Anti-ROR1 antibodies and antibody conjugates, compositions comprising anti-ROR1 antibodies or antibody conjugates, and methods of making and using anti-ROR1 antibodies and antibody conjugates

Abstract

The present disclosure relates to antibodies and antibody conjugates, e.g., antibody-drug conjugates, having binding specificity for receptor tyrosine kinase orphan receptor 1 (ROR1) and its isoforms and homologs, as well as compositions comprising the antibodies or antibody conjugates, including pharmaceutical compositions. Methods of producing the antibodies and antibody conjugates and compositions thereof, and methods of using the antibodies and antibody conjugates and compositions thereof, such as in therapeutic and diagnostic methods, are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 357,442, filed June 30, 2022, U.S. Provisional Patent Application No. 63 / 389,741, filed July 15, 2022, U.S. Provisional Patent Application No. 63 / 382,262, filed November 3, 2022, U.S. Provisional Patent Application No. 63 / 487,706, filed March 1, 2023, U.S. Provisional Patent Application No. 63 / 489,926, filed March 13, 2023, and U.S. Provisional Patent Application No. 63 / 495,635, filed April 12, 2023. Each of these applications is incorporated herein in its entirety for all purposes.

[0002] Provided herein are antibodies and antibody conjugates, e.g., antibody-drug conjugates, having binding specificity for receptor tyrosine kinase orphan receptor 1 (ROR1), as well as compositions comprising the antibodies or antibody conjugates, including pharmaceutical compositions. Also provided herein are methods of producing the antibodies and conjugates, and methods of therapeutically using the antibodies or conjugates and compositions. The antibodies, conjugates, and compositions are useful in methods of treating and preventing cell proliferation and cancer, e.g., by activating anti-tumor immunity; detecting cell proliferation and cancer; and diagnosing cell proliferation and cancer. The antibodies, conjugates, and compositions are also useful in methods of treating, preventing, detecting, and diagnosing autoimmune diseases, infectious diseases, and inflammatory conditions. [Background technology]

[0003] Receptor tyrosine kinase-like orphan receptor (ROR1) is a member of the receptor tyrosine kinase (RTK) family. Its OMIM entry is 602336. Receptor tyrosine kinases function as cell surface receptors, and they are postulated to be involved in the regulation of cell proliferation, differentiation, migration, and metabolism. Afzal & Jeffery, 2003, Hum. Mutat. 22:1-11. Based on conserved sequences from other receptor tyrosine kinases, ROR1 was first identified in 1992. Masiakowski & Carroll, 1992, J. Biol. Chem. 267:26181-26190. The ROR1 gene encodes a type I glycosylated membrane protein with a predicted length of 937 amino acids. See ibid.; Entrez Gene ID 4919. The ROR1 gene has been mapped to chromosome 1 p32-p31 (Reddy et al., 1997, Genomics 41: 283-285). ROR1 expression has been observed in human heart, lung, and kidney, and weakly in the central nervous system (Reddy et al.). Truncated expression has been observed in various human cancers, including those originating from the CNS or PNS neuroectoderm (Reddy, 1996, Oncogene 13:1555-1559). ROR1 knockout mice did not have obvious skeletal or cardiac abnormalities, but these mice died shortly after birth due to respiratory dysfunction (Nomi et al., 2001, Molec. Cell. Biol. 21:8329-8335).

[0004] ROR1 has recently been shown to be expressed on cancer cells, including ovarian cancer cells, and on cancer stem cells. Zhang et al., 2014, Proc. Natl. Acad. Sci. USA 111:17266-71. Treatment with a monoclonal antibody specific for ROR1 inhibits the development of ovarian cancer cells, suggesting that ROR1 is a potential target for cancer therapeutics. See ibid.

[0005] Improved methods of targeting and / or modulating the activity of ROR1 are needed. Given the specific expression of ROR1 in cancer cells and cancer stem cells, improved therapeutic agents are needed that can specifically target cells and tissues that express or overexpress ROR1. Antibody conjugates with ROR1 could be used to deliver therapeutic or diagnostic payload moieties to target cells that express ROR1 for the treatment or diagnosis of such diseases. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Afzal & Jeffery, 2003, Hum. Mutat. 22:1-11 [Non-patent document 2] Masiakowski & Carroll, 1992, J. Biol. Chem. 267:26181-26190 [Non-patent document 3] Reddy et al., 1997, Genomics 41: 283-285 [Non-patent document 4] Reddy, 1996, Oncogene 13:1555-1559 [Non-patent document 5] Nomi et al., 2001, Molec. Cell. Biol. 21:8329-8335 [Non-patent document 6] Zhang et al., 2014, Proc. Natl. Acad. Sci. USA 111:17266-71 Summary of the Invention [Means for solving the problem]

[0007] Provided herein are antibodies that selectively bind to ROR1. In some embodiments, the antibodies bind to human ROR1. In some embodiments, the antibodies also bind to homologs of human ROR1.

[0008] In some embodiments, the antibody comprises one or more of the illustrative CDRs, V H or V L The present invention includes sequences, or variants thereof. In some embodiments, variants have one or more conservative amino acid substitutions. In some embodiments, variants have sequence identity to the illustrative sequence or sequences.

[0009] Compositions and kits comprising the antibodies are also provided. In some embodiments, the compositions are pharmaceutical compositions. Any suitable pharmaceutical composition may be used. In some embodiments, the pharmaceutical composition is a composition for parenteral administration.

[0010] The present disclosure also provides methods of using the anti-ROR1 antibodies provided herein. In some embodiments, the method is a therapeutic method. In some embodiments, the method is a diagnostic method. In some embodiments, the method is an analytical method. In some embodiments, the method is a method for purifying and / or quantifying ROR1.

[0011] In some embodiments, the antibody is used to treat a disease or condition, hi some aspects, the disease or condition is selected from cancer, an autoimmune disease, and an infectious disease.

[0012] Also provided herein are antibody conjugates that selectively bind to receptor tyrosine kinase orphan receptor 1 (ROR1). The antibody conjugates comprise an antibody that binds to ROR1 linked to one or more payload moieties. The antibody may be directly covalently linked to the payload or indirectly linked via a linker. ROR1 antibodies are described in detail herein, and useful payload moieties and useful linkers are also described in detail herein.

[0013] In another aspect, a composition comprising the antibody conjugate is provided. In some embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition may be used. In some embodiments, the pharmaceutical composition is a composition for parenteral administration. In a further aspect, provided herein is a kit comprising the antibody conjugate or the pharmaceutical composition.

[0014] In another aspect, provided herein are methods of using anti-ROR1 antibody conjugates. In some embodiments, the method is a method of delivering one or more payload moieties to a target cell or tissue expressing ROR1. In some embodiments, the method is a therapeutic method. In some embodiments, the method is a diagnostic method. In some embodiments, the method is an analytical method. In some embodiments, the antibody conjugate is used to treat a disease or condition. In some aspects, the disease or condition is selected from cancer, autoimmune disease, and infectious disease. In certain embodiments, the anti-ROR1 antibody conjugate treats a disease or condition, e.g., cancer, by activating anti-tumor or protective immunity.

[0015] In some embodiments, the antibody conjugate binds to human ROR1. In some embodiments, the antibody conjugate also binds to a homolog of human ROR1. In some aspects, the antibody conjugate also binds to a homolog of the cynomolgus monkey and / or mouse receptor ROR1.

[0016] These and other embodiments of the present invention, along with many of its features, are described in more detail in the following text and in connection with the accompanying drawings. [Brief explanation of the drawings]

[0017] [Figure 1] Figure providing a comparison of Kabat and Chothia numbering systems for CDR-H1. Source: Martin ACR (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In R. Kontermann & S. Dubel (Eds.), Antibody Engineering vol. 2 (pp. 33-51). Springer-Verlag, Berlin Heidelberg. [Figure 2-1] ~ [Figure 2-3]

[0023] Figure 1 provides an alignment of VH sequences from variant antibodies provided herein (SEQ ID NOS: 854-1020), with CDRs according to Chothia highlighted and CDRs according to Kabat boxed. [Figure 3-1] ~ [Figure 3-3]

[0023] Figure 1 provides an alignment of VH sequences from variant antibodies provided herein (SEQ ID NOS: 854-1020), with CDRs according to Chothia highlighted and CDRs according to Kabat boxed. [Figure 4-1] ~ [Figure 4-3]

[0023] Figure 1 provides an alignment of VH sequences from variant antibodies provided herein (SEQ ID NOS: 854-1020), with CDRs according to Chothia highlighted and CDRs according to Kabat boxed. [Figure 5-1] ~ [Figure 5-3]

[0023] Figure 1 provides an alignment of VH sequences from variant antibodies provided herein (SEQ ID NOS: 854-1020), with CDRs according to Chothia highlighted and CDRs according to Kabat boxed. [Figure 6-1] ~ [Figure 6-3]

[0023] Figure 1 provides an alignment of VH sequences from variant antibodies provided herein (SEQ ID NOS: 854-1020), with CDRs according to Chothia highlighted and CDRs according to Kabat boxed. [Figure 7]

[0023] Figure 1 provides an alignment of VL sequences (SEQ ID NOS: 1021-1026) from trastuzumab and variant antibodies provided herein, with CDRs according to Chothia highlighted and CDRs according to Kabat underlined. [Figure 8A] ~ [Figure 8C] FIG. 1 provides ELISA binding curves for selected heavy chains and three different light chains. [Figure 9A] ~ [Figure 9H] FIG. 1 provides the results of a kinetic screen for selected heavy chains and four different light chains. [Figure 10A] FIG. 1 provides a formulation buffer comparison for conjugate 46 at 4° C. [Figure 10B] FIG. 1 provides a formulation buffer comparison for conjugate 46 at 25° C. and 37° C. conditions. [Figure 10C] FIG. 1 provides a formulation buffer comparison for conjugate 47 at 4° C. [Figure 10D] FIG. 1 provides a formulation buffer comparison for conjugate 47 at 25° C. and 37° C. conditions. [Figure 10E] FIG. 10 provides HPLC-SEC results over 5× freeze / thaw cycles for conjugate 46. [Figure 10F] FIG. 10 provides HPLC-SEC results over 5× freeze / thaw cycles for conjugate 47. [Figure 10G] FIG. 10 provides protein concentration results over 5× freeze / thaw cycles for conjugate 46. [Figure 10H] FIG. 10 provides protein concentration results over 5× freeze / thaw cycles for conjugate 47. [Figure 10I] ~ [Figure 10J] FIG. 1 provides SEC % monomer with increasing protein concentration held at 4° C. for 3 weeks. [Figure 11A] FIG. 1 provides the calculated DAR of conjugate 47 over 7 days. [Figure 11B] FIG. 1 provides the calculated DAR of conjugate 46 over 7 days. [Figure 11C] FIG. 1 provides the calculated DAR of conjugate 48 over 7 days. [Figure 11D] FIG. 1 provides the calculated DAR of conjugate 50 over 7 days. [Figure 11E] FIG. 1 provides a deconvoluted mass spectrum of an aROR1 ADC sample obtained from an in vivo linker-payload stability study for conjugate 46. [Figure 11F] FIG. 1 provides a deconvoluted mass spectrum of an aROR1 ADC sample obtained from an in vivo linker-payload stability study for conjugate 47. [Figure 11G] FIG. 1 provides a deconvoluted mass spectrum of an aROR1 ADC sample obtained from an in vivo linker-payload stability study for conjugate 48. [Figure 11H] FIG. 1 provides a deconvoluted mass spectrum of an aROR1 ADC sample obtained from an in vivo linker-payload stability study for conjugate 50. [Figure 12A] ~ [Figure 12B]FIG. 10 demonstrates that conjugates 46 and 47 exhibited potent cell killing against ROR1-positive Ntera-2 cells, whereas anti-GFP antibodies conjugated with LP3 or LP4 exhibited no detectable cell killing against Ntera-2 cells. [Figure 12C] ~ [Figure 12D] FIG. 10 demonstrates that the cell-killing activity of both conjugate 46 and conjugate 47 was inhibited in the presence of 1 μM unconjugated anti-ROR1 antibody 2188-D04. [Figure 13A] ~ [Figure 13C] Figures 11A and 11B provide MDA-MB-231 tumor growth curves in response to treatment with four weekly doses (qw × 4) of an ADC targeting ROR1, using doses ranging from (11A) 2 mg / kg to (11B) 5 mg / kg. (11C) Scatter plots of individual tumor volumes at day 42 after treatment, when control tumors reached the study endpoint. Arrows represent the day of administration. Statistical analysis of tumor volumes at day 42 was performed using one-way ANOVA and Dunnett's multiple comparison test against the vehicle group. A probability of less than 5% (p<0.05) was considered significant. ***=p<0.001; ****=p<0.0001. All graphs are presented as individual values or mean ± SEM. [Figure 14A] ~ [Figure 14C] Figures 12A and 12B provide MDA-MB-231 tumor growth curves in response to treatment with four weekly doses (qw x 4) of an ADC targeting ROR1, using doses ranging from (12A) 2 mg / kg to (12B) 5 mg / kg. (12C) Scatter plots of individual tumor volumes at day 43 post-treatment, when control tumors reached the study endpoint. Arrows represent the day of administration. Statistical analysis of tumor volumes at day 43 was performed using one-way ANOVA and Dunnett's multiple comparison test against the vehicle group. A probability of less than 5% (p<0.05) was considered significant. ****=p<0.0001. All graphs are presented as individual values or mean ± SEM. [Figure 15A] ~ [Figure 15C]Figures 13A and 13B provide MDA-MB-231 tumor growth curves in response to treatment with three weekly doses (qw × 3) of an ADC targeting ROR1, using doses ranging from (13A) 2 mg / kg to (13B) 5 mg / kg. (13C) Scatter plots of individual tumor volumes at day 37 after treatment, when control tumors reached the study endpoint. Arrows represent the day of treatment. Statistical analysis of tumor volumes at day 37 was performed using one-way ANOVA and Dunnett's multiple comparison test against the vehicle group. A probability of less than 5% (p<0.05) was considered significant. *=p<0.05; **=p<0.01; ***p=<0.001; ****=p<0.0001. All graphs are presented as individual values or mean ± SEM. [Figure 16A] ~ [Figure 16C] Figures 14A and 14B provide MDA-MB-231 tumor growth curves in response to treatment with four weekly doses (qw x 4) of ROR1-targeting ADCs (14A) conjugate 49 and (14B) conjugate 46, using doses ranging from 1 mg / kg to 5 mg / kg. (14C) Scatter plots of individual tumor volumes on study day 29, when control tumors reached the study endpoint. Arrows represent the day of dosing. Statistical analysis of tumor volumes on study day 29 was performed using one-way ANOVA and Dunnett's multiple comparison test against the vehicle group. A probability of less than 5% (p<0.05) was considered significant. *=p<0.05; **=p<0.01; ***p=<0.001; ****=p<0.0001. All graphs are presented as individual values or mean ± SEM. [Figure 17A] ~ [Figure 17D]Figure 15 provides H1975 tumor growth curves in response to treatment with two weekly doses (qw x 2) of ROR1-targeting ADC (15A) conjugate 46, ADC (15B) conjugate 47, and (15C) conjugate 44, using doses ranging from 1 mg / kg to 10 mg / kg. (15D) Scatter plot of individual tumor volumes on study day 14, when control tumors reached the study endpoint. Arrows represent the day of dosing. Statistical analysis of tumor volumes on study day 14 was performed using one-way ANOVA and Dunnett's multiple comparison test against the vehicle group. A probability of less than 5% (p<0.05) was considered significant. **=p<0.01. All graphs are presented as individual values or mean ± SEM. [Figure 18A]

[0023] Figure 1 provides PDX tumor growth curves in response to treatment with up to five weekly doses (qw x 5) of ROR1-targeting ADC conjugates 46, 47, and 49 administered at 10 mg / kg in different NSCLC PDx models. Arrows represent days of administration. All graphs are presented as mean ± SEM. [Figure 18B] ~ [Figure 18I]

[0023] Figure 1 provides PDX tumor growth curves in response to treatment with up to five weekly doses (qw x 5) of ROR1-targeting ADC conjugates 46, 47, and 49 administered at 10 mg / kg in different NSCLC PDx models. Arrows represent days of administration. All graphs are presented as mean ± SEM. [Figure 19A] ~ [Figure 19D]

[0023] Figure 1 provides PDX tumor growth curves in response to treatment with up to three weekly doses (qwx3) of conjugate 46 administered at 5 mg / kg and 28 daily doses (qdx28) of olaparib administered at 50 mg / kg in different TNBC PDX models. Arrows represent dosing days for conjugate 46, and dotted lines represent dosing days for olaparib. All graphs are presented as mean ± SEM. [Figure 20A]FIG. 10 provides calreticulin expression in Ntera-2 cells after treatment with conjugate 46 or exatecan compared to the antibody alone and the isotype control of conjugate 46. [Figure 20B] FIG. 10 provides HMGB1 release in Ntera-2 cells after treatment with conjugate 46 or exatecan compared to the antibody alone and the isotype control of conjugate 46. [Figure 21A] FIG. 1 provides the percent of viable target cells in Ntera-2 cells after treatment with conjugate 46 or exatecan compared to the antibody alone and the isotype control of conjugate 46. [Figure 21B] 1 is a graph showing monocyte activation in Ntera-2 cells after treatment with conjugate 46 or exatecan compared to antibody alone and conjugate 46 isotype control. [Figure 21C] 1 is a graph showing the percent of cell surface calreticulin of Ntera-2 cells after treatment with conjugate 46 or exatecan compared to the antibody alone and an isotype control of conjugate 46. Calreticulin surface expression is measured as a percentage compared to untreated cells. [Figure 22A] ~ [Figure 22F] Figure 22A provides bar graphs of (Figure 22A) total T cells, (Figure 22B) CD4+ T cells, (Figure 22C) CD8+ T cells, (Figure 22D) and tumor-associated macrophage (TAM) percentages, (Figure 22E) median CD80 fluorescence intensity (MFI) of TAMs, and (Figure 22F) percentage of arginase 1+ (Arg1+) TAMs in tumors from mice treated with vehicle, 10 mg / kg conjugate 46 (qw × 2), and / or 8 mg / kg anti-PD-1 (q3d × 3). All graphs are presented as individual values and mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION

[0018] 1.Definition Unless otherwise defined, all technical terms, notations, and other scientific terms used herein are intended to have the meaning commonly understood by those of ordinary skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference, but the inclusion of such definitions herein should not necessarily be construed as presenting a deviation from what is commonly understood in the art. The techniques and procedures described and referred to herein are generally well understood by those of ordinary skill in the art and are commonly employed using conventional methodologies, such as the widely used molecular cloning methodology described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Unless otherwise noted, procedures involving the use of commercially available kits and reagents are generally performed according to manufacturer-defined protocols and conditions, as appropriate.

