Anti-ROR-2 Antibodies and Methods of Use

Abstract

Provided herein are 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 contain novel light and heavy chain domain CDRs and framework regions 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 priority to U.S. Provisional Application No. 62 / 936,900, filed November 18, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under CA236361 and CA81534 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Reference to a sequence listing, table, or computer program listing appendix submitted as an ASCII text file The sequence listing set forth in file 48537-632001WO_ST25.TXT, created on November 18, 2020, 122,880 bytes, machine format IBM-PC, MS Windows operating system, is incorporated herein by reference. [Background technology]

[0004] Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a developmentally restricted receptor for Wnt5a. Human ROR2 is a 943-amino acid single-pass type I membrane protein with a calculated molecular weight of 104.8 kDa. It is highly conserved across several species, with 92% amino acid identity between the mouse and human proteins. ROR2 can regulate Wnt signaling by repressing transcription of Wnt target genes and sequestering canonical Wnt ligands, thereby functioning as a tumor suppressor in different cellular contexts. Recently, ROR2 has been implicated in the progression of numerous cancers, including breast, ovarian, pancreatic, cervical, gastric, renal, head and neck, bone, skin, and prostate. Therefore, 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 therapeutics and diagnostics. The compositions and methods provided herein address these and other needs in the art. Summary of the Invention

[0005] In one aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, and CDR H3 set forth in SEQ ID NO: 27, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, and CDR L3 set forth in SEQ ID NO: 30.

[0006] In one aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36.

[0007] In another aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, and CDR H3 set forth in SEQ ID NO: 39, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, and CDR L3 set forth in SEQ ID NO: 42.

[0008] In another aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48.

[0009] In one aspect, provided is 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.

[0010] In one aspect, provided is 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.

[0011] In another aspect, a method is provided for detecting a ROR2-expressing cell, 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.

[0012] 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 is conjugated to the therapeutic agent.

[0013] In another aspect, a method is provided for inhibiting migration of ROR2-expressing cells, the method comprising contacting the ROR2-expressing cells with an antibody provided herein, including embodiments thereof.

[0014] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, and CDR H3 set forth in SEQ ID NO: 27, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, and CDR L3 set forth in SEQ ID NO: 30.

[0015] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO: 2 and a light chain variable domain of SEQ ID NO: 4.

[0016] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 1 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 3.

[0017] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36.

[0018] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO: 6 and a light chain variable domain of SEQ ID NO: 8.

[0019] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 5 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 7.

[0020] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, and CDR H3 set forth in SEQ ID NO: 39, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, and CDR L3 set forth in SEQ ID NO: 42.

[0021] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO: 10 and a light chain variable domain of SEQ ID NO: 12.

[0022] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 9 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 11.

[0023] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48.

[0024] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO: 14 and a light chain variable domain of SEQ ID NO: 16.

[0025] In one aspect, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody, wherein the anti-ROR2 antibody comprises a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 13 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 15.

[0026] In another aspect, there is provided a chimeric antigen receptor comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO:28, CDR L2 set forth in SEQ ID NO:29, and CDR L3 set forth in SEQ ID NO:30; and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO:25, CDR H2 set forth in SEQ ID NO:26, and CDR H3 set forth in SEQ ID NO:27; and (ii) a transmembrane domain.

[0027] In one aspect, there is provided a chimeric antigen receptor comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36; and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33; and (ii) a transmembrane domain.

[0028] In one aspect, there is provided a chimeric antigen receptor comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, and CDR L3 set forth in SEQ ID NO: 42; and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, and CDR H3 set forth in SEQ ID NO: 39; and (ii) a transmembrane domain.

[0029] In one aspect, there is provided a chimeric antigen receptor comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48; and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45; and (ii) a transmembrane domain.

[0030] In another aspect, provided is 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.

[0031] In another aspect, an anti-receptor tyrosine kinase-like orphan receptor 2 (ROR2) antibody is provided that is capable of binding to the extracellular domain of ROR2 comprising the amino acid sequence of SEQ ID NO:22. [Brief explanation of the drawings]

[0032] [Figure 1] Comparison of the extracellular domains of human and mouse 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 specified by single-letter amino acid codons. The Ig-like, CRD, and Kringle domains are labeled and indicated by lines above the sequences. [Figure 2A]The amino acid sequence and alignment to the closest mouse IGHV (upper sequence) or IGKV (lower sequence) germline gene are shown for each of the four mouse anti-human ROR2 hybridomas, designated (Figure 2A) 6E6, (Figure 2B) 4G9, (Figure 2C) 5C11, and (Figure 2D) 5G3. For each alignment, the upper sequence shows the amino acid sequence of the heavy or light chain variable region, starting from the first codon of the first framework region and ending with the last codon of the fourth framework region. The lower sequence shows the amino acid sequence of the heavy or light chain variable region of the most homologous mouse IGHV or IGKV germline gene. The framework (FR) and complementarity-determining (CDR) regions are marked above the sequences, and differences between the two sequences are listed below the aligned sequences and designated as bold single-letter amino acid codons. [Figure 2B] The amino acid sequence and alignment to the closest mouse IGHV (upper sequence) or IGKV (lower sequence) germline gene are shown for each of the four mouse anti-human ROR2 hybridomas, designated (Figure 2A) 6E6, (Figure 2B) 4G9, (Figure 2C) 5C11, and (Figure 2D) 5G3. For each alignment, the upper sequence shows the amino acid sequence of the heavy or light chain variable region, starting from the first codon of the first framework region and ending with the last codon of the fourth framework region. The lower sequence shows the amino acid sequence of the heavy or light chain variable region of the most homologous mouse IGHV or IGKV germline gene. The framework (FR) and complementarity-determining (CDR) regions are marked above the sequences, and differences between the two sequences are listed below the aligned sequences and designated as bold single-letter amino acid codons. [Figure 2C]The amino acid sequence and alignment to the closest mouse IGHV (upper sequence) or IGKV (lower sequence) germline gene are shown for each of the four mouse anti-human ROR2 hybridomas, designated (Figure 2A) 6E6, (Figure 2B) 4G9, (Figure 2C) 5C11, and (Figure 2D) 5G3. For each alignment, the upper sequence shows the amino acid sequence of the heavy or light chain variable region, starting from the first codon of the first framework region and ending with the last codon of the fourth framework region. The lower sequence shows the amino acid sequence of the heavy or light chain variable region of the most homologous mouse IGHV or IGKV germline gene. The framework (FR) and complementarity-determining (CDR) regions are marked above the sequences, and differences between the two sequences are listed below the aligned sequences and designated as bold single-letter amino acid codons. [Figure 2D] The amino acid sequence and alignment to the closest mouse IGHV (upper sequence) or IGKV (lower sequence) germline gene are shown for each of the four mouse anti-human ROR2 hybridomas, designated (Figure 2A) 6E6, (Figure 2B) 4G9, (Figure 2C) 5C11, and (Figure 2D) 5G3. For each alignment, the upper sequence shows the amino acid sequence of the heavy or light chain variable region, starting from the first codon of the first framework region and ending with the last codon of the fourth framework region. The lower sequence shows the amino acid sequence of the heavy or light chain variable region of the most homologous mouse IGHV or IGKV germline gene. The framework (FR) and complementarity-determining (CDR) regions are marked above the sequences, and differences between the two sequences are listed below the aligned sequences and designated as bold single-letter amino acid codons. [Figure 3]Assessment of anti-ROR2 mAb binding to recombinant human ROR2 with varying amounts of immobilized protein and varying concentrations of soluble mAb. Wells were coated overnight with recombinant human ROR2 extracellular domain (ROR2-ECD) at 27, 9, 3, and 1 nM, washed, and blocked with sample buffer (1x BBS + 1% BSA) at 37°C for 90 min. Serial dilutions ranging from 500 to 31 ng / ml of 6E6, 4G9, 5C11, or 5G3 mAb were added to the wells, incubated for 60 min at ambient temperature, washed, and detected with HRP-conjugated goat anti-mouse IgG and developed with TMB microwell peroxidase substrate. Development was terminated by the addition of 1 M O-phosphate, and absorbance was read at 450 nM on a SpectraMax 340 microplate reader. Absorbance values ​​are plotted on the ordinate against mAb concentration (ng / ml) on the abscissa. Higher absorbance values ​​at lower plate coating concentrations and lower amounts of soluble mAb indicate relatively higher binding affinities for 6E6 and 4G9 compared to 5C11 and 5G3. [Figure 4A] Affinity measurements of 6E6 and 4G9 mAb binding to recombinant ROR2 protein. (Figure 4A) Analysis was performed using a KinExA 3200 instrument. The percentage of anti-human ROR2 mAb bound to particles coated with ROR2 protein (y-axis) in the presence of increasing molar (M) concentrations of soluble ROR2 competitor (x-axis) is shown for 6E6 (upper panel) and 4G9 (lower panel). (Figure 4B) Illustration of 95% confidence intervals for the measured Kd of 6E6 (upper panel) and 4G9 (lower panel) for binding to human ROR2. [Figure 4B]Affinity measurements of 6E6 and 4G9 mAb binding to recombinant ROR2 protein. (Figure 4A) Analysis was performed using a KinExA 3200 instrument. The percentage of anti-human ROR2 mAb bound to particles coated with ROR2 protein (y-axis) in the presence of increasing molar (M) concentrations of soluble ROR2 competitor (x-axis) is shown for 6E6 (upper panel) and 4G9 (lower panel). (Figure 4B) Illustration of 95% confidence intervals for the measured Kd of 6E6 (upper panel) and 4G9 (lower panel) for binding to human ROR2. [Figure 5] Identification of the binding region of anti-human ROR2 mAbs by assessing binding to chimeric human / house recombinant ROR2 proteins. The left panel shows a schematic diagram of the chimeric constructs of the extracellular portion of ROR2 used to map the binding region of each of the four ROR2 mAbs. The dark areas in each construct indicate the hatched subregions of human ROR2 and 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 and kringle domains of human ROR2. Each recombinant protein was transferred onto a nylon membrane and probed with 6E6, 4G9, 5C11, 5G3, or anti-His tag mAb, and detected with an anti-mouse IgG antibody conjugated with horseradish peroxidase, as shown in the right panel. 6E5 and 5C11 mAbs bind to ROR2 recombinant proteins containing the human kringle domain. The 4G9 and 5G3 mAbs bind to the ROR2 recombinant protein within the first 111 aa of human ROR2, which contains the Ig-like domain. [Figure 6]Identification of amino acids required for binding of anti-human ROR2 mAb to the Kringle domain of human ROR2. Binding of 6E6, 4G9, and 5C11 mAbs was assessed using recombinant human ROR2 protein, in which one amino acid that differs between human and mouse ROR2 in the Kringle domain was replaced with the corresponding amino acid in mouse ROR2. Each recombinant protein was transferred onto a nylon membrane, probed with 6E6, 4G9, or 5C11 mAb, and detected with an anti-mouse IgG antibody conjugated with horseradish peroxidase, as indicated in the upper panel. The protein sequence alignment of the Kringle domains of human and mouse ROR2 is shown in the lower panel, with boxed amino acids indicating the amino acid changes that occurred for each recombinant protein. [Figure 7A] The 6E6 and 4G9 anti-human ROR2 mAbs specifically bind to human ROR2. (Figure 7A) Binding of 6E6 and 4G9 mAbs to human ROR2 was assessed by flow cytometry staining and analysis of several cell lines known to express ROR2. Cells were stained with 10 μg / ml of 6E6 or 4G9 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. The histograms show the relative fluorescence intensity (x-axis) of viable cells, as determined by light scattering properties. (Figure 7B) Specificity was verified by the absence of binding to HCT116 colorectal cancer cells and HEK293 cells, in which ROR2 expression had been ablated using CRISPR-cas9, compared to the parental cell lines. [Figure 7B]The 6E6 and 4G9 anti-human ROR2 mAbs specifically bind to human ROR2. (Figure 7A) Binding of 6E6 and 4G9 mAbs to human ROR2 was assessed by flow cytometry staining and analysis of several cell lines known to express ROR2. Cells were stained with 10 μg / ml of 6E6 or 4G9 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. The histograms show the relative fluorescence intensity (x-axis) of viable cells, as determined by light scattering properties. (Figure 7B) Specificity was verified by the absence of binding to HCT116 colorectal cancer cells and HEK293 cells, in which ROR2 expression had been ablated using CRISPR-cas9, compared to the parental cell lines. [Figure 8] 6E6 and 4G9 anti-human ROR2 mAbs bind to ROR2 expressed by BR1936 breast cancer PDX cells. BR1936 and BR1367 (ROR2-negative) breast cancer PDX cells were stained with 10 μg / ml of 6E6 or 4G9 anti-human ROR2-Alexa647 conjugated mAbs (shaded histograms) or an equivalent amount of an isotype-matched control mAb (open histograms). Cells were stained for 20 minutes on ice, washed, and analyzed by flow cytometry. The histograms show the relative fluorescence intensity (x-axis) of viable cells, as determined by light scattering properties. Both 6E6 and 4G9 bind to BR1936 cells but not to BR1367 cells, which do not express human ROR2. [Figure 9]The 6E6 and 4G9 anti-human ROR2 mAbs do not bind to peripheral blood mononuclear cells (PBMCs) or lymphocytes isolated from healthy donors. PBMCs were isolated by Ficoll density centrifugation from whole blood obtained with consent from healthy donors. Cells were stained with 5 μg / ml of 6E6 or 4G9 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 by flow cytometry. Histograms show staining of viable mononuclear cells or lymphocytes, as determined by light scatter characteristics. Staining of K562 cells was performed as a positive control. [Figure 10A]The 6E6 and 4G9 anti-human ROR2 mAbs were internalized by K562 but not JEKO cells. K562 and JEKO (ROR2-negative) cells were stained with 10 μg / ml of 6E6 or 4G9 anti-human ROR2-pHrodo conjugated mAb for 30 minutes on ice, washed, and divided into four fractions. One plate was kept on ice, while the other three were transferred to 37°C for 30, 60, or 120 minutes. After incubation, the cells were washed and analyzed by flow cytometry. (Figure 10A) The histogram shows the relative fluorescence intensity (x-axis) of viable cells, as determined by light scattering properties. Shaded histograms show stained cells incubated for 120 min at 37°C, dashed histograms show stained cells incubated for 120 min at 4°C, and open histograms show unstained cells incubated for 120 min at 37°C. Compared to stained cells incubated for 120 min at 4°C or unstained cells incubated for 120 min at 37°C, an increase in relative fluorescence is shown for both 6E6 (upper panel) and 4G9 (lower panel) pHrodo-conjugated mAbs for ROR2-expressing K562 cells, but not for ROR2-negative JEKO cells. (Figure 10B) Graphical representation of the increase in mean fluorescence (y-axis) of 6E6 or 4G9 pHrodo-conjugated mAbs on K562 cells over time (x-axis). ΔMFI is the mean fluorescence intensity of K562 cells stained with one of the pHrodo-conjugated mAbs incubated at 37°C minus the mean fluorescence intensity of an aliquot of the same stained cells incubated for an equivalent period at 4°C. [Figure 10B]The 6E6 and 4G9 anti-human ROR2 mAbs were internalized by K562 but not JEKO cells. K562 and JEKO (ROR2-negative) cells were stained with 10 μg / ml of 6E6 or 4G9 anti-human ROR2-pHrodo conjugated mAb for 30 minutes on ice, washed, and divided into four fractions. One plate was kept on ice, while the other three were transferred to 37°C for 30, 60, or 120 minutes. After incubation, the cells were washed and analyzed by flow cytometry. (Figure 10A) The histogram shows the relative fluorescence intensity (x-axis) of viable cells, as determined by light scattering properties. Shaded histograms show stained cells incubated for 120 min at 37°C, dashed histograms show stained cells incubated for 120 min at 4°C, and open histograms show unstained cells incubated for 120 min at 37°C. Compared to stained cells incubated for 120 min at 4°C or unstained cells incubated for 120 min at 37°C, an increase in relative fluorescence is shown for both 6E6 (upper panel) and 4G9 (lower panel) pHrodo-conjugated mAbs for ROR2-expressing K562 cells, but not for ROR2-negative JEKO cells. (Figure 10B) Graphical representation of the increase in mean fluorescence (y-axis) of 6E6 or 4G9 pHrodo-conjugated mAbs on K562 cells over time (x-axis). ΔMFI is the mean fluorescence intensity of K562 cells stained with one of the pHrodo-conjugated mAbs incubated at 37°C minus the mean fluorescence intensity of an aliquot of the same stained cells incubated for an equivalent period at 4°C. [Figure 11A]The 6E6 and 4G9 anti-human ROR2 mAbs inhibit Wnt5a-induced invasion of MCF7-ROR breast cancer cells. MCF7 breast cancer cells transfected with either a control vector or a ROR2 expression vector were cultured overnight in growth factor-free Dulbecco's modified Eagle's medium (DMEM) supplemented with 0.5% fetal bovine serum (FBS). The next day, cells were removed and suspended at 105 cells in 0.5% FBS DMEM medium containing 100 ng / ml recombinant Wnt5a and 25 μg / ml mouse IgG, 6E6, or 4G9 anti-human ROR2 mAbs in Matrigel-coated, growth factor-reduced, 8 μM pore-size invasion chambers. After 24 hours of incubation at 37°C, the wells were washed with phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde. Cells on the apical side of each insert were removed by scraping, while cells that had migrated to the basal side of the membrane were stained with Diff-Quick staining reagent and visualized with a Nikon inverted microscope. (Figure 11A) Histograms show the average number of invaded cells in each of the three chambers for MCF7 or MCF7-ROR2 cells treated with mouse IgG (gray bars), 6E6 mAb (white bars), or 4G9 (black bars), normalized to MCF7 cells treated with control mIgG. Data are shown as mean + / - SD (n=3). (Figure 11B) Representative photomicrographs of invaded cells from MCF7 (upper panel) or MCF7-ROR2 cells (lower panel) treated with either 25 μg / ml of control antibody (left panel), 6E6 anti-ROR2 mAb (middle panel), or 4G9 anti-human ROR2 mAb. [Figure 11B]The 6E6 and 4G9 anti-human ROR2 mAbs inhibit Wnt5a-induced invasion of MCF7-ROR breast cancer cells. MCF7 breast cancer cells transfected with either a control vector or a ROR2 expression vector were cultured overnight in growth factor-free Dulbecco's modified Eagle's medium (DMEM) supplemented with 0.5% fetal bovine serum (FBS). The next day, cells were removed and suspended at 105 cells in 0.5% FBS DMEM medium containing 100 ng / ml recombinant Wnt5a and 25 μg / ml mouse IgG, 6E6, or 4G9 anti-human ROR2 mAbs in Matrigel-coated, growth factor-reduced, 8 μM pore-size invasion chambers. After 24 hours of incubation at 37°C, the wells were washed with phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde. Cells on the apical side of each insert were removed by scraping, while cells that had migrated to the basal side of the membrane were stained with Diff-Quick staining reagent and visualized with a Nikon inverted microscope. (Figure 11A) Histograms show the average number of invaded cells in each of the three chambers for MCF7 or MCF7-ROR2 cells treated with mouse IgG (gray bars), 6E6 mAb (white bars), or 4G9 (black bars), normalized to MCF7 cells treated with control mIgG. Data are shown as mean + / - SD (n=3). (Figure 11B) Representative photomicrographs of invaded cells from MCF7 (upper panel) or MCF7-ROR2 cells (lower panel) treated with either 25 μg / ml of control antibody (left panel), 6E6 anti-ROR2 mAb (middle panel), or 4G9 anti-human ROR2 mAb. [Figure 12A]Affinity measurement and binding specificity of 6E6 single-chain variable fragment (scFv) for human ROR2. Analysis was performed using a KinExA 3200 instrument. (Figure 12A) Shows the percentage of 6E6 anti-human ROR2 scFv bound to particles coated with recombinant ROR2 protein (y-axis) in the presence of increasing molar (M) concentrations of soluble ROR2 competitors (x-axis). (Figure 12B) Illustration of the 95% confidence interval for the measured Kd of 6E6 scFv for binding to recombinant human ROR2. (Figure 12C) Binding of 6E6 scFv to ROR2 was assessed by flow cytometry staining and analysis of K562 (ROR2-positive) and JEKO (ROR2-negative) cells. Cells were stained with approximately 1 μg / ml of 6E6 anti-human ROR2 scfv 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 viable cells stained with 6E6 scfv, as determined by light scattering properties, compared to viable cells stained with anti-human IgG1-PE antibody alone (open histogram). 6E6 scFv binds to K562 cells but not to JEKO cells, which do not express human ROR2. [Figure 12B]Affinity measurement and binding specificity of 6E6 single-chain variable fragment (scFv) for human ROR2. Analysis was performed using a KinExA 3200 instrument. (Figure 12A) Shows the percentage of 6E6 anti-human ROR2 scFv bound to particles coated with recombinant ROR2 protein (y-axis) in the presence of increasing molar (M) concentrations of soluble ROR2 competitors (x-axis). (Figure 12B) Illustration of the 95% confidence interval for the measured Kd of 6E6 scFv for binding to recombinant human ROR2. (Figure 12C) Binding of 6E6 scFv to ROR2 was assessed by flow cytometry staining and analysis of K562 (ROR2-positive) and JEKO (ROR2-negative) cells. Cells were stained with approximately 1 μg / ml of 6E6 anti-human ROR2 scfv 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 viable cells stained with 6E6 scfv, as determined by light scattering properties, compared to viable cells stained with anti-human IgG1-PE antibody alone (open histogram). 6E6 scFv binds to K562 cells but not to JEKO cells, which do not express human ROR2. [Figure 12C]Affinity measurement and binding specificity of 6E6 single-chain variable fragment (scFv) for human ROR2. Analysis was performed using a KinExA 3200 instrument. (Figure 12A) Shows the percentage of 6E6 anti-human ROR2 scFv bound to particles coated with recombinant ROR2 protein (y-axis) in the presence of increasing molar (M) concentrations of soluble ROR2 competitors (x-axis). (Figure 12B) Illustration of the 95% confidence interval for the measured Kd of 6E6 scFv for binding to recombinant human ROR2. (Figure 12C) Binding of 6E6 scFv to ROR2 was assessed by flow cytometry staining and analysis of K562 (ROR2-positive) and JEKO (ROR2-negative) cells. Cells were stained with approximately 1 μg / ml of 6E6 anti-human ROR2 scfv 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 viable cells stained with 6E6 scfv, as determined by light scattering properties, compared to viable cells stained with anti-human IgG1-PE antibody alone (open histogram). 6E6 scFv binds to K562 cells but not to JEKO cells, which do not express human ROR2. [Figure 13]The 6E6 and 4G9 anti-human ROR2 chimeric antigen receptor (CAR) constructs specifically bind to recombinant human ROR2 protein. HEK293 cells were transfected with either the 6E6 or 4G9 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, consisting of the ROR2 extracellular domain and CH2-CH3 constant region domains of human IgG1, by flow cytometry 48 hours later. Cells were stained with 1 μg / ml recombinant ROR2-Ig (upper panel) or 1 μg / ml control ROR1-Ig (lower 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 viable cells stained with either ROR2-Ig or ROR1-Ig compared to cells stained with anti-human IgG1-PE antibody alone (open histograms). HEK293 cells transfected with either the 6E6 or 4G9 CAR construct bind ROR2-Ig (upper panel) but not ROR1-Ig, which is composed of the same human IgG domain fused to the extracellular region of human ROR1. Conversely, ROR1 CAR-transfected cells bind only ROR1-Ig. DETAILED DESCRIPTION OF THE INVENTION

