proteins (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

[0060] "Ligand" refers to an agent (e.g., a polypeptide or other molecule) that can bind to a receptor or to an antibody, antibody variant, antibody region, or fragment thereof.

[0061] Techniques for conjugating therapeutic agents to antibodies are well known (see, for example, Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy," in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery," in Controlled Drug Delivery (2 nd (Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987), Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review" in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62:119-58 (1982). As used herein, the term "antibody-drug conjugate" or "ADC" refers to a therapeutic agent that is conjugated or otherwise covalently attached to an antibody.

[0062] As used herein, the term "ROR2 protein" or "ROR2" includes any recombinant or native form of the tyrosine protein kinase transmembrane receptor ROR2, receptor tyrosine kinase-like orphan receptor 2, also known as neurotrophic tyrosine kinase receptor-associated 2, or a variant or homolog thereof that maintains ROR2 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to ROR2). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring ROR2 protein. In embodiments, the ROR2 protein is substantially identical to the protein identified by SEQ ID NO: 18. In embodiments, the ROR2 protein is substantially identical to the protein identified by UniProt reference number Q01974 or a variant or homolog having substantial identity thereto. In embodiments, the ROR2 protein is substantially identical to the protein identified by UniProt reference number A1L4F5 or a variant or homolog having substantial identity thereto. In embodiments, the ROR2 protein is substantially identical to the protein identified by UniProt reference number Q8C3W2 or a variant or homolog having substantial identity thereto.

[0063] For particular proteins described herein, the named protein includes any naturally occurring form, variant, or homolog of the protein that maintains protein transcription factor activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the native protein). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to the naturally occurring form. In other embodiments, the protein is a protein identified by its NCBI sequence reference. In other embodiments, the protein is a protein identified by its NCBI sequence reference, a homolog, or a functional fragment thereof.

[0064] The term "gene" refers to a segment of DNA involved in producing a protein, including regions preceding and following the coding region (leader and trailer), and intervening sequences (introns) between individual coding segments (exons). Leaders, trailers, and introns contain regulatory elements required during transcription and translation of a gene. Furthermore, a "protein gene product" is a protein expressed from a particular gene.

[0065] The terms "plasmid," "vector," or "expression vector" refer to a nucleic acid molecule that encodes genes and / or regulatory elements necessary for expression of genes. Expression of genes from a plasmid can occur in cis or trans. When a gene is expressed in cis, the gene and regulatory elements are encoded by the same plasmid. Expression in trans refers to the case where the gene and regulatory elements are encoded by separate plasmids.

[0066] The terms "transfection," "transduction," "transfecting," or "transducing" can be used interchangeably and are defined as the process of introducing a nucleic acid molecule or protein into a cell. Nucleic acids are introduced into cells using non-viral or viral-based methods. Nucleic acid molecules may be gene sequences encoding complete proteins or functional portions thereof. Non-viral methods of transfection include any suitable transfection method that does not use viral DNA or viral particles as a delivery system for introducing nucleic acid molecules into cells. Exemplary non-viral transfection methods include calcium phosphate transfection, liposome transfection, nucleofection, sonoporation, heat shock transfection, magnetifection, and electroporation. In some embodiments, nucleic acid molecules are introduced into cells using electroporation, according to standard procedures well known in the art. For viral-based methods of transfection, any useful viral vector can be used in the methods described herein. Examples of viral vectors include, but are not limited to, retroviral vectors, adenoviral vectors, lentiviral vectors, and adeno-associated viral vectors. In some embodiments, nucleic acid molecules are introduced into cells using retroviral vectors according to standard procedures well known in the art. The terms "transfection" or "transduction" also refer to the introduction of proteins into cells from the external environment. Typically, protein transduction or transfection relies on the binding of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, e.g., Ford et al. (2001) Gene Therapy 8:1-4 and Prochiantz (2007) Nat. Methods 4:119-20.

[0067] A "label" or a "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include phosphorus-32 ( 32 Examples of suitable radiolabels include radioactive ions (P), fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in ELISA), biotin, digoxigenin, or haptens, as well as proteins or other entities that can be made detectable, for example, by incorporating a radioactive label into a peptide or an antibody that specifically reacts with a target peptide. Any suitable method known in the art for conjugating an antibody to a label can be used, for example, the method described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

[0068] If the label or detectable moiety is a radioactive metal or paramagnetic ion, the agent may be reacted with another long-tailed reagent having one or more chelating groups attached to the long tail for binding these ions. The long tail can be a polymer (e.g., polylysine, polysaccharide, or other derivatized or derivatizable chain with pendant groups to which metals or ions can be attached for binding). Examples of chelating groups that can be used in accordance with the present disclosure include, but are not limited to, groups such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), DOTA, NOTA, NETA, TETA, porphyrins, polyamines, crown ethers, bisthiosemicarbazones, and polyoximes. The chelate is typically linked to the PSMA antibody or functional antibody fragment by a group that allows for the formation of a bond to the molecule with minimal loss of immunoreactivity and minimal aggregation and / or internal cross-linking. The same chelating agents, when complexed with non-radioactive metals such as manganese, iron, and gadolinium, are useful for magnetic resonance imaging (MRI) when used with the antibodies and carriers described herein. Macrocyclic chelators such as NOTA, DOTA, and TETA are used with a variety of metals and radiometals, including, but not limited to, gallium, yttrium, and copper, respectively. Radium-223 ( 223 Other ring-type chelators, such as macrocyclic polyethers, intended for stably binding nuclides such as Ra, may be used. In certain embodiments, the chelating moiety is a PET imaging agent (e.g., Al-) for use in positron emission tomography (PET). 18 F complex) to a targeting molecule.

[0069] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two different species (e.g., an antibody and an antigen) to come into sufficient proximity to react, interact, or come into physical contact. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate from one or more added reagents that may be produced in the reaction mixture.

[0070] The term "contacting" can include allowing two species to react, interact, or come into physical contact, where the two species can be, for example, a pharmaceutical composition provided herein and a cell. In embodiments, contacting includes, for example, allowing a pharmaceutical composition described herein to interact with a cell.

[0071] As used herein, a "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a particular dye, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells of plant and animal origin, such as mammalian, insect (e.g., Spodoptera), and human cells.

[0072] The term "recombinant," when used in reference to, for example, a cell, nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein, or vector has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a naturally occurring nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, a recombinant cell expresses a gene that is not found in the native (non-recombinant) form of the cell, or expresses a naturally occurring gene that is otherwise abnormally expressed, under-expressed, or not expressed at all. Transgenic cells and plants are typically those that express heterologous genes or coding sequences as a result of recombinant methods.

[0073] The term "isolated," when applied to a nucleic acid or protein, indicates that the nucleic acid or protein is essentially free from other cellular components with which it is naturally associated. It can be, for example, in a homogeneous state, either a dry solution or an aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0074] The term "heterologous," when used with reference to portions of a nucleic acid, indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For example, a nucleic acid is typically produced recombinantly, having two or more sequences from unrelated genes, e.g., a promoter from one source and a coding region from another source, arranged to create a new functional nucleic acid. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[0075] The term "exogenous" refers to a molecule or substance (e.g., a compound, nucleic acid, or protein) that originates from outside a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that does not originate from the cell or organism in which it is expressed. Conversely, the terms "endogenous" or "endogenous promoter" refer to a molecule or substance that is native to or derived from a given cell or organism.

[0076] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to cell proliferation (e.g., cancer cell proliferation), mean to adversely affect a cell (e.g., reduce proliferation) or kill a cell. In embodiments, inhibition refers to the alleviation of a disease or disease symptom (e.g., cancer, cancer cell proliferation). Thus, inhibition includes at least partially, partially or completely blocking a stimulus; reducing, preventing, or delaying activation; or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a protein (e.g., ROR2 protein). Similarly, an "inhibitor" is a compound or protein that inhibits a receptor or another protein, for example, by binding to, partially or completely blocking, reducing, preventing, delaying, inactivating, desensitizing, or downregulating activity (e.g., receptor activity or protein activity).

[0077] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, in reference to protein-inhibitor interactions, refer to adversely affecting (e.g., decreasing) the activity or function of a protein (e.g., a ROR2 protein) relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to adversely affecting (e.g., decreasing) the concentration or level of ROR2 relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to a reduction in a disease or disease symptom. In embodiments, inhibition refers to a decrease in the activity of ROR2. Thus, inhibition includes, at least in part, partially or completely blocking a stimulus; reducing, preventing, or delaying activation; or inactivating, desensitizing, or downregulating signaling or enzymatic activity or the amount of ROR2. In embodiments, inhibition refers to a decrease in the activity of ROR2 due to a direct interaction (e.g., an inhibitor binds to ROR2). In embodiments, inhibition refers to a decrease in the activity of ROR2 from an indirect interaction (e.g., an inhibitor binds to a protein that activates ROR2, thereby preventing activation of the target protein).

[0078] The terms "inhibitor," "repressor," "antagonist," or "downregulator" interchangeably refer to a substance that can detectably reduce the expression or activity of a given gene or protein (e.g., ROR2 protein). An antagonist can reduce ROR2 expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of the antagonist. In certain cases, ROR2 expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or less than the expression or activity in the absence of the antagonist.

[0079] The term "expression" includes any step involved in producing a polypeptide, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0080] "Biological sample" or "sample" refers to a material obtained from or derived from a subject or patient. Biological samples can also include sections of tissue, such as biopsy and autopsy samples, as well as frozen sections taken for histological purposes. Such samples include body fluids, such as blood and blood fractions or blood products (e.g., serum, plasma, platelets, red blood cells, etc.), sputum, tissues, cultured cells (e.g., primary cultures, explants, and transformed cells), stool, urine, synovial fluid, articular tissue, synovial tissue, synoviocytes, fibroblast-like synoviocytes, macrophage-like synoviocytes, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, and the like. Biological samples are typically obtained from eukaryotic organisms, such as mammals such as primates (e.g., chimpanzees or humans), cows, dogs, cats, rodents (e.g., guinea pigs, rats, mice), rabbits, or birds, reptiles, or fish.

[0081] A "control" or "standard control" refers to a sample, measurement, or value that serves as a reference (usually a known reference) for comparison with a test sample, measurement, or value. For example, a test sample can be collected from a patient suspected of having a given disease (e.g., cancer) and compared to a known normal (non-disease) individual (e.g., a standard control subject). A standard control can also represent an average measurement or mean value collected from a population of similar individuals (e.g., standard control subjects) who do not have the given disease (i.e., a standard control population), e.g., healthy individuals with a similar medical background, the same age, weight, etc. A standard control value can also be obtained from the same individual, e.g., from a sample previously obtained from the patient before the onset of the disease. For example, a control can be designed to compare therapeutic benefits (e.g., comparing side effects) based on pharmacological data (e.g., half-life) or therapeutic procedures. Controls are also useful for determining the significance of data. For example, if the value of a given parameter varies widely in the control, the variation in the test sample is not considered significant. Those skilled in the art will recognize that standard controls can be designed for evaluation of any number of parameters (e.g., RNA levels, protein levels, particular cell types, particular body fluids, particular tissues, etc.).

[0082] Those skilled in the art can understand which standard control is most appropriate in a given situation and can analyze data based on comparison with standard control value.Standard control is also useful for determining the significance (e.g., statistical significance) of data.For example, if the value of a given parameter varies greatly in standard control, the variation of test sample is not considered significant.

[0083] "Patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a composition or pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is a human.

[0084] The term "disease" or "condition" refers to the state or health of a patient or subject that can be treated with the compounds or methods provided herein. The disease can be cancer. Cancer can refer to leukemia, lymphoma, or solid tumor malignancies. Solid tumor malignancies include malignancies that may not have fluid or cysts. The solid tumor malignancies can be any of various types of cancer (e.g., breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, prostate cancer). In some further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias (including solid tumors and lymphatic cancers), renal cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer (including hepatocellular carcinoma), lymphomas (including B-acute lymphoblastic lymphoma), non-Hodgkin's lymphomas (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma, leukemias (including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML), multiple myeloma, or hairy cell leukemia).

[0085] As used herein, the term "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemias, carcinomas, and sarcomas. Exemplary cancers that may be treated using the compounds or methods provided herein include breast cancer, colon cancer, kidney cancer, leukemia, lung cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer, brain cancer, liver cancer, stomach cancer, or sarcoma.

[0086] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs, generally characterized by the abnormal proliferation and development of white blood cells and their precursor cells in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease (acute or chronic), (2) the type of cell involved: bone marrow (myeloid), lymph (lymphoid), or monocytic, and (3) whether the number of abnormal cells in the blood is increased or not (leukemic or non-leukemic (subleukemic)). Exemplary leukemias that may be treated with the compounds or methods provided herein include, for example, acute myeloid leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, leukemia), lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0087] The term "sarcoma" generally refers to a tumor composed of closely packed cells embedded in a substance similar to embryonic connective tissue and generally consisting of fibrous or homogeneous cells. Sarcomas that may be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloromatous sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, and fibroblastic sarcoma. Cellular sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0088] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0089] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.Exemplary cancers that may be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, adenocystic carcinoma, acinarcarcinoma, acinouscarcinoma, adenoid cysticcarcinoma, adenoidcysticcarcinoma, adenomatous carcinoma, alveolar carcinoma, alveolar cell carcinoma, basalcellcarcinoma, carcinomabasocellulare, basal cell carcinoma, and thyroid carcinoma. Basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, encephalomyeloma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, comedocarcinoma, uterine carcinoma, cribriform carcinoma, armor carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, compact carcinoma, embryonal carcinoma, encephalomyeloma, epidermoid carcinoma, adenoid carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinoid carcinoma, gelatinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, nitrite Pediatric carcinoma, hypernephroid carcinoma, childhood embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, carcinoma in situ, Krompecher's carcinoma, Kurticayskii cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma (carcinomalenticulare), lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma (carcinoma medullary), melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous adenocarcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, mucinous carcinoma (carcinoma mucosum), mucinous carcinoma (muc ouscarcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, atheromatous carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, striated carcinoma, telangiectatic carcinoma, telangiectasia-like carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), nodular carcinoma (tuberous carcinoma), verrucous carcinoma, or choriocarcinoma.

[0090] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., cancer) from one organ or another non-adjacent organ or part of the body. Cancer begins at a site of origin (e.g., the breast), which is called the primary tumor (e.g., primary breast cancer). Some cancer cells from the primary tumor or site of origin acquire the ability to penetrate and infiltrate the surrounding normal tissues of the local area and / or penetrate the walls of the lymphatic or vascular system and circulate to other sites and tissues in the body. A second, clinically detectable tumor formed from cancer cells of the primary tumor is called a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the breast site will consist of abnormal lung cells, not abnormal breast cells. The secondary tumor in the breast is called metastatic lung cancer. Therefore, the phrase metastatic cancer refers to a disease in which a subject has or has had a primary tumor, and has one or more secondary tumors. The phrase non-metastatic cancer or a subject with non-metastatic cancer can refer to a disease in which a subject has a primary tumor but does not have one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject who has or has a history of a primary lung tumor, and has one or more secondary tumors in a second location or multiple locations (e.g., breast).

[0091] In the context of a substance or the activity or function of a substance associated with a disease (e.g., a protein-related disease, a cancer associated with ROR2 activity, a ROR2-related cancer, or a ROR2-related disease (e.g., cancer, an inflammatory disease, an autoimmune disease, or an infectious disease)), the term "associated with" or "related to" means that the disease (e.g., cancer, an inflammatory disease, an autoimmune disease, or an infectious disease) is caused (in whole or in part) or the symptoms of the disease are caused (in whole or in part) by the substance or the activity or function of the substance. As used herein, something that is described as associated with a disease, if it is a causative agent, may be a target for treating the disease. For example, if increased ROR2 activity or function (e.g., signaling pathway activity) causes the disease (e.g., cancer, an inflammatory disease, an autoimmune disease, or an infectious disease), the cancer or ROR2-related disease (e.g., cancer, an inflammatory disease, an autoimmune disease, or an infectious disease) associated with ROR2 activity or function can be treated with a ROR2 modulator or a ROR2 inhibitor. For example, inflammatory diseases associated with ROR2 activity or function or ROR2-associated inflammatory diseases may be treated with ROR2 modulators or ROR2 inhibitors, where increased ROR2 activity or function (e.g., signal transduction pathway activity) causes the disease.

[0092] As used herein, the term "signaling pathway" refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that can transmit a change in one component to one or more other components, which can in turn transmit changes to additional components, which, optionally, are propagated to other signaling pathway components.

[0093] As used herein, the term "aberrant" refers to something that is different from normal. Abnormal, when used to describe enzyme activity, refers to activity that is greater than or less than the average of a normal control or normal, non-disease control sample. Abnormal activity may refer to an amount of activity that results in disease; restoring the abnormal activity to a normal or non-disease-associated amount (e.g., by using the methods described herein) results in alleviation of the disease or one or more disease symptoms.

[0094] A "therapeutic agent" as referred to herein is a composition useful for the treatment or prevention of a disease such as cancer (e.g., leukemia). In some embodiments, the therapeutic agent is an anti-cancer agent. "Anticancer agent" is used according to their plain and ordinary meaning to refer to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has anti-neoplastic properties or the ability to inhibit cell growth or proliferation. In embodiments, the anti-cancer agent is a chemotherapeutic agent. In embodiments, the anti-cancer agent is an agent identified herein that has utility in methods of treating cancer. In embodiments, the anti-cancer agent is an agent approved by the FDA or similar regulatory agency in a country other than the United States to treat cancer.