[0019] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0020] The term "about" refers to and encompasses the stated value and a range above and below that value. In certain embodiments, the term "about" refers to the stated value ±10%, ±5%, or ±1% of the stated value. In certain embodiments, the term "about" refers to the stated value ±1 standard deviation of that value.

[0021] The term "combinations thereof" includes all possible combinations of the elements to which the term refers.

[0022] The terms "ROR1" and "receptor tyrosine kinase-like orphan receptor 1" are used interchangeably herein. ROR1 is also known by synonyms, including NTRKR1 neurotrophic tyrosine kinase, receptor-associated 1, and dJ537F10.1, among others. Unless otherwise specified, these terms include any variants, isoforms, and species homologs of human ROR1 that are naturally expressed by a cell or that are expressed by a cell transfected with ROR1 or the ROR1 gene. ROR1 proteins include, for example, human ROR1 (SEQ ID NO: 1). In some embodiments, ROR1 proteins include cynomolgus monkey ROR1 (SEQ ID NO: 2). In some embodiments, ROR1 proteins include murine ROR1 (SEQ ID NO: 3).

[0023] The term "immunoglobulin" refers to a class of structurally related proteins that generally contain two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an "intact immunoglobulin," all four chains are interconnected by disulfide bonds. The structure of immunoglobulins is well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically contains a heavy chain variable region (V H , heavy chain variable region) and heavy chain constant region (C H The heavy chain constant region typically comprises C H1 , C H2 and C H3 Each light chain typically contains three domains, abbreviated as V L The light chain constant region typically comprises a C L It contains one domain, abbreviated as .

[0024] The term "antibody" describes a type of immunoglobulin molecule and is used herein in its broadest sense. Antibodies specifically include intact antibodies (e.g., intact immunoglobulins) and antibody fragments. Antibodies contain at least one antigen-binding domain. An example of an antigen-binding domain is V H -V L The antigen-binding domain is formed by a dimer. An "ROR1 antibody," "anti-ROR1 antibody," "ROR1 Ab," "ROR1-specific antibody," "anti-ROR1 Ab," "ROR1 antibody," "anti-ROR1 antibody," "ROR1 Ab," "ROR1-specific antibody," or "anti-ROR1 Ab" is an antibody described herein that specifically binds to ROR1 or ROR1. In some embodiments, the antibody binds to the extracellular domain of ROR1.

[0025] V H and V L The regions can be further subdivided into regions of hypervariability (HVRs), also called complementarity determining regions (CDRs), interspersed with more highly conserved regions called framework regions (FRs). H and V L Generally, an antibody comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The CDRs are involved in antigen binding and affect the antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, which is incorporated herein by reference in its entirety.

[0026] Light chains from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of their constant domain.

[0027] Heavy chains from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and μ, respectively. The IgG and IgA classes are further divided into subclasses based on sequence and functional differences. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0028] The amino acid sequence boundaries of the CDRs can be determined by one of skill in the art using any of several known numbering schemes, including those described by Kabat et al., supra (the "Kabat" numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (the "Chothia" numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (the "Contact" numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (the "IMGT" numbering scheme); and Honegge and Pluckthun, J. Mol. Biol., 2001, 309:657-70 ("AHo" numbering scheme), each of which is incorporated herein by reference in its entirety.

[0029] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat numbering scheme and the Chothia numbering scheme. [Table 1] *When numbered using the Kabat numbering convention, the C-terminus of CDR-H1 ranges from H32 to H34 depending on the length of the CDR, as shown in Figure 1.

[0030] Unless otherwise specified, the numbering scheme used to identify a particular CDR herein is the Kabat / Chothia numbering scheme. For residues encompassed by these two numbering schemes (e.g., CDR-H1 and / or CDR-H2), the numbering scheme is specified as either Kabat or Chothia. For convenience, CDR-H3 may also be referred to herein as either Kabat or Chothia. However, this is not intended to imply sequence differences where they do not exist, and one skilled in the art can easily ascertain whether the sequences are the same or different by examining the sequences.

[0031] CDRs can be designated, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, which is incorporated herein by reference in its entirety.

[0032] The "EU numbering scheme" is generally used when referring to residues in antibody heavy chain constant regions (e.g., as reported in Kabat et al., supra). Unless otherwise stated, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0033] An "antibody fragment" comprises a portion of an intact antibody, such as the antigen-binding or variable region of the intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0034] An "Fv" fragment comprises a dimer of one heavy- and one light-chain variable domain non-covalently associated.

[0035] A "Fab" fragment contains the heavy and light chain variable domains, as well as the constant domain of the light chain and the first constant domain of the heavy chain (C H1 , the first constant domain of the heavy chain). Fab fragments can be produced, for example, by recombinant methods or by papain digestion of a full-length antibody.

[0036] An "F(ab')2" fragment contains two Fab' fragments joined by disulfide bonds near the hinge region. F(ab')2 fragments can be produced, for example, by recombinant methods or by pepsin digestion of intact antibodies. F(ab')2 fragments can be dissociated, for example, by treatment with β-mercaptoethanol.

[0037] "Single-chain Fv" or "sFv" or "scFv" antibody fragments contain V in a single polypeptide chain. H Domain and V L Includes domain. V H and V Lare generally linked by a peptide linker. See Pluckthun A. (1994). In some embodiments, the linker is SEQ ID NO: 1034. In some embodiments, the linker is SEQ ID NO: 1035. Escherichia coli-derived antibodies in Rosenberg M. & Moore GP (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, incorporated herein by reference in its entirety.

[0038] An "scFv-Fc" fragment comprises an scFv linked to an Fc domain. For example, the Fc domain may be linked to the C-terminus of the scFv. The Fc domain may be linked to the orientation of the variable domains in the scFv (i.e., V H -V L or V L -V H ) depending on V H May be followed by V L Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG1 Fc domain. In some embodiments, the IgG1 Fc domain comprises SEQ ID NO: 1027, or a portion thereof. SEQ ID NO: 1027 is the C sequence of the human IgG1 constant region. H1 , C H2 and C H3 provides an array of

[0039] The term "monoclonal antibody" refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies contains antibodies that are substantially similar and bind to the same epitope, except for variants that may normally arise during the production of monoclonal antibodies. Such variants are generally present in small amounts. Monoclonal antibodies are typically obtained by a process that includes selection of a single antibody from a plurality of antibodies. For example, the selection process can be selection of a unique clone from a plurality of clones, such as hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further modified, for example, to improve its affinity for the target ("affinity maturation"), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0040] The term "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0041] "Humanized" forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from a non-human antibody. Humanized antibodies are typically human immunoglobulins (recipient antibodies) in which residues from one or more CDRs have been replaced with residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, e.g., a mouse, rat, rabbit, chicken, or non-human primate antibody, with the desired specificity, affinity, or biological effect. In some cases, selected framework region residues of the recipient antibody are replaced with corresponding framework region residues from the donor antibody. Humanized antibodies may also contain residues that are not found in either the recipient antibody or the donor antibody. Such modifications can be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated herein by reference in its entirety.

[0042] A "human antibody" is one that has an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or that is derived from a non-human source (e.g., obtained from a human source or designed de novo) that utilizes the human antibody repertoire or human antibody coding sequences. Human antibody specifically excludes humanized antibodies.

[0043] An "isolated antibody" is one that has been separated and / or recovered from a component of its natural environment. Components of natural environment may include enzymes, hormones, and other proteinaceous or non-proteinaceous substances. In some embodiments, an isolated antibody is purified sufficiently to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example, by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or non-reducing conditions and detection by Coomassie blue or silver staining. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. In some aspects, an isolated antibody is prepared by at least one purification step.

[0044] In some embodiments, the isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, the isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, the isolated antibody is provided in a solution that constitutes at least 85%, 90%, 95%, 98%, 99%, or 100% by volume. In some embodiments, the isolated antibody is provided in a solution that constitutes at least 85%, 90%, 95%, 98%, 99%, or 100% by volume.

[0045] "Affinity" refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity, which represents a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is determined by the dissociation constant (K D) Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore® instrument. In some embodiments, affinity is determined at 25°C.

[0046] With respect to antibody binding to a target molecule, a particular antigen (e.g., a polypeptide target), or epitope on a particular antigen, the terms "specific binding," "specifically binds to," "specific for," "selectively binds to," and "selective for" refer to binding that is distinct from nonspecific or nonselective interactions. Specific binding can be determined, for example, by determining binding of a molecule relative to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that mimics the antibody binding site on the target. Specific binding is then demonstrated when binding of the antibody to the target is competitively inhibited by the control molecule.

[0047] The term "k" d " (sec -1 ) as used herein refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is known as k off It is also called the value.

[0048] The term "k" a " (M -1 ×sec -1 ) as used herein refers to the association rate constant of a particular antibody-antigen interaction. This value is known as k on It is also called the value.

[0049] The term “K D " (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. K D =k d / k a .

[0050] The term “K A" (M -1 ) as used herein refers to the association equilibrium constant of a particular antibody-antigen interaction. A =k a / k d .

[0051] An "affinity matured" antibody is an antibody with one or more alterations in one or more CDRs or FRs that result in an improvement in the affinity of the antibody for its antigen compared to a parent antibody that does not have those alterations. In one embodiment, the affinity matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies can be produced using a variety of methods known in the art. For example, Marks et al. (Bio / Technology, 1992, 10:779-783, incorporated herein by reference in its entirety) report on V H Domains and V L Affinity maturation by domain shuffling has been described. Random mutagenesis of CDR and / or framework residues has been described, for example, by Barbas et al. (Proc. Nat. Acad. Sci. USA, 1994, 91:3809-3813); Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199; and Hawkins et al., J. Mol. Biol., 1992, 226:889-896, each of which is incorporated herein by reference in its entirety.

[0052] As used herein in the context of two or more antibodies, the terms "compete with" or "cross-compete with" indicate that two or more antibodies compete for binding to an antigen (e.g., receptor tyrosine kinase orphan receptor 1, or ROR1). In one exemplary assay, ROR1 is coated onto a plate and allowed to bind to a first antibody, after which a second, labeled antibody is added. If the presence of the first antibody reduces binding of the second antibody, the antibodies compete. In another exemplary assay, a first antibody is coated onto a plate and allowed to bind to the antigen, after which a second antibody is added. The term "compete with" also includes antibody combinations in which one antibody reduces binding of another antibody, but no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit each other's binding, regardless of the order in which they are added. In some embodiments, one antibody reduces binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0053] The term "epitope" refers to a portion of an antigen that can specifically bind to an antibody. Epitopes often consist of surface-accessible amino acid residues and / or sugar side chains and may have specific charge characteristics as well as specific three-dimensional structural characteristics. Conformational and nonconformational epitopes are distinguished by the fact that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may include amino acid residues directly involved in binding and other amino acid residues not directly involved in binding. The epitope to which an antibody binds can be determined using known techniques for determining epitopes, such as, for example, testing antibody binding to variants of ROR1 with different point mutations.

[0054] The percent "identity" between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to those in the reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment to determine percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared.

[0055] A "conservative substitution" or "conservative amino acid substitution" refers to the substitution of an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences with such substitutions are known as "conservatively modified variants." Such conservatively modified variants are in addition to, and do not exclude, polymorphic variants, interspecies homologs, and alleles. By way of example, the groups of amino acids provided in Tables 2-4 are, in some embodiments, considered conservative substitutions for one another. [Table 2] [Table 3] [Table 4]

[0056] Additional conservative substitutions can be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W.H. Freeman & Co., New York, N.Y. Antibodies generated by making one or more conservative substitutions of amino acid residues in a parent antibody are referred to as "conservatively modified variants."

[0057] The term "payload" refers to a portion of a molecule that can be conjugated to an antibody. In certain embodiments, the payload is selected from the group consisting of a therapeutic moiety and a labeling moiety.

[0058] "Triple-negative breast cancer" (TNBC) refers to breast cancer characterized as estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor-2-negative (HER2-negative). TNBC can be BRCA1 / 2 wild-type or BRCA1 / 2 mutant. Determination of the negative status of estrogen, progesterone, and Her2 / neu expression is readily determined by those skilled in the art, for example, according to currently accepted guidelines. For example, the guidelines set forth by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) are widely accepted. ASCO / CAP recommends testing by immunohistochemistry (IHC) or in situ hybridization (ISH) techniques. Furthermore, a cancer is Her2-negative if a single test (or all tests) performed on a tumor specimen shows (a) IHC-negative, IHC 1+, or IHC 0, or (b) ISH-negative using single-probe or dual-probe ISH. Those skilled in the art will appreciate that the triple-negative cancer described herein does not include any cancer with obvious histopathological discrepancies upon review by a pathologist. Wolff, AC et al. J Clin Oncol. 2013 Nov. 1:31(31):3997-4013. A cancer is ER-negative or PR-negative if <1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample expresses ER or PR (i.e., a positive endogenous control is observed).

[0059] "PARP inhibitor resistance" refers to a decreased effectiveness of a PARP inhibitor in treating, curing, or reversing triple-negative breast cancer in a subject. In certain embodiments, PARP inhibitor resistance occurs with prolonged exposure to one or more PARP inhibitors.

[0060] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of an antibody, antibody conjugate, or composition that, when administered to a subject, is effective to treat a disease or disorder. In some embodiments, a therapeutically effective amount or effective amount refers to an amount of an antibody, antibody conjugate, or composition that, when administered to a subject, is effective to prevent or ameliorate a disease, or disease progression, or results in improvement of symptoms. A "therapeutically effective amount" can vary depending, among other things, on the compound, the disease or disorder and its severity, and the age, weight, etc., of the subject to be treated.

[0061] As used herein, the term "inhibit proliferation" (e.g., with reference to cells such as tumor cells) is intended to include any measurable decrease in cell proliferation (e.g., tumor cell proliferation) when contacted with a ROR1 antibody or antibody conjugate described herein, compared to the proliferation of the same cells not contacted with the ROR1 antibody. In some embodiments, proliferation may be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. The decrease in cell proliferation may occur by various mechanisms, including, but not limited to, antibody internalization, apoptosis, necrosis, and / or effector function-mediated activity.

[0062] In some chemical structures depicted herein, certain substituents, chemical groups, and atoms are depicted with curved / wavy lines (e.g., [ka] ) for example, but not limited to: [ka] In some structures, such as, but not limited to, the curved / wavy line indicates an atom in the backbone of the conjugate or linker-payload structure to which the depicted chemical entity is attached. [ka] In some structures, such as, the curved / wavy line represents atoms in the backbone of the conjugate or linker-payload structure, as well as atoms in the antibody or antibody fragment, to which the depicted chemical entity is attached.

[0063] Spiro compounds depicted with overlapping rings indicate that the rings may be attached at either vertex. For example, a spiro group [ka] In , the two rings may be joined at any of the three available vertices of both rings.

[0064] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there are multiple definitions for terms herein, those in this section prevail unless stated otherwise.

[0065] "Alkoxy" and "alkoxyl" refer to the group -OR" where R" is alkyl or cycloalkyl. Alkoxy groups, in certain embodiments, include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0066] The term "alkoxyamine," as used herein, refers to an -alkylene-O-NH group, where alkylene is as defined herein. In some embodiments, an alkoxyamine group can react with an aldehyde to form an oxime residue. Examples of alkoxyamine groups include -CHCH-O-NH, -CH-O-NH, and -O-NH.

[0067] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated straight-chain or branched hydrocarbon. In certain embodiments, an alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkyl group contains 1 to 10 carbon atoms (i.e., C1-C 10 In certain embodiments, alkyl is a lower alkyl, e.g., C 1-6 and alkyl. In certain embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. In certain embodiments, "substituted alkyl" refers to an alkyl substituted with one, two, or three groups independently selected from, for example, halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, -CN, -NO, amido, -C(O)-, -C(S)-, ester, carbamate, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, dialkylamino, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, the alkyl is unsubstituted.

[0068] The term "alkylene," as used herein, unless otherwise specified, refers to a divalent alkyl group, as defined herein. "Substituted alkylene" refers to an alkylene group that is substituted as described herein for alkyl. In some embodiments, the alkylene is unsubstituted.

[0069] "Alkenyl" refers, in certain embodiments, to an olefinically unsaturated hydrocarbon group which may be straight-chained or branched, having up to about 11 carbon atoms or from 2 to 6 carbon atoms (e.g., "lower alkenyl") and having at least 1, or from 1 to 2 sites of olefinic unsaturation. "Substituted alkenyl" refers to an alkenyl group that is substituted as described herein for alkyl.