[0033] 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 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.

[0034] The section headings used herein are for organizational purposes 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 papers) are expressly incorporated by reference in their entirety for any purpose.

[0035] 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.

[0036] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art.For example, see 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 method, device and material 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 frequently used herein, and do not limit the scope of this disclosure.

[0037] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof, or their complements, or nucleosides (e.g., deoxyribonucleosides or ribonucleosides), in the form of single, double, or multiple strands. In embodiments, "nucleic acid" does not include nucleosides. The terms "polynucleotide," "oligonucleotide," "oligo," and the like, refer, in their usual and conventional sense, to a linear sequence of nucleotides. The term "nucleoside" refers, in its usual and conventional sense, to a glycosylamine containing 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," in its usual and conventional sense, refers to a single unit, i.e., a monomer, of a polynucleotide. A nucleotide may be a ribonucleotide, a deoxyribonucleotide, or a modified form thereof. Examples of polynucleotides contemplated herein include single-stranded and double-stranded DNA, single-stranded and double-stranded RNA, and hybrid molecules containing a mixture of single-stranded and double-stranded DNA and RNA. Examples of nucleic acids, e.g., polynucleotides, contemplated herein include any type of RNA, such as mRNA, siRNA, miRNA, and guide RNA, as well as any type of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragment thereof. The term "double-stranded" in the context of polynucleotides refers to double-strandedness in the usual and conventional sense. Nucleic acids can be linear or branched. For example, nucleic acids can be linear chains of nucleotides, or nucleic acids can be branched, for example, such that the nucleic acid contains one or more arms or branches of nucleotides. Optionally, branched nucleic acids are repeatedly branched to form higher-order structures, such as dendrimers.

[0038] For example, nucleic acids, including nucleic acids with phosphothioate backbones, can contain one or more reactive moieties. As used herein, the term reactive moiety includes any group that can react with another molecule, such as a nucleic acid or polypeptide, through a covalent bond, a non-covalent bond, or other interaction. For example, a nucleic acid can contain an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent bond, a non-covalent bond, or other interaction.

[0039] This term also encompasses the nucleic acid that contains synthetic, naturally occurring, and non-naturally occurring known nucleotide analogs or modified backbone residues or bonds, which have similar binding properties as reference nucleic acid and are metabolized in a similar manner as reference nucleotide.Examples of such analogs include, but are not limited to, for example, phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate, which replaces the oxygen in phosphate with double bond sulfur), phosphorodithioate, phosphonocarboxylic acid, phosphonocarboxylate, phosphonoacetic acid, phosphonoformic acid, methylphosphonate, boronphosphonate, or phosphodiester derivatives containing O-methylphosphoramidite bond (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press), and modifications to nucleotide bases such as 5-methylcytidine or pseudouridine, and peptide nucleic acid backbone and bond. 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. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, 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 of the ribose-phosphate backbone can be made for various reasons, such as to increase 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, or 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 the DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0040] Nucleic acid can contain non-specific sequence.As used herein, the term "non-specific sequence" refers to a nucleic acid sequence that contains 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.

[0041] Polynucleotides are typically composed of a specific sequence of four nucleotide bases: adenine (A), cytosine (C), guanine (G), and thymine (T) (or uracil (U) for thymine (T) if the polynucleotide is RNA). Thus, the term "polynucleotide sequence" is an alphabetical representation of a polynucleotide molecule; alternatively, the term can 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. Polynucleotides can optionally include one or more non-standard nucleotides, nucleotide analogs, and / or modified nucleotides.

[0042] 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 guanidine 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 nucleotides of the complement can partially or completely match the nucleotides of the second nucleic acid sequence. When the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. When the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence, only a portion of the nucleotides of the complement form base pairs with the nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and non-coding sequences, where the non-coding sequence contains complementary nucleotides to the coding sequence, thus forming the complement of the coding sequence. Further examples of complementary sequences are sense and antisense sequences, where the sense sequence contains complementary nucleotides to the antisense sequence, thus forming the complement of the antisense sequence.

[0043] As described herein, sequence complementarity can be partial, where only a portion of the nucleic acids match according to base pairing, or can be complete, where all of the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other can have a certain percentage of identical nucleotides (i.e., about 60% identity over a certain region, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity).

[0044] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly 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. Amino acid analogs refer to compounds that have 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, such as homoserine, norleucine, methionine sulfoxide, and 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. Amino acid mimetics refer to compounds that have a structure different from the general chemical structure of an amino acid but function similarly 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.

[0045] 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. Similarly, nucleotides may be referred to by their commonly accepted single-letter codes.

[0046] 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 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.

[0047] The "position" of an amino acid or nucleotide base is indicated by a number that consecutively identifies 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, determined simply by counting from the N-terminus, will generally not be identical to the number at that corresponding position in the reference sequence. For example, if a variant has a deletion relative to the aligned reference sequence, the variant will not have an amino acid corresponding to the reference sequence position at the site of the deletion. If there is an insertion in the 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 either the reference sequence or the aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0048] When used in the context of the numbering of a given amino acid or polynucleotide sequence, the term "numbered with reference to" or "corresponding to" refers 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 of a protein (e.g., ROR-1) in other proteins using different numbering systems. For example, by performing a simple sequence alignment with a protein (e.g., ROR-1), the identity and position of a residue that corresponds to a particular position of the protein will be identified in other protein sequences that align to this protein. For example, a selected residue of a selected protein corresponds to glutamic acid at position 138 if the selected residue occupies the same essential spatial or other structural relationship as glutamic acid at position 138. In some embodiments, when the selected proteins are aligned for maximum homology with the protein, a position in the aligned selected protein that aligns with glutamic acid 138 is said to correspond to glutamic acid 138. Instead of a primary sequence alignment, a three-dimensional structural alignment can also be used, for example, the structures of the selected proteins are aligned for maximum correspondence with glutamic acid at position 138, and the overall structures are compared. In this case, the amino acid that occupies the same essential position in the structural model as glutamic acid 138 is the one that corresponds to the glutamic acid 138 residue.

[0049] "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 those nucleic acids that encode the same or essentially identical amino acid sequences. Due to the degeneracy of the genetic code, many 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," a type of conservatively modified variation. Every nucleic acid sequence herein that encodes a polypeptide also describes all possible silent variations of the nucleic acid. Those skilled 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 inherent in each described sequence.

[0050] With respect to amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions, or additions to nucleic acid, peptide, polypeptide, or protein sequences 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 alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to, and do not exclude, the polymorphic variants, interspecies homologs, and alleles of the present disclosure.

[0051] 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)).

[0052] 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 are identical or have 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 more identity over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region), as measured using the BLAST or BLAST 2.0 sequence comparison algorithm with the 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 can also refer to or apply to the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, preferred algorithms are able to 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.

[0053] "Percentage of 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 the reference sequence (which does not contain additions or deletions) for optimal alignment of the two sequences. This percentage is calculated by determining the number of positions where the same nucleic acid base or amino acid residue is present in both sequences to generate 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 generate the percentage of sequence identity.

[0054] As used herein, the term "comparison window" refers to, for example, the entire sequence or any segment of a sequence having a number of consecutive positions selected from the group consisting of 20 to 600, about 50 to 200, or about 100 to 150 amino acids or nucleotides. After optimal alignment of two sequences, the sequence can be compared to a reference sequence of the same number of consecutive positions. 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, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by a search for similar methods of Pearson and Lipman (1988) Proc. Nat'l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0055] Examples of suitable algorithms for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are 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 from the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high-scoring sequence pairs (HSPs) by identifying short words of length W in a 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. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. For nucleotide sequences, the cumulative score is 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 amino acid sequences, a scoring matrix is ​​used to calculate the cumulative score. Extension of the word hits in each direction is stopped when the cumulative alignment score drops by a quantity X from the highest achieved score, when the cumulative score falls below 0 due to the accumulation of one or more negatively 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. 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 defaults a word length of 3 and an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) uses as defaults an alignment (B) of 50, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0056] 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 to be 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.

[0057] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid immunologically cross-reacts with an antibody 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.

[0058] Antibodies are large, complex molecules (molecular weight approximately 150,000, or approximately 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. The light and heavy chains, in turn, are each composed 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 variable regions of the light and heavy chains (also referred to herein as the light chain variable (VL) domain and the heavy chain variable (VH) domain, respectively) combine in three-dimensional space to form the variable region that binds to antigens (e.g., receptors on the surface of cells). Within each variable region of the light or heavy chain are three short segments (averaging 10 amino acids in length) called complementarity-determining regions ("CDRs"). The six CDRs of 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, which 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 periphery of the CDRs.

[0059] 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, bispecific antibodies, 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 antibodies and variable regions thereof from camelids, and methods of their production, isolation, and use, can be found in references WO97 / 49805 and WO97 / 49805, which are incorporated herein by reference in their entirety for all purposes. Similarly, antibodies and variable regions thereof from cartilaginous fish, and methods of their production, isolation, and use, can be found in WO2005 / 118629, which is incorporated herein by reference in its entirety for all purposes.

[0060] 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 chain (L) of an antibody. In embodiments, the variable light chains provided herein comprise, from N- to C-terminus, 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 chain (H) of an antibody. In embodiments, the variable heavy chains provided herein comprise, from N- to C-terminus, CDR H1, CDR H2, and CDR H3.

[0061] 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- 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 light chain provided herein comprises, from N- to C-terminal, FR H1, FR H2, FR H3, and FR H4.

[0062] 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" (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 and heavy chain regions, respectively. As referred to herein, the terms variable light chain (VL), variable light chain (VL) domain, and light chain variable region may be used interchangeably. As referred to 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. By binding to specific proteins, the Fc region ensures 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.