[0095] As used herein, "anti-cancer agent" refers to a molecule (e.g., a compound, peptide, protein, nucleic acid, etc.) used to treat cancer by destroying or inhibiting cancer cells or tissues. Anti-cancer agents may be selective for a particular cancer or a particular tissue. In embodiments, anti-cancer agents herein may include epigenetic inhibitors and multikinase inhibitors, and "anti-cancer agent" and "anti-cancer agent" are used according to their plain and ordinary meaning to refer to compositions (e.g., compounds, drugs, antagonists, inhibitors, modulators) that have anti-neoplastic properties or the ability to inhibit cell growth or proliferation. In some embodiments, an anti-cancer agent is a chemotherapeutic agent. In some embodiments, an anti-cancer agent is an agent identified herein that has utility in methods of treating cancer. In some embodiments, an anti-cancer agent is an agent approved by the FDA or similar regulatory agency in a country other than the United States to treat cancer. Examples of anticancer agents include MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine), and thiazides, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, mayphalan), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate),or pyrimidine analogues (e.g., fluorouracil, floxuridine, cytarabine), purine analogues (e.g., mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etc.), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-amycin, sparginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin, or LY294002), Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituxan), gossyphol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5 -Aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol,Adzelesin, aldesleukin, ALL-TK antagonist, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, anti-dorsal morphogenetic protein-1, antiandrogen, prostate cancer, antiestrogen, antitumor agent, antisense oligonucleotide, aphidicolin glycinate, apoptosis gene regulator, apoptosis regulator, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivatives, balanol, batimastat, BCR / ABL antagonists, benzochlorins, benzoylstaurosporine, β-lactam derivatives, β-arretin, betaclamycin B, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistraten A, bizelesin, brefullate, bropirimine, budotitanium, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamidotriazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitors, carzelesin, casein kinase inhibitors, castanospermine, cecropin B, cetrorelix, chlorin, chloroquinoxaline sulfonamides, cicaprost, cis-porphyrin, cladribine, clomiphene analogs, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analogs, conagenin, crambecidin 816, crisnatol, kryptof Cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentanethraquinones, cycloplatam, sipemycin, cytarabine ocphosphate, cytolytic factors, cytostatin, dacliximab, decitabine, dehydrodidemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexverapamil, diazicon, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine,9-dioxamycin, diphenylspiromustine, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emiteflu, epirubicin, epristeride, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, fresera fluasterone, fludarabine, fluorodaunorubicin hydrochloride, forfenimex, formestane, fostricin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridones, imiquimod, immunostimulating peptides, insulin-like growth factor-1 receptor Interferon inhibitors, interferon agonists, interferon, interleukin, iobenguane, iododoxorubicin, ipomeanol, 4-, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole, Liarozole, linear polyamine analogues, lipophilic disaccharide peptides, lipophilic platinum compounds, lisoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lisofylline, lytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalone, meterelin, methioninase, metoclopramide, MIF inhibitors, mifepristone,Miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, human chorionic gonadotropin monoclonal antibody, monophosphoryl lipid A + Myobacterium cell wall SK, mopidamol, multidrug resistance gene inhibitors, multiple tumor suppressor 1-based therapy, mustard-based anticancer drugs, mycaperoxide B, Mycobacterium tuberculosis cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzyl alcohol Amides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidants, nitrulline, O6-benzylguanine, octreotide, oxenon, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducers, ormaplatin, osatelon, oxaliplatin, oxaunomycin, palmitate, palmitoyl Lurizoxin, pamidronate, panaxytriol, panomifen, parabactin, pazeliptin, pegaspargase, perdecin, pentosan polysulfate sodium, pentostatin, pentorozole, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetic acid, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, prasetin A, prasetin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum triamine complexes, porfimer sodium, porfiromycin , prednisone, propylbisacridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, protein kinase C inhibitors, protein kinase C inhibitors, microalgae, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridines, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, demethylated reteliptin,Rhenium Re186 etidronate, rhizoxin, ribozyme, RII retinamide, logletimide, rohitukaine, romultide, roquinimex, rubiginone B1, ruboxil, safingol, centupin, sarcophytol A, sargramostim, Sdi 1 mimetic, semustine, aging-derived, inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single-stranded antigen binding protein, schizofuran, sobuzoxane, sodium borocaptate, sodium phenylacetate, sorberol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, stipiamid, stromelysin inhibitor, sulfinosine, superactive vasoactive intestinal peptide antagonist, sulagist, suramin, swainsonine, synthetic guanylate Lycosaminoglycans, talimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, terlapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, thiocoraline, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor agonists, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector systems, erythrocyte gene therapy, veraresol, veramine, verudin, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorb, zinostatin, stimalamer, adriamycin, Dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adzelesin, aldesleukin, altretamine, ambomycin, amethanthrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide mesylate, bizeresin, bleomycin sulfate, brequinar sodium, bropirimine,Busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziconazole, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, dexorumaplatin Duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, foskidone, fostricin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea A, idarubicin hydrochloride, ifosfamide, imofosine, interleukin I1 (including recombinant interleukin II, or rlL-2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-1a, interferon gamma-1b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride , megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromin, mitogillin, mitomarcin, mitomycin, mitospar, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, pegaspargase, periomycin, pentamstine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,Piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ribopurine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, te Loxantrone hydrochloride, temoporfin, teniposide, teloxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubrozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vincrisine sulfate, vinleurosine sulfate, vinorelbine tartrate , vinrocidin sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, drugs that arrest cells in the G2-M phase and / or drugs that modulate the formation or stability of microtubules (e.g., Taxol™ (paclitaxel), Taxotere™, compounds containing a taxane skeleton), elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobrin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide ( i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altorhyrtin (e.g., altorhyrtin A and altorhyrtin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B,Epothilone C (i.e., desoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4559-P (Pharmacia, i.e., LS-4577), and LS-4559-P are available. 578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), cryptophycin 52 (LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitrebroside, tubulysin A, kale Nadensol, Centaueragin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker-Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e., BTO-956 and DIME),DDE-313 (Parker-Hughes Laboratories), physianolide B, laulimalide, SPA-2 (Parker-Hughes Laboratories), SPA-1 (Parker-Hughes Laboratories, i.e., SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Astamedica), A-105972 (Abbott), hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularic), monsatrol, inanosin (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine, i.e., NSC-698666), Medicine), A-204197 (Abbott), T-607 (Tuialik, i.e., T-900607), RPR-115781 (Aventis), eleutherobin (desmethyleleutherobin, desaethyleleutherobin, isoeleutherobin A, Z-eleutherobin, etc.), carbaeoside, carbaeolin, halichondrin B, D-64131 (Astamedica), D-68144 (Astamedica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahisteine ​​(Sutamedica) i.e., NSCL-96F037), D-68838 (Astamedica), D-68836 (Astamedica), Myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resbelastatin sodium phosphate, BPR-OY-007 (National Institutes of Health), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,Gonadotropin-releasing hormone agonists (GnRH) such as goserelin and leuprolide, corticosteroids (prednisone, etc.), progestins (hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate, etc.), estrogens (diethylstilbestrol, ethinyl estradiol, etc.), antiestrogens (tamoxifen, etc.), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG)), levamisole, interleukin-2, α-interferon, etc., monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugates, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibodies conjugated to indium-111 (111In), yttrium-90 (90Y), or iodine-131 (131I), etc.), triptolide, homoharitonin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, benzylparaben, Rafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapy or treatment (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272) CP-72 4714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, and the like.

[0096] As used herein, "treating" or "treatment" of a condition, disease, or disorder, or symptoms associated with a condition, disease, or disorder, refers to an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, partial or total alleviation or amelioration of one or more symptoms or conditions, reduction in the severity of the condition, disorder, or disease, stabilization of the condition, disorder, or disease state, prevention of the onset of the condition, disorder, or disease, prevention of the spread of the condition, disorder, or disease, delaying or slowing the progression of the condition, disorder, or disease, delaying or slowing the onset of the condition, disorder, or disease, improvement or palliation of the condition, disorder, or disease state, and remission. "Treating" can also mean prolonging the survival of a subject compared to expected survival in the absence of treatment. "Treating" can also mean inhibiting the progression of the condition, disorder, or disease, slowing the progression of the condition, disorder, or disease temporarily, although in some cases, involving permanently halting the progression of the condition, disorder, or disease. As used herein, the terms treatment, therapy, or therapy refer to a method of alleviating the effects of one or more symptoms of a disease or condition characterized by protease expression, or a method of alleviating the symptoms of a disease or condition characterized by protease expression. Thus, in the disclosed methods, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptoms of a disease or condition. For example, a method for treating a disease is considered therapeutic if it results in a 10% reduction in one or more symptoms of the disease in a subject compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percentage reduction between 10% and 100% compared to native or control levels. It is understood that treatment does not necessarily refer to a cure of a disease or condition, or a complete disappearance of signs of a disease or condition.Furthermore, as used herein, references to reduction, decrease, or inhibition include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control level, and such terms can include, but do not necessarily include, complete elimination.

[0097] The terms "dose" and "dosage" are used interchangeably herein. Dose refers to the amount of active ingredient given to an individual at each administration. Dosage varies depending on several factors, including the usual dosage range for a given therapy, the frequency of administration, the size and tolerance of the individual, the severity of symptoms, the risk of side effects, and the route of administration. One skilled in the art will recognize that dosage may vary depending on the above factors or based on the progress of treatment. The term "dosage form" refers to the specific format of a medicament or pharmaceutical composition and depends on the route of administration. For example, the dosage form may be in the form of a liquid for nebulization, e.g., a tablet or liquid for inhalation, e.g., for oral delivery, or in saline, e.g., for injection.

[0098] As used herein, a "therapeutically effective dose or amount" refers to a dose that produces the desired effect (e.g., treatment or prevention of a disease) for which it is administered. The exact dose and formulation depend on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, Editor (2003); and Pickar, Dosage Calculations (1999)). For example, for a given parameter, a therapeutically effective amount represents an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The therapeutic effectiveness can also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount can be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than a standard control. A therapeutically effective dose or amount can ameliorate one or more symptoms of a disease. A therapeutically effective dose or amount can prevent or delay the onset of a disease or one or more symptoms of a disease when the effect for which it is administered is to treat a person at risk of developing a disease.

[0099] As used herein, the term "administration" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration to a subject, or implantation of a sustained-release device, e.g., a mini-osmotic pump. Administration may be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Coadministration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, e.g., cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered alone or coadministered to a patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined with other active substances (e.g., to reduce metabolic degradation) if necessary. The compositions of the present invention can be delivered by transdermal administration, topical administration, or formulated as an applicator stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, paint, powder, or aerosol.

[0100] The compositions of the present invention may further comprise ingredients that provide sustained release and / or comfort. Such ingredients include high molecular weight, anionic mucus-mimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These ingredients are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres for subcutaneous sustained release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In embodiments, formulations of the compositions of the invention can be delivered by the use of liposomes that fuse with or are endocytosed by cell membranes, i.e., by using receptor ligands attached to liposomes that bind to cell surface membrane protein receptors, resulting in endocytosis. The use of liposomes can target the delivery of the compositions of the present invention to target cells in vivo, especially when the liposome surface carries receptor ligands specific to the target cells or is otherwise preferentially directed to a particular organ. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989.) The compositions of the present invention can also be delivered as nanoparticles.

[0101] As used herein, the term "pharmaceutically acceptable" is used interchangeably with "physiologically acceptable" and "pharmacologically acceptable." Pharmaceutical compositions generally include agents for buffering and preservation during storage, and may include buffers and carriers for appropriate delivery, depending on the route of administration.

[0102] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of an active agent by a subject and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if necessary, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0103] The term "pharmaceutically acceptable salts" refers to salts derived from a variety of organic and inorganic counterions well known in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the molecule contains a basic functional group, includes salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0104] The term "preparation" is intended to include formulations of an active compound with an encapsulating material as a carrier to provide a capsule. In a capsule, the active ingredient is surrounded by a carrier, with or without other carriers, and is thus associated with the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0105] The pharmaceutical preparation is optionally in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form. The unit dosage form can also be a cryodispersion.

[0106] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or alterations thereto will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0107] Anti-ROR2 antibody Provided herein are, inter alia, antibodies (e.g., humanized antibodies, monoclonal antibodies), antibody fragments (e.g., scFvs), and antibody compositions (e.g., chimeric antigen receptors, bispecific antibodies) that bind to human tyrosine kinase-like orphan receptor 2 (ROR2) with high efficiency and specificity. The antibodies and antibody compositions provided herein comprise novel light chain domain CDRs and heavy chain domain CDRs and framework regions and are identified to bind to the extracellular domain of human ROR2. For example, the antibodies provided herein (including embodiments thereof) may bind to the kringle or Ig-like domain of ROR2 with high affinity and specificity. Furthermore, applicants have characterized amino acid residues in the ROR2 extracellular domain that are important for binding of the antibodies described herein (including embodiments thereof). Antibodies that specifically bind to the epitopes described herein (including embodiments thereof) bind to human ROR2 with high efficacy and affinity and are useful for inhibiting ROR2 signaling in cells expressing ROR2. The antibodies described herein (including embodiments thereof) may be used for diagnostic and therapeutic purposes for cancer and other ROR2-related diseases. The variable light chain domains and variable heavy chain domains provided herein may form part of, inter alia, an anti-ROR2 chimeric antigen receptor or an anti-ROR2 bispecific antibody. Furthermore, due to their internalization properties, some of the anti-ROR2 antibodies provided herein may be conjugated to a therapeutic moiety and used as an antibody-drug conjugate (ADC), or conjugated to a detectable moiety and used for diagnostic purposes. The antibodies provided herein (including embodiments thereof) have the ability to inhibit metastasis of ROR2-expressing metastatic cells and thus can reduce the risk of metastasis in patients with ROR2-expressing cancer cells.

[0108] As mentioned above, the term "light chain variable (VL) domain" as provided herein refers to the variable region of the light chain of an antibody, antibody variant, or fragment thereof. Similarly, the term "heavy chain variable (VH) domain" as provided herein refers to the variable region of the heavy chain of an antibody, antibody variant, or fragment thereof. The light chain variable domain and the heavy chain variable domain together form a paratope that binds to an antigen (epitope). The paratope or antigen-binding site is formed at the N-terminus of an antibody, antibody variant, or fragment thereof. In embodiments, the light chain variable (VL) domain comprises CDRs L1, L2, L3, and FRs L1, L2, L3, and L4 (framework regions) of an antibody light chain. In embodiments, the heavy chain variable (VH) domain comprises CDRs H1, H2, H3, and H1, H2, H3, and H4 (framework regions) of an antibody heavy chain. In embodiments, the light chain variable (VL) domain and the light chain constant (CL) domain form part of an antibody light chain. In embodiments, the heavy chain variable (VH) domain and the heavy chain constant (CH1) domain form part of an antibody heavy chain. In embodiments, the heavy chain variable (VH) domain and one or more heavy chain constant (CH1, CH2, or CH3) domains form part of an antibody heavy chain. Thus, in embodiments, the light chain variable (VL) domain forms part of an antibody. In embodiments, the heavy chain variable (VH) domain forms part of an antibody. In embodiments, the light chain variable (VL) domain forms part of a therapeutic antibody. In embodiments, the heavy chain variable (VH) domain forms part of a therapeutic antibody. In embodiments, the light chain variable (VL) domain forms part of a human antibody. In embodiments, the heavy chain variable (VH) domain forms part of a human antibody. In embodiments, the light chain variable (VL) domain forms part of a humanized antibody. In embodiments, the heavy chain variable (VH) domain forms part of a humanized antibody. In embodiments, the light chain variable (VL) domain forms part of a chimeric antibody. In embodiments, the heavy chain variable (VH) domain forms part of a chimeric antibody. In embodiments, the light chain variable (VL) domain forms part of an antibody fragment. In embodiments, the heavy chain variable (VH) domain forms part of an antibody fragment.In embodiments, the light chain variable (VL) domain forms part of an antibody variant. In embodiments, the heavy chain variable (VH) domain forms part of an antibody variant. In embodiments, the light chain variable (VL) domain forms part of a Fab. In embodiments, the heavy chain variable (VH) domain forms part of a Fab. In embodiments, the light chain variable (VL) domain forms part of an scFv. In embodiments, the heavy chain variable (VH) domain forms part of an scFv.

[0109] In embodiments, the antibody does not bind to arginine at the position corresponding to position 349 of SEQ ID NO: 36. In embodiments, the antibody does not bind to glutamic acid at the position corresponding to position 354 of SEQ ID NO: 36. In embodiments, the antibody does not bind to arginine at the position corresponding to position 349 of SEQ ID NO: 36. In embodiments, the antibody does not bind to glutamic acid at the position corresponding to position 354 of SEQ ID NO: 36.

[0110] In embodiments, the antibody binds to the kringle domain of human ROR2.