[0070] "Alkenylene" refers to a divalent alkenyl as defined herein. Lower alkenylene is, for example, C2-C6-alkenylene.

[0071] "Alkynyl," in certain embodiments, refers to an acetylenically unsaturated hydrocarbon group, which may be straight-chained or branched, having up to about 11 carbon atoms or 2 to 6 carbon atoms (e.g., "lower alkynyl") and having at least one, or 1 to 2, sites of acetylenic unsaturation. Non-limiting examples of alkynyl groups include acetylene (-C≡CH), propargyl (-CHC≡CH), and the like. "Substituted alkynyl" refers to an alkynyl group substituted as described herein for alkyl.

[0072] "Alkynylene" refers to a divalent alkynyl as defined herein. Lower alkynylene is, for example, C2-C6-alkynylene.

[0073] "Amino" refers to -NH2.

[0074] The term "alkylamino," as used herein, unless otherwise specified, refers to an -NHR group, where R is, for example, a C alkyl group, as defined herein. 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic ring, 3-membered to 12-membered heterocyclic ring, C 1-10 haloalkyl, etc. In certain embodiments, alkylamino is C 1-6 It is alkylamino.

[0075] The term "dialkylamino," as used herein, unless otherwise specified, refers to a -NR"R" group, where each R" is independently a C, as defined herein. 1-10 In certain embodiments, dialkylamino is, for example, di-C 1-6 Alkylamino, C 2-10Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic ring, 3-membered to 12-membered heterocyclic ring, C 1-10 haloalkyl and the like.

[0076] The term "aryl," as used herein, unless otherwise specified, refers to phenyl, biphenyl, or naphthyl. This term includes both substituted and unsubstituted moieties. Aryl groups can be substituted with any of the listed moieties, including, but not limited to, one or more moieties (e.g., in some embodiments, one, two, or three moieties) selected from the group consisting of halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, each of which independently is unprotected or protected as necessary as understood by one of ordinary skill in the art (see, e.g., Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991), and the aryl in arylamino and aryloxy substituents is not further substituted.

[0077] The term "arylamino", as used herein, unless otherwise specified, refers to the group -NR'R", where R' is hydrogen or C1-C6-alkyl and R" is aryl as defined herein.

[0078] The term "arylene," as used herein, unless otherwise specified, refers to a divalent aryl group, as defined herein.

[0079] The term "aryloxy," as used herein, unless otherwise specified, refers to an --OR group, where R is aryl as defined herein.

[0080] "Alkarylene" refers to an arylene group, as defined herein, in which the aryl ring is substituted with one or two alkyl groups. "Substituted alkarylene" refers to an alkarylene in which the arylene group is further substituted as defined herein for aryl.

[0081] "Aralkylene" refers to the group -CH-arylene-, -arylene-CH-, or -CH-arylene-CH-, where arylene is as defined herein. "Substituted aralkylene" refers to aralkylene in which the aralkylene group is substituted as defined herein for aryl.

[0082] "Carboxyl" or "carboxy" refers to -C(O)OH or -COOH.

[0083] The term "cycloalkyl," as used herein, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, a cycloalkyl group can be saturated, and / or bridged, and / or unbridged, and / or fused bicyclic, and / or spirocyclic bicyclic groups. In certain embodiments, a cycloalkyl group contains 3 to 10 carbon atoms (i.e., C3-C4). 10 In some embodiments, cycloalkyl is a cycloalkyl group having 3 to 15 carbons (C 3-15 ), 3 to 10 carbons (C 3-10 ), 3 to 7 carbons (C 3-7), or 3 to 6 carbons (C3-C6) (i.e., "lower cycloalkyl"). In certain embodiments, a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl. Exemplary "cycloalkyl" or "carbocycle" groups include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. "Cycloalkyl" or "carbocycle" includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic cycloalkyl or carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic cycloalkyl or carbocycle includes any combination of saturated, unsaturated, and aromatic bicyclic rings, where valence allows. Bicyclic cycloalkyl or carbocycle includes any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Non-limiting examples of bridged bicyclic cycloalkyl or carbocyclic groups include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, and 2-oxabicyclo[2.2.2]octyl. Non-limiting examples of spirocyclic cycloalkyl or carbocyclic groups include, but are not limited to, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl, spiro[5.6]dodecyl, and spiro[5.7]tridecyl.

[0084] The term "bicyclic ring system" includes 6- to 12-membered (e.g., 8- to 12-membered, or 9-, 10-, or 11-membered) structures forming two rings, wherein the two rings have at least one atom in common (e.g., two atoms in common). Bicyclic rings may be fused, bridged, or spirocyclic. Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryl, and bicyclic heteroaryl.

[0085] The term "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic alicyclic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include adamantanyl, norbornanyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]onyl, and 2-oxabicyclo[2.2.2]octyl. octyl, 6-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 1-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2-oxabicyclo[3.1.1]heptyl, 2,6-dioxa-tricyclo[3.3.1.0]heptyl. 3,7Bridged bicyclic ring systems include, but are not limited to, alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, aroyl, aryloxy ... and optionally substituted with one or more substituents such as alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0086] The term "spiro bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic alicyclic ring system in which two or three rings are linked together by one shared atom. Spiro compounds depicted with overlapping rings indicate that the rings may be attached at either vertex. For example, a spiro group [ka] In the formula, the two rings may be joined at any of the three available vertex atoms of both rings.

[0087] The term "cycloalkylene," as used herein, refers to a divalent cycloalkyl group, as defined herein. In certain embodiments, the cycloalkylene group is cyclopropylene. [ka] , cyclobutylene [ka] , cyclopentylene [ka] , cyclohexylene [ka] , cycloheptylene [ka] etc. Lower cycloalkylene refers to C3-C6-cycloalkylene.

[0088] The term "cycloalkylalkyl," as used herein, unless otherwise specified, refers to an alkyl group, as defined herein, that is substituted with one or two cycloalkyl groups, as defined herein.

[0089] The term "ester," as used herein, refers to -C(O)OR or -COOR, where R is alkyl as defined herein.

[0090] The term "fluorene," as used herein, refers to a fluorene in which any one or more carbons bearing one or more hydrogens may be substituted with a chemical functional group as described herein. [ka] Refers to...

[0091] The term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more independently selected halogen atoms (e.g., in some embodiments, 1, 2, 3, 4, or 5).

[0092] The term "heteroalkyl" refers to an alkyl, as defined herein, in which one or more atoms are replaced by a heteroatom. As used herein, "heteroalkenyl" refers to an alkenyl, as defined herein, in which one or more carbon atoms are replaced by a heteroatom. As used herein, "heteroalkynyl" refers to an alkynyl, as defined herein, in which one or more carbon atoms are replaced by a heteroatom. Suitable heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl can be substituted. Examples of heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl. "Substituted heteroalkyl" refers to a heteroalkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, a heteroalkyl group can contain one, two, three, or four heteroatoms. One of ordinary skill in the art will recognize that a 4-membered heteroalkyl can typically contain one or two heteroatoms, a 5- or 6-membered heteroalkyl can typically contain one, two, or three heteroatoms, and a 7- to 10-membered heteroalkyl can typically contain one, two, three, or four heteroatoms.

[0093] The term "heteroalkylene," as used herein, refers to a divalent heteroalkyl, as defined herein. "Substituted heteroalkylene" refers to a divalent heteroalkyl, as defined herein, that is substituted as described for heteroalkyl.

[0094] The term "heterocycloalkyl" refers to a monovalent, monocyclic, or polycyclic non-aromatic ring system in which one or more ring atoms are heteroatoms independently selected from oxygen (O), sulfur (S), and nitrogen (N) (e.g., the nitrogen or sulfur atom may be optionally oxidized and the nitrogen atom may be quaternized), and the remaining ring atoms in the non-aromatic ring are carbon atoms. In certain embodiments, a heterocycloalkyl is a monovalent, monocyclic, or polycyclic fully saturated ring system. In certain embodiments, a heterocycloalkyl group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, 4 to 11, or 5 to 6 ring atoms. A heterocycloalkyl may be attached to the core structure at any heteroatom or carbon atom that results in a stable compound. In certain embodiments, heterocycloalkyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused and / or bridged bicyclic and / or spirocyclic bicyclic ring systems, in which the nitrogen or sulfur atoms are optionally oxidized and / or the nitrogen atom is optionally quaternized. In some embodiments, heterocycloalkyl radicals are 2,5-diazabicyclo[2.2.2]octanyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isoxazolidinyl. Heterocycloalkyls include, but are not limited to, tetrahydrofuryl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocycloalkyls can also be optionally substituted as described herein.In certain embodiments, heterocycloalkyl is substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, heterocycloalkyl groups can contain one, two, three, or four heteroatoms. Those skilled in the art will recognize that 4-membered heterocycloalkyls can generally contain one or two heteroatoms, 5- or 6-membered heterocycloalkyls can generally contain one, two, or three heteroatoms, and 7- to 10-membered heterocycloalkyls can generally contain one, two, three, or four heteroatoms. In some embodiments, a "heterocycloalkyl" or "heterocycle" radical is selected from the group consisting of 2,5-diazabicyclo[2.2.2]octanyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, and 2,5-diazabicyclo[2.2.2]octanyl. These include, but are not limited to, sazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl.Non-limiting examples of bridged heterocycloalkyl or heterocyclic groups include 6-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 1-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2-oxabicyclo[3.1.1]heptyl, 2,6-dioxa-tricyclo[3.3.1.0]heptyl. 3,7 ]nonyl. Non-limiting examples of spirocyclic heterocycloalkyl or heterocyclic groups include, but are not limited to, 2,8-diazaspiro[4.5]decyl; 2,7-diazaspiro[3.5]nonyl; 3,9-diazaspiro[5.5]undecyl; 3-azaspiro[5.5]undecyl; 2-oxa-6-azaspiro[3.4]octyl; 2-oxa-9-azaspiro[5.5]undecyl; 3-oxa-9-azaspiro[5.5]undecyl; 7-azaspiro[3.5]nonyl; 2-azaspiro[3.5]nonyl; 7-oxaspiro[3.5]nonyl; and 2-oxaspiro[3.5]nonyl.

[0095] "Heterocycloalkylene" refers to a divalent heterocycloalkyl, as defined herein.

[0096] The term "heteroaryl" refers to a monovalent, monocyclic aromatic and / or polycyclic aromatic group in which at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen within the ring. Each ring of a heteroaryl group can contain one or two oxygen atoms, one or two sulfur atoms, and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and that each ring contains at least one carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. A heteroaryl can be attached to the remainder of the molecule through a nitrogen or carbon atom. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzoindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenalzadinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein.A "substituted heteroaryl" is a heteroaryl that is substituted as defined for aryl.

[0097] The term "heteroarylene" refers to a divalent heteroaryl group, as defined herein. A "substituted heteroarylene" is a heteroarylene that is substituted as defined for aryl.

[0098] The term "protecting group," as used herein, unless otherwise specified, refers to a group added to an oxygen, nitrogen, or phosphorus atom to prevent further reaction at the (protected) oxygen, nitrogen, or phosphorus atom, or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis (see, for example, Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Fourth Edition, 2006, which is incorporated herein by reference in its entirety).

[0099] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art.Such salts may be prepared from (1) organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ... Sulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, or (2) salts formed when an acidic proton present in the parent compound is replaced (a) with a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, or ammonia, or (b) with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, including, but not limited to, ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0100] Pharmaceutically acceptable salts further include, by way of example and without limitation, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and the like, as well as salts of non-toxic organic or inorganic acids when the compound contains a basic functional group, such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, These include picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like.

[0101] The term "substantially free of" or "substantially absent of," with reference to a composition, refers to a composition that comprises at least 85% or 90% by weight, and in certain embodiments, 95%, 98%, 99%, or 100% by weight; or in certain embodiments, 95%, 98%, 99%, or 100% of a specified enantiomer or diastereomer of a compound. In certain embodiments of the methods and compounds provided herein, the compound is substantially free of one of its two enantiomers. In certain embodiments of the methods and compounds provided herein, the compound is substantially free of one of its two diastereomers. In certain embodiments of the methods and compounds provided herein, the compound is substantially free of an enantiomer (i.e., the compound is not a racemic or 50:50 mixture of the compound).

[0102] Similarly, with respect to a composition, the term "isolated" refers to a composition that comprises at least 85%, 90%, 95%, 98% or 99% to 100% by weight of a compound, the remainder comprising other species, enantiomers or diastereomers.

[0103] "Solvate" refers to a compound provided herein, or a salt thereof, that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0104] "Isotopic composition" refers to the amount of each isotope found in a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition are sometimes referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds described herein are intended to represent any stable isotope of that atom. For example, unless otherwise stated, if a position is specifically designated as hydrogen (H), that position in the natural isotopic composition is understood to have hydrogen.

[0105] "Isotopic enrichment" refers to the percentage of a given atom in a molecule that incorporates a specific isotope, instead of the atom's natural isotopic abundance. For example, 1% deuterium (D) enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that particular position. Since the natural distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is also approximately 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0106] "Isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0107] As used herein, "alkyl," "alkylene," "alkylamino," "dialkylamino," "cycloalkyl," "aryl," "arylene," "alkoxy," "amino," "carboxyl," "heterocycloalkyl," "heteroaryl," "heteroarylene," "carboxyl," and "amino acid" groups may contain deuterium (D) in one or more positions where a hydrogen (H) atom would be present, and the deuterium composition of the atom or atoms is other than the natural isotopic composition.

[0108] Also, as used herein, "alkyl," "alkylene," "alkylamino," "dialkylamino," "cycloalkyl," "aryl," "arylene," "alkoxy," "amino," "carboxyl," "heterocycloalkyl," "heteroaryl," "heteroarylene," "carboxyl," and "amino acid" groups refer to groups having 13 carbons (e.g., 13 C) may be contained in an amount other than the natural isotopic composition.

[0109] The term "polymer" or "polymeric moiety" refers to a protein, peptide, antibody, nucleic acid, carbohydrate, or other macromolecule composed of polymerized monomers. They include peptides of two or more residues or ten or eleven or more residues. In certain embodiments, a polymer has a mass of at least 1000 Da. In certain embodiments, a polymer has at least 1000 atoms. In certain embodiments, a polymer can be modified. For example, a protein, peptide, or antibody can be modified with one or more carbohydrates and / or small molecule therapeutic compounds.

[0110] The term "amino acid" refers to the 20 common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V), as well as the less common pyrrolysine and selenocysteine. Naturally occurring amino acids also include citrulline. Naturally encoded amino acids include post-translational variants of the 22 naturally occurring amino acids, such as prenylated amino acids, isoprenylated amino acids, myristoylated amino acids, palmitoylated amino acids, N-linked glycosylated amino acids, O-linked glycosylated amino acids, phosphorylated amino acids, and acylated amino acids. The term "amino acid" also includes non-natural (or unnatural) or synthetic α-, β-, γ-, or δ-amino acids, including, but not limited to, amino acids found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine, and histidine. In certain embodiments, amino acids are present in the L-configuration. In certain embodiments, amino acids are present in the D-configuration.Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl, or β-histidinyl. An unnatural amino acid is neither a proteinogenic amino acid nor a post-translationally modified variant thereof. In particular, the term unnatural amino acid refers to an amino acid that is not one of the 20 common amino acids, pyrrolysine, selenocysteine, or a post-translationally modified variant thereof.

[0111] The term "conjugate" or "antibody conjugate" refers to a compound or drug moiety described herein that is linked to one or more polymeric moieties. The polymeric moiety is as defined herein or any polymer deemed appropriate by one of skill in the art. The compound or drug moiety can be any compound or drug moiety described herein. The compound or drug moiety can be directly linked to the polymeric moiety by a covalent bond, or the compound or drug moiety can be indirectly linked to the polymeric moiety via a linker. Typically, the linker is covalently attached to the polymeric moiety and is also covalently attached to the compound or drug moiety.

[0112] "pAMF," "pAMF residue," or "pAMF mutation" refers to a variant phenylalanine residue (ie, para-azidomethyl-L-phenylalanine) added to or introduced by substitution into a polypeptide.

[0113] The term "linker" refers to a molecular moiety that can form at least two covalent bonds. Typically, a linker can form at least one covalent bond to a polymeric moiety and at least one other covalent bond to a compound or drug moiety. In certain embodiments, a linker can form more than one covalent bond to a polymeric moiety. In certain embodiments, a linker can form more than one covalent bond to a compound or drug moiety, or can form covalent bonds to more than one compound or drug moiety. The remaining structure after a linker forms a bond to a polymeric moiety, or a compound or drug moiety, or both (i.e., the remainder of the linker after one or more covalent bonds have been formed ("linker residue")) may also be referred to herein as a "linker." The term "linker precursor" refers to a linker having one or more reactive groups that can form a covalent bond with a polymer, or a compound or drug moiety, or both. Those of skill in the art will understand, based on the context in which the term linker is used, whether the "linker" is a linker precursor having one reactive group, a linker precursor having more than one reactive group, a linker residue covalently attached to a polymer, a linker residue covalently attached to a compound or drug moiety, and / or a linker residue covalently attached to a polymer and to a compound or drug moiety. In some embodiments, the linker is a cleavable linker. For example, a cleavable linker can be a linker that is released by biolabile or enzymatic action, which may or may not be engineered. In some embodiments, the linker is a non-cleavable linker. For example, a non-cleavable linker can be a linker that is released by degradation of the polymeric moiety.