[0063] The term "antibody" is used in accordance with its commonly known meaning in the art. Antibodies exist, for example, as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests antibodies below the disulfide bonds in the hinge region to produce V fragments that are themselves held together by disulfide bonds. H -C H1 The resulting product is a dimer of Fab, a light chain linked to a light chain of a target antibody, F(ab)'2. F(ab)'2 can be reduced under mild conditions to disrupt the disulfide bond in the hinge region, thereby converting the F(ab)'2 dimer into a Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3rd ed. 1993)). While various antibody fragments have been defined with reference to the digestion of intact antibodies, those skilled in the art will understand that such fragments can be synthesized de novo, either chemically or using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA methodology (e.g., single-chain Fv) or those 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.

[0064] 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 produce antibodies against the polypeptides of the present invention. Transgenic mice, or other organisms such as other mammals, can also 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)).

[0065] Single-chain variable fragments (scFvs) are typically fusion proteins of the variable regions of immunoglobulin heavy (VH) and light (VL) chains, connected by a short linker peptide of 10 to approximately 25 amino acids. The linker typically contains glycine-rich residues for flexibility and serine or threonine-rich residues for solubility. The linker can connect the N-terminus of VH to the C-terminus of VL, or vice versa.

[0066] 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 the binding of the other antibody by at least 30%, 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 antibody. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other antibody.

[0067] Many techniques known in the art can be used for the preparation of suitable antibodies of the invention and for use in accordance with the invention, e.g., recombinant, monoclonal, or polyclonal antibodies (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 the antibody of interest can be cloned from cells; for example, genes encoding monoclonal antibodies can be cloned from hybridomas and used to produce recombinant monoclonal antibodies. Gene libraries encoding the heavy and light chains of monoclonal antibodies can also be produced from hybridomas or plasma cells. Random recombination of heavy and light chain gene products generates a large pool of antibodies with different antigen specificities (see, for example, 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 & (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 engineered to be 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, US Pat. No. 4,676,980, WO 91 / 00360, WO 92 / 200373, and EP 03089).

[0068] Methods for humanizing or primatizing non-human antibodies are well known in the art (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, humanized antibodies have one or more amino acid residues introduced into them from a source that is non-human. These non-human amino acid residues are often referred to as imported residues, typically from an imported variable domain. Humanization can be performed essentially according to the method of Winter and colleagues (see, 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 by substituting multiple rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See Presta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan, Molec. Immun., 28:489-498 (1991), Padlan, Molec. Immun., 31(3):169-217 (1994).) Accordingly, such humanized antibodies are 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 replaced by residues from analogous sites in rodent antibodies.For example, polynucleotides comprising a first sequence encoding humanized immunoglobulin framework regions and a second sequence set encoding 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 various human cells according to well-known procedures.

[0069] A "chimeric antibody" is an antibody molecule in which (a) the constant region, or a portion thereof, has been modified, substituted, or exchanged 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, e.g., an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody, or (b) the variable region, or a portion thereof, has been modified, substituted, or exchanged with a variable region having a different or altered antigen specificity. Preferred antibodies of use and for use in accordance with the present invention include humanized and / or chimeric monoclonal antibodies.

[0070] The phrases "specifically (or selectively) bind" or "specifically (or selectively) immunoreact" with an antibody, when referring to a protein or peptide, often refer to a binding reaction that determines the presence of the protein in a heterogeneous population of proteins and other biologics. Thus, under specified immunoassay conditions, a particular antibody will bind to a particular protein at least twice above background, more typically 10-100 times above 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 that are specifically immunoreactive with a selected antigen and not with other proteins. This selection can be achieved by subtracting antibodies that cross-react with other molecules. A variety of immunoassay formats can be used to select antibodies that are specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (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).

[0071] "Ligand" refers to an agent, e.g., a polypeptide or other molecule, that can bind to a receptor or an antibody, antibody variant, antibody region, or fragment thereof.

[0072] 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 conjugated or otherwise covalently attached to an antibody.

[0073] As used herein, the term "ROR2 protein" or "ROR2" includes any recombinant or naturally occurring form of receptor tyrosine kinase-like orphan receptor 2, also known as tyrosine protein kinase transmembrane receptor ROR2, neurotrophic tyrosine kinase receptor-related 2, or variants or homologs thereof, that maintain ROR2 activity (e.g., in the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) 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.

[0074] For certain proteins described herein, the named protein includes any of the naturally occurring forms, variants, or homologs of the protein that maintain protein transcription factor activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) 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.

[0075] The term "gene" refers to the segment of DNA involved in producing a protein, including the regions preceding and following the coding region (leader and trailer), and the intervening sequences (introns) between individual coding segments (exons). The leader, trailer, and introns contain regulatory elements required during transcription and translation of a gene. Additionally, a "protein gene product" is a protein expressed from a particular gene.

[0076] The terms "plasmid," "vector," or "expression vector" refer to a nucleic acid molecule that encodes a gene and / or regulatory elements required for expression of the gene. Expression of a gene 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 when the gene and regulatory elements are encoded by separate plasmids.

[0077] 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 can be introduced into cells using non-viral or viral-based methods. The nucleic acid molecule can be a genetic sequence encoding an entire protein or a functional portion 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, transfection via heat shock, magnetofection, and electroporation. In some embodiments, the nucleic acid molecule is introduced into cells using electroporation, according to standard procedures well known in the art. In the case of viral-based methods, 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 term "transfection" or "transduction" also refers to the introduction of proteins into cells from the external environment. Usually, protein transduction or transfection depends on the attachment of peptides or proteins that can cross the cell membrane to the target protein. For example, see Ford et al. (2001) Gene Therapy 8:1-4 and Prochiantz (2007) Nat. Methods 4:119-20.

[0078] A "label" or "detectable moiety" is a composition that can be detected by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., commonly used in ELISA), biotin, digoxigenin, or haptens and proteins, or other entities that can be made detectable, for example, by incorporating a radioactive label into a peptide or antibody specifically reactive with the target peptide. Any suitable method known in the art for binding an antibody to a label can be used (e.g., using the methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego).

[0079] If the label or detectable moiety is a radioactive metal or paramagnetic ion, the agent may be reacted with another long-tail reagent having a long tail with one or more chelating groups attached to the long tail to bind these ions. The long tail can be a polymer such as polylysine, a polysaccharide, or other derivatized or derivatizable chain with pendant groups to which metals or ions can be added 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, bis-thiosemicarbazones, and polyoximes. The chelate is typically linked to a PSMA antibody or functional antibody fragment by a group, which 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 chelates, when complexed with non-radioactive metals such as manganese, iron, and gadolinium, are useful for MRI when used with the antibodies and carriers described herein. Macrocyclic chelates such as NOTA, DOTA, and TETA are used with a variety of metals and radiometals, including, but not limited to, radionuclides of gallium, yttrium, and copper, respectively. 223 Other cyclic-type chelates, such as macrocyclic polyethers, may be used that are of interest for stably binding nuclides, such as Ra. In certain embodiments, the chelating moiety is Al- 18 It can be used to attach PET imaging agents such as F complexes to targeting molecules.

[0080] "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 physically contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate derived from one or more of the added reagents that may be produced in the reaction mixture.

[0081] The term "contacting" can include allowing two species to react, interact, or come into physical contact, and 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.

[0082] As used herein, "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 specific 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 derived from plants and animals, such as mammalian, insect (e.g., Spodoptera) and human cells.

[0083] The term "recombinant," when used with 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 native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, a recombinant cell expresses a gene not found within the native (non-recombinant) form of the cell, or expresses a native gene that is otherwise abnormally expressed, under-expressed, or not expressed at all. Transgenic cells and plants are typically those that express a heterologous gene or coding sequence as a result of recombinant methods.

[0084] The term "isolated," when applied to a nucleic acid or protein, means that the nucleic acid or protein is essentially free from other cellular components with which it is associated in its natural state. This can be, for example, a homogeneous state, either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein present as the predominant species in a preparation is substantially purified.

[0085] When used with reference to portions of a nucleic acid, the term "heterologous" indicates that the nucleic acid comprises two or more subsequences that are not found in essentially the same relationship to each other. For example, nucleic acids are typically produced recombinantly, with two or more sequences from unrelated genes arranged to create a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in essentially the same relationship to each other (e.g., a fusion protein).

[0086] 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, as referred to herein, an "exogenous promoter" 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 originates within a given cell or organism.

[0087] As defined herein, with respect to cell proliferation (e.g., cancer cell proliferation), the terms "inhibition," "inhibit," "inhibiting," and the like refer to adversely affecting a cell (e.g., reducing proliferation) or killing a cell. In some embodiments, inhibition refers to the alleviation of a disease or disease symptom (e.g., cancer, cancer cell proliferation). Thus, inhibition includes, at least in part, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or the amount of an enzyme activity or 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).

[0088] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to protein-inhibitor interactions, refer to adversely affecting (e.g., reducing) the activity or function of a protein (e.g., a ROR2 protein) compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of ROR2 compared to the protein concentration or level in the absence of the inhibitor. In embodiments, inhibition refers to the alleviation of a disease or disease symptoms. 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 due to an indirect interaction (e.g., an inhibitor binds to a protein that activates ROR2, thereby preventing activation of the target protein).

[0089] Thus, 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 more lower than the expression or activity in the absence of the antagonist.

[0090] The term "expression" includes any step involved in polypeptide production, 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.).

[0091] "Biological sample" or "sample" refers to material obtained or derived from a subject or patient. Biological samples include sections of tissue, such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include bodily fluids such as blood and blood fractions or 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, etc. Biological samples are typically obtained from eukaryotic organisms, such as mammals, e.g., primates, e.g., chimpanzees or humans, cows, dogs, cats, rodents, e.g., guinea pigs, rats, mice, rabbits, or birds, reptiles, or fish.

[0092] 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 with a known normal (disease-free) individual (e.g., a standard control subject). A standard control can also represent an average measurement or value collected from a population of similar individuals (e.g., standard control subjects) who do not have a 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 disease. For example, a control can be designed to compare the efficacy of treatment based on pharmacological data (e.g., half-life) or therapeutic measures (e.g., comparison of side effects). Controls are also useful for determining the significance of data. For example, if the value of a given parameter varies greatly in the control, the variation in the test sample will not be considered significant. One of skill in the art will recognize that standard controls can be designed to assess any number of parameters (e.g., RNA levels, protein levels, particular cell types, particular body fluids, particular tissues, etc.).

[0093] Those skilled in the art will understand which standard control is most appropriate in a given situation and can analyze data based on the comparison with the value of the standard control.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 the standard control, the variation of the test sample will not be considered significant.

[0094] A "patient" or "subject in need of treatment" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administration of a composition or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0095] The term "disease" or "condition" refers to an existing state or state of 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 solid tumor malignancies. Solid tumor malignancies include malignancies that may not contain liquid or cysts. For example, solid tumor malignancies can include breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In some further instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, e.g., solid cancers and cancers of the lymphatic system, kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testes, glioma, esophagus, and liver, e.g., hepatocellular carcinoma, lymphomas, e.g., B acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), Hodgkin's lymphoma, leukemias (including acute myeloid leukemia (AML), ALL, and CML), or multiple myeloma.

[0096] 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 with the compounds or methods provided herein include colon cancer, kidney cancer, leukemia, lung cancer, melanoma, ovarian cancer, prostate cancer, pancreatic cancer, brain cancer, liver cancer, stomach cancer, or sarcoma.

[0097] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by distorted 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 character of the disease—acute or chronic, (2) the type of cell involved—myeloid, lymphatic, or monocytic, and (3) the increased or absent number of abnormal cells in the blood—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, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, , acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic 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.

[0098] The term "sarcoma" generally refers to a tumor composed of a substance like embryonic connective tissue and generally composed of tightly packed cells embedded in a fibrous or homogeneous substance. 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, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, and fibroblastic sarcoma. These include sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0099] 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.

[0100] The term "carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, acinic cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, carcinoma adenomatous, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, and compact carcinoma. durum, embryonal carcinoma, encephalomyocellular carcinoma, epidermoid carcinoma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, gelatinoid carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, mucinous secretory carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, mucinous carcinoma mucosum, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage 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, porosal carcinoma, squamous cell carcinoma, string carcinomacarcinoma), telangiectatic carcinoma, telangiectatic-like carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), nodular carcinoma, verrucous carcinoma, or choriocarcinoma.

[0101] 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. When cancer begins in a primary site, e.g., the breast, this site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or primary site acquire the ability to penetrate and invade the surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular system, circulating through the system to other sites and tissues in the body. A second, clinically detectable tumor formed from cancer cells of the primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are assumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor in the breast site will consist of abnormal lung cells and not abnormal breast cells. A secondary tumor in the breast will be referred to as metastatic lung cancer. Therefore, the term metastatic cancer refers to the disease that the subject has or has had in the past primary tumor, and has one or more secondary tumors.The term non-metastatic cancer or the subject with non-metastatic cancer refers to the disease that the subject has primary tumor, but does not have one or more secondary tumors.For example, metastatic lung cancer refers to the disease that the subject has or has a history of primary lung tumor, and has one or more secondary tumors at second location or multiple locations, for example, in breast.

[0102] 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" or "associated with" 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 described as associated with a disease may be a target for disease treatment if it is a causative agent. 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-associated disease (e.g., cancer, an inflammatory disease, an autoimmune disease, or an infectious disease) associated with ROR2 activity or function may 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 can be treated with ROR2 modulators or ROR2 inhibitors, where increased ROR2 activity or function (e.g., signal transduction pathway activity) causes the disease.

[0103] 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 transmit a change in one component to one or more other components, which in turn may transmit changes to additional components, which are optionally propagated to other signaling pathway components.

[0104] The term "abnormal" as used herein refers to being different from normal. When used to describe enzyme activity, abnormal refers to activity that is greater than or less than the average of normal control or normal non-disease control samples. Abnormal activity can refer to the amount of activity that causes disease, and restoring the abnormal activity to normal or non-disease-related amounts (for example, by using the methods described herein) results in the reduction of disease or one or more disease symptoms.

[0105] A "therapeutic agent" referred to herein is a composition useful for treating or preventing a disease such as cancer (e.g., leukemia). In embodiments, the therapeutic agent is an anti-cancer agent. "Anticancer agent" is used according to its 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.