[0111] In embodiments, the antibody binds to a cancer cell, hi embodiments, the cancer cell is a breast cancer cell, ovarian cancer cell, pancreatic cancer cell, cervical cancer cell, gastric cancer cell, renal cancer cell, head and neck cancer cell, bone cancer cell, skin cancer cell, or prostate cancer cell.

[0112] In embodiments, the antibody is conjugated to a therapeutic agent. In embodiments, the antibody is conjugated to a diagnostic agent. In embodiments, the diagnostic agent is a detectable moiety.

[0113] In embodiments, the antibody is capable of binding to the ROR2 protein. In embodiments, the ROR2 protein is a human ROR2 protein. In embodiments, the antibody binds to the ROR2 protein. In embodiments, the antibody is capable of binding to the extracellular domain of the ROR2 protein. In embodiments, the antibody binds to the extracellular domain of the ROR2 protein. In embodiments, the extracellular domain is an Ig-like domain.

[0114] The antibodies provided herein (including embodiments thereof) may be humanized antibodies. Thus, in embodiments, the antibody is a humanized antibody. In embodiments, the antibody is a chimeric antibody. In embodiments, the antibody is a Fab' fragment. In embodiments, the antibody is an IgG. In embodiments, the antibody is an IgG. The anti-ROR2 antibodies provided herein may be IgG1, IgG2, IgG3, or IgG4. In embodiments, the antibody is IgG1. In embodiments, the antibody is IgG2. In embodiments, the antibody is IgG2a. In embodiments, the antibody is IgG3. In embodiments, the antibody is IgG4.

[0115] In embodiments, the antibody does not bind to the mouse ROR2 protein. In embodiments, the antibody does not bind to the mouse ROR2 protein identified by UniProt reference number Q9Z138. In embodiments, the antibody provided herein does not bind to a protein comprising the amino acid sequence of SEQ ID NO: 36.

[0116] In one aspect, the ROR2 protein bound by the antibodies provided herein (including embodiments thereof) is expressed by a cell (e.g., a cancer cell). Thus, in embodiments, the ROR2 protein is expressed on a cell. In embodiments, the cell is a cancer cell. In embodiments, the cancer cell is a breast cancer cell, ovarian cancer cell, pancreatic cancer cell, cervical cancer cell, gastric cancer cell, renal cancer cell, head and neck cancer cell, bone cancer cell, skin cancer cell, or prostate cancer cell. In embodiments, the cancer cell is a breast cancer cell. In embodiments, the cancer cell is an ovarian cancer cell. In embodiments, the cancer cell is a pancreatic cancer cell. In embodiments, the cancer cell is a cervical cancer cell. In embodiments, the cancer cell is a gastric cancer cell. In embodiments, the cancer cell is a renal cancer cell. In embodiments, the cancer cell is a head and neck cancer cell. In embodiments, the cancer cell is a bone cancer cell. In embodiments, the cancer cell is a skin cancer cell. In embodiments, the cancer cell is a prostate cancer cell.

[0117] In embodiments, the antibodies provided herein do not bind to ROR2-negative cells. "ROR2-negative cells" provided herein are cells that do not express detectable amounts of ROR2 protein compared to a standard control. In embodiments, the expression level of ROR2-negative cells is undetectable using methods conventionally known in the art for detecting protein expression in cells (e.g., immunofluorescence detection, protein biochemistry, RNA expression levels). In embodiments, the expression level of ROR2-negative cells is 1000-fold, 500-fold, 100-fold, 50-fold, 25-fold, 20-fold, 10, 5-fold, or 1.5-fold lower than the expression level of a standard control (e.g., cells expressing detectable levels of ROR2 using conventional methods). Non-limiting examples of ROR2-negative cells include peripheral blood mononuclear cells (PBMCs) from healthy individuals.

[0118] In one embodiment, a method for identifying an anti-ROR2 antibody is provided, comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising a histidine at a position corresponding to position 349 of SEQ ID NO: 34; (ii) detecting an antibody that binds to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide that does not comprise a histidine at a position corresponding to position 349 of SEQ ID NO: 34; and (iv) detecting an antibody that does not bind to the second ROR2 polypeptide, thereby identifying the anti-ROR2 antibody.

[0119] In one embodiment, a method for identifying an anti-ROR2 antibody is provided, comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising an aspartic acid at position 354 of SEQ ID NO: 34; (ii) detecting an antibody that binds to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide that does not comprise an aspartic acid at position 354 of SEQ ID NO: 34; and (iv) detecting an antibody that does not bind to the second ROR2 polypeptide, thereby identifying the anti-ROR2 antibody.

[0120] In one embodiment, a method for identifying an anti-ROR2 antibody is provided, comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising a methionine at position 386 of SEQ ID NO: 34; (ii) detecting an antibody that binds to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide that does not comprise a methionine at position 386 of SEQ ID NO: 34; and (iv) detecting an antibody that does not bind to the second ROR2 polypeptide, thereby identifying the anti-ROR2 antibody.

[0121] In one aspect, an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody is provided, comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 1, the light chain variable domain comprises the sequence of SEQ ID NO: 2, the heavy chain variable domain comprises the sequence of SEQ ID NO: 3, the light chain variable domain comprises the sequence of SEQ ID NO: 4, the heavy chain variable domain comprises the sequence of SEQ ID NO: 5, the light chain variable domain comprises the sequence of SEQ ID NO: 6, the heavy chain variable domain comprises the sequence of SEQ ID NO: 7, the light chain variable domain comprises the sequence of SEQ ID NO: 8, the heavy chain variable domain comprises the sequence of SEQ ID NO: 9, the light chain variable domain comprises the sequence of SEQ ID NO: 10, the heavy chain variable domain comprises the sequence of SEQ ID NO: 11, the light chain variable domain comprises the sequence of SEQ ID NO: 12, the heavy chain variable domain comprises the sequence of SEQ ID NO: 13, the light chain variable domain comprises the sequence of SEQ ID NO: 14, and the heavy chain variable domain comprises the sequence of SEQ ID NO: 15. wherein the light chain variable domain comprises the sequence of SEQ ID NO: 16, the heavy chain variable domain comprises the sequence of SEQ ID NO: 17, the light chain variable domain comprises the sequence of SEQ ID NO: 18, the heavy chain variable domain comprises the sequence of SEQ ID NO: 19, the light chain variable domain comprises the sequence of SEQ ID NO: 20, the heavy chain variable domain comprises the sequence of SEQ ID NO: 21, the light chain variable domain comprises the sequence of SEQ ID NO: 22, the heavy chain variable domain comprises the sequence of SEQ ID NO: 23, the light chain variable domain comprises the sequence of SEQ ID NO: 24, the heavy chain variable domain comprises the sequence of SEQ ID NO: 25, the light chain variable domain comprises the sequence of SEQ ID NO: 26, the heavy chain variable domain comprises the sequence of SEQ ID NO: 27, the light chain variable domain comprises the sequence of SEQ ID NO: 28, the heavy chain variable domain comprises the sequence of SEQ ID NO: 29, the light chain variable domain comprises the sequence of SEQ ID NO: 30, or the heavy chain variable domain comprises the sequence of SEQ ID NO: 31 and the light chain variable domain comprises the sequence of SEQ ID NO: 32.

[0122] In one aspect, an anti-ROR2 antibody is provided that is capable of binding to the same epitope as the antibodies provided herein (including embodiments thereof).

[0123] In one aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof).

[0124] In one aspect, a method of inhibiting metastasis of a ROR2-expressing cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof).

[0125] In one aspect, a CDR H1 is provided which comprises: (i) a CDR H1 comprising an amino acid sequence of the formula GFTFS-X1-YG-X2-X3 (I), wherein X1 is A, D, E, F, G, H, K, N, P, Q, R, S, T, or V; X2 is A, H, I, L, M, Q, S, T, or V; and X3 is S or N; provided that when X2 is M and X3 is S, X1 is not N; (ii) a CDR H2 is provided which comprises an amino acid sequence of the formula X4-ISSGGGYT-X5-Y-X6 (II), wherein X4 is T or S; X5 is H or Y; and X6 is V or A; (iii) a CDR H3 is provided which comprises an amino acid sequence of the formula ARHPRDFSYA-X7-DY (III). H3, (wherein X7 is A, F, H, I, K, L, M, N, Q, S, T, or V), (iv) CDR L1 comprising the amino acid sequence of the formula QDVGHY(IV), (v) CDR L2 comprising the amino acid sequence of the formula WAS(V), and (vi) CDR L3 comprising the sequence of SEQ ID NO: 53.

[0126] In embodiments, the antibody further comprises a FR H3 comprising an amino acid sequence of the formula X11-SVKG(VI), wherein X11 is A, D, E, G, H, P, Q, or T.

[0127] In another embodiment, a CDR H1 comprises an amino acid sequence of the formula GFTFS-X1-YG-X2-X3 (I), wherein X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y; X2 is A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; and X3 is S or N; provided that when X2 is M and X3 is S, X1 is not N. (iii) CDR H3 comprising an amino acid sequence of the formula DFSYA-X7-DYWG(III), wherein X7 is A, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; (iv) CDR L1 comprising an amino acid sequence of the formula X8-ASQDVGHY-X9-A(IV), wherein X8 is K or R, X9 is V or L, and when X8 is K, X9 is not V; (v) CDR L2 comprising an amino acid sequence of the formula WASTR-X10-T(V), wherein X8 is K or R, X9 is V or L, and when X8 is K, X9 is not V; and (vi) CDR L3 comprising the sequence of SEQ ID NO: 53.

[0128] In another aspect, a CDR H1 is provided comprising: (i) a CDR H1 comprising an amino acid sequence of the formula GFTFS-X1-YG-X2-X3 (I), wherein X1 is A, D, E, F, G, H, K, N, P, Q, R, S, T, or V; X2 is A, , H, I, , L, M, , Q, S, T, or V; and X3 is S or N, provided that when X2 is M and X3 is S, X1 is not N; (ii) a CDR H2 is provided comprising an amino acid sequence of the formula X4-ISSGGGYT-X5-Y-X6 (II), and (iii) a CDR H2 is provided comprising an amino acid sequence of the formula ARHPRDFSYA-X7-DY (III). H3, (wherein X7 is A, F, H, I, K, L, M, N, P, Q, S, T, or V), (iv) CDR L1 comprising an amino acid sequence of the formula QDVGHY, (v) CDR L2 comprising an amino acid sequence of the formula WAS, and (vi) CDR L3 comprising the sequence of SEQ ID NO: 53.

[0129] In an embodiment, X1 is A. In an embodiment, X1 is D. In an embodiment, X1 is E. In an embodiment, X1 is F. In an embodiment, X1 is G. In an embodiment, X1 is H. In an embodiment, X1 is I. In an embodiment, X1 is K. In an embodiment, X1 is L. In an embodiment, X1 is N. In an embodiment, X1 is P. In an embodiment, X1 is Q. In an embodiment, X1 is R. In an embodiment, X1 is S. In an embodiment, X1 is T. In an embodiment, X1 is V. In an embodiment, X1 is W. In an embodiment, X1 is Y.

[0130] In embodiments, X2 is A. In embodiments, X2 is E. In embodiments, X2 is F. In embodiments, X2 is G. In embodiments, X2 is H. In embodiments, X2 is I. In embodiments, X2 is K. In embodiments, X2 is L. In embodiments, X2 is M. In embodiments, X2 is P. In embodiments, X2 is Q. In embodiments, X2 is R. In embodiments, X2 is S. In embodiments, X2 is T. In embodiments, X2 is V. In embodiments, X2 is W. In embodiments, X2 is Y.

[0131] In embodiments, X3 is S. In embodiments, X3 is N.

[0132] In embodiments, when X2 is M and X3 is S, X1 is not N. In embodiments, when X2 is M, X1 is not N. In embodiments, when X3 is S, X1 is not N. In embodiments, when X2 is M and X3 is S, X1 is A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, W, or Y. In embodiments, X2 is M and X1 is A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, W, or Y. In embodiments, X3 is S and X1 is A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, W, or Y. In embodiments, X2 is M and X3 is S. In embodiments, when X2 is M and X3 is S, X1 is A. In an embodiment, when X2 is M and X3 is S, X1 is D. In an embodiment, when X2 is M and X3 is S, X1 is E. In an embodiment, when X2 is M and X3 is S, X1 is F. In an embodiment, when X2 is M and X3 is S, X1 is G. In an embodiment, when X2 is M and X3 is S, X1 is H. In an embodiment, when X2 is M and X3 is S, X1 is I. In an embodiment, when X2 is M and X3 is S, X1 is K. In an embodiment, when X2 is M and X3 is S, X1 is L. In an embodiment, when X2 is M and X3 is S, X1 is P. In an embodiment, when X2 is M and X3 is S, X1 is Q. In an embodiment, when X2 is M and X3 is S, X1 is R. In an embodiment, when X2 is M and X3 is S, X1 is S. In an embodiment, when X2 is M and X3 is S, X1 is T. In an embodiment, when X2 is M and X3 is S, X1 is V. In an embodiment, when X2 is M and X3 is S, X1 is W. In an embodiment, when X2 is M and X3 is S, X1 is Y. In an embodiment, X2 is M, X3 is S, and X1 is A. In an embodiment, X2 is M, X3 is S, and X1 is D. In an embodiment, X2 is M, X3 is S, and X1 is E. In an embodiment, X2 is M, X3 is S, and X1 is F. In an embodiment, X2 is M, X3 is S, and X1 is G.In embodiments, X2 is M, X3 is S, and X1 is H. In embodiments, X2 is M, X3 is S, and X1 is I. In embodiments, X2 is M, X3 is S, and X1 is K. In embodiments, X2 is M, X3 is S, and X1 is L. In embodiments, X2 is M, X3 is S, and X1 is P. In embodiments, X2 is M, X3 is S, and X1 is Q. In embodiments, X2 is M, X3 is S, and X1 is R. In embodiments, X2 is M, X3 is S, and X1 is S. In embodiments, X2 is M, X3 is S, and X1 is T. In embodiments, X2 is M, X3 is S, and X1 is V. In embodiments, X2 is M, X3 is S, and X1 is W. In embodiments, X2 is M, X3 is S, and X1 is Y.

[0133] In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is A. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is E. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is F. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is G. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is H. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is I. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is K. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is L. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is M. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is P. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is Q. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is R. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is S. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is T. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is V. In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is W.In embodiments, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y, and X2 is Y. In a further embodiment, X3 is N. In another further embodiment, X3 is S.

[0134] In embodiments, X4 is T. In embodiments, X4 is S. In embodiments, X5 is H. In embodiments, X5 is Y. In embodiments, X6 is V. In embodiments, X6 is A. In embodiments, when X5 is H and X6 is V, X4 is not T. In embodiments, X5 is H, X6 is V, and X4 is S. In embodiments, X5 is Y, X6 is V, and X4 is T. In embodiments, X5 is Y, X6 is V, and X4 is S. In embodiments, X5 is Y, X6 is A, and X4 is T. In embodiments, X5 is Y, X6 is A, and X4 is S. In embodiments, X5 is H, X6 is A, and X4 is T. In embodiments, X5 is H, X6 is A, and X4 is S. In embodiments, when X5 is H, X4 is not T. In embodiments, when X6 is V, X4 is not T. In embodiments, when X5 is H and X6 is V, X4 is S. In embodiments, X4 is T or S, and X5 is H. In embodiments, X4 is T or S, and X5 is Y. In a further embodiment, X6 is V. In another further embodiment, X6 is A.

[0135] In embodiments, X7 is A. In embodiments, X7 is D. In embodiments, X7 is E. In embodiments, X7 is F. In embodiments, X7 is G. In embodiments, X7 is H. In embodiments, X7 is I. In embodiments, X7 is K. In embodiments, X7 is L. In embodiments, X7 is M. In embodiments, X7 is P. In embodiments, X7 is Q. In embodiments, X7 is R. In embodiments, X7 is S. In embodiments, X7 is T. In embodiments, X7 is V. In embodiments, X7 is W. In embodiments, X7 is Y.

[0136] In embodiments, X8 is K. In embodiments, X8 is R. In embodiments, X9 is V. In embodiments, X9 is L. In embodiments, when X8 is K, X9 is not V. In embodiments, when X8 is K, X9 is L. In embodiments, X8 is K or R, and X9 is L. In embodiments, X9 is V or L, and X8 is R. In embodiments, X8 is K, and X9 is L. In embodiments, X8 is R, and X9 is V. In embodiments, X8 is R, and X9 is L. In embodiments, X8 is K, and X9 is L.

[0137] In an embodiment, X10 is H. In an embodiment, X10 is A. In an embodiment, when X8 is K and X9 is V, X10 is not H. In an embodiment, when X8 is K and X9 is V, X10 is A. In an embodiment, X8 is K, X9 is V, and X10 is A.

[0138] In embodiments, the antibody further comprises a FR H3 comprising an amino acid sequence of the formula YTHYV-X11-SVKG(VI), wherein X11 is A, D, E, G, H, P, Q, T, or V.

[0139] In embodiments, the antibody further comprises a FR H3 comprising an amino acid sequence of the formula X11-SVKG(VI), wherein X11 is A, D, E, G, H, P, Q, or T.