[0114] As used herein, the term "EC 50 " refers to the dosage, concentration or amount of a particular test compound that elicits a dose-dependent response that is 50% of the maximal expression of the particular response induced, elicited or potentiated by the particular test compound.

[0115] As used herein, unless otherwise specified, the term "IC 50 " refers to an amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures such response.

[0116] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "subjects" refer to animals, e.g., mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, mice, camels, birds, goats, and sheep) and primates (e.g., monkeys, e.g., cynomolgus monkeys, chimpanzees, and humans), and in certain embodiments, humans. In certain embodiments, the subject is a livestock animal (e.g., a horse, cow, pig, etc.) or a pet (e.g., a dog or cat). In certain embodiments, the subject is a human. In some embodiments, the subject has a disease that can be treated or diagnosed by an antibody or antibody conjugate provided herein. In some embodiments, the disease is gastric cancer, colon cancer, renal cell carcinoma, cervical cancer, non-small cell lung cancer, ovarian cancer, breast cancer, triple-negative breast cancer, endometrial cancer, prostate cancer, and / or cancer of epithelial origin.

[0117] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent that can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes an antibody or antibody conjugate provided herein. In certain embodiments, a therapeutic agent is an agent that is known to be useful, has been used, or is currently being used to treat or prevent a disorder or one or more symptoms thereof.

[0118] "Treating" or "treatment" of any disease or disorder refers, in certain embodiments, to ameliorating the disease or disorder present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" includes either physically modulating the disease or disorder (e.g., stabilizing discernible symptoms) or physiologically modulating the disease or disorder (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treating" or "treatment" includes delaying or preventing the onset of the disease or disorder, or delaying or preventing the recurrence of the disease or disorder. In yet another embodiment, "treating" or "treatment" includes reducing or eliminating either the disease or disorder, or slowing the progression of the disease or disorder or one or more symptoms of the disease or disorder, or reducing the severity of the disease or disorder or one or more symptoms of the disease or disorder.

[0119] As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to any agent that can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes a compound, drug moiety, or conjugate provided herein. In certain other embodiments, the term "prophylactic agent" does not refer to a compound, drug moiety, or conjugate provided herein. For example, a prophylactic agent is an agent that is known to be useful in, or has been used to, or is currently used to prevent or prevent the onset, development, progression, and / or severity of a disorder.

[0120] As used herein, the phrase "prophylactically effective amount" refers to an amount of a therapy (e.g., another prophylactic agent) sufficient to result in the prevention or alleviation of the occurrence, recurrence, or onset of one or more symptoms associated with a disorder, or sufficient to enhance or enhance the prophylactic effect of another therapy (e.g., another prophylactic agent).

[0121] In some of the chemical structures depicted herein, certain substituents, chemical groups, and atoms are shown with curved / wavy / squiggly lines (e.g., [ka] ) for example, but not limited to: [ka] In some structures, such as, but not limited to, this curved / wavy / squiggly line indicates an atom in the backbone of the conjugate, compound or drug substructure to which the depicted chemical entity is attached. [ka] In some structures, such as, the curved / wavy / squiggly line indicates atoms in the backbone of the conjugate, compound, or drug moiety, as well as atoms in the macromolecule to which the depicted chemical entity is attached.

[0122] As used herein, a graphic depiction showing a substituent attached to a cyclic group (e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl) by a bond between ring atoms is intended to indicate that the cyclic group may be substituted with that substituent at any ring position in a cyclic group, or on any ring in a fused ring group, according to the practices set forth herein or known in the art to which this disclosure pertains. For example, if the subscript q is an integer from 0 to 4 and the substituent R 1The position of the bond is generally described, i.e., the group is not directly attached to any vertex of the bond line structure, i.e., a specific ring carbon atom. [ka] is the substituent R 1 The following non-limiting examples of groups are attached to specific ring carbon atoms: [ka]

[0123] The term "carbocycle," as used herein, unless otherwise specified, refers to a saturated, unsaturated, or aromatic ring in which the ring atoms are carbon. In certain embodiments, a carbocyclic group can be saturated, and / or bridged, and / or unbridged, and / or a fused bicyclic group, and / or a spirocyclic bicyclic group. In certain embodiments, a carbocyclic group contains 3 to 10 carbon atoms (i.e., C3-C4). 10 In some embodiments, a carbocycle is a ring of 3 to 15 carbons (C 3-15 ), 3 to 10 carbons (C 3-10 ), 3 to 7 carbons (C 3-7 ), or 3 to 6 carbons (C3-C6). In certain embodiments, the carbocyclic group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl.

[0124] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms, where the nitrogen or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the remaining ring atoms in non-aromatic rings are carbon atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. In certain embodiments, heterocycles are monovalent, monocyclic, or polycyclic fully saturated ring systems. In certain embodiments, heterocycloalkyl or "heterocycle" groups may be unsaturated and / or bridged and / or unbridged and / or fused bicyclic and / or spirocyclic bicyclic groups.

[0125] The term "site-specific" refers to the modification of a polypeptide at a predetermined sequence position of the polypeptide. The modification is at a single, predictable residue of the polypeptide with little or no alteration. In certain embodiments, a modified amino acid has been introduced at that sequence position, e.g., recombinantly or synthetically. Similarly, a moiety may be "site-specifically" linked to a residue at a particular sequence position of the polypeptide. In certain embodiments, a polypeptide may contain more than one site-specific modification.

[0126] 2. Conjugates Provided herein are conjugates of antibodies against receptor tyrosine kinase orphan receptor 1 (ROR1). The conjugates comprise an antibody against ROR1 covalently linked, either directly or indirectly via a linker, to a payload. In some embodiments, the conjugates comprise an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1) site-specifically linked to at least one payload moiety, wherein the antibody comprises one or more unnatural amino acids. In certain embodiments, the antibody is linked to one payload. In further embodiments, the antibody is linked to more than one payload. In certain embodiments, the antibody is linked to more than 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 payloads.

[0127] The payload can be any payload that the practitioner of the skill finds useful. In certain embodiments, the payload is a therapeutic moiety. In certain embodiments, the payload is a diagnostic moiety, e.g., a label. Useful payloads are described in the sections below and in the Examples.

[0128] The linker can be any linker capable of forming at least one bond to the antibody and at least one bond to the payload. Useful linkers are described in the section below and in the Examples.

[0129] In the conjugates provided herein, the antibody may be any antibody having binding specificity to ROR1. ROR1 may be from any species. In certain embodiments, ROR1 is vertebrate ROR1. In certain embodiments, ROR1 is mammalian ROR1. In certain embodiments, ROR1 is human ROR1. In certain embodiments, ROR1 is mouse ROR1. In certain embodiments, ROR1 is cynomolgus monkey ROR1.

[0130] In certain embodiments, antibodies to ROR1 compete for binding with the antibodies described herein. In certain embodiments, antibodies to ROR1 bind to the same epitope as the antibodies described herein.

[0131] Antibodies are typically proteins comprising multiple polypeptide chains. In certain embodiments, antibodies are heterotetramers comprising two identical light (L) chains and two identical heavy (H) chains. Each light chain may be linked to a heavy chain by one covalent disulfide bond. Each heavy chain may be linked to other heavy chains by one or more covalent disulfide bonds. Each heavy and light chain may also have one or more intrachain disulfide bonds. As known to those skilled in the art, each heavy chain typically comprises a variable domain (V H ), followed by several constant domains. Each light chain typically has a variable domain (V L ) and constant domains. As is known to those skilled in the art, antibodies typically have selective affinity for their target molecules, i.e., antigens.

[0132] The antibodies provided herein may have any antibody form known to those skilled in the art. They may be full-length or fragments. Exemplary full-length antibodies include IgA, IgA1, IgA2, IgD, IgE, IgG, IgG1, IgG2, IgG3, IgG4, IgM, etc. Exemplary fragments include Fv, Fab, Fc, scFv, scFv-Fc, etc.

[0133] In certain embodiments, the antibody of the conjugate comprises one, two, three, four, five, or six of the CDR sequences described herein. In certain embodiments, the antibody of the conjugate comprises a heavy chain variable domain (V) as described herein. H In certain embodiments, the antibody of the conjugate comprises a light chain variable domain (V LIn certain embodiments, the antibody of the conjugate comprises a heavy chain variable domain (V H ) and a light chain variable domain (V L In certain embodiments, the antibody of the conjugate comprises a paired heavy chain variable domain and a paired light chain variable domain (V H -V L Pairs included.

[0134] In certain embodiments, the antibody of the conjugate comprises any of the amino acid sequences of the above antibodies. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 10 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 9 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 8 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 7 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 6 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 5 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 4 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 3 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 2 amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 1 conservative amino acid substitution. In some embodiments, the amino acid substitution is a conservative amino acid substitution. For example, in certain embodiments, the antibody comprises any of the above amino acid sequences with up to 10 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 9 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 8 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 7 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 6 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 5 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 4 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above amino acid sequences with up to 3 conservative amino acid substitutions.In certain embodiments, the antibody comprises any of the above amino acid sequences with up to two conservative amino acid substitutions, hi certain embodiments, the antibody comprises any of the above amino acid sequences with up to one conservative amino acid substitution.

[0135] In certain embodiments, antibody conjugates can be formed from antibodies containing one or more reactive groups. In certain embodiments, antibody conjugates can be formed from antibodies containing all naturally encoded amino acids. Those skilled in the art will recognize that some naturally encoded amino acids contain reactive groups that can be conjugated to a payload or a linker. These reactive groups include cysteine side chains, lysine side chains, and amino terminal groups. In these embodiments, the antibody conjugate can include a payload or linker linked to a residue of the antibody reactive group. In these embodiments, the payload precursor or linker precursor contains a reactive group that can form a bond with the antibody reactive group. Exemplary reactive groups include maleimide groups, activated carbonates (including, but not limited to, p-nitrophenyl esters), and activated esters (including, but not limited to, N-hydroxysuccinimide, p-nitrophenyl esters, and aldehydes). Particularly useful reactive groups include maleimides and succinimides, such as N-hydroxysuccinimide, for forming bonds to cysteine and lysine side chains. Additional reactive groups include alkynes, e.g., linear alkynes, and azides, for forming bonds to unnatural amino acids incorporated into antibody polypeptide chains. Additional reactive groups are described in the sections below and in the Examples.

[0136] In certain embodiments, the antibody comprises one or more modified amino acids having a reactive group as described herein. Typically, the modified amino acids are not naturally encoded amino acids. These modified amino acids may contain a reactive group useful for forming a covalent bond to a linker precursor or to a payload precursor. One skilled in the art can use the reactive group to link a polypeptide to any molecular entity capable of forming a covalent bond to the modified amino acid. Thus, conjugates comprising an antibody comprising a modified amino acid residue linked directly to a payload or indirectly via a linker are provided herein. Exemplary modified amino acids are described in the sections below. Generally, the modified amino acid has a reactive group capable of forming a bond to a linker or payload having a complementary reactive group.

[0137] The unnatural amino acids are placed at selected positions within the polypeptide chain of the antibody. These positions have been identified as providing optimal sites for substitution with unnatural amino acids. Each site can have an unnatural amino acid that is optimal for structure, function, and / or manner for generating the antibody.

[0138] In certain embodiments, the site-specific locations for substitutions provide antibodies that are stable. Stability can be measured by any technique readily apparent to one of skill in the art.

[0139] In certain embodiments, the site-specific locations for substitutions provide antibodies with optimal functional properties. For example, the antibody should exhibit little or no decrease in binding affinity to its target antigen compared to an antibody without the site-specific unnatural amino acid. In certain embodiments, the antibody can exhibit enhanced binding compared to an antibody without the site-specific unnatural amino acid.

[0140] In certain embodiments, the site-specific locations for substitution provide antibodies that can be made advantageously. For example, in certain embodiments, the antibodies exhibit advantageous properties in the synthetic methods discussed below. In certain embodiments, the antibodies should exhibit little or no reduction in production yield compared to antibodies without the site-specific unnatural amino acid. In certain embodiments, the antibodies can exhibit improved production yield compared to antibodies without the site-specific unnatural amino acid. In certain embodiments, the antibodies should exhibit little or no deficit in tRNA inhibition compared to antibodies without the site-specific unnatural amino acid. In certain embodiments, the antibodies can exhibit enhanced tRNA inhibition during production compared to antibodies without the site-specific unnatural amino acid.

[0141] In certain embodiments, the site-specific locations for substitutions provide antibodies with advantageous solubility. In certain embodiments, the antibodies should exhibit little or no reduction in solubility compared to antibodies without the site-specific unnatural amino acid. In certain embodiments, the antibodies can exhibit improved solubility compared to antibodies without the site-specific unnatural amino acid.

[0142] In certain embodiments, the site-specific locations for substitutions provide antibodies with advantageous expression. In certain embodiments, the antibodies should exhibit little or no deficiency in expression compared to antibodies without the site-specific unnatural amino acid. In certain embodiments, the antibodies can exhibit enhanced expression compared to antibodies without the site-specific unnatural amino acid.

[0143] In certain embodiments, the site-specific locations for substitutions provide antibodies with favorable folding. In certain embodiments, the antibodies should exhibit little or no loss of correct folding compared to antibodies without the site-specific unnatural amino acid. In certain embodiments, the antibodies can exhibit improved folding compared to antibodies without the site-specific unnatural amino acid.

[0144] In certain embodiments, the site-specific locations for substitution provide antibodies that can be advantageously conjugated. As described below, some unnatural amino acids have side chains or functional groups that facilitate conjugation of an antibody to a second agent, either directly or via a linker. In certain embodiments, the antibodies can exhibit improved conjugation efficiency compared to antibodies that do not have the same or other unnatural amino acids at other positions. In certain embodiments, the antibodies can exhibit improved conjugation yield compared to antibodies that do not have the same or other unnatural amino acids at other positions. In certain embodiments, the antibodies can exhibit improved conjugation specificity compared to antibodies that do not have the same or other unnatural amino acids at other positions.

[0145] The one or more unnatural amino acids are located at selected site-specific positions in at least one polypeptide chain of the antibody. The polypeptide chain can be any polypeptide chain of the antibody, including, but not limited to, either light chain or either heavy chain. The site-specific positions can be within any domain of the antibody, including any variable domain and any constant domain.

[0146] In certain embodiments, the antibodies provided herein comprise one unnatural amino acid at the site-specific position. In certain embodiments, the antibodies provided herein comprise two unnatural amino acids at the site-specific position. In certain embodiments, the antibodies provided herein comprise three unnatural amino acids at the site-specific position. In certain embodiments, the antibodies provided herein comprise more than three unnatural amino acids at the site-specific position. In certain embodiments, the antibodies provided herein comprise four unnatural amino acids at the site-specific position.

[0147] In certain embodiments, the antibodies provided herein comprise one or more unnatural amino acids at a position selected from the group consisting of heavy or light chain residues HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, and HC-S70, respectively, according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise one or more unnatural amino acids at a position selected from the group consisting of heavy chain or light chain residues HC-F404, HC-Y180, HC-F241, LC-K42, and LC-E161, respectively, according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at position HC-F404 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at position HC-Y180 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at positions HC-F404 and HC-Y180 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at position HC-F241 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at position LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof.In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at position LC-E161 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at positions HC-F404, HC-Y180, and LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at positions HC-F404, HC-Y180, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise an unnatural amino acid at positions HC-F404, HC-Y180, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise unnatural amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or post-translationally modified variants thereof. In certain embodiments, the antibodies provided herein comprise unnatural amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or post-translationally modified variants thereof. In these designations, HC denotes a heavy chain residue, and LC denotes a light chain residue.

[0148] In some aspects, the present disclosure provides a conjugate having the formula: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer or tautomer thereof, wherein: COMP is a residue of the anti-ROR1 antibody; PAY is the payload portion; LINK is a linker; and n2 is an integer from 1 to 10; The COMP comprises one or more unnatural amino acids.

[0149] In certain embodiments, a conjugate having formula (C1) or (C2): [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer or tautomer thereof, provided herein, wherein: COMP is a residue of the anti-ROR1 antibody; PAY is the payload portion; W 1 , W 2 , W 3 , W 4 , and W 5 are each independently a single bond, absent, or a divalent linking group; EG is absent or is an eliminator group; each RT is a release trigger group in the backbone of formula (C1) or (C2) or attached to EG, and each RT is optional; HP is a single bond, is absent, or is a divalent hydrophilic group; each SG is a single bond, absent, or a divalent spacer group; R is hydrogen, a terminal conjugate group, or a divalent residue of a terminal conjugate group; and n2 is an integer from 1 to 10.

[0150] In some embodiments, the conjugate of Formula (C1) or (C2) comprises n2 linked PAY moieties, where n2 is an integer from 1 to 10. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n2 is 10.

[0151] bonding group The linking group facilitates the incorporation of an eliminator group, a release trigger group, a hydrophobic group, a spacer group, and / or a conjugate group into the compound. Useful linking groups are known and readily apparent to those skilled in the art. Examples of useful linking groups are provided herein. In certain embodiments, the linking group is a W 1 , W 2 , W 3 , W 4 , or W 5 In certain embodiments, the linking group can include a divalent ketone, a divalent ester, a divalent ether, a divalent amide, a divalent amine, an alkylene, an arylene, a sulfide, a disulfide, a carbonylene, or a combination thereof. In certain embodiments, the linking group can include -C(O)-, -O-, -C(O)NH-, -C(O)NH-alkyl-, -OC(O)NH-, -SC(O)NH-, -NH-, -NH-alkyl-, -N(CH3)CH2CH2N(CH3)-, -S-, -SS-, -OCH2CHO-, or its reverse (e.g., -NHC(O)-), or a combination thereof.