[0106] As used herein, "anti-cancer agent" refers to a molecule (e.g., a compound, peptide, protein, nucleic acid, etc.) used to treat cancer through the destruction or inhibition of cancer cells or tissues. Anti-cancer agents may be selective for a particular cancer or a particular tissue. "Anti-cancer agent" and "anti-cancer agent" are used according to their plain and ordinary meaning and 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 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 drugs 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, thiotepa, nitrosoureas, nitrogen mustard). (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meifaran), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomciten, semustine, streptozocin), triazenes (decarbazine)), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinoma, etc.), isin, 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, cin, bleomycin), enzymes (e.g., L-asparaginase), 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), gossyfol, genasense, polyphenol E, chlorofusin, aubergine, 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, BAY 11-7082, 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, dorsal dorsal morphogenetic protein-1, antiandrogen, prostate cancer, antiestrogen, antineoplastic agent, antisense oligonucleotide, aphidicolin glycinate, apoptosis gene modulator, apoptosis regulator, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, Azatoxins, azatyrosine, baccatin III derivatives, balanol, batimastat, BCR / ABL antagonists, benzochlorins, benzoylstaurosporine, beta-lactam derivatives, beta-arretin, betaclamycin B, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistrene A, bizelesin, brefulate, bropirimine, budotitanium, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamido-amino-triazoles, carboxyamidotriazoles, CaRest M3, CARN 700, cartilage-derived inhibitor, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, clorins, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analogue, clotrimazole, colismycin A, colismycin B, combretastatin A4, combretastatin analogue, conagenin, clambecidin 816, cristathol, cryptophycin 8 , cryptophycin A derivatives, curacin A, cyclopentanethraquinone, cycloplatam, sipemycin, cytarabine ocfosfate, cytolytic factors, cytostatin, dacliximab, decitabine, dehydrodydemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, 9-dioxamycin,Diphenylspiromustine, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabi methadone, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, fluorodaunorubicin hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylenebisacetamide bisacetamide), hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iobenguane, iododoxorubicin, ipomeanol, 4-, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, leprosy Trozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogues, lipophilic disaccharide peptides, lipophilic platinum compounds, lysocrine amide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalone,Meterelin, methioninase, metoclopramide, MIF inhibitors, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogs, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, monoclonal antibodies, human chorionic gonadotropin, monophosphoryl lipid A+ Myobacterium cell wall sk, mopidamol, multidrug resistance gene inhibitors, multiple tumor suppressor 1-based therapeutics, mustard anticancer drugs, mycaperoxide B, Mycobacterium cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidants, nitrulline, O6-benzylguanine, octreotide, oxenone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducers, Ormaplatin, osaterone, oxaliplatin, oxaunomycin, paralaumin, palmitoylrhizoxin, pamidronate, panaxytriol, panomyphen, parabactin, pazelliptin, pegaspargase, perdecin, pentosan polysulfate sodium, pentostatin, pentorozole, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, prasetin A, prasetin B, plasminol Gen activator inhibitors, platinum complexes, platinum compounds, platinum-triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immune modulators, 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 reterliptin, etidronate rhenium Re 186, rhizoxin, ribozyme, RII retinamide, rogletimide, rohitukin, Romurtide, Roquinimex, Rubiginone B1, Ruboxil, Safingol, Saitopine, SarCNU, Sarcophytol A, Sargramostim, Sdi 1 mimetic, Semustine, Senescence-derived inhibitor 1, Sense oligonucleotide, Signal transduction inhibitor, Signal transduction modulator, Single-chain antigen binding protein, Sizofuran, Sobuzoxane, Borocaptate sodium, Sodium phenylacetate, Soberol, Somatomedin binding protein, Sonermin, Sparfosic acid, Spicamycin D, Spiromustine, Splenopentin, Spongestatin 1, Squalamine, Stem cell inhibitor, Stem cell division inhibitor, Stipiamide, Stromelysin inhibitor, Sulfinosine, Hyperactivator vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, saliblastine, thiocoraline, thrombopoietin, thrombopoietin mimetics, thymalfasin, thymopoietin receptor Receptor agonists, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurpurin, tirapazamine, titanocene bichloride, 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 system, red blood cell gene therapy drug, Veraresol, Veramine, Verdins, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, zinostatin stimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, amethantrone acetate,Aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cladribine, mesilate Crisnatol acid, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziconazole, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropizine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etorubicin Tanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, foskidone, phosphotriesin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, iimofosine, interleukin I1 (including recombinant interleukin II, or rlL.sub.2), interferon alpha-2a, interferon alpha-2b, interferon Interferon alfa-nl, interferon alfa-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, mitodilline, mitomarcin, mitomycin, mitospar, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazoie, nogalamycin, ormaplatin, oxisuran, pegaspargase, periomycin, pentamstine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride Isin, pyrazofurin, ribopurin, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparphosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teroxantrone hydrochloride, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, Triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tuburozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglisinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrocidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride, agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., T axol™ (i.e., 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),Spongestants (e.g., spongiostatin 1, spongiostatin 2, spongiostatin 3, spongiostatin 4, spongiostatin 5, spongiostatin 6, spongiostatin 7, spongiostatin 8, and spongiostatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., dEpoA), epothilone D (i.e., KOS-862, dEpoB, and dEpoB), 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., dsoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-457 ... 78 (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 (i.e., 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), vitilevuamide, tubulysin A, canadensol, centaureydin (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 Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (cytoskeleton / Mt. Sinai School of Medicine) Medicine, i.e., MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), monsatrol, inanosin (i.e., NSC-698666), 3-IAABE (cytoskeleton / Mt. Sinai School of Medicine, i.e., MF-191). Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), eleutherobin (such as desmethyleleutherobin, desacetyleleutherobin, isoeluterobin A, and Z-eleutherobin), caribeoside, caribeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), taccalonolide A,TUB-245 (Aventis), A-259754 (Abbott), diozostatin, (-)-phenylahisteine ​​(i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), myoseverin B, D-43411 (Z, 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), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institute) Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to IFN-γ, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitum Mab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OS These include, but are not limited to, I-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, and dasatinib.

[0107] 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 obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, partial or complete alleviation or amelioration of one or more symptoms or conditions, reduction in the severity of a condition, disorder, or disease, stabilization of the condition, disorder, or disease state, prevention of the onset of a condition, disorder, or disease, prevention of the spread of a condition, disorder, or disease, delay or slowing of the progression of a condition, disorder, or disease, delay or slowing of the onset of a condition, disorder, or disease, improvement or palliation of the condition, disorder, or disease state, and remission. "Treating" can also mean extending the survival of a subject beyond that expected in the absence of treatment. "Treating" can also mean inhibiting the progression of a condition, disorder, or disease, or temporarily slowing the progression of a condition, disorder, or disease, although in some cases, it involves permanently halting the progression of a condition, disorder, or disease. As used herein, the terms "treatment," "treat," or "treating" refer to a method of reducing the effects of one or more symptoms of a disease or condition characterized by the expression of a protease, or a method of reducing the symptoms of a disease or condition characterized by the expression of a protease. 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 symptom of a disease or condition. For example, a method for treating a disease is considered therapeutic if one or more symptoms of the disease are reduced by 10% in a subject compared to a control. Thus, the reduction can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percentage reduction between 10% and 100% compared to the native or control level. It is understood that treatment does not necessarily refer to a cure or complete elimination of the disease, condition, or symptoms of the disease or condition.Furthermore, as used herein, references to decrease, reduction, or inhibition include changes of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to control levels, and such terms can include, but do not necessarily include, complete elimination.

[0108] The terms "dose" and "dosage" are used interchangeably herein. Dose refers to the amount of active ingredient given to an individual in each administration. Dosage will vary depending on many factors, including the usual dosage range for a given treatment, the frequency of administration, the size and tolerance of the individual, the severity of the condition, the risk of side effects, and the route of administration. Those skilled in the art will recognize that dosages can be modified depending on the above factors or based on the progress of treatment. The term "dosage form" refers to the specific format of a pharmaceutical or pharmaceutical composition and depends on the route of administration. For example, the dosage form may be a liquid form for spraying, for example, for an inhaler, a tablet or liquid for oral delivery, or a saline solution for injection, for example.

[0109] As used herein, "therapeutically effective dose or amount" refers to a dose that produces the effect for which it is administered (e.g., treatment or prevention of a disease). The exact dose and formulation depend on the purpose of treatment and can be ascertained by those 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 will exhibit an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness can also be expressed as an increase or decrease of "-fold." For example, a therapeutically effective amount may 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 may improve one or more symptoms of a disease. A therapeutically effective dose or amount may prevent or delay the onset of a disease or one or more symptoms of a disease when administered to a person at risk of developing the disease.

[0110] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, to a subject. Administration can 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 administration. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administering" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, such as cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds (two or more compounds) individually or in combination.Thus, the preparation can also be combined with other active substances if desired (for example, to reduce metabolic degradation).The composition of the present invention can be delivered transdermally by topical route and can be formulated as applicator stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, paint, powder and aerosol.

[0111] The compositions of the present invention may further comprise ingredients to provide sustained release and / or comfort. Such ingredients include high molecular weight, anionic mucus-mimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices. These ingredients are discussed in more detail in U.S. Pat. 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 may also be delivered as microspheres for sustained release in the body. For example, microspheres may be delivered by intradermal injection of drug-containing microspheres for sustained release subcutaneously (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 microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In embodiments, formulations of the compositions of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, i.e., by utilizing receptor ligands attached to the liposomes that bind to cell surface membrane protein receptors and cause endocytosis. By using liposomes The compositions of the present invention can be delivered to target cells in vivo, particularly when the liposome surface has receptor ligands specific to the target cells or is otherwise preferentially directed to a particular organ. (See, e.g., 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.

[0112] As used herein, the term "pharmaceutically acceptable" is used interchangeably with "physiologically acceptable" and "pharmacologically acceptable." Pharmaceutical compositions generally include buffering and preservative agents for storage, and may include buffers and carriers for appropriate delivery, depending on the route of administration.

[0113] "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, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oil, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting 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.

[0114] 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, and the like, and, if the molecule contains a basic functional group, to salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.

[0115] The term "preparation" is intended to include the combination of active compound and encapsulating material as a carrier to provide a capsule, in which the active ingredient, with or without other carriers, is surrounded by the carrier and thus associated with it.Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0116] Pharmaceutical preparations are optionally in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, where the package contains individual 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 frozen dispersion.

[0117] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in light thereof 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 incorporated herein by reference in their entirety for all purposes.

[0118] 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 CDR and framework regions of light and heavy chain domains and have been 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, Applicant has characterized amino acid residues within 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 provided herein, including embodiments thereof, can be used for diagnostic and therapeutic purposes in cancer and other ROR2-related diseases. The variable light and variable heavy chain domains provided herein can form part of, among other things, anti-ROR2 chimeric antigen receptors or anti-ROR2 bispecific antibodies. Furthermore, due to their internalization properties, some of the anti-ROR2 antibodies provided herein can be conjugated to therapeutic moieties and used as antibody-drug conjugates (ADCs), or they can be conjugated to detectable moieties and used for diagnostic purposes. The antibodies provided herein, including embodiments thereof, have the ability to inhibit the migration of ROR2-expressing metastatic cells, and thus can reduce the risk of metastasis in patients with ROR2-expressing cancer cells.

[0119] Exemplary anti-ROR2 antibodies provided herein are referred to by clone name (e.g., 6E6, 4G9, 5C11, and 5G3). In embodiments, the anti-ROR2 antibody is antibody 6E6. In embodiments, antibody 6E6 has a heavy chain variable domain of SEQ ID NO: 2 and a light chain variable domain of SEQ ID NO: 4. In embodiments, antibody 6E6 has a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, and CDR H3 set forth in SEQ ID NO: 27, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, and CDR L3 set forth in SEQ ID NO: 30. In embodiments, the anti-ROR2 antibody is antibody 4G9. In embodiments, antibody 4G9 has a heavy chain variable domain of SEQ ID NO: 6 and a light chain variable domain of SEQ ID NO: 8. In an embodiment, antibody 4G9 has a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36. In an embodiment, the anti-ROR2 antibody is antibody 5C11. In an embodiment, antibody 5C11 has a heavy chain variable domain of SEQ ID NO: 10 and a light chain variable domain of SEQ ID NO: 12. In an embodiment, antibody 5C11 has a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, and CDR H3 set forth in SEQ ID NO: 39, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, and CDR L3 set forth in SEQ ID NO: 42. In embodiments, the anti-ROR2 antibody is antibody 5G3. In embodiments, antibody 5G3 has a heavy chain variable domain of SEQ ID NO: 14 and a light chain variable domain of SEQ ID NO: 16.In embodiments, antibody 5G3 has a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48.

[0120] In one aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, and CDR H3 set forth in SEQ ID NO: 27, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, and CDR L3 set forth in SEQ ID NO: 30.

[0121] As described 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, and L3 of an antibody light chain, and FRs L1, L2, L3, and L4 (framework regions). In embodiments, the heavy chain variable (VH) domain comprises CDRs H1, H2, and H3 of an antibody heavy chain, and FRs H1, H2, H3, and H4 (framework regions). 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.

[0122] In embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 2. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 2. In embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 4. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 4.

[0123] In embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 49, FR H2 set forth in SEQ ID NO: 50, FR H3 set forth in SEQ ID NO: 51, and FR H4 set forth in SEQ ID NO: 52. In embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 53, FR L2 set forth in SEQ ID NO: 54, FR L3 set forth in SEQ ID NO: 55, and FR L4 set forth in SEQ ID NO: 56.

[0124] 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 ROR2 protein comprises the amino acid sequence of SEQ ID NO: 18. 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 comprises the amino acid sequence of SEQ ID NO: 22. In embodiments, the extracellular domain is a kringle domain. In embodiments, the kringle domain comprises the amino acid sequence of SEQ ID NO: 113.

[0125] In embodiments, the ROR2 protein comprises a histidine at a position corresponding to position 349 of SEQ ID NO: 22, or an aspartic acid at a position corresponding to position 354. In embodiments, the ROR2 protein comprises a histidine at a position corresponding to position 349 of SEQ ID NO: 22, and an aspartic acid at a position corresponding to position 354. In embodiments, the ROR2 protein comprises a histidine at a position corresponding to position 349 of SEQ ID NO: 18, or an aspartic acid at a position corresponding to position 354. In embodiments, the ROR2 protein comprises a histidine at a position corresponding to position 349 of SEQ ID NO: 18, and an aspartic acid at a position corresponding to position 354.

[0126] In embodiments, the antibody does not bind to arginine at a position corresponding to position 349 of SEQ ID NO: 20. In embodiments, the antibody does not bind to glutamic acid at a position corresponding to position 354 of SEQ ID NO: 20. In embodiments, the antibody does not bind to arginine at a position corresponding to position 349 of SEQ ID NO: 24. In embodiments, the antibody does not bind to glutamic acid at a position corresponding to position 354 of SEQ ID NO: 24.

[0127] The ability of an antibody to bind to a particular epitope (e.g., ROR2 protein, the Kringle domain or the Ig-like domain of ROR2) is determined by the equilibrium dissociation constant (K D ) can be described by the equilibrium dissociation constant (K D ) is the ratio of the dissociation rate (K-off) to the association rate (K-on) of an antibody against the ROR2 protein. It is described by the following equation: K D =K-off / K-on

[0128] In embodiments, the antibody has an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.3 nM to 10 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.9 nM to 1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K D In embodiments, the antibody binds to the ROR2 protein with a K of 1.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.9 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K DIn embodiments, the antibody binds to the ROR2 protein with a K of 2.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.9 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K D In embodiments, the antibody binds to the ROR2 protein with a K of 4.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.9 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K DIn embodiments, the antibody binds to the ROR2 protein with a K D In embodiments, the antibody binds to the ROR2 protein with a K of 5.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5.9 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K D In embodiments, the antibody binds to the ROR2 protein with a K of 6.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6.9 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7 nM to 10 nM. DIn embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K D In embodiments, the antibody binds to the ROR2 protein with a K of 7.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7.9 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K D In embodiments, the antibody binds to the ROR2 protein with a K of 8.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8.9 nM to 10 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 9 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with an equilibrium dissociation constant (K D In embodiments, the antibody binds to the ROR2 protein with a K D In embodiments, the antibody binds to the ROR2 protein with a K of 9.3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 9.4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 9.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 9.6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 9.7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 9.8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 9.9 nM to 10 nM. D It binds to the ROR2 protein.

[0129] In embodiments, the antibody has a K of 0.01 nM to 9.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.2 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.4 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.6 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.8 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 2 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 1.1 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 0.1 nM. D It binds to the ROR2 protein.

[0130] In embodiments, the antibody is 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 5.48, 5.49, 5.50, 5.51, 5.52 a K of 0.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10 nM D It binds to the ROR2 protein.

[0131] In embodiments, the antibody has a K of about 0.06 nM. D In an embodiment, the antibody is antibody 6E6, which binds to the ROR2 protein with a K of 0.01 nM to 10 nM. D In embodiments, antibody 6E6 binds to ROR2 protein with a K of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM. D In an embodiment, the antibody is antibody 6E6, which binds to the ROR2 protein with a K of 0.06 nM. D It binds to the ROR2 protein.

[0132] 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.

[0133] In one embodiment, the antibody has a heavy chain variable domain of SEQ ID NO: 2 and a light chain variable domain of SEQ ID NO: 4. In one embodiment, the antibody comprises (i) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, CDR H3 set forth in SEQ ID NO: 27, FR H1 set forth in SEQ ID NO: 49, FR H2 set forth in SEQ ID NO: 50, FR H3 set forth in SEQ ID NO: 51, and FR H4 set forth in SEQ ID NO: 52, and (ii) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, CDR L3 set forth in SEQ ID NO: 30, FR L1 set forth in SEQ ID NO: 53, FR L2 set forth in SEQ ID NO: 54, FR L3 set forth in SEQ ID NO: 55, and FR L4 set forth in SEQ ID NO: 56. In a further embodiment, the antibody is antibody 6E6.

[0134] In one aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36.

[0135] In embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 6. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 6. In embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 8. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 8.

[0136] In embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 57, FR H2 set forth in SEQ ID NO: 58, FR H3 set forth in SEQ ID NO: 59, and FR H4 set forth in SEQ ID NO: 60. In embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 61, FR L2 set forth in SEQ ID NO: 62, FR L3 set forth in SEQ ID NO: 63, and FR L4 set forth in SEQ ID NO: 64.

[0137] 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 ROR2 protein comprises the amino acid sequence of SEQ ID NO: 18. 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 comprises the amino acid sequence of SEQ ID NO: 22. In embodiments, the extracellular domain is an Ig-like domain. In embodiments, the Ig-like domain comprises the amino acid sequence of SEQ ID NO: 114.

[0138] In embodiments, the ROR2 protein comprises a methionine at a position corresponding to position 386 of SEQ ID NO: 22. In embodiments, the ROR2 protein comprises a methionine at a position corresponding to position 386 of SEQ ID NO: 18.

[0139] In embodiments, the antibody does not bind to a valine at a position corresponding to position 349 of SEQ ID NO: 20. In embodiments, the antibody does not bind to a valine at a position corresponding to position 349 of SEQ ID NO:24.