[0140] In embodiments, X11 is A. In embodiments, X11 is D. In embodiments, X11 is E. In embodiments, X11 is G. In embodiments, X11 is H. In embodiments, X11 is P. In embodiments, X11 is Q. In embodiments, X11 is T. In embodiments, X11 is V.

[0141] In embodiments, X1 is S, G, N, K, A, or H. In embodiments, X1 is S. In embodiments, X1 is G. In embodiments, X1 is N. In embodiments, X1 is K. In embodiments, X1 is A. In embodiments, X1 is H.

[0142] In embodiments, X2 is M, V, T, I, or L. In embodiments, X2 is M. In embodiments, X2 is V. In embodiments, X2 is T. In embodiments, X2 is I. In embodiments, X2 is L.

[0143] In embodiments, X7 is M, L, or Q. In embodiments, X7 is M. In embodiments, X7 is L. In embodiments, X7 is Q.

[0144] In embodiments, X11 is E, P, D, A, or T. In embodiments, X11 is E. In embodiments, X11 is P. In embodiments, X11 is D. In embodiments, X11 is A. In embodiments, X11 is T.

[0145] In an embodiment, X1 is not N, X2 is not M, X7 is not M, or X11 is not D. In an embodiment, X1 is not N, X2 is not M, X7 is not M, and X11 is not D. In an embodiment, X1 is not N. In an embodiment, X2 is not M. In an embodiment, X7 is not M. In an embodiment, X11 is not D. In an embodiment, X1 is not N, X2 is not M, X7 is not M, and X11 is not D.

[0146] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 305, CDR H2 set forth in SEQ ID NO: 306, and CDR H3 set forth in SEQ ID NO: 307, and CDR L1 set forth in SEQ ID NO: 308, CDR L2 set forth in SEQ ID NO: 309, and CDR L3 set forth in SEQ ID NO: 310. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 203, and a light chain variable domain comprising the sequence of SEQ ID NO: 204. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 203, and a light chain variable domain having the sequence of SEQ ID NO: 204. In embodiments, the antibody is referred to herein as clone h6E6-070.

[0147] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 311, CDR H2 set forth in SEQ ID NO: 312, and CDR H3 set forth in SEQ ID NO: 313, and CDR L1 set forth in SEQ ID NO: 314, CDR L2 set forth in SEQ ID NO: 315, and CDR L3 set forth in SEQ ID NO: 316. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 295, and a light chain variable domain comprising the sequence of SEQ ID NO: 296. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 295, and a light chain variable domain having the sequence of SEQ ID NO: 296. In embodiments, the antibody is referred to herein as clone h6E6-116.

[0148] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 317, CDR H2 set forth in SEQ ID NO: 318, and CDR H3 set forth in SEQ ID NO: 319, and CDR L1 set forth in SEQ ID NO: 320, CDR L2 set forth in SEQ ID NO: 321, and CDR L3 set forth in SEQ ID NO: 322. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 77, and a light chain variable domain comprising the sequence of SEQ ID NO: 78. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 77, and a light chain variable domain having the sequence of SEQ ID NO: 78. In embodiments, the antibody is referred to herein as clone h6E6-007.

[0149] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 323, CDR H2 set forth in SEQ ID NO: 324, and CDR H3 set forth in SEQ ID NO: 325, and CDR L1 set forth in SEQ ID NO: 326, CDR L2 set forth in SEQ ID NO: 327, and CDR L3 set forth in SEQ ID NO: 328. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 121, and a light chain variable domain comprising the sequence of SEQ ID NO: 122. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 121, and a light chain variable domain having the sequence of SEQ ID NO: 122. In embodiments, the antibody is referred to herein as clone h6E6-029.

[0150] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 329, CDR H2 set forth in SEQ ID NO: 330, and CDR H3 set forth in SEQ ID NO: 31, and CDR L1 set forth in SEQ ID NO: 332, CDR L2 set forth in SEQ ID NO: 333, and CDR L3 set forth in SEQ ID NO: 334. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 143, and a light chain variable domain comprising the sequence of SEQ ID NO: 144. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 143, and a light chain variable domain having the sequence of SEQ ID NO: 144. In embodiments, the antibody is referred to herein as clone h6E6-040.

[0151] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 335, CDR H2 set forth in SEQ ID NO: 336, and CDR H3 set forth in SEQ ID NO: 337, and CDR L1 set forth in SEQ ID NO: 338, CDR L2 set forth in SEQ ID NO: 339, and CDR L3 set forth in SEQ ID NO: 340. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 173, and a light chain variable domain comprising the sequence of SEQ ID NO: 174. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 173, and a light chain variable domain having the sequence of SEQ ID NO: 174. In embodiments, the antibody is referred to herein as clone h6E6-055.

[0152] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 341, CDR H2 set forth in SEQ ID NO: 342, and CDR H3 set forth in SEQ ID NO: 343, and CDR L1 set forth in SEQ ID NO: 344, CDR L2 set forth in SEQ ID NO: 345, and CDR L3 set forth in SEQ ID NO: 346. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 175, and a light chain variable domain comprising the sequence of SEQ ID NO: 176. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 175, and a light chain variable domain having the sequence of SEQ ID NO: 176. In embodiments, the antibody is referred to herein as clone h6E6-056.

[0153] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 347, CDR H2 set forth in SEQ ID NO: 348, and CDR H3 set forth in SEQ ID NO: 349, and CDR L1 set forth in SEQ ID NO: 350, CDR L2 set forth in SEQ ID NO: 351, and CDR L3 set forth in SEQ ID NO: 352. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 177, and a light chain variable domain comprising the sequence of SEQ ID NO: 178. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 177, and a light chain variable domain having the sequence of SEQ ID NO: 178. In embodiments, the antibody is referred to herein as clone h6E6-057.

[0154] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 353, CDR H2 set forth in SEQ ID NO: 354, and CDR H3 set forth in SEQ ID NO: 355, and CDR L1 set forth in SEQ ID NO: 356, CDR L2 set forth in SEQ ID NO: 357, and CDR L3 set forth in SEQ ID NO: 358. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 179, and a light chain variable domain comprising the sequence of SEQ ID NO: 180. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 179, and a light chain variable domain having the sequence of SEQ ID NO: 180. In embodiments, the antibody is referred to herein as clone h6E6-058.

[0155] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 359, CDR H2 set forth in SEQ ID NO: 360, and CDR H3 set forth in SEQ ID NO: 361, and CDR L1 set forth in SEQ ID NO: 362, CDR L2 set forth in SEQ ID NO: 363, and CDR L3 set forth in SEQ ID NO: 364. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 189, and a light chain variable domain comprising the sequence of SEQ ID NO: 190. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 189, and a light chain variable domain having the sequence of SEQ ID NO: 190. In embodiments, the antibody is referred to herein as clone h6E6-063.

[0156] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 365, CDR H2 set forth in SEQ ID NO: 366, and CDR H3 set forth in SEQ ID NO: 367, and CDR L1 set forth in SEQ ID NO: 368, CDR L2 set forth in SEQ ID NO: 369, and CDR L3 set forth in SEQ ID NO: 370. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 199, and a light chain variable domain comprising the sequence of SEQ ID NO: 200. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 199, and a light chain variable domain having the sequence of SEQ ID NO: 200. In embodiments, the antibody is referred to herein as clone h6E6-068.

[0157] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 371, CDR H2 set forth in SEQ ID NO: 372, and CDR H3 set forth in SEQ ID NO: 373, and CDR L1 set forth in SEQ ID NO: 374, CDR L2 set forth in SEQ ID NO: 375, and CDR L3 set forth in SEQ ID NO: 376. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 207, and a light chain variable domain comprising the sequence of SEQ ID NO: 208. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 207, and a light chain variable domain having the sequence of SEQ ID NO: 208. In embodiments, the antibody is referred to herein as clone h6E6-072.

[0158] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 377, CDR H2 set forth in SEQ ID NO: 378, and CDR H3 set forth in SEQ ID NO: 379, and CDR L1 set forth in SEQ ID NO: 380, CDR L2 set forth in SEQ ID NO: 381, and CDR L3 set forth in SEQ ID NO: 382. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 217, and a light chain variable domain comprising the sequence of SEQ ID NO: 218. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 217, and a light chain variable domain having the sequence of SEQ ID NO: 218. In embodiments, the antibody is referred to herein as clone h6E6-077.

[0159] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 383, CDR H2 set forth in SEQ ID NO: 384, and CDR H3 set forth in SEQ ID NO: 385, and CDR L1 set forth in SEQ ID NO: 386, CDR L2 set forth in SEQ ID NO: 387, and CDR L3 set forth in SEQ ID NO: 388. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 267, and a light chain variable domain comprising the sequence of SEQ ID NO: 268. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 267, and a light chain variable domain having the sequence of SEQ ID NO: 268. In embodiments, the antibody is referred to herein as clone h6E6-102.

[0160] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 389, CDR H2 set forth in SEQ ID NO: 390, and CDR H3 set forth in SEQ ID NO: 391, and CDR L1 set forth in SEQ ID NO: 392, CDR L2 set forth in SEQ ID NO: 393, and CDR L3 set forth in SEQ ID NO: 394. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 277, and a light chain variable domain comprising the sequence of SEQ ID NO: 278. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 277, and a light chain variable domain having the sequence of SEQ ID NO: 278. In embodiments, the antibody is referred to herein as clone h6E6-107.

[0161] In embodiments, the antibody comprises CDR H1 set forth in SEQ ID NO: 395, CDR H2 set forth in SEQ ID NO: 396, and CDR H3 set forth in SEQ ID NO: 397, and CDR L1 set forth in SEQ ID NO: 398, CDR L2 set forth in SEQ ID NO: 399, and CDR L3 set forth in SEQ ID NO: 400. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 195, and a light chain variable domain comprising the sequence of SEQ ID NO: 196. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 195, and a light chain variable domain having the sequence of SEQ ID NO: 196. In embodiments, the antibody is referred to herein as clone h6E6-066.

[0162] In embodiments, the antibody is a humanized antibody. In embodiments, the antibody is a Fab' fragment. In embodiments, the antibody is a single chain antibody (scFv). In embodiments, the antibody is a chimeric antibody. In embodiments, the antibody is an IgG. In embodiments, the antibody is an IgG1 or IgG2. In embodiments, the antibody is an IgG1. In embodiments, the antibody is an IgG2.

[0163] In embodiments, the antibody is capable of binding to ROR2 protein. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 41, or SEQ ID NO: 42. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 34. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 38. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 41. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 42. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 40. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 36. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 40.

[0164] In embodiments, the antibody can bind to the extracellular domain of the ROR2 protein. In embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 38. In embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 40. In embodiments, the ROR2 protein comprises a histidine at a position corresponding to position 349 or an aspartic acid at a position corresponding to position 354 of SEQ ID NO: 38.

[0165] In embodiments, the extracellular domain is a kringle domain. In embodiments, the kringle domain comprises the amino acid sequence of SEQ ID NO:41.

[0166] In embodiments, the ROR2 protein is expressed on a cell. In embodiments, the cell is a cancer cell. In embodiments, the cancer cell is a breast cancer cell, an ovarian cancer cell, a pancreatic cancer cell, a cervical cancer cell, a gastric cancer cell, a renal cancer cell, a head and neck cancer cell, a bone cancer cell, a skin cancer cell, or a prostate cancer cell. In embodiments, the cancer cell is a breast cancer cell. In embodiments, the cancer cell is an ovarian cancer cell. In embodiments, the cancer cell is a pancreatic cancer cell. In embodiments, the cancer cell is a cervical cancer cell. In embodiments, the cancer cell is a gastric cancer cell. In embodiments, the cancer cell is a renal cancer cell. In embodiments, the cancer cell is a head and neck cancer cell. In embodiments, the cancer cell is a bone cancer cell. In embodiments, the cancer cell is a skin cancer cell. In embodiments, the cancer cell is a prostate cancer cell.

[0167] In an embodiment, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.02 nM to about 6 nM. In an embodiment, the KD is about 0.03 nM to about 6 nM. In an embodiment, the KD is about 0.04 nM to about 6 nM. In an embodiment, the KD is about 0.05 nM to about 6 nM. In an embodiment, the KD is about 0.06 nM to about 6 nM. In an embodiment, the KD is about 0.07 nM to about 6 nM. In an embodiment, the KD is about 0.08 nM to about 6 nM. In an embodiment, the KD is about 0.09 nM to about 6 nM. In an embodiment, the KD is about 0.1 nM to about 6 nM. In an embodiment, the KD is about 0.2 nM to about 6 nM. In an embodiment, the KD is about 0.3 nM to about 6 nM. In one embodiment, the KD is about 0.4 nM to about 6 nM. In one embodiment, the KD is about 0.5 nM to about 6 nM. In one embodiment, the KD is about 0.6 nM to about 6 nM. In one embodiment, the KD is about 0.7 nM to about 6 nM. In one embodiment, the KD is about 0.8 nM to about 6 nM. In one embodiment, the KD is about 0.9 nM to about 6 nM. In one embodiment, the KD is about 1 nM to about 6 nM. In one embodiment, the KD is about 2 nM to about 6 nM. In one embodiment, the KD is about 3 nM to about 6 nM. In one embodiment, the KD is about 4 nM to about 6 nM. In one embodiment, the KD is about 5 nM to about 6 nM.

[0168] In an embodiment, the KD is about 0.02 nM to about 5 nM. In an embodiment, the KD is about 0.02 nM to about 4 nM. In an embodiment, the KD is about 0.02 nM to about 3 nM. In an embodiment, the KD is about 0.02 nM to about 2 nM. In an embodiment, the KD is about 0.02 nM to about 1 nM. In an embodiment, the KD is about 0.02 nM to about 0.9 nM. In an embodiment, the KD is about 0.02 nM to about 0.8 nM. In an embodiment, the KD is about 0.02 nM to about 0.7 nM. In an embodiment, the KD is about 0.02 nM to about 0.6 nM. In an embodiment, the KD is about 0.02 nM to about 0.5 nM. In an embodiment, the KD is about 0.02 nM to about 0.4 nM. In an embodiment, the KD is about 0.02 nM to about 0.3 nM. In an embodiment, the KD is about 0.02 nM to about 0.2 nM. In an embodiment, the KD is about 0.02 nM to about 0.1 nM. In an embodiment, the KD is about 0.02 nM to about 0.09 nM. In an embodiment, the KD is about 0.02 nM to about 0.08 nM. In an embodiment, the KD is about 0.02 nM to about 0.07 nM. In an embodiment, the KD is about 0.02 nM to about 0.06 nM. In an embodiment, the KD is about 0.02 nM to about 0.05 nM. In an embodiment, the KD is about 0.02 nM to about 0.04 nM. In an embodiment, the KD is about 0.02 nM to about 0.03 nM.

[0169] In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.02 nM to 6 nM. In embodiments, the KD is 0.03 nM to 6 nM. In embodiments, the KD is 0.04 nM to 6 nM. In embodiments, the KD is 0.05 nM to 6 nM. In embodiments, the KD is 0.06 nM to 6 nM. In embodiments, the KD is 0.07 nM to 6 nM. In embodiments, the KD is 0.08 nM to 6 nM. In embodiments, the KD is 0.09 nM to 6 nM. In embodiments, the KD is 0.1 nM to 6 nM. In embodiments, the KD is 0.2 nM to 6 nM. In embodiments, the KD is 0.3 nM to 6 nM. In embodiments, the KD is 0.4 nM to 6 nM. In an embodiment, the KD is 0.5 nM to 6 nM. In an embodiment, the KD is 0.6 nM to 6 nM. In an embodiment, the KD is 0.7 nM to 6 nM. In an embodiment, the KD is 0.8 nM to 6 nM. In an embodiment, the KD is 0.9 nM to 6 nM. In an embodiment, the KD is 1 nM to 6 nM. In an embodiment, the KD is 2 nM to 6 nM. In an embodiment, the KD is 3 nM to 6 nM. In an embodiment, the KD is 4 nM to 6 nM. In an embodiment, the KD is 5 nM to 6 nM.

[0170] In an embodiment, the KD is 0.02 nM to 5 nM. In an embodiment, the KD is 0.02 nM to 4 nM. In an embodiment, the KD is 0.02 nM to 3 nM. In an embodiment, the KD is 0.02 nM to 2 nM. In an embodiment, the KD is 0.02 nM to 1 nM. In an embodiment, the KD is 0.02 nM to 0.9 nM. In an embodiment, the KD is 0.02 nM to 0.8 nM. In an embodiment, the KD is 0.02 nM to 0.7 nM. In an embodiment, the KD is 0.02 nM to 0.6 nM. In an embodiment, the KD is 0.02 nM to 0.5 nM. In an embodiment, the KD is 0.02 nM to 0.4 nM. In an embodiment, the KD is 0.02 nM to 0.3 nM. In an embodiment, the KD is 0.02 nM to 0.2 nM. In an embodiment, the KD is 0.02 nM to 0.1 nM. In an embodiment, the KD is 0.02 nM to 0.09 nM. In an embodiment, the KD is 0.02 nM to 0.08 nM. In an embodiment, the KD is 0.02 nM to 0.07 nM. In an embodiment, the KD is 0.02 nM to 0.06 nM. In an embodiment, the KD is 0.02 nM to 0.05 nM. In an embodiment, the KD is 0.02 nM to 0.04 nM. In an embodiment, the KD is 0.02 nM to 0.03 nM.