[0152] Eliminator group The eliminator group facilitates the separation of the biologically active portion of a compound or conjugate described herein from the remainder of the compound or conjugate in vivo and / or in vitro. The eliminator group also cooperates with a release trigger group to facilitate the separation of the biologically active portion of a compound or conjugate described herein. For example, the eliminator group and the release trigger group can react in vivo and / or in vitro in a release reaction to release the biologically active portion of a compound or conjugate described herein from the compound or conjugate. When the release reaction is initiated by the release trigger, the eliminator group cleaves the biologically active portion or a prodrug form of the biologically active portion to form a stable, non-toxic entity that does not further affect the activity of the biologically active portion.

[0153] In certain embodiments, the eliminator group is designated herein as EG. Useful eliminator groups include those described herein. In certain embodiments, the eliminator group is: [ka] where R EG is selected from the group consisting of hydrogen, alkyl, biphenyl, -CF3, -NO2, -CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-. In each structure, the phenyl ring may be joined by one, two, three, or in some cases, four R EG In the second and third structures, one skilled in the art will recognize that EG is attached to an RT that is not within the backbone of formula (C1) as shown in the above description of formula (C1). In some embodiments, R EG is selected from the group consisting of hydrogen, alkyl, biphenyl, -CF3, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-. In a further embodiment, R EGis selected from the group consisting of hydrogen, —NO, —CN, fluoro, bromo, and chloro. In certain embodiments, the eliminator group is [ka] In certain embodiments, the eliminator group is [ka] In certain embodiments, the eliminator group is [ka] is.

[0154] In some embodiments, provided herein is a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein EG comprises phenylene, carboxylene, amine, or a combination thereof. In some embodiments, the eliminator group is [ka] where Z can be CH or N, and R EG is selected from the group consisting of hydrogen, alkyl, biphenyl, -CF3, -NO2, -CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-. In each structure, the phenyl ring may be joined by one, two, three, or in some cases, four R EG It will be appreciated by those skilled in the art that in the first and second structures, EG is attached to an RT that is not within the backbone of formula (C1) as shown in the above description of formula (C1). In some embodiments, R EG is selected from the group consisting of hydrogen, alkyl, biphenyl, -CF3, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-. In a further embodiment, REG is selected from the group consisting of hydrogen, —NO, —CN, fluoro, bromo, and chloro. EG is hydrogen. In certain embodiments, the eliminator group is [ka] In certain embodiments, the eliminator group is [ka] In certain embodiments, the eliminator group is [ka] is.

[0155] Release trigger group The release trigger group facilitates the separation of the biologically active portion of a compound or conjugate described herein from the remainder of the compound or conjugate in vivo and / or in vitro. The release trigger group also cooperates with the eliminator group to facilitate the separation of the biologically active portion of a compound or conjugate described herein. For example, the eliminator group and the release trigger group can react in vivo and / or in vitro in a release reaction to release the biologically active portion of a compound or conjugate described herein from the compound or conjugate. In certain embodiments, the release trigger may be activated by a biologically driven reaction with high tumor:non-tumor specificity, such as the proteolytic action of an enzyme overexpressed in the tumor environment.

[0156] In certain embodiments, the release trigger group is designated herein as RT. In certain embodiments, RT is divalent and attached within the backbone of formula (C1). In other embodiments, RT is monovalent and attached to EG as depicted above. Useful release trigger groups include those described herein. In certain embodiments, the release trigger group comprises a residue of a natural or unnatural amino acid, or a residue of a sugar ring. In certain embodiments, the release trigger group is [ka] Those skilled in the art will recognize that the first structure may be divalent and attached within the backbone of formula (C1) or as depicted in formula (C2), and the second structure may be monovalent and attached to EG as depicted in formula (C1) above. In certain embodiments, the release trigger group is: [ka] In certain embodiments, the release trigger group is: [ka] is.

[0157] In some embodiments, the release trigger group is: [ka] wherein R1 is H, or [ka] and R2 is CH3, CH2CH2CO2H, or (CH2)3NHCONH2. a protease-cleavable R1-Val-X peptide having the structure: [ka] (wherein Z is OH or NH2) a legumain-cleaving Ala-Ala-Asn or Ala-Ala-Asp peptide having the structure: [ka] a β-glucuronidase-cleavable β-glucuronide having the structure: [ka] It is a Val-Lys-Gly peptide having the structure: [ka] It will be appreciated that is a divalent structure and may be attached within the backbone of formula (C1) or as depicted in formula (C2). [ka] is monovalent and may be attached to EG as depicted in formula (C1) above.

[0158] In certain embodiments, the release trigger is selected from the group consisting of Val-Lys-Gly, Val-Ala-Asp, Ala-Ala-Ala, Val-Lys, Gly-Gly-Gly, Val-Ala, Gly-Gly-Phe-Gly, Val-Cit, Val-Cit, Val-Glu, Ala-Ala-Asn, and Gly. In certain embodiments, the release trigger further comprises an unnatural amino acid. In certain embodiments, the unnatural amino acid is [ka] wherein POLY is a polymer, e.g., a hydrophilic polymer. In certain embodiments, the unnatural amino acid is [ka] In this formula, m1 is an integer of 1 to 25, for example, 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25.

[0159] hydrophilic group The hydrophilic group helps increase the hydrophilicity of the compounds described herein. Increased hydrophilicity is believed to allow for greater solubility in aqueous solutions, such as those found in biological systems. The hydrophilic group can also function as a spacer group, as described in more detail herein.

[0160] In certain embodiments, the hydrophilic group is designated herein as HP. Useful hydrophilic groups include those described herein. In certain embodiments, the hydrophilic group is a divalent poly(ethylene glycol). In certain embodiments, the hydrophilic group has the formula: [ka] (wherein m1 is an integer of 1 to 13, may be 1 to 4, may be 2 to 4, or may be 4 to 8). In certain embodiments, m1 is 4. In certain embodiments, m1 is 12. In certain embodiments, m1 is 13.

[0161] In some embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the formula: [ka]

[0162] In some other embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the formula: [ka]

[0163] In other embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the formula: [ka]

[0164] In other embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the formula: [ka]

[0165] In some embodiments, the hydrophilic group is a sulfonic acid. In some embodiments, the hydrophilic group is the side chain of cysteic acid. In some embodiments, the hydrophilic group is a group represented by the formula: [ka] In certain embodiments, the hydrophilic group may have a chain-presenting sulfonic acid having the formula: [ka] In this formula, m1 is an integer of 1 to 25, for example, 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25.

[0166] Spacer group Spacer groups facilitate spacing of the conjugate group and other groups on the compounds described herein. This spacing can result in more efficient conjugation of the compounds described herein to antibodies, as well as more efficient cleavage of active catabolic products. Spacer groups can also stabilize the conjugate group and improve overall antibody-drug conjugate properties.

[0167] In certain embodiments, the spacer group is designated herein as SP. Useful spacer groups include those described herein. In certain embodiments, the spacer group is: [ka] In certain embodiments, the spacer group, W 4 and a hydrophilic group are combined to form a compound of the formula: [ka] (wherein m1 is an integer of 1 to 13, optionally 1 to 4, optionally 2 to 4, or optionally 4 to 8). This forms a divalent poly(ethylene glycol) represented by the formula:

[0168] In some embodiments, the SP [ka] is.

[0169] In some embodiments, the divalent poly(ethylene glycol) has the formula: [ka]

[0170] In some other embodiments, the divalent poly(ethylene glycol) has the formula: [ka]

[0171] In other embodiments, the divalent poly(ethylene glycol) has the formula: [ka]

[0172] In other embodiments, the divalent poly(ethylene glycol) has the formula: [ka]

[0173] In some embodiments, the spacer group has the formula: [ka] The sulfonic acid may have a chain-presenting sulfonic acid having the formula:

[0174] In some embodiments, the spacer group is a diamine. In some embodiments, the spacer group is [ka] This is shown by:

[0175] In some embodiments, the spacer group comprises a fused ring or a spiro ring. [ka] In this formula, each n a , m a , o a , and p a is an integer independently selected from 1, 2, 3, 4, and 5. In some embodiments, the spacer group is [ka] In this formula, each n a , m a , o a , and p a is an integer independently selected from 1, 2, 3, 4, and 5. In some embodiments, the spacer group is [ka] is selected from the group consisting of:

[0176] Conjugate groups and their residues The conjugate group facilitates conjugation of a payload described herein with a second compound, such as an antibody described herein. In certain embodiments, the conjugate group is designated herein as R. The conjugate group may react via any suitable reaction mechanism known to those of skill in the art. In certain embodiments, the conjugate group reacts via a [3+2] alkyne-azide cycloaddition reaction, an inverse electron demand Diels-Alder ligation reaction, a thiol-electrophilic reaction, or a carbonyl-oxyamine reaction, as described in more detail herein. In certain embodiments, the conjugate group comprises an alkyne, a strained alkyne, a tetrazine, a thiol, a para-acetyl-phenylalanine residue, an oxyamine, a maleimide, or an azide. In certain embodiments, the conjugate group comprises [ka] , -N3, or -SH, and R 201 is lower alkyl. In one embodiment, R 201 is methyl, ethyl, or propyl. In some embodiments, R 201 is methyl. Additional conjugate groups are described, for example, in U.S. Patent Application Publication Nos. 2014 / 0356385, 2013 / 0189287, 2013 / 0251783, U.S. Patent Nos. 8,703,936, 9,145,361, 9,222,940, and 8,431,558.

[0177] After conjugation, a divalent residue of the conjugate group is formed and attached to a residue of the antibody. The structure of the divalent residue is determined by the type of conjugation reaction used to form the conjugate.

[0178] In certain embodiments, when the conjugate is formed by a [3+2] alkyne-azide cycloaddition reaction, the divalent residue of the conjugate group comprises a thiazole ring or a fused ring group containing a thiazole ring. In certain embodiments, when the conjugate is formed by a strain-promoted [3+2] alkyne-azide cycloaddition (SPAAC) reaction, the divalent residue of the conjugate group is [ka] is.

[0179] In certain embodiments, when the conjugate is formed by a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the conjugate group comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In certain embodiments, when the conjugate is formed by a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the conjugate group comprises [ka] is.

[0180] In certain embodiments, when the conjugate is formed by a thiol-maleimide reaction, the divalent residue of the conjugate group comprises a succinimidylene and a sulfur linkage. In certain embodiments, when the conjugate is formed by a thiol-maleimide reaction, the divalent residue of the conjugate group comprises: [ka] is.

[0181] In certain embodiments, the conjugate is formed by a thiol-N-hydroxysuccinimide reaction using the following group: [ka] The reaction involved in forming the conjugate involves the following steps: [ka] and the resulting divalent residue of the conjugate group comprises [ka] is.

[0182] In certain embodiments, when the conjugate is formed by a carbonyl-oxyamine reaction, the divalent residue of the conjugate group comprises a divalent residue of a non-natural amino acid. In certain embodiments, when the conjugate is formed by a carbonyl-oxyamine reaction, the divalent residue of the conjugate group comprises [ka] is.

[0183] In certain embodiments, when the conjugate is formed by a carbonyl-oxyamine reaction, the divalent residue of the conjugate group comprises an oxime linkage. In certain embodiments, when the conjugate is formed by a carbonyl-oxyamine reaction, the divalent residue of the conjugate group comprises an oxime linkage. [ka] is.

[0184] In certain embodiments, provided herein are conjugates of Formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, wherein R comprises a triazole ring. In certain embodiments, provided herein are conjugates of Formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, wherein R is a triazole ring or a fused ring group comprising a triazole ring. In certain embodiments, provided herein are conjugates of Formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, wherein R is [ka] Provided herein is a conjugate of formula (C1) or (C2), wherein:

[0185] In one embodiment, provided herein is a conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R comprises a fused bicyclic ring having at least two adjacent nitrogen atoms within the ring. [ka] Provided herein is a conjugate of formula (C1) or (C2), wherein:

[0186] In certain embodiments, provided herein is a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R comprises a sulfur linkage. [ka] Provided herein is a conjugate of formula (C1) or (C2), wherein:

[0187] In certain embodiments, provided herein is a conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R comprises a divalent residue of an unnatural amino acid. [ka] Provided herein is a conjugate of formula (C1) or (C2), wherein:

[0188] In certain embodiments, provided herein are conjugates having the formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which contain an amide linkage. [ka] Provided herein is a conjugate of formula (C1) or (C2), wherein:

[0189] In certain embodiments, provided herein are conjugates having Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which contain an oxime linkage. [ka] Provided herein is a conjugate of formula (C1) or (C2), wherein:

[0190] In one embodiment, R is [ka] Provided herein is a conjugate of formula (C1) or (C2), wherein:

[0191] In some embodiments, provided herein are compounds of Formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, where COMP is a residue of any compound known to be useful for conjugation with a payload described herein and an optional linker described herein. In some embodiments, provided herein are compounds of Formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, where COMP is a residue of an antibody chain.

[0192] In certain aspects, provided herein is an antibody conjugate comprising a payload described herein linked to an anti-ROR1 antibody and an optional linker described herein, wherein COMP is a residue of an antibody. In certain embodiments, provided herein is an antibody conjugate represented by formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody and R comprises a triazole ring or a fused ring group comprising a triazole ring. In certain embodiments, COMP is a residue of an antibody and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0193] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody and R comprises a fused bicyclic ring, the fused bicyclic ring having at least two adjacent nitrogen atoms within the ring. In one embodiment, COMP is a residue of an antibody and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0194] In one embodiment, provided herein is an antibody conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of a polypeptide and R comprises a sulfur linkage. In one embodiment, COMP is a residue of a polypeptide and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0195] In one embodiment, provided herein is an antibody conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of a polypeptide and R comprises a divalent residue of an unnatural amino acid. [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0196] In one embodiment, provided herein is an antibody conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of a polypeptide and R comprises an amide linkage. In one embodiment, COMP is a residue of a polypeptide and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0197] In one embodiment, provided herein is an antibody conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of a polypeptide and R comprises an amide linkage. In one embodiment, COMP is a residue of a polypeptide and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0198] In one aspect, provided herein is an antibody conjugate comprising a payload described herein and an optional linker described herein linked to an antibody of Formula (C1) or (C2), wherein COMP is a residue of an antibody, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. In one embodiment, provided herein is an antibody conjugate of Formula (C1) or (C2), wherein COMP is a residue of an antibody and R comprises a triazole ring or a fused ring group comprising a triazole ring, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. In one embodiment, provided herein is an antibody conjugate of Formula (C1) or (C2), wherein COMP is a residue of an antibody and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0199] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody and R comprises a fused bicyclic ring, the fused bicyclic ring having at least two adjacent nitrogen atoms within the ring. In one embodiment, COMP is a residue of an antibody and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0200] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody and R comprises a sulfur linkage. In one embodiment, COMP is a residue of an antibody and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0201] In certain embodiments, provided herein is an antibody conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody and R comprises a divalent residue of a non-natural amino acid. [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0202] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody and R comprises an amide linkage. In one embodiment, COMP is a residue of an antibody and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0203] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody and R comprises an oxime linkage. In one embodiment, COMP is a residue of an antibody and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0204] In one aspect, provided herein is an antibody conjugate comprising a payload described herein and an optional linker described herein linked to an antibody chain represented by Formula (C1) or (C2), wherein COMP is a residue of an antibody chain, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. In one embodiment, provided herein is an antibody conjugate represented by Formula (C1) or (C2), wherein COMP is a residue of an antibody chain and R comprises a triazole ring or a fused ring group comprising a triazole ring, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. In one embodiment, provided herein is an antibody conjugate represented by Formula (C1) or (C2), wherein COMP is a residue of an antibody chain and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0205] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody chain and R comprises a fused bicyclic ring, the fused bicyclic ring having at least two adjacent nitrogen atoms within the ring. In one embodiment, COMP is a residue of an antibody chain and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0206] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody chain and R comprises a sulfur linkage. In one embodiment, COMP is a residue of an antibody chain and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0207] In one embodiment, provided herein is an antibody conjugate of Formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody chain and R comprises a divalent residue of a non-natural amino acid. [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0208] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody chain and R comprises an amide linkage. In one embodiment, COMP is a residue of an antibody chain and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0209] In one embodiment, provided herein is an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein COMP is a residue of an antibody chain and R comprises an amide linkage. In one embodiment, COMP is a residue of an antibody chain and R is [ka] Provided herein is an antibody conjugate of Formula (C1) or (C2), wherein:

[0210] Conjugates In certain embodiments, provided herein is a conjugate represented by any of the following formulas, where COMP represents a residue of an anti-ROR1 antibody and PAY represents a payload moiety: [ka] JPEG2025525445000098.jpg199170 JPEG2025525445000099.jpg173170

[0211] In certain embodiments, provided herein is a conjugate represented by any of the following formulas, where COMP represents a residue of an anti-ROR1 antibody and PAY represents a payload moiety: [ka]

[0212] In certain embodiments, provided herein is a conjugate represented by any of the following formulas, where COMP represents a residue of an anti-ROR1 antibody and PAY represents a payload moiety: [ka]

[0213] In certain embodiments, provided herein is a conjugate represented by any of Formulas 101a-104b, where COMP represents a residue of an anti-ROR1 antibody and PAY represents a payload moiety: [ka] JPEG2025525445000103.jpg63170

[0214] In any of the above-described embodiments, the conjugate comprises n2 PAY moieties, where n2 is an integer from 1 to 10. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n2 is 9. In some embodiments, n2 is 10.