[0140] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 0.6 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.4 nM to 5 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 1.8 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.2 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.6 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 3 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 3.4 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 3.8 nM to 3.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.2 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.6 nM to 5 nM. D It binds to the ROR2 protein.

[0141] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 4.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 3.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 3.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 2.6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 2.2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 1.8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 1.4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 1 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.2 nM to 0.6 nM. D It binds to the ROR2 protein.

[0142] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 0.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 1.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 2.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 3 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 3.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 4.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 5.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 6.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 7.5 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8 nM to 10 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 8.5 nM to 10 nM.D In embodiments, the antibody binds to the ROR2 protein with a K of 9 nM to 10 nM. D It binds to the ROR2 protein.

[0143] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 9 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 8.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 8 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 7.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 7 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 6.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 6 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 5.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 4.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 4 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 3.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 3 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 2.5 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 2 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 1.5 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.1 nM to 1 nM. D It binds to the ROR2 protein.

[0144] In embodiments, the antibody has an a K of 0.1, 0.4, 0.8, 1.2, 1.6, 2, 2.4, 2.8, 3.2, 3.6, 4, 4.4, 4.8, 5.2, 5.6, 6, 6.4, 6.8, 7.2, 7.6, 8, 8.4, 8.8, 9.2, 9.6, or 10 nM. D It binds to the ROR2 protein.

[0145] In embodiments, the antibody has a K of about 1.9 nM D In an embodiment, the antibody is antibody 4G9, which binds to the ROR2 protein with a K of 0.1 nM to 10 nM. D In embodiments, antibody 4G9 binds to ROR2 protein with a K of 0.1, 0.4, 0.8, 1.2, 1.6, 2, 2.4, 2.8, 3.2, 3.6, 4, 4.4, 4.8, 5.2, 5.6, 6, 6.4, 6.8, 7.2, 7.6, 8, 8.4, 8.8, 9.2, 9.6, or 10 nM. D In an embodiment, the antibody is antibody 4G9, which binds to the ROR2 protein with a K D It binds to the ROR2 protein.

[0146] 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.

[0147] In one embodiment, the antibody has a heavy chain variable domain of SEQ ID NO: 6 and a light chain variable domain of SEQ ID NO: 8. In one embodiment, the antibody comprises (i) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, CDR H3 set forth in SEQ ID NO: 33, FR H1 set forth in SEQ ID NO: 57, FR H2 set forth in SEQ ID NO: 58, FR H3 set forth in SEQ ID NO: 59, and FR H4 set forth in SEQ ID NO: 60, and (ii) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, CDR L3 set forth in SEQ ID NO: 36, FR L1 set forth in SEQ ID NO: 61, FR L2 set forth in SEQ ID NO: 62, FR L3 set forth in SEQ ID NO: 63, and FR L4 set forth in SEQ ID NO: 64. In a further embodiment, the antibody is antibody 4G9.

[0148] In one aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, and CDR H3 set forth in SEQ ID NO: 39, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, and CDR L3 set forth in SEQ ID NO: 42.

[0149] In embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 10. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 10. In embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 12. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 12.

[0150] In embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 65, FR H2 set forth in SEQ ID NO: 66, FR H3 set forth in SEQ ID NO: 67, and FR H4 set forth in SEQ ID NO: 68. In embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 69, FR L2 set forth in SEQ ID NO: 70, FR L3 set forth in SEQ ID NO: 71, and FR L4 set forth in SEQ ID NO: 72.

[0151] 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 ROR2 protein comprises the amino acid sequence of SEQ ID NO: 18. 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 comprises the amino acid sequence of SEQ ID NO: 22. In embodiments, the extracellular domain is a kringle domain. In embodiments, the kringle domain comprises the amino acid sequence of SEQ ID NO: 113.

[0152] In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 22, an aspartic acid at the position corresponding to position 354, or a methionine at the position corresponding to position 386. In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 22, an aspartic acid at the position corresponding to position 354, and a methionine at the position corresponding to position 386. In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 18, an aspartic acid at the position corresponding to position 354, or a methionine at the position corresponding to position 386. In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 18, an aspartic acid at the position corresponding to position 354, and a methionine at the position corresponding to position 386.

[0153] In embodiments, the antibody does not bind to arginine at a position corresponding to position 349 of SEQ ID NO: 20. In embodiments, the antibody does not bind to glutamic acid at a position corresponding to position 354 of SEQ ID NO: 20. In embodiments, the antibody does not bind to valine at a position corresponding to position 386 of SEQ ID NO: 20. In embodiments, the antibody does not bind to arginine at a position corresponding to position 349 of SEQ ID NO: 24. In embodiments, the antibody does not bind to glutamic acid at a position corresponding to position 354 of SEQ ID NO: 24. In embodiments, the antibody does not bind to valine at a position corresponding to position 386 of SEQ ID NO: 24.

[0154] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 20 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 30 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 40 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 50 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 60 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 70 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 80 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 90 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 100 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 110 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 120 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 130 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 140 nM to 150 nM.D It binds to the ROR2 protein.

[0155] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 130 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 120 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 110 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 100 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 90 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 80 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 70 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 60 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 50 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 40 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 30 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 20 nM. D In embodiments, the antibody binds to the ROR2 protein with an a K of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nM. D It binds to the ROR2 protein.

[0156] In embodiments, the antibody is 5C11 and has a K of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nM. D It binds to the ROR2 protein.

[0157] 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.

[0158] In one embodiment, the antibody has a heavy chain variable domain of SEQ ID NO: 10 and a light chain variable domain of SEQ ID NO: 12. In one embodiment, the antibody comprises (i) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, CDR H3 set forth in SEQ ID NO: 39, FR H1 set forth in SEQ ID NO: 65, FR H2 set forth in SEQ ID NO: 66, FR H3 set forth in SEQ ID NO: 67, and FR H4 set forth in SEQ ID NO: 68, and (ii) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, CDR L3 set forth in SEQ ID NO: 42, FR L1 set forth in SEQ ID NO: 69, FR L2 set forth in SEQ ID NO: 70, FR L3 set forth in SEQ ID NO: 71, and FR L4 set forth in SEQ ID NO: 72. In a further embodiment, the antibody is antibody 5C11.

[0159] In one aspect, there is provided an anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48.

[0160] In embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 14. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 14. In embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 16. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 16.

[0161] In embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 73, FR H2 set forth in SEQ ID NO: 74, FR H3 set forth in SEQ ID NO: 75, and FR H4 set forth in SEQ ID NO: 76. In embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 77, FR L2 set forth in SEQ ID NO: 78, FR L3 set forth in SEQ ID NO: 79, and FR L4 set forth in SEQ ID NO: 80.

[0162] 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 ROR2 protein comprises the amino acid sequence of SEQ ID NO: 18. 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 comprises the amino acid sequence of SEQ ID NO: 22. In embodiments, the extracellular domain is an Ig-like domain. In embodiments, the Ig-like domain comprises the amino acid sequence of SEQ ID NO: 114.

[0163] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 20 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 30 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 40 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 50 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 60 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 70 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 80 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 90 nM to 150 nM.D In embodiments, the antibody binds to the ROR2 protein with a K of 100 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 110 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 120 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 130 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 140 nM to 150 nM. D It binds to the ROR2 protein.

[0164] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 130 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 120 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 110 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 100 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 90 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 80 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 70 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 60 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 50 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 40 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 30 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 20 nM. DIn embodiments, the antibody binds to the ROR2 protein with an a K of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nM. D It binds to the ROR2 protein.

[0165] In embodiments, the antibody is 5G3 and has a K of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nM. D It binds to the ROR2 protein.

[0166] 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.

[0167] In one embodiment, the antibody has a heavy chain variable domain of SEQ ID NO: 14 and a light chain variable domain of SEQ ID NO: 16. In one embodiment, the antibody comprises (i) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, CDR H3 set forth in SEQ ID NO: 45, FR H1 set forth in SEQ ID NO: 73, FR H2 set forth in SEQ ID NO: 74, FR H3 set forth in SEQ ID NO: 75, and FR H4 set forth in SEQ ID NO: 76, and (ii) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, CDR L3 set forth in SEQ ID NO: 48, FR L1 set forth in SEQ ID NO: 77, FR L2 set forth in SEQ ID NO: 78, FR L3 set forth in SEQ ID NO: 79, and FR L4 set forth in SEQ ID NO: 80. In a further embodiment, the antibody is antibody 5G3.

[0168] An antibody provided herein, including embodiments thereof (e.g., antibody 6e6, 4G9, 5C11, or 5G3), may be a humanized antibody. 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.

[0169] In embodiments, the antibody does not bind to mouse ROR2 protein. In embodiments, the antibody does not bind to 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: 20. In embodiments, the antibody provided herein does not bind to a protein comprising the amino acid sequence of SEQ ID NO: 24. In embodiments, the antibody provided herein does not bind to the protein of SEQ ID NO: 20 or SEQ ID NO: 24. In embodiments, the antibody provided herein does not bind to the protein of SEQ ID NO: 20. In embodiments, the antibody provided herein does not bind to the protein of SEQ ID NO: 24.

[0170] In one aspect, a ROR2 protein bound by an antibody provided herein, including embodiments thereof (e.g., antibody 6e6, 4G9, 5C11, or 5G3), is provided, which may be 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 cells are bone cancer cells, in embodiments, the cancer cells are skin cancer cells, in embodiments, the cancer cells are prostate cancer cells.

[0171] In embodiments, the antibodies provided herein (e.g., antibodies 6E6, 4G9, 5C11, or 5G3) do not bind to ROR2-negative cells. "ROR2-negative cells" provided herein are cells that do not express detectable amounts of ROR2 protein relative to a standard control. In embodiments, the expression level of ROR2-negative cells is undetectable using conventional methods 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, 500, 100, 50, 25, 20, 10, 5, or 1.5 times lower than the expression level of a standard control (e.g., a detectable level of cellular expression of ROR2 using conventional methods). Non-limiting examples of ROR2-negative cells include peripheral blood mononuclear cells (PBMCs) from a healthy subject.

[0172] Either the variable light chain domain or the variable heavy chain of an antibody provided herein can form part of an scFv. Thus, in embodiments, the antibody is a single-chain antibody (scFv). In embodiments, the light chain variable domain and the heavy chain variable domain form part of the scFv. In embodiments, a linker forms part of the scFv. In embodiments, the linker comprises the sequence of SEQ ID NO: 82. In embodiments, a leader peptide forms part of the scFv. In embodiments, the leader peptide comprises the sequence of SEQ ID NO: 81. In embodiments, the scFv further comprises a heavy chain constant region (CH2-CH3). In embodiments, the heavy chain constant region comprises the sequence of SEQ ID NO: 84.

[0173] In an embodiment, the scFv comprises the sequence of SEQ ID NO: 85. In an embodiment, the scFv is the sequence of SEQ ID NO: 85.

[0174] In embodiments, the scFv has an equilibrium dissociation constant (K D In embodiments, the scFv binds to the ROR2 protein with a K of 0.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.9 nM to 1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1 nM to 10 nM.D In embodiments, the scFv binds to the ROR2 protein with a K of 1.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 2.8 nM to 10 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 2.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 3.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.6 nM to 10 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 4.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 4.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 5.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.4 nM to 10 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 6.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 6.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 7.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.2 nM to 10 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 8.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 8.9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.1 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.2 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.3 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.4 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.5 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.6 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.7 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.8 nM to 10 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 9.9 nM to 10 nM. D It binds to the ROR2 protein.

[0175] In embodiments, the scFv has a K of 0.01 nM to 9.9 nM.D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.2 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.4 nM.D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.7 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.9 nM.D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.2 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 1.1 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.9 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.8 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.7 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.6 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.5 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.4 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.3 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.2 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 0.01 nM to 0.1 nM. D It binds to the ROR2 protein.

[0176] In embodiments, the scFv is 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, a K of 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10 nM D It binds to the ROR2 protein.

[0177] In embodiments, the scFv has a K of about 0.07 nM D In an embodiment, the scFv is 6E6 scFv and binds to the ROR2 protein with a K of 0.01 nM to 10 nM. D In embodiments, the 6E6 scFv binds to the ROR2 protein with a K of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM. D In an embodiment, the scFv is 6E6 scFv and binds to the ROR2 protein with a K of 0.07 nM. D It binds to the ROR2 protein.

[0178] In one embodiment, the scFv comprises, from N- to C-terminus, a leader peptide of SEQ ID NO: 81, a light chain variable domain of SEQ ID NO: 4, a linker domain of SEQ ID NO: 82, a heavy chain variable domain of SEQ ID NO: 2, a spacer of SEQ ID NO: 83, and a constant heavy chain domain (CH2-CH3) of SEQ ID NO: 84. In a further embodiment, the scFv is a 6E6 scFv.

[0179] In an embodiment, the scFv comprises the sequence of SEQ ID NO: 86. In an embodiment, the scFv is the sequence of SEQ ID NO: 86.

[0180] In embodiments, the scFv has a K of 0.01 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 20 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 30 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 40 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 50 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 60 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 70 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 80 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 90 nM to 150 nM. D In an embodiment, the scFv binds to the ROR2 protein with a K of 100 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 110 nM to 150 nM. DIn embodiments, the scFv binds to the ROR2 protein with a K of 120 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 130 nM to 150 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 140 nM to 150 nM. D It binds to the ROR2 protein.

[0181] In embodiments, the scFv has a K of 0.01 nM to 140 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 1 nM to 140 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 140 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 130 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 120 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 110 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 100 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 90 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 80 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 70 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 60 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 50 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 40 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 30 nM. D In embodiments, the scFv binds to the ROR2 protein with a K of 10 nM to 20 nM.D In embodiments, the scFv binds to the ROR2 protein with an a K of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nM. D It binds to the ROR2 protein.

[0182] In embodiments, the scFv is a 4G9 scFv and has a K of 0.01, 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nM. D It binds to the ROR2 protein.

[0183] In one embodiment, the scFv comprises, from N- to C-terminus, a leader peptide of SEQ ID NO: 81, a light chain variable domain of SEQ ID NO: 8, a linker domain of SEQ ID NO: 82, a heavy chain variable domain of SEQ ID NO: 6, a spacer of SEQ ID NO: 83, and a constant heavy chain domain (CH2-CH3) of SEQ ID NO: 84. In a further embodiment, the scFv is a 4G9 scFv.

[0184] In embodiments, the scFv is capable of binding to the ROR2 protein. In embodiments, the ROR2 protein is a human ROR2 protein. In embodiments, the scFv binds to the ROR2 protein. In embodiments, the ROR2 protein comprises the amino acid sequence of SEQ ID NO: 18. In embodiments, the scFv is capable of binding to the extracellular domain of the ROR2 protein. In embodiments, the scFv binds to the extracellular domain of the ROR2 protein. In embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 22. In embodiments, the extracellular domain is a kringle domain. In embodiments, the kringle domain comprises the amino acid sequence of SEQ ID NO: 113. In embodiments, the extracellular domain is an Ig-like domain. In embodiments, the Ig-like domain comprises the amino acid sequence of SEQ ID NO: 114.

[0185] In embodiments, the scFv does not bind to mouse ROR2 protein. In embodiments, the scFv does not bind to mouse ROR2 protein identified by UniProt reference number Q9Z138. In embodiments, the scFv provided herein does not bind to a protein comprising the amino acid sequence of SEQ ID NO: 20. In embodiments, the scFv provided herein does not bind to a protein comprising the amino acid sequence of SEQ ID NO: 24. In embodiments, the scFv provided herein does not bind to the protein of SEQ ID NO: 20 or SEQ ID NO: 24. In embodiments, the scFv provided herein does not bind to the protein of SEQ ID NO: 20. In embodiments, the scFv provided herein does not bind to the protein of SEQ ID NO: 24

[0186] In another aspect, an anti-ROR2 antibody is provided. The anti-ROR2 antibody binds to the same epitope as the anti-ROR2 antibody, comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, and CDR H3 set forth in SEQ ID NO: 27, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, and CDR L3 set forth in SEQ ID NO: 30. In embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 2. In embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 4.

[0187] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO:2 and a light chain variable domain of SEQ ID NO:4.

[0188] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 1 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 3.

[0189] In one aspect, an anti-ROR2 antibody is provided. The anti-ROR2 antibody binds to the same epitope as the anti-ROR2 antibody, comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36. In an embodiment, the heavy chain variable domain comprises the sequence of SEQ ID NO: 6. In an embodiment, the light chain variable domain comprises the sequence of SEQ ID NO: 8.

[0190] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO:6 and a light chain variable domain of SEQ ID NO:8.

[0191] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO:5 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO:7.

[0192] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO: 10 and a light chain variable domain of SEQ ID NO: 12.