[0171] In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.024 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.079 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.155 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.165 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.186 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.187 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.261 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.318 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.319 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.348 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.353 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.362 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.380 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.422 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.463 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.475 nM.

[0172] In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.024 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.079 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.155 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.165 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.186 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.187 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.261 nM. In embodiments, the antibody can bind to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.318 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.319 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.348 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.353 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.362 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.380 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.422 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.463 nM. In embodiments, the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of 0.475 nM.

[0173] In embodiments, the antibody is conjugated to a therapeutic agent. In embodiments, the antibody is conjugated to a diagnostic agent.

[0174] In another aspect, an anti-ROR2 antibody is provided, which binds to the same epitope as the anti-ROR2 antibody provided herein (including embodiments thereof).

[0175] Chimeric Antigen Receptor Protein As described above, the CDRs of the heavy chain variable (VH) domain and the CDRs of the light chain variable (VL) domain (including embodiments thereof) provided herein can each independently form a part of an antibody, an antibody fragment, or a chimeric antigen receptor or bispecific antibody. Provided herein, inter alia, are chimeric antigen receptors and bispecific antibodies comprising the light chain variable (VL) domain and / or the heavy chain variable (VH) domain provided herein and thus capable of effectively and efficiently binding to human ROR2. The antibody region of the chimeric antigen receptor may comprise any of the light chain variable domain and heavy chain variable domain provided herein (including embodiments thereof). The light chain variable (VL) domain and / or the heavy chain variable (VH) domain provided herein may form a part of the chimeric antigen receptor. Thus, in one aspect, a chimeric antigen receptor is provided comprising (i) an antibody region comprising any one of the light chain variable domain and heavy chain variable domain pairs provided herein (including embodiments thereof), and (ii) a transmembrane domain.

[0176] As provided herein, an "antibody region" refers to a monovalent or multivalent protein moiety that forms part of a recombinant protein (e.g., a CAR, a bispecific antibody) provided herein (including embodiments thereof). Accordingly, one of skill in the art will readily recognize that an antibody region is a protein moiety that can bind to an antigen (epitope). Accordingly, an antibody region provided herein can comprise an antibody domain (e.g., a light chain variable (VL) domain, a heavy chain variable (VH) domain) or an antibody fragment (e.g., a Fab). In embodiments, an antibody region is a protein complex. As provided herein, a "protein complex" refers to a construct comprised of two or more polypeptides, wherein the polypeptides are covalently or non-covalently linked together. In embodiments, the polypeptides of the protein complex are encoded by a single nucleic acid molecule. In embodiments, the polypeptides of the protein complex are encoded by different nucleic acid molecules. In embodiments, the polypeptides are linked via a linker. In embodiments, the polypeptides are linked via a chemical linker. In embodiments, the antibody region is an scFv. An antibody region may comprise a light chain variable (VL) domain and / or a heavy chain variable (VH) domain. In embodiments, an antibody region comprises a light chain variable (VL) domain. In embodiments, an antibody region comprises a heavy chain variable (VH) domain.

[0177] As provided herein, a "transmembrane domain" refers to a polypeptide that forms part of a biological membrane. The transmembrane domains provided herein can span from one side of a biological membrane (e.g., a cell membrane) to the other side of the membrane. In embodiments, the transmembrane domain spans from the intracellular side of the cell membrane to the extracellular side. The transmembrane domain can include non-polar hydrophobic residues that anchor the proteins provided herein (including embodiments thereof) to a biological membrane (e.g., the cell membrane of a T cell). Any transmembrane domain capable of anchoring the proteins provided herein (including embodiments thereof) is contemplated. Non-limiting examples of transmembrane domains include the transmembrane domains of CD28, CD8, CD4, or CD3 zeta (also known as CD247). In embodiments, the transmembrane domain is a CD4 transmembrane domain.

[0178] In embodiments, the transmembrane domain is a CD28 transmembrane domain. As provided herein, the term "CD28 transmembrane domain" includes either recombinant or naturally occurring forms of the transmembrane domain of CD28 or variants or homologs thereof that maintain the activity of the CD28 transmembrane domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD28 transmembrane domain). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD28 transmembrane domain polypeptide. In embodiments, CD28 is the protein identified by NCBI sequence reference GI:340545506, a homolog, or a functional fragment thereof.

[0179] In embodiments, the transmembrane domain is a CD8 transmembrane domain. As provided herein, the term "CD8 transmembrane domain" includes either recombinant or naturally occurring forms of the transmembrane domain of CD8 or variants or homologs thereof that maintain the activity of the CD8 transmembrane domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD8 transmembrane domain). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD8 transmembrane domain polypeptide. In embodiments, CD8 is the protein identified by NCBI sequence reference GI:225007534, a homolog, or a functional fragment thereof.

[0180] In embodiments, the transmembrane domain is a CD4 transmembrane domain. As provided herein, the term "CD4 transmembrane domain" includes either recombinant or naturally occurring forms of the transmembrane domain of CD4 or variants or homologs thereof that maintain the activity of the CD4 transmembrane domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD4 transmembrane domain). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD4 transmembrane domain polypeptide. In embodiments, CD4 is the protein identified by NCBI sequence reference GI:303522473, a homolog, or a functional fragment thereof.

[0181] In embodiments, the transmembrane domain is a CD3 zeta (CD247) transmembrane domain. As provided herein, the term "CD3 zeta transmembrane domain" includes any recombinant or naturally occurring form of a CD3 zeta (CD247) transmembrane domain or variant or homolog thereof that maintains the activity of the CD3 zeta (CD247) transmembrane domain (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD3 zeta (CD247) transmembrane domain). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD3 zeta (CD247) transmembrane domain polypeptide. In an embodiment, CD3 zeta is the protein identified by NCBI sequence reference GI:166362721, a homologue or a functional fragment thereof.

[0182] In embodiments, the chimeric antigen receptor further comprises an intracellular T cell signaling domain. An "intracellular T cell signaling domain" provided herein comprises an amino acid sequence capable of providing primary signaling in response to antigen binding to an antibody region provided herein (including embodiments thereof). In embodiments, signaling from the intracellular T cell signaling domain activates a T cell expressing it. In embodiments, signaling from the intracellular T cell signaling domain causes a T cell expressing it to proliferate (division). In embodiments, signaling from the intracellular T cell signaling domain causes the T cell to express proteins known in the art that are characteristic of activated T cells (e.g., CTLA-4 (CD152), PD-1 (CD274), CD28, CD69). In embodiments, the intracellular T cell signaling domain is a CD3ζ intracellular T cell signaling domain.

[0183] In embodiments, the chimeric antigen receptor further comprises an intracellular costimulatory T cell signaling domain. An "intracellular costimulatory signaling domain" provided herein comprises an amino acid sequence capable of providing costimulatory signaling in response to binding of an antigen to an antibody region provided herein (including embodiments thereof). In embodiments, signaling from the costimulatory signaling domain produces cytokines and causes proliferation of T cells expressing the cytokines. In embodiments, the intracellular costimulatory signaling domain is a CD28 intracellular costimulatory signaling domain, a 4-1BB (CD137) intracellular costimulatory signaling domain, or an OX-40 (CD134) intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory signaling domain is a CD28 intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory signaling domain is a 4-1BB (CD137) intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory signaling domain is an OX-40 (CD134) intracellular costimulatory signaling domain.

[0184] In embodiments, the antibody region comprises an Fc domain. In embodiments, the antibody region comprises a spacer region. In embodiments, the spacer region is between the transmembrane domain and the antibody region. A "spacer region" provided herein is a polypeptide that connects the antibody region and the transmembrane domain. In embodiments, the spacer region connects the heavy chain constant region and the transmembrane domain. In embodiments, the spacer region comprises an Fc region. In embodiments, the spacer region is an Fc region. Spacer regions contemplated for the compositions provided herein include, but are not limited to, immunoglobulin molecules or fragments thereof (e.g., IgG1, IgG2, IgG3, IgG4) and immunoglobulin molecules or fragments thereof (e.g., IgG1, IgG2, IgG3, IgG4) containing mutations that affect Fc receptor binding. In embodiments, the spacer region is a hinge region.

[0185] The term "CTLA-4" as referred to herein includes either recombinant or naturally occurring forms of cytotoxic T-lymphocyte-associated protein 4 protein, also known as CD152 (cluster of differentiation 152), or variants or homologs thereof, that maintain CTLA-4 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to CTLA-4). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CTLA-4 protein. In embodiments, the CTLA-4 protein is substantially identical to the protein identified by UniProt reference number P16410, or a variant or homolog having substantial identity thereto.

[0186] The term "CD28" as referred to herein includes either recombinant or naturally occurring forms of cluster of differentiation 28 protein or variants or homologs thereof that maintain CD28 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to CD28). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD28 protein. In embodiments, the CD28 protein is substantially identical to the protein identified by UniProt reference number P10747 or a variant or homolog having substantial identity thereto.

[0187] The term "CD69" as referred to herein includes either recombinant or naturally occurring forms of cluster of differentiation 69 protein or variants or homologs thereof that maintain CD69 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to CD69). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD69 protein. In embodiments, the CD69 protein is substantially identical to the protein identified by UniProt reference number Q07108 or a variant or homolog having substantial identity thereto.

[0188] The term "4-1BB" as referred to herein includes either recombinant or naturally occurring forms of tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as cluster of differentiation 137 (CD137), and induced by lymphocyte-activating factor (ILA), 4-1BB protein, or variants or homologs thereof, that maintain 4-1BB activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to 4-1BB). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring EGFR protein. In an embodiment, the 4-1BB protein is substantially identical to the protein identified by UniProt reference number Q07011 or a variant or homologue having substantial identity thereto.

[0189] In another aspect, there is provided a chimeric antigen receptor comprising: (i) an anti-ROR2 antibody provided herein (including embodiments thereof); and (ii) a transmembrane domain.

[0190] In embodiments, the antibody comprises CDR H1 as set forth in SEQ ID NO: 305, CDR H2 as set forth in SEQ ID NO: 306, and CDR H3 as set forth in SEQ ID NO: 307, and CDR L1 as set forth in SEQ ID NO: 308, CDR L2 as set forth in SEQ ID NO: 309, and CDR L3 as set forth in SEQ ID NO: 310. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 203, and a light chain variable domain comprising the sequence of SEQ ID NO: 204. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 203, and a light chain variable domain having the sequence of SEQ ID NO: 204.

[0191] In embodiments, the antibody comprises CDR H1 as set forth in SEQ ID NO: 311, CDR H2 as set forth in SEQ ID NO: 312, and CDR H3 as set forth in SEQ ID NO: 313, and CDR L1 as set forth in SEQ ID NO: 314, CDR L2 as set forth in SEQ ID NO: 315, and CDR L3 as set forth in SEQ ID NO: 316. In embodiments, the antibody comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 295, and a light chain variable domain comprising the sequence of SEQ ID NO: 296. In embodiments, the antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO: 295, and a light chain variable domain having the sequence of SEQ ID NO: 296.

[0192] In embodiments, the chimeric antigen receptor further comprises an intracellular T cell signaling domain, hi embodiments, the intracellular T cell signaling domain is a CD3ζ intracellular T cell signaling domain.

[0193] In embodiments, the chimeric antigen receptor further comprises an intracellular costimulatory T cell signaling domain. In embodiments, the intracellular costimulatory T cell signaling domain is a CD28 intracellular costimulatory signaling domain, a 4-1BB intracellular costimulatory signaling domain, an intracellular costimulatory signaling domain, or an OX-40 (CD134) intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory T cell signaling domain is a CD28 intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory T cell signaling domain is a 4-1BB intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory T cell signaling domain is an intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory T cell signaling domain is an OX-40 (CD134) intracellular costimulatory signaling domain.

[0194] In embodiments, the chimeric antigen receptor further comprises a spacer region. In embodiments, the spacer region further comprises a hinge region. In embodiments, the chimeric antigen receptor further comprises a linker domain. In embodiments, the chimeric antigen receptor further comprises a heavy chain constant domain.

[0195] bispecific antibody The light chain variable (VL) domain and heavy chain variable (VH) domain provided herein may form part of a bispecific antibody. Thus, the second antibody region may comprise any of the light chain variable domains and / or heavy chain variable domains provided herein (including embodiments thereof).

[0196] The term "effector cell ligand" provided herein refers to a cell surface molecule expressed on effector cells of the immune system (e.g., cytotoxic T cells, helper T cells, B cells, natural killer cells). When a first antibody region binds to an effector cell ligand expressed on an effector cell, the effector cell is activated and can exert its function (e.g., selective killing or eradication of malignant, infected, or otherwise unhealthy cells). In embodiments, the effector cell ligand is a CD3 protein. In embodiments, the effector cell ligand is a CD16 protein. In embodiments, the effector cell ligand is a CD32 protein. In embodiments, the effector cell ligand is an NKp46 protein. The first antibody region provided herein may be an antibody, an antibody variant, a fragment of an antibody, or a fragment of an antibody variant.

[0197] As referred to herein, a "CD3 protein" includes either a recombinant or naturally occurring form of cluster of differentiation 3 (CD3) protein or a variant or homolog thereof, comprising a CD3 complex that mediates signaling and maintains CD3 complex activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD3 complex). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD3 protein in the CD3 complex.

[0198] As referred to herein, a "CD16 protein" includes either a recombinant or naturally occurring form of cluster of differentiation 16 (CD16) protein, also known as low-affinity immunoglobulin gamma Fc-region receptor III-A, or a variant or homolog thereof, that maintains CD16 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity of CD16). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD16 protein. In embodiments, the CD16 protein is substantially identical to the protein identified by UniProt reference number P08637, or a variant or homolog having substantial identity thereto.

[0199] As referred to herein, a "CD32 protein" includes either a recombinant or naturally occurring form of the cluster of differentiation 32 (CD32) protein, also known as the low-affinity immunoglobulin gamma Fc-region receptor II-A, or a variant or homolog thereof, that maintains the activity of CD32 (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to CD32). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring CD32 protein. In embodiments, the CD32 protein is substantially identical to the protein identified by UniProt reference number P12318, or a variant or homolog having substantial identity thereto.

[0200] As referred to herein, "NKp46 protein" includes any recombinant or naturally occurring form of the NKp46 protein, also known as native cytotoxicity-inducing receptor 1, or a variant or homolog thereof, that maintains the activity of NKp46 (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to NKp46). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a portion of 50, 100, 150, or 200 contiguous amino acids) compared to a naturally occurring NKp46 protein. In embodiments, the NKp46 protein is substantially identical to the protein identified by UniProt reference number O76036, or a variant or homolog having substantial identity thereto.

[0201] Treatment method The compositions (e.g., anti-ROR2 antibodies, CARs, and bispecific antibodies) provided herein (including embodiments thereof) are believed to provide effective treatments for diseases such as cancer (e.g., breast cancer).

[0202] Thus, in one aspect, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof). In another aspect, there is provided a method of inhibiting metastasis of a ROR2-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof).

[0203] In another aspect, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a chimeric antigen receptor provided herein (including embodiments thereof).

[0204] In embodiments, the cancer is a solid tumor malignancy. In embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is cervical cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is renal cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is bone cancer. In embodiments, the cancer is skin cancer. In embodiments, the cancer is prostate cancer.

[0205] In one aspect, a method of treating cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of an antibody provided herein (including embodiments thereof).

[0206] In embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is cervical cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is renal cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is bone cancer. In embodiments, the cancer is skin cancer. In embodiments, the cancer is prostate cancer.

[0207] In another aspect, a method for detecting a ROR2-expressing cell is provided, the method comprising: (i) contacting a ROR2-expressing cell with an antibody provided herein (including embodiments thereof); and (ii) detecting binding of the antibody to ROR2 protein expressed by the cell.

[0208] In embodiments, the antibody is conjugated to a detectable moiety.

[0209] In embodiments, the ROR2-expressing cells are present in a subject.

[0210] In embodiments, the subject has or is at risk of having cancer. In embodiments, the subject has cancer. In embodiments, the subject is at risk of having cancer.

[0211] In embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is cervical cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is renal cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is bone cancer. In embodiments, the cancer is skin cancer. In embodiments, the cancer is prostate cancer.

[0212] In embodiments, the contacting occurs in vitro.

[0213] In another aspect, a method of delivering a therapeutic agent to a ROR2-expressing cell is provided, the method comprising contacting the ROR2-expressing cell with an antibody provided herein (including embodiments thereof), wherein the antibody binds to the therapeutic agent.

[0214] In embodiments, the therapeutic agent is an anti-cancer agent.

[0215] In embodiments, the ROR2-expressing cells are present in a subject.

[0216] In embodiments, the subject has or is at risk of having cancer. In embodiments, the subject has cancer. In embodiments, the subject is at risk of having cancer.

[0217] In embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is cervical cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is renal cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is bone cancer. In embodiments, the cancer is skin cancer. In embodiments, the cancer is prostate cancer.

[0218] In embodiments, the contacting occurs in vitro.

[0219] In another aspect, a method of inhibiting metastasis of ROR2-expressing cells is provided, the method comprising contacting ROR2-expressing cells with an antibody provided herein (including embodiments thereof).