[0215] In some embodiments, provided herein are anti-ROR1 antibody conjugates comprising a modified hemiasterlin and a linker, e.g., as described in PCT Publication No. 2016 / 123582. For example, the conjugate may have a structure comprising any of formulas 1000-1000b, 1001-1001b, 1002-1002b, and I-XIXb-2, 101-111b, or 1-8b, as described in PCT Publication No. 2016 / 2016 / 123582. Examples of conjugates comprising modified hemiasterlin and a linker are provided below.

[0216] In some embodiments, the conjugate of formula (I) [ka] (I) or a pharmaceutically acceptable salt thereof (wherein COMP is a residue of an anti-ROR1 antibody provided herein; L 1 -C 1-6 alkylene-; Y is -X 1 -C 1-6 Alkylene-[X 1 -C 1-6 alkylene] n -[X 1 ] p -, -X 1 -C 2-6 Alkenylene-[X 1 -C 2-6 Alkenylene] n -[X 1 ] p -, -X 1 -C 2-6 Alkynylene-[X 1 -C 2-6 Alkynylene] n -[X 1 ] p -, and at least one alkylene, alkenylene or alkynylene in Y is R 50 and The alkylene, alkenylene, or alkynylene in Y is R 51 may be substituted with one or more substituents selected from R 50 -C 1-6 Alkylene-X 2 -[C 1-6 alkylene] m -POLY, -C 2-6 Alkenylene-X 2 -[C 2-6 Alkenylene] m -POLY or -C 2-6 Alkynylene-X 2 -[C 2-6 Alkynylene] m -POLY, R 50 Each alkylene, alkenylene, or alkynylene is selected from the group consisting of halogen, —CN, —NO2, —OH, —N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 optionally substituted with one or more substituents selected from haloalkyl; R 51 are independently halogen, -CN, -NO2, -OH, -N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 haloalkyl; X 1 and X 2 are independently —C(O)— and —N(R 10 )C(O)-; R 10Each occurrence of represents hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 independently selected from haloalkyl; POLY is a water-soluble polymer; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0 and 1; p is an integer selected from 0 and 1; Su is a hexose monosaccharide; D is a drug moiety; and RL is a reactive group residue) is provided.

[0217] In some embodiments, a conjugate of formula (II) [ka] (II) or a pharmaceutically acceptable salt thereof (wherein COMP is a residue of an anti-ROR1 antibody provided herein; L 1 -C 1-6 alkylene-; Y is -X 1 -C 1-6 Alkylene-[X 1 -C 1-6 alkylene] n -X 1 -, -X 1 -C 2-6 Alkenylene-[X 1 -C 2-6 Alkenylene] n -X 1 -, -X 1 -C 2-6 Alkynylene-[X 1 -C 2-6 Alkynylene] n -X 1 -, and at least one alkylene, alkenylene or alkynylene in Y is R50 and is substituted with one or more substituents selected from: R 50 -C 1-6 Alkylene-X 2 -[C 1-6 alkylene] m -POLY, -C 2-6 Alkenylene-X 2 -[C 2-6 Alkenylene] m -POLY or -C 2-6 Alkynylene-X 2 -[C 2-6 Alkynylene] m -POLY, R 50 Each alkylene, alkenylene, or alkynylene is selected from the group consisting of halogen, —CN, —NO2, —OH, —N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 optionally substituted with one or more substituents selected from haloalkyl; X 1 and X 2 are independently —C(O)— and —N(R 10 )C(O)-; R 10 Each occurrence of represents hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 independently selected from haloalkyl; POLY is a water-soluble polymer; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0 and 1; Su is a hexose monosaccharide; D is a drug moiety; and RL is a reactive group residue) is provided.

[0218] In some embodiments, a conjugate of formula (IIA) [ka] (IIA) or a pharmaceutically acceptable salt thereof is provided.

[0219] In some embodiments, the compound of formula (II) has the formula (IIB): [ka] (IIB) or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments of Formula (I), (II), (IIA), or (IIB), L 1 -C 1-3 In some embodiments, L 1 In some embodiments of Formula (I), (II), (IIA), or (IIB), L 1 is -CHCH-. In some embodiments, L 1 is -CH2CH2CH2-.

[0221] In some embodiments of Formula (I), including any of those described above, p is 0. In some embodiments of Formula (I), including any of those described above, p is 1.

[0222] In some embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is -X 1 -C 1-6 Alkylene-[X 1 -C 1-6 alkylene] n -X 1 - and at least one alkylene in Y is R 50In some embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is substituted with one or more substituents selected from -X 1 -C 1-6 Alkylene-[X 1 -C 1-6 alkylene] n - and at least one alkylene in Y is R 50 In some embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is substituted with one or more substituents selected from -X 1 -C 2-6 Alkenylene-[X 1 -C 2-6 Alkenylene] n -X 1 - and at least one alkenylene in Y is R 50 In some embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is substituted with one or more substituents selected from -X 1 -C 2-6 Alkenylene-[X 1 -C 2-6 Alkenylene] n - and at least one alkenylene in Y is R 50 In some embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is substituted with one or more substituents selected from -X 1 -C 2-6 Alkynylene-[X 1 -C 2-6 Alkynylene] n -X 1 - and at least one alkynylene in Y is R 50 In some embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is substituted with one or more substituents selected from -X 1 -C 2-6 Alkynylene-[X 1 -C 2-6 Alkynylene]n - and at least one alkynylene in Y is R 50 In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n is 0. In some embodiments of Formula (I), (II), (IIA), or (IIB), n is 1. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n is 2. In some embodiments, including any of those described above, n is 3.

[0223] In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is -X 1 -C 1-4 Alkylene-[X 1 -C 1-4 alkylene] n -X 1 - and at least one alkylene in Y is R 50 In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n is 0. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n is 1. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n is 2. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n is 3.

[0224] In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is -X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1- and at least one alkylene in Y is R 50 In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is substituted with one or more substituents selected from -X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 - and at least one alkylene in Y is R 50 In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, Y is substituted with one or more substituents selected from -X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 - and at least one alkylene in Y is R 50 and is substituted with one or more substituents selected from:

[0225] In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, R 50 -C 1-6 Alkylene-X 2 -[C 1-6 alkylene] m -POLY, R 50 Each alkylene is a halogen, -CN, -NO2, -OH, -N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, R 50 -C 1-4 Alkylene-X 2 -[C 1-4 alkylene] m -POLY, R 50 Each alkylene is a halogen, -CN, -NO2, -OH, -N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, R 50 Each alkylene is a halogen, -OH, -N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 and optionally substituted with one or more substituents selected from haloalkyl. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, m is 0. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, m is 1.

[0226] In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, R 50 -C 2-6 Arkenine-X 2 -[C 2-6 Alkenine]m -POLY, R 50 Each alkenylene is a halogen, -CN, -NO2, -OH, -N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 and optionally substituted with one or more substituents selected from haloalkyl. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, m is 0. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, m is 1.

[0227] In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, R 50 -C 2-6 Alkinin-X 2 -[C 2-6 Alkynylene] m -POLY, R 50 Each alkynylene is a halogen, -CN, -NO2, -OH, -N(R 10 )2, -C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic rings, 3- to 12-membered heterocyclic rings, and C 1-10 and optionally substituted with one or more substituents selected from haloalkyl. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, m is 0. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, m is 1.

[0228] In certain embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), a copolymer of ethylene glycol and propylene glycol, a poly(oxyethylated polyol), a poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), polysarcosine, or a combination thereof. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is polyethylene glycol (PEG). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is methoxypolyethylene glycol (mPEG). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is poly(propylene glycol) (PPG). In some embodiments, POLY is a copolymer of ethylene glycol and propylene glycol. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a poly(oxyethylenated polyol). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a poly(olefinic alcohol). In some embodiments, POLY is poly(vinylpyrrolidone). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is poly(hydroxyalkylmethacrylamide).In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a poly(hydroxyalkyl methacrylate). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a poly(saccharide). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a poly(α-hydroxy acid). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a poly(vinyl alcohol). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a polyphosphazene. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is polyoxazoline (POZ). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is poly(N-acryloylmorpholine). In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is polysarcosine. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is a nonpeptidic, water-soluble polymer. In certain embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, POLY comprises polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG). In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of those described above, POLY is: [ka] where: [ka] represents a bond to the remainder of the compound, and n1 is an integer from 1 to 20. In certain embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is an integer from 5 to 15. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 1. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 2. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 3. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 4. In some embodiments of Formula (II), (IIA), or (IIB), including any of those described above, n1 is 5. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 6. In some embodiments of Formula (I), (II), (IIA), or (IIB), n1 is 7. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 8. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 9. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 10. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 11. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 12. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 13. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 14. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 15. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 16.In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 17. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 18. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 19. In some embodiments of Formula (II), (IIA), or (IIB), including any of those described above, n1 is 20. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 21. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 22. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 23. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 24. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 25. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 26. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 27. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 28. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 29. In some embodiments of Formula (I), (II), (IIA), or (IIB), including any of those described above, n1 is 30.

[0229] In certain embodiments, R comprises an alkyne, cyclooctyne, strained alkene, tetrazine, amine, methylcyclopropene, thiol, para-acetyl-phenylalanine residue, oxyamine, maleimide, or azide. In some embodiments, R comprises an alkyne. In some embodiments, R comprises a cyclooctyne. In some embodiments, R comprises a strained alkene. In some embodiments, R comprises a tetrazine. In some embodiments, R comprises an amine. In some embodiments, R comprises a methylcyclopropene. In some embodiments, R comprises a thiol. In some embodiments, R comprises a para-acetyl-phenylalanine residue. In some embodiments, R comprises an oxyamine. In some embodiments, R comprises a maleimide. In some embodiments, R comprises an azide. In some embodiments, R comprises [ka] is selected from the group consisting of [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] and [ka] represents the bond to the remainder of the compound. In one embodiment, R L is [ka] and [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] and [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] and [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] and [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] In this equation, [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] and [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] and [ka] represents the bond to the rest of the compound. In some embodiments, R L is [ka] and [ka] represents the bond to the remainder of the compound. In some embodiments, Su is a sugar moiety. In some embodiments, Su is a hexose-type monosaccharide. Su can be a glucuronic acid or mannose residue. In certain embodiments, Su is [ka] In this equation, [ka] represents the bond to the remainder of the compound. In certain embodiments, Su is [ka] In this equation, [ka] represents the bond to the rest of the compound.

[0230] In one aspect, a conjugate of formula (III): [ka] (III) or a pharmaceutically acceptable salt and / or positional isomer thereof provided herein; During the ceremony, L 1a teeth, [ka] Selected from; Ring A is an optionally substituted bridged, fused, or spirocyclic bicyclic carbocycle or an optionally substituted bridged, fused, or spirocyclic bicyclic heterocycle, and the carbocycle or heterocycle of Ring A is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO, -OH, -N(R 2 R 3)2, -C(O)-, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , optionally substituted with one or more substituents selected from aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Ring B is an optionally substituted N-linked bridged, fused, or spirocyclic bicyclic heterocycle, wherein Ring B is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO, —OH, —N(R 2 R 3 )2, -C(O)-, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , optionally substituted with one or more substituents selected from aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R a and R b are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; a is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; R 1 is hydrogen or cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 alkyl optionally substituted with one or more substituents selected from aryl, aryl, and heteroaryl; R2 and R 3 is independently selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Y a is *-C(O)-(CR a R b ) c -NH- or *-C(O)-(CR a R b ) c - and * in these formulas represents Y a represents the site of binding to RL; c is an integer selected from 1, 2, 3, 4, 5, or 6; RL is a reactive group residue; L 2 is a linker that is absent or comprises a hydrophilic polymer residue; L 3 is absent or -C(O)-AA-, -C(O)-AA-Z-(CR a R b ) a -Z-(CR a R b ) a -C(O)-, -C(O)-Z-(CR a R b ) a -C(O)-ZL 4 -OC(O)-, -Z-AA-, -AA-, -C(O)-, -C(O)-AA-Z-(CR a R b ) a -, -AA-C(O)-, -C(O)-(CR a R b ) a -Z-(CR a R b )-Z-AA-C(O)-, -C(O)OL 4 -ZC(O)-(CR a R b ) a -ZC(O)-, -AA-Z-, or -(CR a R b ) a -Z-AA-C(O)-; Z is -NR 2- and -O-; AA is an amino acid residue or a peptide residue; L 4 teeth, [ka] where Su is a hexose monosaccharide; d is an integer independently selected from 1, 2, and 3; D is a drug moiety; COMP is a residue of the ROR1 antibody; and [ka] represents the bond to the rest of the compound.

[0231] In certain embodiments, the compound of formula (III) is a compound of formula (IIIA): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integers c, RL, R a , R b , Ring B, L 2 , L 3 , D, and COMP are as defined herein.

[0232] In certain embodiments, the compound of formula (IIIA) is selected from: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0233] In certain embodiments, the compound of formula (III) is a compound of formula (IIIB): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integers c, RL, R a , R b , Ring B, L 2 , L 3 , D, and COMP are as defined herein.

[0234] In certain embodiments, the compound of formula (IIIB) is selected from: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0235] In certain embodiments, the compound of formula (III) is a compound of formula (IIIC): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integer a, integer c, RL, R a , R b , ring A, L 2 , L 3 , D, and COMP are as defined herein.

[0236] In certain embodiments, the compound of formula (IIIC) is selected from: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0237] In certain embodiments, the compound of formula (III) is a compound of formula (IIID): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integer a, integer c, RL, R a , R b , ring A, L 2 , L 3, D, and COMP are as defined herein.

[0238] In certain embodiments, the compound of formula (IIID) is selected from: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0239] In certain embodiments, the compound of formula (III) is a compound of formula (IIIE): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integer a, integer c, RL, R a , R b , Ring B, L 3 , POLY 2 , D, and COMP are as defined herein.

[0240] In certain embodiments, the compound of formula (IIIE) is selected from: [ka] JPEG2025525445000148.jpg113170 or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0241] In certain embodiments, the compound of formula (III) is a compound of formula (IIIF): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integer a, integer c, RL, R a , R b , Ring B, L 3 , POLY 2 , D, and COMP are as defined herein.

[0242] In certain embodiments, the compound of formula (IIIF) is selected from: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0243] In certain embodiments, the compound of formula (III) is a compound of formula (IIIG): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integer a, integer c, RL, R a , R b , ring A, L 3 , POLY 2 , D, and COMP are as defined herein.

[0244] In certain embodiments, the compound of formula (IIIG) is selected from: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0245] In certain embodiments, the compound of formula (III) is a compound of formula (IIIH): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integer a, integer c, RL, R a , R b , ring A, L 3 , POLY 2 , D, and COMP are as defined herein.

[0246] In certain embodiments, the compound of formula (IIIH) is selected from: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0247] In one aspect, a conjugate of formula (V): [ka] (V) or a pharmaceutically acceptable salt and / or positional isomer thereof, as provided herein: During the ceremony, L 5 is a linker comprising an unnatural amino acid; and RL, COMP, Y a , L 2 , L 3 , and D are as defined herein.

[0248] In certain embodiments, the compound of formula (V) is a compound of formula (VA): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, RL, COMP, Y a , L 2 , L 3 , and D are as defined herein.

[0249] In certain embodiments, the compound of formula (V) is a compound of formula (VB): [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof, In the formula, integer a, integer c, RL, COMP, R a , R b , POLY 1 , AA, and D are as defined herein.

[0250] In certain embodiments, the compound of formula (VB) has the formula: [ka] or a pharmaceutically acceptable salt and / or positional isomer thereof.

[0251] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] is.

[0252] In certain embodiments of Formulas (III)-(VB), including any of those described above, L1a teeth, [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] is.

[0253] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a wherein ring B is an optionally substituted 5- to 12-membered N-linked bridged, fused, or spirocyclic bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, including the N to which the ring is attached; and ring B is selected from alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO, —OH, —N(R 2 R 3 )2, -C(O)-, -C(O)N(R 2 R 3 )2, -C(O)OR 2 In certain embodiments of formulas (III)-(VB), including any of those described above, L is optionally substituted with one or more substituents selected from: aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. 1a Ring B is an optionally substituted 5- to 12-membered N-linked spirocyclic bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, including the N to which the ring is attached.

[0254] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] (In the formula, m ais an integer selected from 1, 2, 3, 4, and 5; n a and o a each is independently an integer selected from 1, 2, and 3. is selected from.

[0255] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), L 1a Ring B of [ka] In certain embodiments, ring B is [ka] is.

[0256] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), L 1a Ring B of [ka] In certain embodiments of formulas (III)-(VB), L 1a Ring B of [ka] is.

[0257] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) is.

[0258] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] is.

[0259] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] (In the formula, m a is 1, 2, or 3) is.

[0260] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] In certain embodiments, [ka] teeth, [ka] In certain embodiments of formulas (III)-(VB), [ka] teeth, [ka] is.

[0261] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] is.

[0262] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] is selected from.

[0263] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] is selected from.

[0264] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] (In the formula, m a is an integer selected from 1, 2, 3, 4, and 5; n a and o a each is independently an integer selected from 1, 2, and 3. is selected from.

[0265] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] is selected from.

[0266] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] and JPEG2025525445000233.jpg21170 (in the formula, X 1a , X 2a , X 3 , and X 4 are independently -C(R 4 ) selected from -2-, -NH-, -O-, and -S-; X 1a , X 2a and X 3 If there is an X 1a ~X 3 At least one of the -C(R 4 )2- and X 1a , X 2a , X 3 and X 4 If there is an X 1a~X 4 At least two of the -C(R 4 )2- and; and R 4 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or two R on the same carbon 4 groups together form an oxo group) is selected from.