[0193] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO:9 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO:11.

[0194] In one aspect, an anti-ROR2 antibody is provided. The anti-ROR2 antibody binds to the same epitope as the anti-ROR2 antibody, comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48. In embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 14. In embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 16.

[0195] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain of SEQ ID NO: 14 and a light chain variable domain of SEQ ID NO: 16.

[0196] In one embodiment, an anti-ROR2 antibody is provided that binds to the same epitope as an anti-ROR2 antibody comprising a heavy chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 13 and a light chain variable domain encoded by the nucleic acid sequence of SEQ ID NO: 15.

[0197] 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 ROR2 protein comprises the amino acid sequence of SEQ ID NO: 18. 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 comprises the amino acid sequence of SEQ ID NO: 22. In embodiments, the extracellular domain is a kringle domain. In embodiments, the kringle domain comprises the amino acid sequence of SEQ ID NO: 113. In embodiments, the extracellular domain is an Ig-like domain. In embodiments, the Ig-like domain comprises the amino acid sequence of SEQ ID NO: 114.

[0198] In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 22, an aspartic acid at the position corresponding to position 354, or a methionine at the position corresponding to position 386. In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 22, an aspartic acid at the position corresponding to position 354, and a methionine at the position corresponding to position 386. In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 18, an aspartic acid at the position corresponding to position 354, or a methionine at the position corresponding to position 386. In embodiments, the ROR2 protein comprises a histidine at the position corresponding to position 349 of SEQ ID NO: 18, an aspartic acid at the position corresponding to position 354, and a methionine at the position corresponding to position 386.

[0199] In embodiments, the ROR2 protein comprises a methionine at a position corresponding to position 386 of SEQ ID NO: 22. In embodiments, the ROR2 protein comprises a histidine at a position corresponding to position 349 of SEQ ID NO: 22. In embodiments, the ROR2 protein comprises an aspartic acid at a position corresponding to position 354 of SEQ ID NO: 22. In embodiments, the ROR2 protein comprises a methionine at a position corresponding to position 386 of SEQ ID NO: 18. In embodiments, the ROR2 protein comprises a histidine at a position corresponding to position 349 of SEQ ID NO: 18. In embodiments, the ROR2 protein comprises an aspartic acid at a position corresponding to position 354 of SEQ ID NO: 18.

[0200] 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 ROR2 protein comprises the amino acid sequence of SEQ ID NO: 18. 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 comprises the amino acid sequence of SEQ ID NO: 22. In embodiments, the extracellular domain is an Ig-like domain. In embodiments, the Ig-like domain comprises residues corresponding to positions 79 to 147 of SEQ ID NO: 22.

[0201] 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.

[0202] In embodiments, the antibody has a K D In embodiments, the antibody binds to the ROR2 protein with a K of 1 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 20 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 30 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 40 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 50 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 60 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 70 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 80 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 90 nM to 150 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 100 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 110 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 120 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 130 nM to 150 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 140 nM to 150 nM. D It binds to the ROR2 protein.

[0203] In embodiments, the antibody has a K of 0.01 nM to 140 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 140 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 130 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 120 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 110 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 100 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 90 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 80 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 70 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 60 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 50 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 40 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 30 nM. DIn embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 20 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 10 nM to 20 nM. D In embodiments, the antibody binds to the ROR2 protein with a K of 0.01 nM to 20 nM. D In embodiments, the antibody binds to the ROR2 protein with an a K of 0.01, 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nM. D It binds to the ROR2 protein.

[0204] Antibodies that bind to epitopes provided herein 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.

[0205] In embodiments, the antibody does not bind to mouse ROR2 protein. In embodiments, the antibody does not bind to 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: 20. In embodiments, the antibody provided herein does not bind to a protein comprising the amino acid sequence of SEQ ID NO: 24. In embodiments, the antibody provided herein does not bind to the protein of SEQ ID NO: 20 or SEQ ID NO: 24. In embodiments, the antibody provided herein does not bind to the protein of SEQ ID NO: 20. In embodiments, the antibody provided herein does not bind to the protein of SEQ ID NO: 24.

[0206] In embodiments, the antibody does not bind to arginine at a position corresponding to position 349 of SEQ ID NO: 20. In embodiments, the antibody does not bind to glutamic acid at a position corresponding to position 354 of SEQ ID NO: 20. In embodiments, the antibody does not bind to valine at a position corresponding to position 386 of SEQ ID NO: 20. In embodiments, the antibody does not bind to arginine at a position corresponding to position 349 of SEQ ID NO: 24. In embodiments, the antibody does not bind to glutamic acid at a position corresponding to position 354 of SEQ ID NO: 24. In embodiments, the antibody does not bind to valine at a position corresponding to position 386 of SEQ ID NO: 24.

[0207] 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 relative to a standard control. In embodiments, the expression level of ROR2-negative cells is undetectable using conventional methods 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, 500, 100, 50, 25, 20, 10, 5, or 1.5 times lower than the expression level of a standard control (e.g., a detectable level of cellular expression of ROR2 using conventional methods). Non-limiting examples of ROR2-negative cells include peripheral blood mononuclear cells (PBMCs) from a healthy subject.

[0208] Chimeric Antigen Receptor Protein As described above, the heavy chain variable (VH) domain and light chain variable (VL) domain provided herein, including embodiments thereof, can each independently form part of an antibody, antibody fragment, chimeric antigen receptor, or bispecific antibody. In particular, chimeric antigen receptors and bispecific antibodies are provided herein, which comprise the light chain variable (VL) domain and / or heavy chain variable (VH) domain provided herein and thus can effectively and efficiently bind to human ROR2. The antibody region of a chimeric antigen receptor can comprise any of the light and heavy chain variable domains provided herein, including embodiments thereof. The light chain variable (VL) domain and / or heavy chain variable (VH) domain provided herein can form part of a chimeric antigen receptor. Thus, in one aspect, a chimeric antigen receptor is provided, comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, and CDR L3 set forth in SEQ ID NO: 30; and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, and CDR H3 set forth in SEQ ID NO: 27; and (ii) a transmembrane domain. In one embodiment, the chimeric antigen receptor comprises the light chain variable domain of antibody 6E6 and the heavy chain variable domain of antibody 6E6.

[0209] In another aspect, a chimeric antigen receptor is provided, comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36, and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33; and (ii) a transmembrane domain. In one embodiment, the chimeric antigen receptor comprises the light chain variable domain of antibody 4G9 and the heavy chain variable domain of antibody 4G9.

[0210] In another aspect, a chimeric antigen receptor is provided, comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, and CDR L3 set forth in SEQ ID NO: 42; and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, and CDR H3 set forth in SEQ ID NO: 39; and (ii) a transmembrane domain. In one embodiment, the chimeric antigen receptor comprises the light chain variable domain of antibody 5C11 and the heavy chain variable domain of antibody 5C11.

[0211] In one aspect, a chimeric antigen receptor is provided, comprising: (i) an antibody region comprising: (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48; and (b) a heavy chain variable region domain comprising CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45; and (ii) a transmembrane domain. In one embodiment, the chimeric antigen receptor comprises the light chain variable domain of antibody 5G3 and the heavy chain variable domain of antibody 5G3.

[0212] 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 skilled 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 include 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 conjugate. As provided herein, a "protein conjugate" refers to a construct consisting of more than one polypeptide, wherein the polypeptides are covalently or non-covalently linked together. In embodiments, the polypeptides of the protein conjugate are encoded by a single nucleic acid molecule. In embodiments, the polypeptides of the protein conjugate are encoded by different nucleic acid molecules. In embodiments, the polypeptides are connected via a linker. In embodiments, the polypeptides are connected 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.

[0213] As provided herein, a "transmembrane domain" refers to a polypeptide that forms part of a biological membrane. The transmembrane domains provided herein can span a biological membrane (e.g., a cell membrane) from one side of the membrane through 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 may 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. In embodiments, the transmembrane domain is a CD4 transmembrane domain.

[0214] In embodiments, the transmembrane domain is a CD28 transmembrane domain. As provided herein, the term "CD28 transmembrane domain" includes any recombinant or naturally occurring form of the transmembrane domain of CD28, or a variant or homolog thereof that maintains CD28 transmembrane domain activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring CD28 transmembrane domain peptide. In an embodiment, CD28 is the protein identified by NCBI sequence reference GI:340545506, a homologue or a functional fragment thereof.

[0215] In embodiments, the transmembrane domain is a CD8 transmembrane domain. The term "CD8 transmembrane domain" as provided herein includes any recombinant or naturally occurring form of the transmembrane domain of CD8, or a variant or homolog thereof that maintains CD8 transmembrane domain activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring CD8 transmembrane domain peptide. In embodiments, CD8 is a protein identified by NCBI sequence reference GI:225007534, a homolog, or a functional fragment thereof.

[0216] In embodiments, the transmembrane domain is a CD4 transmembrane domain. The term "CD4 transmembrane domain" as provided herein includes any recombinant or naturally occurring form of the transmembrane domain of CD4, or a variant or homolog thereof that maintains CD4 transmembrane domain activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring CD4 transmembrane domain peptide. In embodiments, CD4 is a protein identified by NCBI sequence reference GI:303522473, a homolog, or a functional fragment thereof.

[0217] In embodiments, the transmembrane domain is a CD3-zeta (also known as CD247) transmembrane domain. As provided herein, the term "CD3-zeta transmembrane domain" includes any recombinant or naturally occurring form of the CD3-zeta transmembrane domain, or a variant or homolog thereof that maintains CD3-zeta transmembrane domain activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the CD3-zeta 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 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring CD3-zeta transmembrane domain peptide. In an embodiment, CD3-zeta is the protein identified by NCBI sequence reference GI:166362721, a homologue or functional fragment thereof.

[0218] 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 binding of an antigen to an antibody region provided herein, including embodiments thereof. In embodiments, signaling by the intracellular T cell signaling domain results in activation of a T cell expressing it. In embodiments, signaling by the intracellular T cell signaling domain results in proliferation (cell division) of a T cell expressing it. In embodiments, signaling by the intracellular T cell signaling domain results in expression by the T cell of proteins known in the art to be characteristic of activated T cells (e.g., CTLA-4, PD-1, CD28, CD69). In embodiments, the intracellular T cell signaling domain is a CD3ζ intracellular T cell signaling domain.

[0219] 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 of the costimulatory signaling domain results in cytokine production and proliferation of T cells expressing it. In embodiments, the intracellular costimulatory signaling domain is a CD28 intracellular costimulatory signaling domain, a 4-1BB intracellular costimulatory signaling domain, an ICOS intracellular costimulatory signaling domain, or an OX-40 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 intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory signaling domain is an ICOS intracellular costimulatory signaling domain. In embodiments, the intracellular costimulatory signaling domain is an OX-40 intracellular costimulatory signaling domain.

[0220] 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 an antibody region with a transmembrane domain. In embodiments, the spacer region connects a heavy chain constant region with a transmembrane domain. In embodiments, the spacer region comprises an Fc region. In embodiments, the spacer region is an Fc region. Examples of 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.

[0221] The term "CTLA-4," as referred to herein, includes any recombinant or naturally occurring form of cytotoxic T-lymphocyte-associated protein 4 protein, also known as CD152 (cluster of differentiation 152), or a variant or homolog thereof that maintains CTLA-4 activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to CTLA-4). 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 50, 100, 150, or 200 contiguous amino acid portion) 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.

[0222] The term "CD28" as referred to herein includes any recombinant or naturally occurring form of cluster of differentiation 28 protein, or a variant or homolog thereof that maintains CD28 activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) 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.

[0223] The term "CD69" as referred to herein includes any recombinant or naturally occurring form of cluster of differentiation 69 protein, or a variant or homolog thereof that maintains CD69 activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) 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.

[0224] The term "4-1BB" as referred to herein includes any recombinant or naturally occurring form of the 4-1BB protein, tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as cluster of differentiation 137 (CD137), induced by lymphocyte activation (ILA), or a variant or homolog thereof that maintains 4-1BB activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring EGFR protein. In embodiments, 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.

[0225] The chimeric antigen receptors provided herein can comprise any of the anti-ROR2 antibodies or fragments thereof described herein. Thus, the chimeric antigen receptors can comprise any of the CDRs, FRs, heavy chain variable domains, or light chain variable domains provided herein. For example, the heavy chain variable domain can comprise the sequence of SEQ ID NO:2, SEQ ID NO:6, SEQ ID NO:10, or SEQ ID NO:14. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:2, SEQ ID NO:6, SEQ ID NO:10, or SEQ ID NO:14. For example, the light chain variable domain can comprise the sequence of SEQ ID NO:4, SEQ ID NO:8, SEQ ID NO:12, or SEQ ID NO:16. In embodiments, the light chain variable domain is the sequence of SEQ ID NO:4, SEQ ID NO:8, SEQ ID NO:12, or SEQ ID NO:16.

[0226] In embodiments, the chimeric antigen receptor further comprises a heavy chain constant domain. In embodiments, the chimeric antigen receptor further comprises a spacer region. In embodiments, the spacer region is between the transmembrane domain and the antibody region. In embodiments, the spacer region further comprises a hinge region. In embodiments, the spacer region comprises the sequence of SEQ ID NO: 94. In embodiments, the spacer region comprises the sequence of SEQ ID NO: 95. In embodiments, the spacer region comprises the sequence of SEQ ID NO: 96.

[0227] In embodiments, the chimeric antigen receptor further comprises a linker domain. In embodiments, the linker domain is between the heavy chain variable domain and the light chain variable domain. In embodiments, the linker domain comprises the sequence of SEQ ID NO: 82. In embodiments, the chimeric antigen receptor further comprises a leader peptide. In embodiments, the leader peptide comprises the sequence of SEQ ID NO: 93.

[0228] In embodiments, the chimeric antigen receptor comprises the sequence of SEQ ID NO: 100. In embodiments, the chimeric antigen receptor is the sequence of SEQ ID NO: 100. In embodiments, the chimeric antigen receptor comprises the sequence of SEQ ID NO: 101. In embodiments, the chimeric antigen receptor is the sequence of SEQ ID NO: 101.

[0229] In one embodiment, the chimeric antigen receptor comprises, from N-terminus to C-terminus, a leader peptide of SEQ ID NO:93, a light chain variable domain of SEQ ID NO:4, a linker domain of SEQ ID NO:82, a heavy chain variable domain of SEQ ID NO:2, a spacer domain of SEQ ID NO:96, a transmembrane domain of SEQ ID NO:97, an intracellular costimulatory signaling domain of SEQ ID NO:98, and an intracellular T cell signaling domain of SEQ ID NO:99.

[0230] In one embodiment, the protein comprises, from N-terminus to C-terminus, a leader peptide of SEQ ID NO:93, a light chain variable domain of SEQ ID NO:8, a linker domain of SEQ ID NO:82, a heavy chain variable domain of SEQ ID NO:6, a spacer domain of SEQ ID NO:96, a transmembrane domain of SEQ ID NO:97, an intracellular costimulatory signaling domain of SEQ ID NO:98, and an intracellular T cell signaling domain of SEQ ID NO:99.

[0231] bispecific antibody The light chain variable (VL) domain and heavy chain variable (VH) domain provided herein can form part of a bispecific antibody. Thus, the second antibody region can comprise any of the light chain and / or heavy chain variable domains provided herein, including embodiments thereof.

[0232] Thus, in another aspect, there is provided a bispecific antibody comprising: (i) a first antibody region capable of binding to an effector cell ligand; and (ii) a second antibody region comprising: (a) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO:25, CDR H2 set forth in SEQ ID NO:26, and CDR H3 set forth in SEQ ID NO:27; and (b) CDR L1 set forth in SEQ ID NO:28, CDR L2 set forth in SEQ ID NO:29, and CDR L3 set forth in SEQ ID NO:30.

[0233] In another aspect, there is provided a bispecific antibody comprising: (i) a first antibody region capable of binding to an effector cell ligand; and (ii) a second antibody region comprising: (a) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 31, CDR H2 set forth in SEQ ID NO: 32, and CDR H3 set forth in SEQ ID NO: 33; and (b) CDR L1 set forth in SEQ ID NO: 34, CDR L2 set forth in SEQ ID NO: 35, and CDR L3 set forth in SEQ ID NO: 36.

[0234] In another aspect, there is provided a bispecific antibody comprising: (i) a first antibody region capable of binding to an effector cell ligand; and (ii) a second antibody region comprising: (a) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 37, CDR H2 set forth in SEQ ID NO: 38, and CDR H3 set forth in SEQ ID NO: 39; and (b) CDR L1 set forth in SEQ ID NO: 40, CDR L2 set forth in SEQ ID NO: 41, and CDR L3 set forth in SEQ ID NO: 42.