[0220] In embodiments, the ROR2-expressing cells are in a subject having or at risk of having cancer. In embodiments, the subject is a subject having cancer. In embodiments, the subject is a subject at risk of having cancer.

[0221] In embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is cervical cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is renal cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is bone cancer. In embodiments, the cancer is skin cancer. In embodiments, the cancer is prostate cancer.

[0222] In embodiments, the contacting occurs in vitro.

[0223] In embodiments, the ROR2-expressing cells are cancer cells.

[0224] In embodiments, the cancer cells are breast cancer cells, ovarian cancer cells, pancreatic cancer cells, cervical cancer cells, gastric cancer cells, renal cancer cells, head and neck cancer cells, bone cancer cells, skin cancer cells, or prostate cancer cells. In embodiments, the cancer cells are breast cancer cells. In embodiments, the cancer cells are ovarian cancer cells. In embodiments, the cancer cells are pancreatic cancer cells. In embodiments, the cancer cells are cervical cancer cells. In embodiments, the cancer cells are gastric cancer cells. In embodiments, the cancer cells are renal cancer cells. In embodiments, the cancer cells are head and neck cancer cells. In embodiments, the cancer cells are bone cancer cells. In embodiments, the cancer cells are skin cancer cells. In embodiments, the cancer cells are prostate cancer cells.

[0225] In another aspect, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a chimeric antigen receptor provided herein (including embodiments thereof).

[0226] In embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is ovarian cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is cervical cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is renal cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is bone cancer. In embodiments, the cancer is skin cancer. In embodiments, the cancer is prostate cancer. [Example]

[0227] Example 1: Humanized ROR2 mAb

[0228] Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a developmentally restricted receptor for certain Wnt factors, such as Wnt5a. Human ROR2 (interchangeably referred to as ROR2) is a 943-amino acid, single-pass type I membrane protein with a calculated molecular weight of 104.8 kilodaltons (kDa). ROR2 is highly conserved across multiple species, with 92% amino acid sequence identity between the mouse and human proteins. ROR2 regulates Wnt signaling by repressing the transcription of Wnt target genes and sequestering canonical Wnt ligands, thereby functioning as a tumor suppressor in various cellular environments. Recently, ROR2 has been implicated in the progression of many cancers, including breast, ovarian, pancreatic, cervical, gastric, renal, head and neck, bone, skin, and prostate cancers. Its expression in cancer cells makes it potentially useful as a diagnostic and therapeutic target.

[0229] The generated monoclonal antibodies (mAbs) specifically targeted the extracellular portion of human ROR2. To generate such antibodies, mice were immunized with a recombinant protein of the extracellular portion of the ROR2 protein (AA 1-403), which contains the Ig-like cysteine-rich domain (CRD) and kringle domain, as shown in Figure 1. Due to the high homology between mouse and human molecules, immunostimulants such as Freund's complete adjuvant were used in combination to maximize the production of anti-human ROR2 antibodies. Hybridomas generated after fusion of spleen cells with myeloma fusion partners were screened for the expression of anti-ROR2 mAbs using ELISA or flow cytometry, and clones producing antibodies that specifically bound to human ROR2 were identified. One mAb, designated 6E6, was selected for further development and humanized. The murine framework regions of both the immunoglobulin heavy chain variable region gene (IGHV) and the immunoglobulin kappa variable cluster (IGKV) were replaced with homologous framework regions from human IGHV and IGKV, and the constant regions were converted to human IgG1. To maintain binding specificity and reactivity to human ROR2, 16 humanized mAbs were generated. These mAbs are designated in this disclosure as mAbs N-LN or in their more common form h6E6-NNN and are listed in Table 1. All 16 mAbs bind to ROR2 with high affinity, with binding affinities (Kd) ranging from 24 picomolar (pM) to 500 pM, as measured by surface plasmon resonance. Furthermore, biochemical analyses of thermal stability and aggregation demonstrate that all mAbs have highly stable profiles. The sequences of the heavy and light chain variable regions are included in the informal sequence listing section of this application.

[0230] The parental 6E6 mouse anti-human ROR2 mAb was previously shown to bind to the kringle region of human ROR2. Furthermore, the histidine residue at position 349 and the aspartic acid residue at position 354 were required for binding to the kringle domain of human ROR2, and replacing these amino acids with the corresponding arginine and glutamic acid residues in the mouse molecule inhibited binding to human ROR2. Therefore, a series of recombinant human / mouse hybrid proteins were developed to isolate specific domains of the human ROR2 protein. As shown in Figure 2A, these recombinant proteins were used to identify the specific binding domains targeted by each mAb. As shown in Figure 2C, 6E6 mAb binds to the kringle domain of human ROR2, but not to mouse ROR2. As shown in Figure 2B, human / mouse chimeric ROR2 recombinant proteins were used to identify specific amino acids important for binding of anti-ROR2 mAbs that bind within the kringle domain. Therefore, several recombinant human ROR2 proteins were generated in which one of the four amino acids that differ between human and mouse ROR2 in the Kringle domain was replaced with the corresponding amino acid in mouse ROR2. Evaluation of the binding of 6E6 showed that this mAb requires the histidine residue at position 349 and the aspartic acid residue at position 354 to bind to the Kringle domain of human ROR2; when these amino acids were replaced with the arginine and glutamic acid residues, respectively, of the mouse molecule, the 6E6 mAb no longer bound to the recombinant ROR2 protein.

[0231] As shown in Figure 3, each of the 16 humanized 6E6 (h6E6) mAbs binds to the same determinants within the human Kringle domain and therefore retains the same binding specificity as the parent 6E6 mAb. The same set of recombinant ROR2 proteins was used to evaluate the binding reactivity of each of the 16 h6E6 mAbs. Each of the 16 humanized mAbs retains the same binding pattern / profile as the parent 6E6 mAb and binds to human ROR2 and human / mouse hybrid proteins containing the human Kringle domain, but not to either mouse ROR2 or human / mouse hybrid proteins containing the mouse Kringle domain. More importantly, none of the 16 h6E6 mAbs bind to human ROR2 constructs in which the histidine residue at position 349 of human ROR2 was replaced with arginine (H349R) or the aspartic acid at position 354 was replaced with glutamic acid (D345E). Amino acid substitutions at position 327 (T327M) and 386 (M386V) did not affect mAb binding, and neither humanized mAb bound to recombinant ROR1 or negative control supernatant.

[0232] Based on these findings, it is clear that these humanized anti-human ROR2 mAbs have high affinity and specificity for human ROR2 and may be used to target ROR2 in various human cancers. table: Table 1 shows the biochemical properties of h6E6 mAb. The names of the 16 humanized ROR2 mAbs are listed in the first column. mAb binding affinity (k) for human ROR2 as measured by surface plasmon resonance. d ) are listed in nM concentrations. UNCLE thermal stability measurements are in degrees Celsius (°C). Tm1 and Tm2 are measurements of fluorescence over time that relate to the stability of the mAb, and T agg is a measure of thermal aggregation. [Table 1]

[0233] Example 2: Humanization of anti-ROR2 antibodies To humanize the murine 6E6 antibody, the heavy and light chain variable region protein sequences were aligned with human germline protein sequences to identify potential acceptor framework sequences. Based on this approach, VK1-12*01, VK1-8*01, and VK3-15*01 were evaluated as acceptors for the light chain, and VH3-21*01 and VH3-11*03 were evaluated as acceptors for the heavy chain. The murine 6E6 CDRs (IMGT or extended) were then grafted into the acceptor frameworks. The grafted CDRs are shown in Table 2. In certain cases, the use of extended CDR definitions resulted in additional sequence differences between the murine donor CDRs and the human acceptor germline frameworks. [Table 2]

[0234] Twenty-four humanized variants using different acceptor frameworks and CDR definitions were expressed as IgG, purified, and assessed for binding activity to human ROR2 by SPR. As summarized in Table 3, several combinations were active binders, while others were inactive. Several variants showed KDs similar to that of chimeric 6E6 (KD = 0.38 nM), such as the extended CDR grafted onto both VK1-12*01 and VH3-21*01 (KD = 0.67 nM), and the combination of the IMGT CDR grafted onto VK3-15*01 and the extended CDR grafted onto VH3-21*01 (KD = 0.58 nM). [Table 3]

[0235] Example 3: Synthesis and screening of libraries to remove potential post-translational modification sites (PTMs) Four potential post-translational modification (PTM) sites were identified in the variable heavy chain. These include an asparagine deamidation and methionine oxidation site in HCDR1, an aspartate isomerization site in framework 3 adjacent to HCDR2, and a methionine oxidation site in HCDR3. The PTMs and adjacent sequences are shown in Table 4 (PTM sequences are in bold). [Table 4]

[0236] To remove as many PTMs as possible, combinatorial libraries were synthesized, expressed, and screened. Libraries were designed to replace the PTMs at each site with specific amino acids, as shown in Table 4. Additionally, the combinatorial libraries contained murine or human residues at positions that differed between the murine donor and human acceptor sequences in the extended CDR definitions, as shown in Table 5 (differences are shown in bold). [Table 5]

[0237] The combinatorial library was synthesized and expressed as scFv using a phagemid system. The most active binders were enriched through four rounds of selection against human ROR2, with decreasing concentrations of human ROR2 used in each enrichment round. After the final round of selection, enriched clones were screened by ELISA for binding to human ROR2. 125 clones that showed higher binding than the parent antibody were sequenced, yielding 120 unique VH / VL sequences (SEQ ID NO: 65 to SEQ ID NO: 304). The screening results are summarized in Tables 6 to 8.

[0238] For all four PTMs, alternative amino acids were identified. For example, multiple suitable mutations at PTM site 1 were identified, with serine being the most common substitution (Table 6). [Table 6]

[0239] Similarly, multiple active substituents were identified at PTM site 2 with valine being most common (Table 6), at PTM site 3 with glutamic acid being most common (Table 7), and at PTM site 4 with leucine being most common (Table 7). Note that multiple suitable substituents were identified at each of the four variable heavy chain PTM sites. [Table 7]

[0240] Example 4: Characterization of enriched clones Sixty-four clones were reformatted, expressed, and purified as IgG, and their binding to human ROR2 was characterized by SPR (summarized in Table 8). [Table 8]

[0241] The majority of clones (58%) had affinity (K ) within 2-fold of the chimeric parent 6E6 antibody. D The clones showed a cytotoxicity of <0.340 nM. Furthermore, 21 of the clones had all of the target sequence defects (PTMs) removed. Sixteen clones with the target sequence defects removed were selected for larger-scale expression. All 16 clones expressed well, yielding protein ranging from 400 to 1920 micrograms from 8 mL of culture. After purification, the purity of the clones was verified by SDS-capillary electrophoresis with sodium dodecyl sulfate (CE-SDS). Additionally, the monomer content of the antibodies was assessed by analytical SEC, and the thermostability of the antibodies was characterized using an Uncle instrument (Unchained Laboratories). The results of these characterization studies are summarized in Table 9. [Table 9]

[0242] Unofficial sequence listing SEQ ID NO: 1, h6E6-007 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSGYGLSWVRQAPGKGLEWVSTISSGGGYTHYAPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAQDYWGQGTTVTVSS

[0243] SEQ ID NO: 2, h6E6-007 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYVAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0244] SEQ ID NO: 3, h6E6-029 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSHYGVSWVRQAPGKGLEWVSTISSGGGYTHYAQSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAQDYWGQGTTVTVSS

[0245] SEQ ID NO: 4, h6E6-029 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYVAWYQQKPGQAPRLLIYWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0246] SEQ ID NO: 5, h6E6-040 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGHSWVRQAPGKGLEWVSTISSGGGYTHYAPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAHDYWGQGTTVTVSS

[0247] SEQ ID NO: 6, h6E6-040 VK sequence EIVMTQSPATLSVSPGERATLSCRASQDVGHYVAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0248] SEQ ID NO: 7, h6E6-055 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSQYGHSWVRQAPGKGLEWVSTISSGGGYTHYAESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAQDYWGQGTTVTVSS

[0249] SEQ ID NO: 8, h6E6-055 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0250] SEQ ID NO: 9, h6E6-056 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSKYGTSWVRQAPGKGLEWVSTISSGGGYTHYAPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAQDYWGQGTTVTVSS

[0251] SEQ ID NO: 10, h6E6-056 VK sequence EIVMTQSPATLSVSPGERATLSCRASQDVGHYVAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0252] SEQ ID NO: 11, h6E6-057 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSHYGVSWVRQAPGKGLEWVSTISSGGGYTHYVASVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYALDYWGQGTTVTVSS

[0253] SEQ ID NO: 12, h6E6-057 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYVAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWAFGQGTKVEIK

[0254] SEQ ID NO: 13, h6E6-058 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSVYGLSWVRQAPGKGLEWVSTISSGGGYTQYAPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAFDYWGQGTTVTVSS

[0255] SEQ ID NO: 14, h6E6-058 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0256] SEQ ID NO: 15, h6E6-063 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSAYGTSWVRQAPGKGLEWVSTISSGGGYTYYAASVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAIDYWGQGTTVTVSS

[0257] SEQ ID NO: 16, h6E6-063 VK sequence EIVMTQSPATLSVSPGERATLSCRASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0258] SEQ ID NO: 17, h6E6-066 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSAYGSSWVRQAPGKGLEWVSTISSGGGYTHYAPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAHDYWGQGTTVTVSS

[0259] SEQ ID NO: 18, h6E6-066 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYVAWYQQKPGQAPRLLIYWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0260] SEQ ID NO: 19, h6E6-068 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGISWVRQAPGKGLEWVSTISSGGGYTHYAHSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYALDYWGQGTTVTVSS

[0261] SEQ ID NO: 20, h6E6-068 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0262] SEQ ID NO: 21, h6E6-070 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSQYGHSWVRQAPGKGLEWVSTISSGGGYTHYAHSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYANDYWGQGTTVTVSS

[0263] SEQ ID NO: 22, h6E6-070 VK sequence EIVMTQSPATLSVSPGERATLSCRASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0264] SEQ ID NO: 23, h6E6-072 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSQYGHSWVRQAPGKGLEWVSTISSGGGYTHYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAQDYWGQGTTVTVSS

[0265] SEQ ID NO: 24, h6E6-072 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYLAWYQQKPGQAPRLLIYWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0266] SEQ ID NO: 25, h6E6-077 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSHYGTSWVRQAPGKGLEWVSTISSGGGYTHYAPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYAIDYWGQGTTVTVSS

[0267] SEQ ID NO: 26, h6E6-077 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYVAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0268] SEQ ID NO: 27, h6E6-102 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSKYGLSWVRQAPGKGLEWVSTISSGGGYTHYVESVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYASDYWGQGTTVTVSS

[0269] SEQ ID NO: 28, h6E6-102 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYVAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0270] SEQ ID NO: 29, h6E6-107 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYGASWVRQAPGKGLEWVSTISSGGGYTHYAPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYALDYWGQGTTVTVSS

[0271] SEQ ID NO: 30, h6E6-107 VK sequence EIVMTQSPATLSVSPGERATLSCKASQDVGHYVAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0272] SEQ ID NO: 31, h6E6-116 VH sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYGVSWVRQAPGKGLEWVSTISSGGGYTHYAGSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPRDFSYALDYWGQGTTVTVSS

[0273] SEQ ID NO: 32, h6E6-116 VK sequence EIVMTQSPATLSVSPGERATLSCRASQDVGHYLAWYQQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK

[0274] SEQ ID NO: 33, human ROR2 full length

[0275] SEQ ID NO: 34, human ROR2 full length MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVEVLDPNDPLGPLDGQDGPIPTLKGYFLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYG SRLRIQDLDTTDTGYYQCVATNGMKTITATGVLFVRLGPTHSPNHNFQDDYHEDGFCQPYRGIACARFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTHLSDQCSQFAIPSFCHFV FPLCDARSRTPKPRELCRDECEVLESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANCMRIGIPAERLGRYHQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSST DFPELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMGILYILVPSIAIPLVIACLFFLVCMCRNKQKASASTPQRRQLMASPSQDMEMPLINQHKQAKLKEISLS AVRFMEELGEDRFGKVYKGHLFGPAPGEQTQAVAIKTLKDKAEGPLREEFRHEAMLRARLQHPNVVCLLGVVTKDQPLSMIFSYCSHGDLHEFLVMRSPHSDVGSTDDDRTVKSALEP PDFVHLVAQIAAGMEYLSSHHVVHKDLATRNVLVYDKLNVKISDLGLFREVYAADYYKLLGNSLLPIRWMAPEAIMYGKFSIDSDIWSYGVVLWEVFSYGLQPYCGYSNQDVVEMIRN RQVLPCPDDCPAWVYALMIECWNEFPSRRPRFKDIHSRLRAWGNLSNYNSSAQTSGASNTTQTSSLSTSPVSNVSNARYVGPKQKAPPFPQPQFIPMKGQIRPMVPPPQLYVPVNGYQ PVPAYGAYLPNFYPVQIPMQMAPQQVPPQMVPKPSSHHSGSGSTSTGYVTTAPSNTSMADRAALLSEGADDTQNAPEDGAQSTVQEAEEEEEGSVPETELLGDCDTLQVDEAQVQLEA