[0267] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring B of [ka] (In the formula, X 1a , X 2a , X 3 , and X 4 are independently -C(R 4 ) selected from -2-, -NH-, -O-, and -S-; X 1a , X 2a and X 3 If there is an X 1a ~X 3 At least one of the -C(R 4 )2- and X 1a , X 2a , X 3 and X 4 If there is an X 1a ~X 4 At least two of the -C(R 4 )2- and; and R4 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or two R on the same carbon 4 groups together form an oxo group) is selected from.

[0268] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a wherein ring A is an optionally substituted bridged, fused, or spirocyclic bicyclic carbocycle, and the carbocycle or heterocycle of ring A is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO, -OH, -N(R 2 R 3 )2, -C(O)-, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. In certain embodiments, including any of the above, L 1a Ring A is optionally substituted C 4-12 In certain embodiments of formulas (III) through (VB), including any of those described above, L 1a Ring A is optionally substituted C 4-12 In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a Ring A is optionally substituted C4-8 It is a bridged bicyclic carbocycle.

[0269] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring A of [ka] (In the formula, X 1a , X 2a , X 3 , and X 4 are independently -C(R 4 ) selected from -2-, -NH-, -O-, and -S-; X 1a , X 2a and X 3 If there is an X 1a ~X 3 At least one of the -C(R 4 )2- and X 1a , X 2a , X 3 and X 4 If there is an X 1a ~X 4 At least two of the -C(R 4 )2 yes; X 5 is CR 4 or N; and R 4 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or two R on the same carbon 4 groups together form an oxo group) is selected from.

[0270] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring A of [ka] is selected from.

[0271] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring A of [ka] is selected from.

[0272] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring A of [ka] is selected from.

[0273] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring A of [ka] is selected from.

[0274] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a Ring A of [ka] In certain embodiments of formulas (III)-(VB), including any of those described above, L 1a Ring A of [ka] is.

[0275] In certain embodiments of formulas (III)-(VB), including any of those described above, X 1a , X 2a , X 3 , and / or X 4 is -C(R 4 In certain embodiments of formulas (III)-(VB), including any of those described above, X 1a and X 2a is -C(R 4 In certain embodiments of formulas (III)-(VB), including any of those described above, X 1a , X 2a , and X 3 is -C(R 4 In certain embodiments of formulas (III)-(VB), including any of those described above, X 1a , X 2a , X 3 , and X 4 is -C(R 4 In certain embodiments of formulas (III)-(VB), including any of those described above, X 1a In certain embodiments of formulas (III)-(VB), including any of those described above, X 2a In certain embodiments of formulas (III)-(VB), including any of those described above, X 3 In certain embodiments of formulas (III)-(VB), including any of those described above, X 4 In certain embodiments, including any of those described above, X 1a In certain embodiments of formulas (III)-(VB), including any of those described above, X 2a In certain embodiments of formulas (III)-(VB), including any of those described above, X 3In certain embodiments of formulas (III)-(VB), including any of those described above, X 4 is -O-.

[0276] In certain embodiments of Formulas (III)-(VB), including any of those described above, L 1a teeth, [ka] In certain embodiments, L 1a teeth, [ka] is.

[0277] In certain embodiments, including any of the above, a is 0. In certain embodiments, including any of the above, a is 1. In certain embodiments, including any of the above, a is 2. In certain embodiments, including any of the above, a is 3. In certain embodiments, including any of the above, a is 4. In certain embodiments, including any of the above, a is 5. In certain embodiments, including any of the above, a is 6.

[0278] In certain embodiments of Formulas (III)-(VB), b is 0. In certain embodiments, b is 1.

[0279] In certain embodiments of Formulas (III)-(VB), b is 0 and a is 0. In certain embodiments of Formulas (III)-(VB), b is 0 and a is 1. In certain embodiments of Formulas (III)-(VB), b is 0 and a is 2. In certain embodiments of Formulas (III)-(VB), b is 0 and a is 3. In certain embodiments of Formulas (III)-(VB), b is 0 and a is 4. In certain embodiments of Formulas (III)-(VB), b is 0 and a is 5. In certain embodiments of Formulas (III)-(VB), b is 0 and a is 6. In certain embodiments of Formulas (III)-(VB), b is 1 and a is 1. In certain embodiments of Formulas (III)-(VB), b is 1 and a is 2. In certain embodiments of Formulas (III)-(VB), b is 1 and a is 3. In certain embodiments of Formulas (III)-(VB), b is 1 and a is 4. In certain embodiments of Formulas (III)-(VB), b is 1 and a is 5. In certain embodiments of Formulas (III)-(VB), b is 1 and a is 6.

[0280] In certain embodiments of formulas (III)-(VB), including any of those described above, R 1 is hydrogen. In certain embodiments of formulas (III)-(VB), including any of those described above, R 1 is unsubstituted alkyl. In certain embodiments of formulas (III)-(VB), including any of those described above, R 1 is methyl. In certain embodiments of Formulas (III)-(VB), including any of those described above, R 1 is alkyl optionally substituted with one or more substituents selected from cycloalkyl, halogen, alkoxy, —CN, —NO 2 and —OH.

[0281] In certain embodiments of Formulas (III)-(IVB), L 5 is a linker comprising at least one amino acid selected from sulfoalanine, hydroxyproline (Hyp), beta-alanine, citrulline (Cit), ornithine (Orn), norleucine (Nle), 3-nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr), naphthylalanine (Nal), 2,4-diaminobutyric acid (DAB), methionine, sulfoxide, and methionine sulfone. In certain embodiments of Formulas (III)-(IVB), L 5 teeth, [ka] In certain embodiments of formulas (III)-(IVB), L 5 teeth, [ka] In certain embodiments of formulas (III)-(IVB), L 5 teeth, [ka] In certain embodiments of formulas (III)-(IVB), L 5 teeth, [ka] is.

[0282] In certain embodiments, including any of those described above, R a is hydrogen and R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3)2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 In certain embodiments, including any of the above, R a is hydrogen and R b is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, —C(O)OH, aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. In certain embodiments, including any of the above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH. In certain embodiments, including any of the above, R a and R b are both hydrogen.

[0283] In certain embodiments of formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; R 1 is hydrogen, a is 1, and b is 1. In certain embodiments of formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; R 1 is hydrogen, a is 2, and b is 1. In certain embodiments of formulas (III)-(VB), including any of those described above, R a is hydrogen and Rb is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; R 1 is hydrogen, a is 3, and b is 1.

[0284] In certain embodiments of formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; a is 1; and b is 0. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; a is 2; and b is 0. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO 2 , —OH, —NH 2 , —C(O)NH 2 , and —C(O)OH; a is 3; and b is 0.

[0285] In certain embodiments of formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; R 1 is methyl, a is 1, and b is 1. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; R 1is methyl, a is 2, and b is 1. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; R 1 is methyl, a is 3, and b is 1.

[0286] In certain embodiments, including any of the above of formulas (III)-(VB), R a and R b are both hydrogen, and R 1 is hydrogen, a is 1, and b is 1. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is hydrogen, a is 2, and b is 1. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is hydrogen, a is 3, and b is 1. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is hydrogen, a is 4, and b is 1. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is hydrogen, a is 5, and b is 1. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is hydrogen, a is 6, and b is 1.

[0287] In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, a is 1, and b is 0. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, a is 2, and b is 0. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, a is 3, and b is 0. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, a is 4, and b is 0. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, a is 5, and b is 0. In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, a is 6, and b is 0.

[0288] In certain embodiments of formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is methyl, a is 1, and b is 0. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is methyl, a is 2, and b is 0. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1is methyl, a is 3, and b is 0. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is methyl, a is 4, and b is 0. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is methyl, a is 5, and b is 0. In certain embodiments of Formulas (III)-(VB), including any of those described above, R a and R b are both hydrogen, and R 1 is methyl, a is 6, and b is 0.

[0289] In certain embodiments of formulas (III)-(IVB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; a is 1; and c is 1. In certain embodiments of Formulas (III)-(IVB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO, —OH, —NH, —C(O)NH, and —C(O)OH; a is 2; and c is 1. In certain embodiments of Formulas (III)-(IVB), including any of those described above, R a is hydrogen and R b is selected from hydrogen, alkyl, halogen, alkoxy, —CN, —NO 2 , —OH, —NH 2 , —C(O)NH 2 , and —C(O)OH; a is 3; and c is 1.

[0290] In certain embodiments of formulas (III)-(IVB), including any of those described above, Ya is *-C(O)-(CR a R b ) c -NH-, and * in this formula represents Y a represents the point at which Y is attached to R. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2) c In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH)-NH-. In certain embodiments, including any of the above, Y a is *-C(O)-(CH2)2-NH-. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)3-NH-. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)4-NH-. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)5-NH-. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)6-NH-.

[0291] In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a Rb In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b )6-NH-.

[0292] In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b ) c -NH- and R a is hydrogen and R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 In certain embodiments of formulas (III) through (IVB), including any of those described above, Y is selected from the group consisting of: aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. a is *-C(O)-(CR a R b )2-NH-, *-C(O)-(CR a R b )3-NH-, or *-C(O)-(CR a R b )4-NH-, and R in these formulas a is hydrogen and R bis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0293] In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b ) c -, where * is Y a represents the point at which Y is attached to R. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2) c In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)-. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)2-. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)3-. In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)4-. In certain embodiments of Formulas (III)-(IVB), including any of those described above for Formulas (III)-(IVB), Y a is *-C(O)-(CH2)5-. In certain embodiments, including any of the above, Y a is *-C(O)-(CH2)6-.

[0294] In certain embodiments, including any of those of formulas (III)-(IVB) above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b )6-.

[0295] In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CR a R b ) c - and R a is hydrogen and R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2In certain embodiments of formulas (III) through (IVB), including any of those described above, Y is selected from the group consisting of: aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. a is *-C(O)-(CR a R b )2-, *-C(O)-(CR a R b )3-, or *-C(O)-(CR a R b )4-, and R in these formulas a is hydrogen and R b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R 2 R 3 )2, -C(O)N(R 2 R 3 )2, -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0296] In certain embodiments of formulas (III)-(IVB), including any of those described above, Y a is *-C(O)-(CH2)2-NH- or *-C(O)-(CH2)4-.

[0297] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is a linker comprising a hydrophilic polymer residue.

[0298] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 -CH2-POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)3-POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)4-POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 -(CH2)5-POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)6-POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 -CR a R b -POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b )2-POLY 1 In certain embodiments, including any of those described above, L 2 is -(CR a R b )3-POLY 1 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b )4-POLY 1 -It is.

[0299] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 -POLY 1 -It is.

[0300] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a -, where a is independently selected from 0, 1, 2, 3, 4, 5, or 6. In certain embodiments of formulas (III) through (IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 -(CH2) a -, where a is independently selected from 0, 1, 2, 3, 4, 5, or 6. In certain embodiments of formulas (III) through (IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 -(CR a R b ) a -, where a is selected from 1, 2, 3, 4, 5, or 6. In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 -(CH2) a- in which a is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0301] In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of a non-peptidic, hydrophilic polymer. In certain embodiments of Formulas (III)-(IVB), POLY 1 is a divalent residue of polyethylene glycol (PEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), polysarcosine, or combinations thereof. In certain embodiments of Formulas (III) through (IVB), including any of the above, POLY 1 is the divalent residue of polyethylene glycol (PEG), poly(propylene glycol) (PPG), or a copolymer of ethylene glycol and propylene glycol.

[0302] In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of polyethylene glycol (PEG). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of poly(propylene glycol) (PPG). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 1 is the divalent residue of a copolymer of ethylene glycol and propylene glycol. In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 1is a divalent residue of a poly(oxyethylated polyol). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of a poly(olefin alcohol). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of poly(vinylpyrrolidone). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of poly(hydroxyalkylmethacrylamide). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of poly(hydroxyalkyl methacrylate). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of a poly(saccharide). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of a poly(α-hydroxy acid). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of poly(vinyl alcohol). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of a polyphosphazene. In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of polyoxazoline (POZ). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 is a divalent residue of poly(N-acryloylmorpholine). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 1 is the divalent residue of polysarcosine.

[0303] In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 1 teeth, [ka] and R in this formula 5 is hydrogen or methyl, and x is an integer from 1 to 100 inclusive; [ka] represents the bond to the remainder of the compound or conjugate. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 1 to 25. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 5 to 15. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 1. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 2. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 3. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 4. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 5. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 6. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 7. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 8. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 9. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 10. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 11. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 12. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 13. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 14. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 15. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 16. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 17. In some embodiments, including any of those described above, x is 18. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 19.In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 20. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 25 to 50. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 35 to 45. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 50 to 75. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 55 to 65. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 75 to 100. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 85 to 95. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer ranging from 1 to 25, 20 to 45, 40 to 65, 60 to 85, 70 to 95, or 75 to 100.

[0304] In some embodiments of formulas (III)-(IVB), including any of those described above, R 5 is hydrogen. In some embodiments, including any of those described above, R 5 is methyl.

[0305] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a-POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L2 is -(CH2)2-POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and POLY in this formula 1 teeth, [ka] is.

[0306] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments, including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a - and POLY in this formula 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 -(CR a Rb ) a - and POLY in this formula 1 teeth, [ka] is.

[0307] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] is.

[0308] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] is.

[0309] In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of a non-peptidic, hydrophilic polymer. In certain embodiments of formulas (III)-(IVB), POLY 2 is a residue of polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), polysarcosine, or a combination thereof. In certain embodiments of Formulas (III) through (IVB), including any of the above, POLY 2 is a residue of polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), or a copolymer of ethylene glycol and propylene glycol. In certain embodiments of Formulas (III)-(IVB), including any of the above, POLY 2 is the residue of methoxypolyethylene glycol (mPEG).

[0310] In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of polyethylene glycol (PEG). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of poly(propylene glycol) (PPG). In certain embodiments, including any of those described above, POLY 2 is the residue of a copolymer of ethylene glycol and propylene glycol. In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 2 is the residue of a poly(oxyethylated polyol). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is the residue of a poly(olefin alcohol). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of poly(vinylpyrrolidone). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of poly(hydroxyalkylmethacrylamide). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of poly(hydroxyalkyl methacrylate). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of a poly(saccharide). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of a poly(α-hydroxy acid). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of poly(vinyl alcohol). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2is a residue of a polyphosphazene. In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of polyoxazoline (POZ). In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 is a residue of poly(N-acryloylmorpholine). In certain embodiments of Formulas (III)-(IVB), including any of those described above, POLY 2 is the residue of polysarcosine.

[0311] In certain embodiments of formulas (III)-(IVB), including any of those described above, POLY 2 teeth, [ka] and R in this formula 5 is hydrogen or methyl, and x is an integer from 1 to 100 inclusive; [ka] represents the bond to the remainder of the compound or conjugate. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 1 to 25. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 5 to 15. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 1. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 2. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 3. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 4. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 5. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 6. In some embodiments, including any of those described above, x is 7. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 8. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 9. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 10. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 11. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 12. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 13. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 14. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 15. In some embodiments of Formulas (III) through (IVB), including any of those described above, x is 16. In some embodiments of Formulas (III)-(IVB), including any of Formulas (III)-(IVB) described above, x is 17. In some embodiments, including any of Formulas (III)-(IVB) described above, x is 18.In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 19. In some embodiments of Formulas (III)-(IVB), including any of those described above, x is 20. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 25 to 50. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 35 to 45. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 50 to 75. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 55 to 65. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 75 to 100. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer from 85 to 95. In certain embodiments of Formulas (III)-(IVB), including any of those described above, x is an integer ranging from 1 and 25, 20 and 45, 40 and 65, 60 and 85, 70 and 95, or 75 and 100.

[0312] In some embodiments of formulas (III)-(IVB), including any of those described above, R 5 is hydrogen. In some embodiments of formulas (III)-(IVB), including any of those described above, R 5 is methyl.

[0313] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] is selected from the group consisting of:

[0314] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] is selected from the group consisting of:

[0315] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] is.

[0316] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] is.

[0317] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-.

[0318] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-Z-(CR a R b ) a -Z-(CR a R b ) aIn certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-NR 2 -(CR a R b ) a -NR 2 -(CR a R b ) a In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-NH-(CR a R b ) a -NH-(CR a R b ) a In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-NH-(CH2) a -NH-(CH2) a In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-NH-(CH2) a -NH-(CH2) a -C(O)-, where a is selected from 1, 2, and 3. In certain embodiments, including any of those described above, L 3 is -C(O)-AA-NH-CH2-NH-CH2-C(O)-.

[0319] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-Z-(CR a R b ) a In certain embodiments, including any of those described above, L 3 is -C(O)-AA-NR 2 -(CH2) aIn certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-AA-NH-(CH2)2.

[0320] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -AA-. In certain embodiments, including any of those described above, L 3 teeth, [ka] is.

[0321] In certain embodiments of Formulas (III)-(IVB), including any of those described above, -AA- is an amino acid residue. In certain embodiments of Formulas (III)-(IVB), including any of those described above, -AA- is a peptide residue. In certain embodiments of Formulas (III)-(IVB), including any of those described above, -AA- is a dipeptide residue, tripeptide residue, tetrapeptide residue, or pentapeptide residue. In certain embodiments of Formulas (III)-(IVB), including any of those described above, -AA- comprises at least one amino acid residue selected from alanine, glycine, valine, and asparagine. In certain embodiments of Formulas (III)-(IVB), including any of those described above, -AA- comprises at least one amino acid residue selected from alanine and glycine. In certain embodiments of Formulas (III)-(IVB), including any of those described above, -AA- is [ka] is selected from the group consisting of:

[0322] In certain embodiments of formulas (III)-(IVB), including any of those described above, -AA- is [ka] is selected from the group consisting of:

[0323] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-.