[0235] In another aspect, there is provided a bispecific antibody comprising: (i) a first antibody region capable of binding to an effector cell ligand; and (ii) a second antibody region comprising: (a) a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 43, CDR H2 set forth in SEQ ID NO: 44, and CDR H3 set forth in SEQ ID NO: 45; and (b) CDR L1 set forth in SEQ ID NO: 46, CDR L2 set forth in SEQ ID NO: 47, and CDR L3 set forth in SEQ ID NO: 48.

[0236] The term "effector cell ligand" provided herein refers to a cell surface molecule expressed on an effector cell 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 other unhealthy cells). In an embodiment, the effector cell ligand is a CD3 protein. In an embodiment, the effector cell ligand is a CD16 protein. In an embodiment, the effector cell ligand is a CD32 protein. In an embodiment, the effector cell ligand is an NKp46 protein. The first antibody region provided herein can be an antibody, an antibody variant, a fragment of an antibody, or a fragment of an antibody variant.

[0237] As referred to herein, a "CD3 protein" includes any 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% 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 50, 100, 150, or 200 contiguous amino acid portion) compared to the naturally occurring CD3 protein in the CD3 complex.

[0238] As referred to herein, a "CD16 protein" includes any 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 the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to CD16). 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 50, 100, 150, or 200 contiguous amino acid portion) 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 homologue having substantial identity thereto.

[0239] As referred to herein, a "CD32 protein" includes any recombinant or naturally occurring form of cluster of differentiation 32 (CD32) protein, also known as low-affinity immunoglobulin gamma Fc-region receptor II-A, or a variant or homolog thereof that maintains CD32 activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to CD32). In some embodiments, a 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 50, 100, 150, or 200 contiguous amino acid portion) 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 homologue having substantial identity thereto.

[0240] As referred to herein, "NKp46 protein" includes any recombinant or naturally occurring form of the NKp46 protein, also known as native cytotoxicity triggering receptor 1, or a variant or homolog thereof that maintains NKp46 activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% 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 50, 100, 150, or 200 contiguous amino acid portion) 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.

[0241] The bispecific antibodies provided herein may comprise any of the ROR2 antibodies or fragments thereof described herein. Accordingly, the second antibody region may comprise any of the CDRs, FRs, heavy chain variable domains, or light chain variable domains provided herein. In embodiments, the second antibody region comprises a heavy chain variable domain comprising the sequence of SEQ ID NO:2. In embodiments, the second antibody region comprises a light chain variable domain comprising the sequence of SEQ ID NO:4. In embodiments, the second antibody region comprises a heavy chain variable domain having the sequence of SEQ ID NO:2. In embodiments, the second antibody region comprises a light chain variable domain having the sequence of SEQ ID NO:4.

[0242] Thus, the heavy chain variable domain of the second antibody region may comprise, for example, FR H1 set forth in SEQ ID NO: 49, FR H2 set forth in SEQ ID NO: 50, FR H3 set forth in SEQ ID NO: 51, and FR H4 set forth in SEQ ID NO: 52. The light chain variable domain of the second antibody region a may comprise any of the CDRs or FRs provided herein. For example, the light chain variable domain may comprise, for example, FR L1 set forth in SEQ ID NO: 53, FR L2 set forth in SEQ ID NO: 54, FR L3 set forth in SEQ ID NO: 55, and FR L4 set forth in SEQ ID NO: 56.

[0243] In embodiments, the second antibody region comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 6. In embodiments, the second antibody region comprises a light chain variable domain comprising the sequence of SEQ ID NO: 8. In embodiments, the second antibody region comprises a heavy chain variable domain having the sequence of SEQ ID NO: 6. In embodiments, the second antibody region comprises a light chain variable domain having the sequence of SEQ ID NO: 8.

[0244] The heavy chain variable domain of the second antibody region can comprise, for example, FR H1 set forth in SEQ ID NO: 57, FR H2 set forth in SEQ ID NO: 58, FR H3 set forth in SEQ ID NO: 59, and FR H4 set forth in SEQ ID NO: 60. The light chain variable domain of the bispecific antibodies provided herein can comprise, for example, FR L1 set forth in SEQ ID NO: 61, FR L2 set forth in SEQ ID NO: 62, FR L3 set forth in SEQ ID NO: 63, and FR L4 set forth in SEQ ID NO: 64.

[0245] In embodiments, the second antibody region comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 10. In embodiments, the second antibody region comprises a light chain variable domain comprising the sequence of SEQ ID NO: 12. In embodiments, the second antibody region comprises a heavy chain variable domain having the sequence of SEQ ID NO: 10. In embodiments, the second antibody region comprises a light chain variable domain having the sequence of SEQ ID NO: 12.

[0246] The heavy chain variable domain of the second antibody region can comprise, for example, FR H1 set forth in SEQ ID NO: 65, FR H2 set forth in SEQ ID NO: 66, FR H3 set forth in SEQ ID NO: 67, and FR H4 set forth in SEQ ID NO: 68. The light chain variable domain of the bispecific antibodies provided herein can comprise, for example, FR L1 set forth in SEQ ID NO: 69, FR L2 set forth in SEQ ID NO: 70, FR L3 set forth in SEQ ID NO: 71, and FR L4 set forth in SEQ ID NO: 72.

[0247] In embodiments, the second antibody region comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 14. In embodiments, the second antibody region comprises a light chain variable domain comprising the sequence of SEQ ID NO: 16. In embodiments, the second antibody region comprises a heavy chain variable domain having the sequence of SEQ ID NO: 14. In embodiments, the second antibody region comprises a light chain variable domain having the sequence of SEQ ID NO: 16.

[0248] The heavy chain variable domain of the second antibody region can comprise, for example, FR H1 set forth in SEQ ID NO: 73, FR H2 set forth in SEQ ID NO: 74, FR H3 set forth in SEQ ID NO: 75, and FR H4 set forth in SEQ ID NO: 76. The light chain variable domain of the bispecific antibodies provided herein can comprise, for example, FR L1 set forth in SEQ ID NO: 77, FR L2 set forth in SEQ ID NO: 78, FR L3 set forth in SEQ ID NO: 79, and FR L4 set forth in SEQ ID NO: 80.

[0249] In embodiments, the first antibody region is a first Fab' fragment or the second antibody region is a second Fab' fragment. In embodiments, the first antibody region is a single-chain variable fragment (scFv) or the second antibody region is a second single-chain variable fragment (scFv).

[0250] In an embodiment, the scFv of the second antibody region has a K D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.1 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 1 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 10 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 20 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 30 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 40 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 50 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 60 nM to 150 nM. DIn one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 70 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 80 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 90 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 100 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 110 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 120 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 130 nM to 150 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 140 nM to 150 nM. D It binds to the ROR2 protein.

[0251] In an embodiment, the scFv of the second antibody region has a K D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 130 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 120 nM. D In an embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 110 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 100 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 90 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 80 nM. DIn one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 70 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 60 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 50 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 40 nM. D In one embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 30 nM. D In an embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 20 nM. D In an embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 10 nM. D In an embodiment, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.01 nM to 1 nM. D It binds to the ROR2 protein.

[0252] In embodiments, the scFv of the second antibody region has a K D In embodiments, the scFv of the second antibody region binds to the ROR2 protein with a K of 0.07 nM. D In an embodiment, the scFv of the second antibody region is 6E6 scFv, which binds to the ROR2 protein with a K of 0.07 nM. D It binds to the ROR2 protein.

[0253] The second antibody region may comprise a light chain variable (VL) domain or a heavy chain variable (VH) domain. In embodiments, the second antibody region comprises a light chain variable (VL) domain. In embodiments, the second antibody region comprises a heavy chain variable (VH) domain.

[0254] In embodiments, the second antibody region binds to ROR2 protein. 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.

[0255] Nucleic acid composition The compositions provided herein include nucleic acid molecules encoding the anti-ROR2 antibodies, CARs, and bispecific antibodies, or portions thereof, provided herein, including embodiments thereof. Antibodies, CARs, and bispecific antibodies encoded by isolated nucleic acids are described in detail throughout this application (including in the Description and Examples sections above). Thus, in one aspect, isolated nucleic acids encoding the antibodies provided herein, including embodiments thereof, are provided.

[0256] In embodiments, the isolated nucleic acid encodes a variable heavy chain domain or a variable light chain domain provided herein. In embodiments, the isolated nucleic acid encodes a variable heavy chain domain. In embodiments, the isolated nucleic acid encodes a variable light chain domain. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 1. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 3. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 5. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 7. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 9. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 11. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 13. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 15.

[0257] In another aspect, provided is an isolated nucleic acid encoding an antibody provided herein, including embodiments thereof. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 91. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 92.

[0258] In another aspect, provided is an isolated nucleic acid encoding a chimeric antigen receptor provided herein, including embodiments thereof. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 111. In embodiments, the isolated nucleic acid comprises the sequence of SEQ ID NO: 112.

[0259] Pharmaceutical Composition Compositions provided herein include pharmaceutical compositions comprising the anti-ROR2 antibodies, CARs, and bispecific antibodies provided herein, including embodiments thereof. Accordingly, in one aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of an antibody provided herein, including embodiments thereof, and a pharmaceutically acceptable excipient.

[0260] In another aspect, provided is a pharmaceutical composition comprising a therapeutically effective amount of a CAR provided herein, including embodiments thereof, and a pharmaceutically acceptable excipient.

[0261] In another aspect, provided is a pharmaceutical composition comprising a therapeutically effective amount of a bispecific antibody provided herein, including embodiments thereof, and a pharmaceutically acceptable excipient.

[0262] Treatment method The compositions provided herein, including embodiments thereof (e.g., anti-ROR2 antibody CARs and bispecific antibodies), are contemplated as providing effective treatments for diseases such as cancer (e.g., breast cancer).

[0263] 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.

[0264] In another aspect, provided is 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.

[0265] In embodiments, the cancer is a solid tumor malignancy. In embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, kidney 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 kidney 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.

[0266] In one 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. In embodiments, the antibody is conjugated to a detectable moiety.

[0267] In one aspect, there is provided a method for delivering a therapeutic agent to a ROR2-expressing cell, the method comprising contacting the ROR2-expressing cell with an antibody provided herein, including embodiments thereof, wherein the antibody is conjugated to the therapeutic agent. In embodiments, the therapeutic agent is an anti-cancer agent. Exemplary anti-cancer agents include any anti-cancer agent conventionally used and known in the art, such as, but not limited to, calicheamicin, duocarmycin, pyrrolobenzodiazepine (PBD), SN-38, DXd, and anti-tubulin. Methods for producing antibody-drug conjugates are well known in the art and are described, for example, in Hafeez, U. et al. Antibody-Drug Conjugates for Cancer Therapy; Molecules 2020, 25, 4764; doi:10.3390 / molecules25204764. Ponziani, S. et al. Antibody-Drug Conjugates; The New Frontier of Chemotherpy. Int. J. Mol. Sci. 2020, 21, 5510; doi:10.3390 / ijms21155510. and Joubert, N. et al. Antibody-Drug Conjugates: The Last Decade. Pharmaceuticals 2020, 13, 245; doi:10.3390 / ph13090245, which are incorporated by reference herein in their entirety and for all purposes.

[0268] With respect to the methods provided herein, in embodiments, the contacting occurs in vitro. In embodiments, the ROR2-expressing cell is present in a subject. In embodiments, the subject is a healthy subject. In embodiments, the subject is a subject with cancer. 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.

[0269] With respect to the methods provided herein, in embodiments, the ROR2-expressing cells are cancer cells. 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.

[0270] With respect to the methods provided herein, in embodiments, the antibody is administered in an amount of about 0.01 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 0.05 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 0.1 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 0.5 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 1 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 2 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 4 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 6 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 4 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 8 nM to about 10 nM. In embodiments, the antibody is administered in an amount of about 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM, 1 nM, 2 nM, 2 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, or 10 nM.

[0271] In embodiments, the antibody is administered in an amount of 0.01 nM to 10 nM. In embodiments, the antibody is administered in an amount of 0.05 nM to 10 nM. In embodiments, the antibody is administered in an amount of 0.1 nM to 10 nM. In embodiments, the antibody is administered in an amount of 0.5 nM to 10 nM. In embodiments, the antibody is administered in an amount of 1 nM to 10 nM. In embodiments, the antibody is administered in an amount of 2 nM to 10 nM. In embodiments, the antibody is administered in an amount of 4 nM to 10 nM. In embodiments, the antibody is administered in an amount of 6 nM to 10 nM. In embodiments, the antibody is administered in an amount of 4 nM to 10 nM. In embodiments, the antibody is administered in an amount of 8 nM to 10 nM. In embodiments, the antibody is administered in an amount of 0.01 nM, 0.05 nM, 0.1 nM, 0.5 nM, 1 nM, 2 nM, 2 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, or 10 nM.

[0272] In embodiments, the antibody is administered in an amount of about 0.01 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 0.05 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 0.1 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 0.5 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 1 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 2 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 4 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 6 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 4 nM to about 8 nM.

[0273] In embodiments, the antibody is administered in an amount of 0.01 nM to 8 nM. In embodiments, the antibody is administered in an amount of 0.05 nM to 8 nM. In embodiments, the antibody is administered in an amount of 0.1 nM to 8 nM. In embodiments, the antibody is administered in an amount of 0.5 nM to 8 nM. In embodiments, the antibody is administered in an amount of 1 nM to 8 nM. In embodiments, the antibody is administered in an amount of 2 nM to 8 nM. In embodiments, the antibody is administered in an amount of 4 nM to 8 nM. In embodiments, the antibody is administered in an amount of 6 nM to 8 nM. In embodiments, the antibody is administered in an amount of 4 nM to 8 nM.

[0274] In embodiments, the antibody is administered in an amount of about 0.01 nM to about 6 nM. In embodiments, the antibody is administered in an amount of about 0.05 nM to about 6 nM. In embodiments, the antibody is administered in an amount of about 0.1 nM to about 6 nM. In embodiments, the antibody is administered in an amount of about 0.5 nM to about 8 nM. In embodiments, the antibody is administered in an amount of about 1 nM to about 6 nM. In embodiments, the antibody is administered in an amount of about 2 nM to about 6 nM. In embodiments, the antibody is administered in an amount of about 4 nM to about 6 nM.

[0275] In embodiments, the antibody is administered in an amount of 0.01 nM to 6 nM. In embodiments, the antibody is administered in an amount of 0.05 nM to 6 nM. In embodiments, the antibody is administered in an amount of 0.1 nM to 6 nM. In embodiments, the antibody is administered in an amount of 0.5 nM to 6 nM. In embodiments, the antibody is administered in an amount of 1 nM to 6 nM. In embodiments, the antibody is administered in an amount of 2 nM to 6 nM. In embodiments, the antibody is administered in an amount of 4 nM to 6 nM.

[0276] In embodiments, the antibody is administered in an amount of about 0.01 nM to about 4 nM. In embodiments, the antibody is administered in an amount of about 0.05 nM to about 4 nM. In embodiments, the antibody is administered in an amount of about 0.1 nM to about 4 nM. In embodiments, the antibody is administered in an amount of about 0.5 nM to about 4 nM. In embodiments, the antibody is administered in an amount of about 1 nM to about 4 nM. In embodiments, the antibody is administered in an amount of about 2 nM to about 4 nM.

[0277] In embodiments, the antibody is administered in an amount of 0.01 nM to 4 nM. In embodiments, the antibody is administered in an amount of 0.05 nM to 4 nM. In embodiments, the antibody is administered in an amount of 0.1 nM to 4 nM. In embodiments, the antibody is administered in an amount of 0.5 nM to 4 nM. In embodiments, the antibody is administered in an amount of 1 nM to 4 nM. In embodiments, the antibody is administered in an amount of 2 nM to 4 nM.

[0278] In embodiments, the antibody is administered in an amount of about 0.01 nM to about 2 nM. In embodiments, the antibody is administered in an amount of about 0.05 nM to about 2 nM. In embodiments, the antibody is administered in an amount of about 0.1 nM to about 2 nM. In embodiments, the antibody is administered in an amount of about 0.5 nM to about 2 nM. In embodiments, the antibody is administered in an amount of about 1 nM to about 2 nM.

[0279] In embodiments, the antibody is administered in an amount of 0.01 nM to 2 nM. In embodiments, the antibody is administered in an amount of 0.05 nM to 2 nM. In embodiments, the antibody is administered in an amount of 0.1 nM to 2 nM. In embodiments, the antibody is administered in an amount of 0.5 nM to 2 nM. In embodiments, the antibody is administered in an amount of 1 nM to 2 nM.