[0276] SEQ ID NO: 35, mouse ROR2 full length

[0277] SEQ ID NO: 36, mouse ROR2 full length MARGWVRPSRVPLCARAVWTAAALLLWTPWTAGEVEDSEAIDTLGQPDGPDSPLPTLKGYFLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRVVIRKTEYGSRLRIQDLDTTDTGYYQCVATNGLKTITATGVLYVRLGPTHSPNHNFQDDDQEDGFCQPYRGIACARFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTQLSDQCSQFAIPSFCHFVFPLCDACSRAPKPRELCRDECEVLENDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANCMRIGIPAERLGRYHQCYNGSGADYRGMASTTKSGHQCQPWALQHPHSHRLSSTEFPELGGGHAYCRNPGGQMEGPWCFTQNKNVRVELCDVPPCSPRYGSKMGILYILVPSIAIPLVIACLFFLVCMCRNKQKASASTPQRRQLMASPSQDMEMPLISQHKQAKLKEISLSTVRFMEELGEDRFGKVYKGHLFGPAPGEPTQAVAIKTLKDKAEGPLREEFRQEAMLRARLQHPNIVCLLGVVTKDQPLSMIFSYCSHGDLHEFLVMRSPHSDVGSTDDDRTVKSALEPPDFVHVVAQIAAGMEFLSSHHVCHKDLATRNVLVYDKLNVRISDLGLFREVYSADYYKLMGNSLLPIRWMSPEAVMYGKFSIDSDIWSYGVVLWEVFSYGLQPYCGYSNQDVVEMIRSRQVLPCPDDCPAWVYALMIECWNEFPSRRPRFKDIHSRLRSWGNLSNYNSSAQTSGASNTTQTSSLSTSPVSNVSNARYMAPKQKAQPFPQPQFIPMKGQIRPLVPPAQLYIPVNGYQPVPAYGAYLPNFYPVQIPMQMAPQQVPPQMVPKPSSHHSGSGSTSTGYVTTAPSNTSVADRAALLSEGTEDVQNIAEDVAQSPVQEAEEEEEGSVPETELLGDNDTLQVTEAAHVQLEA

[0278] Sequence number 37, human ROR2 extracellular region

[0279] SEQ ID NO: 38, human ROR2 extracellular domain MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVEVLDPNDPLGPLDGQDGPIPTLKGYFLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYGSRLRIQDLDTTDTGYYQCVATNGMKTITATGVLFVRLGPTHSSPNHNFQDDYHEDGFCQPYRGIACARFIGNRTIYVDSLQMQGE IENRITAAFTMIGTSTHLSDQCSQFAIPSFCHFVFPLCDARSRTPKPRELCRDECEVLESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANCMRIGIPAERLGRYHQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMG

[0280] SEQ ID NO: 39, mouse ROR2 extracellular domain

[0281] SEQ ID NO: 40, mouse ROR2 extracellular domain MARGWVRPSRVPLCARAVWTAAALLLWTPWTAGEVEDSEAIDTLGQPDGPDSPLPTLKGYFLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDA PVVQEPRRVVIRKTEYGSRLRIQDLDTTDTGYYQCVATNGLKTITATGVLYVRLGPTHSPNHNFQDDDQEDGFCQPYRGIACARFIGNRTIYVDSLQMQGE IENRITAAFTMIGTSQLSDQCSQFAIPSFCHFVFPLCDACSRAPKPRELCRDECEVLENDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANCMRIGIPAERLGRYHQCYNGSGADYRGMASTTKSGHQCQPWALQHPHSHRLSSTEFPELGGGHAYCRNPGGQMEGPWCFTQNKNVRVELCDVPPCSPRYGSKMG

[0282] SEQ ID NO: 41, human ROR2 kringle domain HQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCS

[0283] SEQ ID NO: 42, human ROR2 Ig-like domain AILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYGSRLRIQDLDTTDTGYYQCVATNGMKTITAT [Table 10] [Table 11] [Table 12] TIFF2026501564000014.tif254170TIFF2026501564000015.tif254170TIFF2026501564000016.tif254170TIFF2026501564000017.tif254170TIFF202 6501564000018.tif254170TIFF2026501564000019.tif254170TIFF2026501564000020.tif254170TIFF2026501564000021.tif254170TIFF2026501564 000022.tif254170TIFF2026501564000023.tif254170TIFF2026501564000024.tif254170TIFF2026501564000025.tif254170TIFF2026501564000026. tif254170TIFF2026501564000027.tif254170TIFF2026501564000028.tif254170TIFF2026501564000029.tif254170TIFF2026501564000030.tif77170 [Table 13] TIFF2026501564000032.tif254170TIFF2026501564000033.tif33170

[0284] P embodiment P Embodiment 1. A method for identifying an anti-ROR2 antibody, comprising: A method comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising a histidine at a position corresponding to position 349 of SEQ ID NO: 34; (ii) detecting the antibody binding to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide not comprising a histidine at a position corresponding to position 349 of SEQ ID NO: 34; and (iv) detecting the antibody not binding to the second ROR2 polypeptide, thereby identifying an anti-ROR2 antibody.

[0285] P Embodiment 2. A method for identifying an anti-ROR2 antibody, comprising: A method comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising an aspartic acid at a position corresponding to position 354 of SEQ ID NO: 34; (ii) detecting the antibody binding to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide not comprising an aspartic acid at a position corresponding to position 354 of SEQ ID NO: 34; and (iv) detecting the antibody not binding to the second ROR2 polypeptide, thereby identifying an anti-ROR2 antibody.

[0286] P Embodiment 3. A method for identifying an anti-ROR2 antibody, comprising: A method comprising: (i) contacting an antibody with a first ROR2 polypeptide comprising a methionine at position 386 of SEQ ID NO: 34; (ii) detecting the antibody binding to the first ROR2 polypeptide; (iii) contacting the antibody with a second ROR2 polypeptide not comprising a methionine at position 386 of SEQ ID NO: 34; and (iv) detecting the antibody not binding to the second ROR2 polypeptide, thereby identifying an anti-ROR2 antibody.

[0287] P Embodiment 4. An anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody The antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 1, the light chain variable domain comprises the sequence of SEQ ID NO: 2, the heavy chain variable domain comprises the sequence of SEQ ID NO: 3, the light chain variable domain comprises the sequence of SEQ ID NO: 4, the heavy chain variable domain comprises the sequence of SEQ ID NO: 5, the light chain variable domain comprises the sequence of SEQ ID NO: 6, the heavy chain variable domain comprises the sequence of SEQ ID NO: 7, the light chain variable domain comprises the sequence of SEQ ID NO: 8, the heavy chain variable domain comprises the sequence of SEQ ID NO: 9, the light chain variable domain comprises the sequence of SEQ ID NO: 10, the heavy chain variable domain comprises the sequence of SEQ ID NO: 11, the light chain variable domain comprises the sequence of SEQ ID NO: 12, the heavy chain variable domain comprises the sequence of SEQ ID NO: 13, the light chain variable domain comprises the sequence of SEQ ID NO: 14, the heavy chain variable domain comprises the sequence of SEQ ID NO: 15, and the light chain variable domain comprises the sequence of SEQ ID NO: 16. wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 17, the light chain variable domain comprises the sequence of SEQ ID NO: 18, the heavy chain variable domain comprises the sequence of SEQ ID NO: 19, the light chain variable domain comprises the sequence of SEQ ID NO: 20, the heavy chain variable domain comprises the sequence of SEQ ID NO: 21, the light chain variable domain comprises the sequence of SEQ ID NO: 22, the heavy chain variable domain comprises the sequence of SEQ ID NO: 23, the light chain variable domain comprises the sequence of SEQ ID NO: 24, the heavy chain variable domain comprises the sequence of SEQ ID NO: 25, the light chain variable domain comprises the sequence of SEQ ID NO: 26, the heavy chain variable domain comprises the sequence of SEQ ID NO: 27, the light chain variable domain comprises the sequence of SEQ ID NO: 28, the heavy chain variable domain comprises the sequence of SEQ ID NO: 29, the light chain variable domain comprises the sequence of SEQ ID NO: 30, the heavy chain variable domain comprises the sequence of SEQ ID NO: 31, and the light chain variable domain comprises the sequence of SEQ ID NO: 32.

[0288] P Embodiment 5. The antibody of P embodiment 4, wherein the antibody binds to the kringle domain of human ROR2.

[0289] P Embodiment 6. The antibody of P embodiment 4, wherein the antibody binds to cancer cells.

[0290] P Embodiment 7. The antibody of P embodiment 6, wherein the cancer cells are breast cancer cells, ovarian cancer cells, pancreatic cancer cells, cervical cancer cells, gastric cancer cells, renal cancer cells, head and neck cancer cells, bone cancer cells, skin cancer cells, or prostate cancer cells.

[0291] P Embodiment 8. The antibody of P embodiment 4, wherein the antibody is conjugated to a therapeutic agent.

[0292] P Embodiment 9. The antibody of P embodiment 4, wherein the antibody is conjugated to a diagnostic agent.

[0293] P Embodiment 10. A method of treating cancer in a subject in need thereof, comprising: A method comprising administering to a subject a therapeutically effective amount of the antibody described in 4.

[0294] P Embodiment 11. A method of inhibiting metastasis of a ROR2-expressing cancer in a subject in need thereof, comprising: A method comprising administering to a subject a therapeutically effective amount of the antibody of embodiment 4.

[0295] P Embodiment 12. A chimeric antigen receptor, A chimeric antigen receptor comprising: (i) an antibody region comprising any one of the light chain variable domain and heavy chain variable domain pairs described in embodiment 4; and (ii) a transmembrane domain.

[0296] P Embodiment 13.P An anti-ROR2 antibody capable of binding to the same epitope as the antibody of embodiment 4.

[0297] Embodiment Embodiment 1. (i) a CDR H1 comprising an amino acid sequence of the formula GFTFS-X1-YG-X2-X3 (I), wherein X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y; X2 is A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; and X3 is S or N; provided that when X2 is M and X3 is S, X1 is not N; and (ii) a CDR H1 comprising an amino acid sequence of the formula X4-ISSGGGYT-X5-Y-X6 (II). (iii) CDR H3 comprising an amino acid sequence of the formula DFSYA-X7-DYWG(III), wherein X7 is A, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; (iv) CDR L1 comprising an amino acid sequence of the formula X8-ASQDVGHY-X9-A(IV), wherein X8 is K or R, X9 is V or L, and when X8 is K, X9 is not V; (v) CDR L2 comprising an amino acid sequence of the formula WASTR-X10-T(V), wherein X8 is K or R, X9 is V or L, and when X8 is K, X9 is not V; and (vi) CDR L3 comprising the sequence of SEQ ID NO: 53, wherein X10 is H or A, and when X8 is K and X9 is V, X10 is not H.

[0298] Embodiment 2. The antibody of embodiment 1, further comprising an FR H3 comprising an amino acid sequence of the formula YTHYV-X11-SVKG(VI), wherein X11 is A, D, E, G, H, P, Q, T, or V.

[0299] Embodiment 3. The antibody of embodiment 1 or embodiment 2, wherein X1 is S, G, N, K, A, or H.

[0300] Embodiment 4. The antibody of any one of embodiments 1 to 3, wherein X1 is S.

[0301] Embodiment 5. The antibody of any one of embodiments 1 to 4, wherein X2 is M, V, T, I or L.

[0302] Embodiment 6. The antibody of any one of embodiments 1 to 5, wherein X2 is V.

[0303] Embodiment 7. The antibody of any one of embodiments 1 to 6, wherein X7 is M, L, or Q.

[0304] Embodiment 8. The antibody of any one of embodiments 1 to 7, wherein X7 is L.

[0305] Embodiment 9. An antibody described in any one of embodiments 2 to 8, wherein X11 is E, P, D, A, or T.

[0306] Embodiment 10. An antibody according to any one of embodiments 2 to 9, wherein X11 is E.

[0307] Embodiment 11. The antibody of any one of embodiments 2 to 10, wherein X1 is not N, X2 is not M, X7 is not M, or X11 is not D.

[0308] Embodiment 12. The antibody of any one of embodiments 2 to 11, wherein X1 is not N, X2 is not M, X7 is not M, and X11 is not D.

[0309] Embodiment 13. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 305, CDR H2 as set forth in SEQ ID NO: 306, and CDR H3 as set forth in SEQ ID NO: 307, and CDR L1 as set forth in SEQ ID NO: 308, CDR L2 as set forth in SEQ ID NO: 309, and CDR L3 as set forth in SEQ ID NO: 310.

[0310] Embodiment 14. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 311, CDR H2 as set forth in SEQ ID NO: 312, and CDR H3 as set forth in SEQ ID NO: 313, and CDR L1 as set forth in SEQ ID NO: 314, CDR L2 as set forth in SEQ ID NO: 315, and CDR L3 as set forth in SEQ ID NO: 316.

[0311] Embodiment 15. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 317, CDR H2 as set forth in SEQ ID NO: 318, and CDR H3 as set forth in SEQ ID NO: 319, and CDR L1 as set forth in SEQ ID NO: 320, CDR L2 as set forth in SEQ ID NO: 321, and CDR L3 as set forth in SEQ ID NO: 322.

[0312] Embodiment 16. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 323, CDR H2 as set forth in SEQ ID NO: 324, and CDR H3 as set forth in SEQ ID NO: 325, and CDR L1 as set forth in SEQ ID NO: 326, CDR L2 as set forth in SEQ ID NO: 327, and CDR L3 as set forth in SEQ ID NO: 328.

[0313] Embodiment 17. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 329, CDR H2 as set forth in SEQ ID NO: 330, and CDR H3 as set forth in SEQ ID NO: 31, and CDR L1 as set forth in SEQ ID NO: 332, CDR L2 as set forth in SEQ ID NO: 333, and CDR L3 as set forth in SEQ ID NO: 334.

[0314] Embodiment 18. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 335, CDR H2 as set forth in SEQ ID NO: 336, and CDR H3 as set forth in SEQ ID NO: 337, and CDR L1 as set forth in SEQ ID NO: 338, CDR L2 as set forth in SEQ ID NO: 339, and CDR L3 as set forth in SEQ ID NO: 340.

[0315] Embodiment 19. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 341, CDR H2 as set forth in SEQ ID NO: 342, and CDR H3 as set forth in SEQ ID NO: 343, and CDR L1 as set forth in SEQ ID NO: 344, CDR L2 as set forth in SEQ ID NO: 345, and CDR L3 as set forth in SEQ ID NO: 346.

[0316] Embodiment 20. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 347, CDR H2 as set forth in SEQ ID NO: 348, and CDR H3 as set forth in SEQ ID NO: 349, and CDR L1 as set forth in SEQ ID NO: 350, CDR L2 as set forth in SEQ ID NO: 351, and CDR L3 as set forth in SEQ ID NO: 352.

[0317] Embodiment 21. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 353, CDR H2 as set forth in SEQ ID NO: 354, and CDR H3 as set forth in SEQ ID NO: 355, and CDR L1 as set forth in SEQ ID NO: 356, CDR L2 as set forth in SEQ ID NO: 357, and CDR L3 as set forth in SEQ ID NO: 358.

[0318] Embodiment 22. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 359, CDR H2 as set forth in SEQ ID NO: 360, and CDR H3 as set forth in SEQ ID NO: 361, and CDR L1 as set forth in SEQ ID NO: 362, CDR L2 as set forth in SEQ ID NO: 363, and CDR L3 as set forth in SEQ ID NO: 364.

[0319] Embodiment 23. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 365, CDR H2 as set forth in SEQ ID NO: 366, and CDR H3 as set forth in SEQ ID NO: 367, and CDR L1 as set forth in SEQ ID NO: 368, CDR L2 as set forth in SEQ ID NO: 369, and CDR L3 as set forth in SEQ ID NO: 370.

[0320] Embodiment 24. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 371, CDR H2 as set forth in SEQ ID NO: 372, and CDR H3 as set forth in SEQ ID NO: 373, and CDR L1 as set forth in SEQ ID NO: 374, CDR L2 as set forth in SEQ ID NO: 375, and CDR L3 as set forth in SEQ ID NO: 376.

[0321] Embodiment 25. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 377, CDR H2 as set forth in SEQ ID NO: 378, and CDR H3 as set forth in SEQ ID NO: 379, and CDR L1 as set forth in SEQ ID NO: 380, CDR L2 as set forth in SEQ ID NO: 381, and CDR L3 as set forth in SEQ ID NO: 382.

[0322] Embodiment 26. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 383, CDR H2 as set forth in SEQ ID NO: 384, and CDR H3 as set forth in SEQ ID NO: 385, and CDR L1 as set forth in SEQ ID NO: 386, CDR L2 as set forth in SEQ ID NO: 387, and CDR L3 as set forth in SEQ ID NO: 388.

[0323] Embodiment 27. The antibody of embodiment 1, wherein the antibody comprises CDR H1 as set forth in SEQ ID NO: 389, CDR H2 as set forth in SEQ ID NO: 390, and CDR H3 as set forth in SEQ ID NO: 391, and CDR L1 as set forth in SEQ ID NO: 392, CDR L2 as set forth in SEQ ID NO: 393, and CDR L3 as set forth in SEQ ID NO: 394.

[0324] Embodiment 28. The antibody of any one of embodiments 1 to 27, wherein the antibody is a humanized antibody.

[0325] Embodiment 29. The antibody of any one of embodiments 1 to 27, wherein the antibody is a Fab′ fragment.

[0326] Embodiment 30. The antibody of any one of embodiments 1 to 27, wherein the antibody is a single-chain antibody (scFv).

[0327] Embodiment 31. The antibody of any one of embodiments 1 to 27, wherein the antibody is a chimeric antibody.

[0328] Embodiment 32. The antibody of any one of embodiments 1 to 27, wherein the antibody is an IgG.

[0329] Embodiment 33. The antibody of any one of embodiments 1 to 27, wherein the antibody is an IgG1 or IgG2.

[0330] Embodiment 34. The antibody of any one of embodiments 1 to 33, wherein the antibody is capable of binding to ROR2 protein.

[0331] Embodiment 35. The antibody of any one of embodiments 1 to 33, wherein the antibody is capable of binding to the extracellular domain of the ROR2 protein.

[0332] Embodiment 36 The antibody of embodiment 35, wherein the extracellular domain is a kringle domain.

[0333] Embodiment 37. The antibody of any one of embodiments 34 to 36, wherein the ROR2 protein is expressed on a cell.

[0334] Embodiment 38. The antibody of embodiment 37, wherein the cell is a cancer cell.

[0335] Embodiment 39. The antibody of embodiment 38, wherein the cancer cells are breast cancer cells, ovarian cancer cells, pancreatic cancer cells, cervical cancer cells, gastric cancer cells, renal cancer cells, head and neck cancer cells, bone cancer cells, skin cancer cells, or prostate cancer cells.

[0336] Embodiment 40. The antibody of any one of embodiments 34 to 39, wherein the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.02 nM to about 6 nM.

[0337] Embodiment 41. The antibody of any one of embodiments 1 to 40, wherein the antibody is conjugated to a therapeutic agent.

[0338] Embodiment 42. The antibody of any one of embodiments 1 to 40, wherein the antibody is conjugated to a diagnostic agent.

[0339] Embodiment 43. A method of treating cancer in a subject in need thereof, comprising: A method comprising administering to a subject a therapeutically effective amount of the antibody of any one of embodiments 1 to 41.

[0340] Embodiment 44. The method of embodiment 43, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

[0341] Embodiment 45. A method for detecting ROR2-expressing cells, comprising: A method comprising: (i) contacting a ROR2-expressing cell with the antibody of any one of embodiments 1 to 40; and (ii) detecting binding of the antibody to the ROR2 protein expressed by the cell.

[0342] Embodiment 46 The method of embodiment 45, wherein the antibody is conjugated to a detectable moiety.

[0343] Embodiment 47. The method of embodiment 45, wherein the ROR2-expressing cell is in a subject.

[0344] Embodiment 48 The method of embodiment 47, wherein the subject has or is at risk of having cancer.

[0345] Embodiment 49. The method of embodiment 48, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

[0346] Embodiment 50 The method of embodiment 45, wherein said contacting occurs in vitro.

[0347] Embodiment 51. A method of delivering a therapeutic agent to ROR2-expressing cells, comprising: A method comprising contacting a ROR2-expressing cell with the antibody of any one of embodiments 1 to 40, wherein the antibody is conjugated to a therapeutic agent.

[0348] Embodiment 52. The method of embodiment 51, wherein the therapeutic agent is an anti-cancer agent.

[0349] Embodiment 53 The method of embodiment 51, wherein the ROR2-expressing cell is in a subject.

[0350] Embodiment 54 The method of embodiment 51, wherein the subject has or is at risk of having cancer.

[0351] Embodiment 55. The method of embodiment 54, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

[0352] Embodiment 56 The method of embodiment 51, wherein said contacting occurs in vitro.

[0353] Embodiment 57. A method for inhibiting the migration of ROR2-expressing cells, comprising: A method comprising contacting a ROR2-expressing cell with the antibody of any one of embodiments 1 to 40.

[0354] Embodiment 58. The method of embodiment 57, wherein the ROR2-expressing cells are in a subject having or at risk of having cancer.

[0355] Embodiment 59. The method of embodiment 58, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

[0356] Embodiment 60 The method of embodiment 57, wherein said contacting occurs in vitro.

[0357] Embodiment 61. The method of embodiment 57, wherein the ROR2-expressing cells are cancer cells.

[0358] Embodiment 62. The method of embodiment 61, wherein the cancer cells are breast cancer cells, ovarian cancer cells, pancreatic cancer cells, cervical cancer cells, gastric cancer cells, renal cancer cells, head and neck cancer cells, bone cancer cells, skin cancer cells, or prostate cancer cells.

[0359] Embodiment 63. An anti-ROR2 antibody, wherein the anti-ROR2 antibody binds to the same epitope as the anti-ROR2 antibody of any one of Embodiments 1 to 40.

[0360] Embodiment 64. A chimeric antigen receptor comprising (i) an anti-ROR2 antibody described in any one of embodiments 1 to 40, and (ii) a transmembrane domain.

[0361] Embodiment 65. A method of treating cancer in a subject in need thereof, comprising: 65. A method comprising administering to the subject a therapeutically effective amount of the chimeric antigen receptor of embodiment 64.

[0362] Embodiment 66. The method of embodiment 65, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

Claims

1. (i) a CDR H1 comprising the amino acid sequence of the following formula: G-F-T-F-S-X1-Y-G-X2-X3 (I) During the ceremony, X1 is A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W, or Y; X2 is A, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; X3 is S or N; When X2 is M and X3 is S, then X1 is not N; (ii) a CDR H2 comprising the amino acid sequence of the following formula: X4-I-S-S-G-G-G-Y-T-X5-Y-X6 (II) During the ceremony, X4 is T or S; X5 is H or Y; X6 is V or A; When X5 is H and X6 is V, then X4 is not T; (iii) a CDR H3 comprising the amino acid sequence of the following formula: D-F-S-Y-A-X7-D-Y-W-G (III) During the ceremony, X7 is A, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y (iv) a CDR L1 comprising the amino acid sequence of the following formula: X8-A-S-Q-DV-G-HY-X9-A (IV) During the ceremony, X8 is K or R; X9 is V or L; When X8 is K, X9 is not V; (v) a CDR L2 comprising the amino acid sequence of the following formula: W-A-S-TR-X10-T (V) During the ceremony, X10 is H or A; When X8 is K and X9 is V, then X10 is not H; (vi) a CDR L3 comprising the sequence of SEQ ID NO: 53; and An anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising:

2. 2. The antibody of claim 1, further comprising an FR H3 comprising the amino acid sequence of the following formula: Y-T-H-Y-V-X11-S-V-K-G (VI) During the ceremony, X11 is A, D, E, G, H, P, Q, T, or V.

3. 3. The antibody of claim 2, wherein X1 is S, G, N, K, A, or H.

4. The antibody of claim 3, wherein X1 is S.

5. The antibody of claim 4, wherein X2 is M, V, T, I or L.

6. The antibody of claim 5, wherein X2 is V.

7. The antibody of claim 6, wherein X7 is M, L, or Q.

8. The antibody of claim 7, wherein X7 is L.

9. The antibody of claim 8, wherein X11 is E, P, D, A, or T.

10. The antibody of any one of claims 2 to 9, wherein X11 is E.

11. 3. The antibody of claim 2, wherein X1 is not N, X2 is not M, X7 is not M, or X11 is not D.

12. 3. The antibody of claim 2, wherein X1 is not N, X2 is not M, X7 is not M, and X11 is not D.

13. The antibody CDR H1 set forth in SEQ ID NO: 305, CDR H2 set forth in SEQ ID NO: 306, and CDR H3 set forth in SEQ ID NO: 307; CDR L1 set forth in SEQ ID NO: 308, CDR L2 set forth in SEQ ID NO: 309, and CDR L3 set forth in SEQ ID NO: 310; The antibody of claim 1, comprising:

14. The antibody CDR H1 set forth in SEQ ID NO: 311, CDR H2 set forth in SEQ ID NO: 312, and CDR H3 set forth in SEQ ID NO: 313; CDR L1 set forth in SEQ ID NO: 314, CDR L2 set forth in SEQ ID NO: 315, and CDR L3 set forth in SEQ ID NO: 316; The antibody of claim 1, comprising:

15. The antibody CDR H1 set forth in SEQ ID NO: 317, CDR H2 set forth in SEQ ID NO: 318, and CDR H3 set forth in SEQ ID NO: 319; CDR L1 set forth in SEQ ID NO: 320, CDR L2 set forth in SEQ ID NO: 321, and CDR L3 set forth in SEQ ID NO: 322; The antibody of claim 1, comprising:

16. The antibody CDR H1 set forth in SEQ ID NO: 323, CDR H2 set forth in SEQ ID NO: 324, and CDR H3 set forth in SEQ ID NO: 325; CDR L1 set forth in SEQ ID NO: 326, CDR L2 set forth in SEQ ID NO: 327, and CDR L3 set forth in SEQ ID NO: 328; The antibody of claim 1, comprising:

17. The antibody CDR H1 set forth in SEQ ID NO: 329, CDR H2 set forth in SEQ ID NO: 330, and CDR H3 set forth in SEQ ID NO: 31; CDR L1 set forth in SEQ ID NO: 332, CDR L2 set forth in SEQ ID NO: 333, and CDR L3 set forth in SEQ ID NO: 334; The antibody of claim 1, comprising:

18. The antibody CDR H1 set forth in SEQ ID NO: 335, CDR H2 set forth in SEQ ID NO: 336, and CDR H3 set forth in SEQ ID NO: 337; CDR L1 set forth in SEQ ID NO: 338, CDR L2 set forth in SEQ ID NO: 339, and CDR L3 set forth in SEQ ID NO: 340; The antibody of claim 1, comprising:

19. The antibody CDR H1 set forth in SEQ ID NO: 341, CDR H2 set forth in SEQ ID NO: 342, and CDR H3 set forth in SEQ ID NO: 343; CDR L1 set forth in SEQ ID NO: 344, CDR L2 set forth in SEQ ID NO: 345, and CDR L3 set forth in SEQ ID NO: 346; The antibody of claim 1, comprising:

20. The antibody CDR H1 set forth in SEQ ID NO: 347, CDR H2 set forth in SEQ ID NO: 348, and CDR H3 set forth in SEQ ID NO: 349; CDR L1 set forth in SEQ ID NO: 350, CDR L2 set forth in SEQ ID NO: 351, and CDR L3 set forth in SEQ ID NO: 352; The antibody of claim 1, comprising:

21. The antibody CDR H1 set forth in SEQ ID NO: 353, CDR H2 set forth in SEQ ID NO: 354, and CDR H3 set forth in SEQ ID NO: 355; CDR L1 set forth in SEQ ID NO: 356, CDR L2 set forth in SEQ ID NO: 357, and CDR L3 set forth in SEQ ID NO: 358; The antibody of claim 1, comprising:

22. The antibody CDR H1 set forth in SEQ ID NO: 359, CDR H2 set forth in SEQ ID NO: 360, and CDR H3 set forth in SEQ ID NO: 361; CDR L1 set forth in SEQ ID NO: 362, CDR L2 set forth in SEQ ID NO: 363, and CDR L3 set forth in SEQ ID NO: 364; The antibody of claim 1, comprising:

23. The antibody CDR H1 set forth in SEQ ID NO: 365, CDR H2 set forth in SEQ ID NO: 366, and CDR H3 set forth in SEQ ID NO: 367; CDR L1 set forth in SEQ ID NO: 368, CDR L2 set forth in SEQ ID NO: 369, and CDR L3 set forth in SEQ ID NO: 370; The antibody of claim 1, comprising:

24. The antibody CDR H1 set forth in SEQ ID NO: 371, CDR H2 set forth in SEQ ID NO: 372, and CDR H3 set forth in SEQ ID NO: 373; CDR L1 set forth in SEQ ID NO: 374, CDR L2 set forth in SEQ ID NO: 375, and CDR L3 set forth in SEQ ID NO: 376; The antibody of claim 1, comprising:

25. The antibody CDR H1 set forth in SEQ ID NO: 377, CDR H2 set forth in SEQ ID NO: 378, and CDR H3 set forth in SEQ ID NO: 379; CDR L1 set forth in SEQ ID NO: 380, CDR L2 set forth in SEQ ID NO: 381, and CDR L3 set forth in SEQ ID NO: 382; The antibody of claim 1, comprising:

26. The antibody CDR H1 set forth in SEQ ID NO: 383, CDR H2 set forth in SEQ ID NO: 384, and CDR H3 set forth in SEQ ID NO: 385; CDR L1 set forth in SEQ ID NO: 386, CDR L2 set forth in SEQ ID NO: 387, and CDR L3 set forth in SEQ ID NO: 388; The antibody of claim 1, comprising:

27. The antibody CDR H1 set forth in SEQ ID NO: 389, CDR H2 set forth in SEQ ID NO: 390, and CDR H3 set forth in SEQ ID NO: 391; CDR L1 set forth in SEQ ID NO: 392, CDR L2 set forth in SEQ ID NO: 393, and CDR L3 set forth in SEQ ID NO: 394; The antibody of claim 1, comprising:

28. The antibody of claim 1 , wherein the antibody is a humanized antibody.

29. The antibody of claim 1 , wherein the antibody is a Fab′ fragment.

30. The antibody of claim 1 , wherein the antibody is a single-chain antibody (scFv).

31. The antibody of claim 1 , wherein the antibody is a chimeric antibody.

32. The antibody of claim 1 , wherein the antibody is an IgG.

33. The antibody of claim 1 , wherein the antibody is IgG1 or IgG2.

34. The antibody of claim 1 , wherein the antibody is capable of binding to a ROR2 protein.

35. The antibody of claim 1 , wherein the antibody is capable of binding to the extracellular domain of the ROR2 protein.

36. 36. The antibody of claim 35, wherein the extracellular domain is a kringle domain.

37. 35. The antibody of claim 34, wherein the ROR2 protein is expressed on a cell.

38. 38. The antibody of claim 37, wherein the cell is a cancer cell.

39. 39. The antibody of claim 38, wherein the cancer cell is a breast cancer cell, an ovarian cancer cell, a pancreatic cancer cell, a cervical cancer cell, a gastric cancer cell, a renal cancer cell, a head and neck cancer cell, a bone cancer cell, a skin cancer cell, or a prostate cancer cell.

40. 35. The antibody of claim 34, wherein the antibody is capable of binding to the ROR2 protein with an equilibrium dissociation constant (KD) of about 0.02 nM to about 6 nM.

41. The antibody of claim 1 , wherein the antibody is conjugated to a therapeutic agent.

42. The antibody of claim 1 , wherein the antibody is conjugated to a diagnostic agent.

43. 1. A method of treating cancer in a subject in need thereof, comprising: A method comprising administering to a subject a therapeutically effective amount of the antibody of claim 1.

44. 44. The method of claim 43, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

45. A method for detecting ROR2-expressing cells, comprising: (i) contacting a ROR2-expressing cell with the antibody of claim 1; (ii) detecting binding of said antibody to ROR2 protein expressed by said cell.

46. 46. ​​The method of claim 45, wherein the antibody is conjugated to a detectable moiety.

47. 46. ​​The method of claim 45, wherein the ROR2-expressing cell is in a subject.

48. 48. The method of claim 47, wherein the subject has or is at risk of having cancer.

49. 49. The method of claim 48, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

50. 46. ​​The method of claim 45, wherein said contacting occurs in vitro.

51. 1. A method for delivering a therapeutic agent to a ROR2-expressing cell, comprising: A method comprising contacting a ROR2-expressing cell with the antibody of claim 1, wherein the antibody is conjugated to a therapeutic agent.

52. 52. The method of claim 51, wherein the therapeutic agent is an anti-cancer agent.

53. 52. The method of claim 51, wherein the ROR2-expressing cell is in a subject.

54. 52. The method of claim 51, wherein the subject has or is at risk of having cancer.

55. 55. The method of claim 54, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

56. 52. The method of claim 51, wherein said contacting occurs in vitro.

57. 1. A method for inhibiting migration of ROR2-expressing cells, comprising: A method comprising contacting a ROR2-expressing cell with the antibody of claim 1.

58. 58. The method of claim 57, wherein the ROR2-expressing cell is in a subject having or at risk of having cancer.

59. 59. The method of claim 58, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

60. 58. The method of claim 57, wherein said contacting occurs in vitro.

61. 58. The method of claim 57, wherein the ROR2-expressing cell is a cancer cell.

62. 62. The method of claim 61, wherein the cancer cells are breast cancer cells, ovarian cancer cells, pancreatic cancer cells, cervical cancer cells, gastric cancer cells, renal cancer cells, head and neck cancer cells, bone cancer cells, skin cancer cells, or prostate cancer cells.

63. An anti-ROR2 antibody, which binds to the same epitope as the anti-ROR2 antibody of claim 1.

64. A chimeric antigen receptor comprising: (i) the anti-ROR2 antibody of claim 1; and (ii) a transmembrane domain.

65. 1. A method of treating cancer in a subject in need thereof, comprising:

65. A method comprising administering to the subject a therapeutically effective amount of the chimeric antigen receptor of claim 64.

66. 66. The method of claim 65, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

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