[0280] In embodiments, the antibody is administered in an amount of about 0.01 nM to about 1 nM. In embodiments, the antibody is administered in an amount of about 0.05 nM to about 1 nM. In embodiments, the antibody is administered in an amount of about 0.1 nM to about 1 nM. In embodiments, the antibody is administered in an amount of about 0.5 nM to about 1 nM.

[0281] In embodiments, the antibody is administered in an amount of 0.01 nM to 1 nM. In embodiments, the antibody is administered in an amount of 0.05 nM to 1 nM. In embodiments, the antibody is administered in an amount of 0.1 nM to 1 nM. In embodiments, the antibody is administered in an amount of 0.5 nM to 1 nM.

[0282] In embodiments, the antibody is administered in an amount of about 3.15 nM. In embodiments, the antibody is administered in an amount of 3.15 nM. In embodiments, the antibody is administered in an amount of about 1.05 nM. In embodiments, the antibody is administered in an amount of 1.05 nM.

[0283] It is understood that the bispecific antibodies or chimeric antigen receptors provided herein, including embodiments thereof, can be administered at any of the concentrations described herein for administration of antibodies (e.g., 0.01 nM to 10 nM).

[0284] In embodiments, the antibody is administered in an amount of about 10 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 20 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 30 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 40 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 50 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 60 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 70 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 80 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 90 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 100 μg to about 500 μg.

[0285] In embodiments, the antibody is administered in an amount of about 110 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 120 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 130 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 140 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 150 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 160 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 170 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 180 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 190 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 200 μg to about 500 μg.

[0286] In embodiments, the antibody is administered in an amount of about 210 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 220 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 230 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 240 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 250 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 260 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 270 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 280 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 290 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 300 μg to about 500 μg.

[0287] In embodiments, the antibody is administered in an amount of about 310 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 320 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 330 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 340 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 350 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 360 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 370 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 380 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 390 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 400 μg to about 500 μg.

[0288] In embodiments, the antibody is administered in an amount of about 410 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 420 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 430 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 440 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 450 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 460 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 470 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 480 μg to about 500 μg. In embodiments, the antibody is administered in an amount of about 490 μg to about 500 μg.

[0289] In embodiments, the antibody is administered in an amount of about 10 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 20 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 30 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 40 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 50 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 60 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 70 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 80 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 90 μg to about 400 μg. In embodiments, the antibody is administered in an amount of about 100 μg to about 400 μg.

[0290] In embodiments, the antibody is administered in an amount of about 10 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 20 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 30 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 40 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 50 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 60 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 70 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 80 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 90 μg to about 300 μg. In embodiments, the antibody is administered in an amount of about 100 μg to about 300 μg.

[0291] In embodiments, the antibody is administered in an amount of about 10 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 20 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 30 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 40 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 50 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 60 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 70 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 80 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 90 μg to about 200 μg. In embodiments, the antibody is administered in an amount of about 100 μg to about 200 μg.

[0292] In embodiments, the antibody is administered in an amount of about 10 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 20 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 30 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 40 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 50 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 60 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 70 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 80 μg to about 100 μg. In embodiments, the antibody is administered in an amount of about 90 μg to about 100 μg.

[0293] In embodiments, the antibody is administered at a concentration of about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, g, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, or 500 μg.

[0294] In embodiments, the antibody is administered at a concentration of 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, g, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, or 500 μg.

[0295] It is understood that the bispecific antibodies or chimeric antigen receptors provided herein, including embodiments thereof, can be administered at any of the concentrations described herein for administration of antibodies (e.g., 10 μg to 500 μg).

[0296] Methods for inhibiting cell migration The compositions provided herein, including embodiments thereof, are further intended for inhibiting cell migration. Thus, in one aspect, a method for inhibiting migration of ROR2-expressing cells is provided, the method comprising contacting ROR2-expressing cells with an antibody provided herein, including embodiments thereof. In embodiments, the antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 25, CDR H2 set forth in SEQ ID NO: 26, and CDR H3 set forth in SEQ ID NO: 27, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 28, CDR L2 set forth in SEQ ID NO: 29, and CDR L3 set forth in SEQ ID NO: 30.

[0297] With respect to the methods provided herein, in embodiments, the ROR2-expressing cells are cancer cells. 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 is breast cancer. 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.

[0298] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in light thereof 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 incorporated herein by reference in their entirety for all purposes. [Example]

[0299] Example 1: Due to its expression in cancer cells, ROR2 has the potential to serve as a diagnostic and therapeutic target. There are monoclonal antibodies generated that reportedly bind to ROR2 and are available from commercial sources. However, applicants found that some reacted with cells expressing ROR2 by immunoblotting and / or flow cytometry. Furthermore, applicants unexpectedly discovered that some of these antibodies also reacted with cells in which ROR2 had been deleted using CRISPR-Cas9 technology. This unexpected binding revealed that many commercially available antibodies are not specific for ROR2.

[0300] Therefore, we generated monoclonal antibodies that specifically target the extracellular portion of human ROR2. To this end, we immunized mice with a recombinant protein of the extracellular portion of the ROR2 protein (AA1-403), which contains the Ig-like cysteine-rich domain (CRD) and kringle domain (Figure 1). Due to the high degree of homology between the mouse and human molecules, we co-injected immune stimulants, such as Freund's complete adjuvant, to maximize the generation of anti-human ROR2 antibodies. Hybridomas generated after fusion of splenocytes with myeloma fusion partners were screened for the expression of anti-ROR2 mAbs using ELISA and flow cytometry to identify clones that produced antibodies that specifically bound to human ROR2. These antibodies, designated in this disclosure as mAb N-LN or its more commonly known form, 6-E6, are listed in Table 1, and the sequences of the heavy and light chain variable regions are shown in Figure 2. [Table 1]

[0301] Applicants evaluated the binding specificity and relative affinity of each mAb using recombinant ROR2-extracellular protein in an ELISA assay. Binding was measured using reduced / limiting amounts of ROR2 protein, in combination with reduced concentrations of each of the four mAbs (Figure 3). The higher absorbance values ​​for 6E6 and 4G9 at both lower ROR2 protein amounts and lower mAb concentrations indicate that these mAbs have higher affinity compared to 5C11 and 5G3. Equilibrium dissociation constants (Kd) were measured using Kinetic Exclusion Assay (KExA), which measures equilibrium binding affinity and kinetics between unmodified molecules in solution. 6E6 mAb binds to the target ROR2 extracellular sequence with a Kd of approximately 0.1 nM. 4G9 binds to the extracellular domain of human ROR2 with a Kd of approximately 2 nM (Figures 4A and 4B). Analysis of 5C11 and 5G3 mAbs determined that each had a Kd of greater than approximately 40 nM, consistent with the results from the ELISA analysis described above.

[0302] The applicant developed a series of recombinant human / mouse hybrid proteins to isolate specific domains of the human ROR2 protein. Using these recombinant proteins, the specific binding domains targeted by each of four mAbs were identified (Figure 5). The 6E6 and 5C11 mAbs bind to the human kringle domain but not to mouse ROR2. The 4G9 and 5G3 mAbs bind within the first 111 aa of human ROR2, including the Ig-like domain. None of the four mAbs bind to mouse ROR2.

[0303] Applicant also refined this procedure to identify specific amino acids important for binding of two anti-ROR2 mAbs that bind within the Kringle domain (Figure 6). Applicant generated several recombinant human ROR2 proteins and replaced one of the amino acids that differ between human and mouse ROR2 within the Kringle domain with the corresponding amino acid from mouse ROR2. Evaluation of the binding of 6E6 and 5C11 mAbs showed that they required a histidine residue at position 349 and an aspartic acid residue at position 354 to bind to the Kringle domain of human ROR2, and as these amino acids were replaced with the arginine and glutamic acid residues, respectively, of the mouse molecule, 6E6 and 5C11 mAbs no longer bound to the ROR2 protein. Furthermore, 5C11 requires a methionine residue at position 386, as binding was lost upon replacement of the methionine with valine in mouse ROR2.

[0304] The binding of each mAb to human ROR2 was verified by flow cytometry staining and analysis of several cell lines known to express ROR2 using each mAb conjugated with Alexa647 (Figure 7A). Specificity was verified by the absence of binding to HCT116 colorectal cancer cells and HEK293 cells, in which ROR2 expression had been eliminated using CRISPR-Cas9 (Figure 7B). The specificity of these mAbs differs from many commercially available anti-human ROR2 polyclonal and monoclonal antibodies, some of which have been widely used in published studies for the past several years. However, they were subsequently withdrawn and are no longer available because they were determined not to be specific for ROR2.

[0305] Furthermore, the 6E6 and 4G9 mAbs have been tested on primary human cells. Compared to staining with an equivalent amount of an isotype-matched Alex647-conjugated control antibody, 6E6 and 4G9 each stain ROR2 on BR1936, but not BR1367 (ROR2-negative), human breast cancer PDX cells (Figure 8). Neither 6E6 nor 4G9 shows binding to peripheral blood mononuclear cells isolated from several healthy donors (Figure 9).

[0306] Initial functional studies of 6E6 and 4G9 demonstrate that each mAb is internalized, as assessed by the relative increase in fluorescence, for 6E6 and 4G9 mAbs conjugated to the pH-sensitive dye pHrodo. After staining with saturating amounts of pHrodo-conjugated mAb, cells were washed, incubated at either 37°C or 4°C for 2 hours, and analyzed by flow cytometry for changes in relative cellular fluorescence associated with pHrodo and lower intracellular pH (Figure 10). This indicates that the antibodies were internalized into primary endosomes and lysosomes in treated cells expressing ROR2. Both 6E6 and 4G9 mAbs showed an increase in relative fluorescence in K562 cells at 37°C compared to unstained cells or cells incubated at 4°C, whereas JEKO cells, which lack ROR2 expression, showed no difference at either temperature. Applicants discovered that 6E6 was internalized more efficiently than 4G9. Because antibodies that internalize into primary endosomes / lysosomes have been shown to be effective vehicles for delivering drugs or other molecules conjugated to them to cells expressing a target antigen, in this case ROR2, Applicants conclude from these data that 6E6 will be highly effective as an antibody in an antibody-drug conjugate (or ADC) that can subsequently target cells expressing ROR2.

[0307] Therefore, antibodies targeting the epitope recognized by 6E6 can be used to efficiently deliver drugs or other compounds to cells expressing ROR2 in a manner that allows the drug / compound to be internalized and activated within the cells. This allows for selective targeting of ROR2-positive cells in vivo. Furthermore, these antibodies can be used to target ROR2-expressing cells with agents that can identify them for diagnostic imaging or fluorescent identification during surgical removal of ROR2-positive cancer cells.

[0308] Tumor cell expression of ROR2 may have functional significance. Transfection of the breast cancer cell line MCF7 with an expression vector encoding ROR2 generated MCF7-ROR2 cells, which expressed surface ROR2. MCF7-ROR2 cells had enhanced motility and tissue invasiveness in response to Wnt5a compared with parental MCF7 cel...

Claims

1. An anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising a heavy chain variable domain and a light chain variable domain, the heavy chain variable domain comprising a CDR H1 set forth in SEQ ID NO:25, a CDR H2 set forth in SEQ ID NO:26, and a CDR H3 set forth in SEQ ID NO:27; the light chain variable domain An anti-tyrosine kinase-like orphan receptor 2 (ROR2) antibody comprising CDR L1 set forth in SEQ ID NO:28, CDR L2 set forth in SEQ ID NO:29, and CDR L3 set forth in SEQ ID NO:

30.

2. The antibody of claim 1, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO:

2.

3. The antibody of claim 1 or 2, wherein the light chain variable domain comprises the sequence of SEQ ID NO:

4.

4. The antibody according to any one of claims 1 to 3, wherein the antibody is a humanized antibody, a Fab' fragment, a single chain antibody (scFv) or a chimeric antibody.

5. The antibody of any one of claims 1 to 4, wherein the antibody is IgG1 or IgG2.

6. The antibody of claim 1 , wherein the antibody binds to a ROR2 protein comprising the amino acid sequence of SEQ ID NO:

18.

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

8. The antibody of claim 7, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO:

22.

9. The antibody of claim 7 or 8, wherein the extracellular domain is a kringle domain.

10. The antibody of claim 1, wherein the antibody binds to a ROR2 protein containing a histidine at a position corresponding to position 349 of SEQ ID NO: 22 or an aspartic acid at a position corresponding to position 354.

11. The antibody has an equilibrium dissociation constant (K Ｄ 2. The antibody of claim 1, which is capable of binding to the ROR2 protein at 200 bp.

12. The antibody has an equilibrium dissociation constant (K Ｄ 2. The antibody of claim 1, which is capable of binding to the ROR2 protein at 200 bp.

13. The antibody of any one of claims 6 to 12, wherein the ROR2 protein is expressed on a cell.

14. The antibody of claim 13, wherein the cell is a cancer cell.

15. 15. The antibody of claim 14, wherein the cancer cells are breast cancer cells, ovarian cancer cells, pancreatic cancer cells, cervical cancer cells, gastric cancer cells, kidney cancer cells, head and neck cancer cells, bone cancer cells, skin cancer cells, or prostate cancer cells.

16. The antibody of any one of claims 1 to 15, wherein the antibody is conjugated to a therapeutic agent.

17. The antibody of any one of claims 1 to 16, wherein the antibody is conjugated to a diagnostic agent.

18. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of an antibody according to any one of claims 1 to 17.

19. 20. A pharmaceutical composition for inhibiting metastasis of a ROR2-expressing cancer in a subject in need thereof, comprising a therapeutically effective amount of any one of claims 1 to 17.

20. 19. The pharmaceutical composition of claim 18, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

21. A composition for use in a method for detecting ROR2-expressing cells, comprising an antibody according to any one of claims 1 to 15, said method comprising: (i) contacting a ROR2-expressing cell with the antibody of any one of claims 1 to 15; (ii) detecting binding of said antibody to ROR2 protein expressed by said cell.

22. 22. The composition of claim 21, wherein the antibody is conjugated to a detectable moiety.

23. 22. The composition of claim 21, wherein the ROR2-expressing cell is present in a subject.

24. 24. The composition of claim 23, wherein the subject has cancer.

25. 25. The composition of claim 24, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

26. 22. The composition of claim 21, wherein said contacting occurs in vitro.

27. 16. A composition for use in a method of delivering a therapeutic agent to a ROR2-expressing cell, the composition comprising the antibody of any one of claims 1 to 15, the method comprising contacting a ROR2-expressing cell with the antibody of any one of claims 1 to 15, wherein the antibody is bound to a therapeutic agent.

28. 28. The composition of claim 27, wherein the therapeutic agent is an anti-cancer agent.

29. 28. The composition of claim 27, wherein the ROR2-expressing cell is present in a subject.

30. 30. The composition of claim 29, wherein the subject has cancer.

31. 31. The composition of claim 30, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

32. 29. The composition of claim 28, wherein said contacting occurs in vitro.

33. 18. A composition for use in a method for inhibiting migration of ROR2-expressing cells, the composition comprising an antibody according to any one of claims 1 to 17, the method comprising contacting ROR2-expressing cells with the antibody according to any one of claims 1 to 17.

34. 34. The composition of claim 33, wherein the ROR2-expressing cell is present in a subject with cancer.

35. 35. The composition of claim 34, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

36. 34. The composition of claim 33, wherein said contacting occurs in vitro.

37. 34. The composition of claim 33, wherein the ROR2-expressing cell is a cancer cell.

38. 38. The composition of claim 37, 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.

39. A chimeric antigen receptor, (i) an anti-ROR2 antibody region, (a) a light chain variable domain comprising CDR L1 set forth in SEQ ID NO:28, CDR L2 set forth in SEQ ID NO:29, and CDR L3 set forth in SEQ ID NO:30; (b) a heavy chain variable region domain comprising a CDR H1 set forth in SEQ ID NO:25, a CDR H2 set forth in SEQ ID NO:26, and a CDR H3 set forth in SEQ ID NO:27; and (ii) a transmembrane domain.

40. 40. The chimeric antigen receptor of claim 39, further comprising an intracellular T cell signaling domain.

41. The chimeric antigen receptor of claim 40, wherein the intracellular T cell signaling domain is a CD3ζ intracellular T cell signaling domain.

42. 41. The chimeric antigen receptor of claim 40, further comprising an intracellular costimulatory T cell signaling domain.

43. The chimeric antigen receptor of claim 42, wherein the intracellular costimulatory signaling domain is a CD28 intracellular costimulatory signaling domain, a 4-1BB intracellular costimulatory signaling domain, an ICOS intracellular costimulatory signaling domain, or an OX-40 intracellular costimulatory signaling domain.

44. 40. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of the chimeric antigen receptor of claim 39.

45. 45. The pharmaceutical composition of claim 44, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, kidney cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer.

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