[0324] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-Z-(CR a R b ) a -C(O)-ZL 4 -OC(O)-, and L in this formula 4 teeth, [ka] wherein Su is a hexose-type monosaccharide and d is an integer independently selected from 1, 2, and 3. In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-NR 2 -(CR a R b ) a -C(O)-NR 2 -L 4 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-NR 2 -(CH2)2-C(O)-NR 2 -L 4 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-NH-(CR a R b ) a -C(O)-NH-L 4 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-NH-(CH2)2-C(O)-NH-L4 -OC(O)-.

[0325] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 4 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 4 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 4 teeth, [ka] is.

[0326] In some embodiments of Formulas (III)-(IVB), including any of those described above, Su is a sugar moiety. In some embodiments, Su is a hexose-type monosaccharide. Su can be a glucuronic acid or mannose residue. In certain embodiments of Formulas (III)-(IVB), including any of those described above, Su is [ka] and in this formula: [ka] represents the bond to the remainder of the compound. In certain embodiments of formulas (III)-(IVB), including any of those described above, Su is [ka] and in this formula: [ka] represents the bond to the rest of the compound.

[0327] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 4 teeth, [ka] is.

[0328] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-NH-(CH2)2-C(O)-NH-L 4 -OC(O)-, and L in this formula 4 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 3 is -C(O)-NH-(CH2)2-C(O)-NH-L 4 -OC(O)-, and L in this formula 4 teeth, [ka] is.

[0329] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is -C(O)-AA-. In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is -C(O)-AA-, and POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 - and L 3 is -C(O)-AA-, and POLY 1 teeth, [ka] and x is an integer from 10 to 15. In certain embodiments of formulas (III) through (IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 is -C(O)-AA-, and POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 is -C(O)-AA-, and POLY 1 teeth, [ka] and AA is a dipeptide residue, a tripeptide residue, a tetrapeptide residue, or a pentapeptide residue.

[0330] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is -C(O)-AA-Z-(CR a R b )a -Z-(CR a R b ) a In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is -C(O)-AA-Z-(CR a R b ) a -Z-(CR a R b ) a -C(O)-, POLY 1 teeth, [ka] and Z is -NH-. In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 - and L 3 is -C(O)-AA-NH-(CH2) a -NH-(CH2) a -C(O)-, POLY 1 teeth, [ka] and x is an integer from 10 to 15. In certain embodiments of formulas (III) through (IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 is -C(O)-AA-NH-CH2-NH-CH2-C(O)-, and POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2is -(CH2)2-POLY 1 - and L 3 is -C(O)-AA-NH-CH2-NH-CH2-C(O)-, and POLY 1 teeth, [ka] and AA is a dipeptide residue, a tripeptide residue, a tetrapeptide residue, or a pentapeptide residue.

[0331] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is —C(O). In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is -C(O) and POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 - and L 3 is -C(O) and POLY 1 teeth, [ka] and x is an integer from 10 to 15. In certain embodiments of formulas (III) through (IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 is -C(O) and POLY1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 is -C(O) and POLY 1 teeth, [ka] and AA is a dipeptide residue, a tripeptide residue, a tetrapeptide residue, or a pentapeptide residue.

[0332] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 does not exist, POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 - and L 3 does not exist, POLY 1 teeth, [ka] and x is an integer from 10 to 15. In certain embodiments of formulas (III) through (IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 does not exist, POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 does not exist, POLY 1 teeth, [ka] and AA is a dipeptide residue, a tripeptide residue, a tetrapeptide residue, or a pentapeptide residue.

[0333] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is -C(O)-AA-Z-(CR a R b ) a In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is -C(O)-AA-Z-(CR a R b ) a - and POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2) a -POLY 1 -;-C(O)-AA-NR 2 -(CR a R b ) a - and POLY 1 teeth, [ka] and x is an integer from 10 to 15. In certain embodiments of formulas (III) through (IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 is -C(O)-AA-NH-(CR a R b ) a - and POLY 1 teeth, [ka] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 is -(CH2)2-POLY 1 - and L 3 is -C(O)-AA-NH-(CR a R b ) a - and POLY 1 teeth, [ka] and AA is a dipeptide residue, a tripeptide residue, a tetrapeptide residue, or a pentapeptide residue.

[0334] -L 2 -L 3 Non-limiting examples of: [ka] Examples include:

[0335] -L 2 -L 3 Additional non-limiting examples include: [ka] Examples include:

[0336] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] and L 3 is -C(O)-Z-(CR a R b ) a -C(O)-ZL 4 -OC(O)-, and L in this formula 4 teeth, [ka] wherein Su is a hexose-type monosaccharide and d is an integer independently selected from 1, 2, and 3. In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] and L 3 is -C(O)-Z-(CR a R b ) a -C(O)-ZL 4 -OC(O)-.

[0337] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] and L 3is —C(O). In certain embodiments, including any of those described above, L 2 teeth, [ka] and L 3 does not exist.

[0338] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] and L 3 is -C(O)-NH-(CR a R b ) a -C(O)-NH-L 4 -OC(O)-.

[0339] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] and L 3 is -C(O)-NH-(CR a R b ) a -C(O)-NH-L 4 -OC(O)-.

[0340] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] and L 3 is -C(O)-NH-(CH2)2-C(O)-NH-L 4 -OC(O)-, and L in this formula 4 teeth, [ka] is.

[0341] In certain embodiments of formulas (III)-(IVB), including any of those described above, L 2 teeth, [ka] and L 3 is -C(O).

[0342] In certain embodiments, including any of the above, D is a cytotoxic payload selected from a tubulin inhibitor, a DNA topoisomerase I inhibitor, and a DNA topoisomerase II inhibitor. In some embodiments, including any of the above, D is a tubulin inhibitor. In some embodiments, including any of the above, D is a DNA topoisomerase I inhibitor. In some embodiments, including any of the above, D is a DNA topoisomerase I inhibitor selected from the group consisting of irinotecan, SN-38, topotecan, and exatecan. In some embodiments, including any of the above, D is irinotecan. In some embodiments, including any of the above, D is SN-38. In some embodiments, including any of the above, D is topotecan. In some embodiments, including any of the above, D is exatecan. In some embodiments, including any of the above, D is a DNA topoisomerase II inhibitor. In some embodiments, including any of the above, D is a DNA topoisomerase II inhibitor selected from the group consisting of etoposide, teniposide, and tafluposide. In some embodiments, including any of the above, D is etoposide. In some embodiments, including any of the above, D is teniposide. In some embodiments, including any of the above, D is tafluposide. In some embodiments, including any of the above, D is selected from the group consisting of hemiasterlin, camptothecin, and anthracyclines. Anthracyclines may include PNU-159682 and EDA PNU-159682 derivatives. In some embodiments, including any of the above, D is an anthracycline selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin. In some embodiments, including any of the above, D is daunorubicin. In some embodiments, including any of those described above, D is doxorubicin. In some embodiments, including any of those described above, D is epirubicin.In some embodiments, including any of the above, D is idarubicin. In some embodiments, including any of the above, D is mitoxantrone. In some embodiments, including any of the above, D is valrubicin. In some embodiments, including any of the above, D is hemiasterlin. In some embodiments, including any of the above, D is camptothecin. In some embodiments, including any of the above, D is an anthracycline. In some embodiments, including any of the above, D is PNU-159682. In some embodiments, including any of the above, D is an EDA PNU compound. In some embodiments, including any of the above, D is an EDA PNU-159682 derivative. In some embodiments, including any of the above, D is hemiasterlin, exatecan, PNU-159682, or an EDA PNU-159682 derivative. In some embodiments, including any of the above, D is hemiasterlin. In some embodiments, including any of the above, D is exatecan. In some embodiments, including any of the above, D is PNU-159682. In some embodiments, including any of the above, D is an EDA PNU-159682 compound or derivative. In some embodiments, including any of the above, D is an immunostimulatory compound.

[0343] In some embodiments, including any of the above, D is an alkylating agent. In some embodiments, including any of the above, D is a bifunctional alkylating agent. In some embodiments, including any of the above, D is a bifunctional alkylating agent selected from the group consisting of cyclophosphamide, mechlorethamine, chlorambucil, and melphalan. In some embodiments, including any of the above, D is cyclophosphamide. In some embodiments, including any of the above, D is mechlorethamine. In some embodiments, including any of the above, D is chlorambucil. In some embodiments, including any of the above, D is melphalan. In some embodiments, including any of the above, D is a monofunctional alkylating agent. In some embodiments, including any of the above, D is a monofunctional alkylating agent selected from the group consisting of dacabazine, nitrosourea, and temozolomide. In some embodiments, including any of the above, D is dacarbazine. In some embodiments, including any of the above, D is a nitrosourea. In some embodiments, including any of the above, D is temozolomide. In some embodiments, including any of the above, D is a cytoskeletal disrupting agent (e.g., a taxane). In some embodiments, including any of the above, D is a cytoskeletal disrupting agent selected from the group consisting of paclitaxel, docetaxel, Abraxane, and taxotere. In some embodiments, including any of the above, D is paclitaxel. In some embodiments, including any of the above, D is docetaxel. In some embodiments, including any of the above, D is Abraxane. In some embodiments, including any of the above, D is taxotere. In some embodiments, including any of the above, D is an epothilone. In some embodiments, including any of those described above, D is an epothilone selected from the group consisting of epothilone A, epothilone B, epothilone C, epothilone D, and ixabepilone. In some embodiments, including any of those described above, D is epothilone A.In some embodiments, including any of the above, D is epothilone B. In some embodiments, including any of the above, D is epothilone C. In some embodiments, including any of the above, D is epothilone D. In some embodiments, including any of the above, D is ixabepilone. In some embodiments, including any of the above, D is a histone deacetylase inhibitor. In some embodiments, including any of the above, D is a histone deacetylase inhibitor selected from the group consisting of vorinostat and romidepsin. In some embodiments, including any of the above, D is vorinostat. In some embodiments, including any of the above, D is romidepsin. In some embodiments, including any of the above, D is a kinase inhibitor. In some embodiments, including any of the above, D is a kinase inhibitor selected from the group consisting of bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib. In some embodiments, including any of the above, D is bortezomib. In some embodiments, including any of the above, D is erlotinib. In some embodiments, including any of the above, D is gefitinib. In some embodiments, including any of the above, D is imatinib. In some embodiments, including any of the above, D is vemurafenib. In some embodiments, including any of the above, D is vismodegib. In some embodiments, including any of the above, D is a nucleotide analog and / or precursor analog. In some embodiments, including any of those described above, D is a nucleotide analog and / or precursor analog selected from the group consisting of azacitidine, azathioprine, capecitabine, cyatarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and tioguanine (formerly thioguanine). In some embodiments, including any of those described above, D is azacitidine.In some embodiments, including any of the above, D is azathioprine. In some embodiments, including any of the above, D is capecitabine. In some embodiments, including any of the above, D is cytarabine. In some embodiments, including any of the above, D is doxifluridine. In some embodiments, including any of the above, D is fluorouracil. In some embodiments, including any of the above, D is gemcitabine. In some embodiments, including any of the above, D is hydroxyurea. In some embodiments, including any of the above, D is mercaptopurine. In some embodiments, including any of the above, D is methotrexate. In some embodiments, including any of the above, D is tioguanine (formerly thioguanine). In some embodiments, including any of the above, D is a peptide antibiotic. In some embodiments, including any of the above, D is a peptide antibiotic selected from the group consisting of bleomycin and actinomycin. In some embodiments, including any of the above, D is bleomycin. In some embodiments, including any of the above, D is actinomycin. In some embodiments, including any of the above, D is a platinum-based drug. In some embodiments, including any of the above, D is a platinum-based drug selected from the group consisting of carboplatin, cisplatin, and oxaliplatin. In some embodiments, including any of the above, D is carboplatin. In some embodiments, including any of the above, D is cisplatin. In some embodiments, including any of the above, D is oxaliplatin. In some embodiments, including any of the above, D is a retinoid. In some embodiments, including any of the above, D is a retinoid selected from the group consisting of tretinoin, alitretinoin, and bexarotene. In some embodiments, including any of the above, D is tretinoin.In some embodiments, including any of the above, D is alitretinoin. In some embodiments, including any of the above, D is bexarotene. In some embodiments, including any of the above, D is a vinca alkaloid and derivatives thereof. In some embodiments, including any of the above, D is a vinca alkaloid and derivatives thereof selected from the group consisting of vinblastine, vincristine, vindesine, and vinorelbine. In some embodiments, including any of the above, D is a residue of vinblastine. In some embodiments, including any of the above, D is vincristine. In some embodiments, including any of the above, D is vindesine.

[0344] In any of the above-described embodiments, the conjugate comprises n2 linker-payloads, where n2 is an integer from 1 to 10. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n2 is 9. In some embodiments, n2 is 10.

[0345] In some embodiments, provided herein is an anti-ROR1 antibody conjugate having the structure of any of conjugates A-MM in the table below. In some embodiments, n2 is an integer from 1 to 8. In some embodiments, n2 is 2. In some embodiments, n2 is 4. In some embodiments, n2 is 6. In some embodiments, n2 is 8. The present disclosure encompasses each and every positional isomer of the conjugate structures depicted below. [ka] JPEG2025525445000330.jpg231170 JPEG2025525445000331.jpg204170 JPEG2025525445000332.jpg212170 JPEG2025525445000333.jpg221170 JPEG2025525445000334.jpg206170 JPEG2025525445000335.jpg207170 JPEG2025525445000336.jpg222170 JPEG2025525445000337.jpg162170 JPEG2025525445000338.jpg215170 JPEG2025525445000339.jpg180170 JPEG2025525445000340.jpg230170 JPEG2025525445000341.jpg213170

[0346] In some embodiments, provided herein is an anti-ROR1 antibody conjugate having the structure of any of conjugates A1-MM1 in the table below. In some embodiments, n2 is an integer from 1 to 8. In some embodiments, n2 is 2. In some embodiments, n2 is 4. In some embodiments, n2 is 6. In some embodiments, n2 is 8. The present disclosure encompasses each and every positional isomer of the conjugate structures depicted below. [ka] JPEG2025525445000343.jpg181170 JPEG2025525445000344.jpg230170 JPEG2025525445000345.jpg180170 JPEG2025525445000346.jpg230170 JPEG2025525445000347.jpg180170 JPEG2025525445000348.jpg213170 JPEG2025525445000349.jpg197170 JPEG2025525445000350.jpg197170 JPEG2025525445000351.jpg196170 JPEG2025525445000352.jpg196170 JPEG2025525445000353.jpg54170 JPEG2025525445000354.jpg229170 JPEG2025525445000355.jpg229170 JPEG2025525445000356.jpg71170

[0347] In any of the above-described embodiments in which the anti-ROR1 antibody conjugate has a structure shown in any one of conjugates A-GG, the bracketed structures can be covalently attached to one or more unnatural amino acids of the antibody, wherein the one or more unnatural amino acids are located at a site selected from the group consisting of HC-F404, HC-Y180, HC-F241, LC-K42, and LC-E161, according to the Kabat or EU numbering scheme of Kabat. In some embodiments, the bracketed structures are covalently attached to one or more unnatural amino acids at site HC-F404 of the antibody. In some embodiments, the bracketed structures are covalently attached to one or more unnatural amino acids at site HC-Y180 of the antibody. In some embodiments, the bracketed structures are covalently attached to one or more unnatural amino acids at site HC-F241 of the antibody. In some embodiments, the bracketed structure is covalently linked to one or more unnatural amino acids at site LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently linked to one or more unnatural amino acids at site LC-E161 of the antibody. In some embodiments, the bracketed structure is covalently linked to unnatural amino acids at sites HC-F404 and HC-Y180 of the antibody. In some embodiments, the bracketed structure is covalently linked to unnatural amino acids at sites HC-F404, HC-Y180, and LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently linked to unnatural amino acids at sites HC-F404, HC-Y180, LC-K42, and LC-E161 of the antibody. In some embodiments, the bracketed structure is covalently linked to unnatural amino acids at sites HC-F404, HC-Y180, and HC-F241 of the antibody. In some embodiments, the bracketed structures are covalently attached to unnatural amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42 of the antibody.

[0348] In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue of the unnatural amino acid represented by formula (30) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 404 of the heavy chain according to the EU numbering system of the unnatural amino acid represented by formula (30) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 180 of the heavy chain according to the EU numbering system of the unnatural amino acid represented by formula (30) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 241 of the heavy chain according to the EU numbering system of the unnatural amino acid represented by formula (30) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 222 of the heavy chain according to the EU numbering system of the unnatural amino acid shown below in formula (30). In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 7 of the light chain according to the Kabat or Chothia numbering system of the unnatural amino acid shown below in formula (30). In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 42 of the light chain according to the Kabat or Chothia numbering system of the unnatural amino acid shown below in formula (30).In certain embodiments, PAY is selected from the group consisting of maytansine, hemiasterlin, amanitin, camptothecan, exatecan, exatecan derivative (DXd), SN-38, anthracyclines, PNU-159682, PNU derivative (PNU-EDA), pyrrolobenzodiazepine (PBD), MMAF, and MMAE. In certain embodiments, PAY is maytansine. In certain embodiments, PAY is hemiasterlin. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is exutecan. In certain embodiments, PAY is the exatecan derivative Dxd. In certain embodiments, PAY is an anthracycline. In certain embodiments, PAY is PNU-159682. In certain embodiments, PAY is a PNU derivative (PNU-EDA). In certain embodiments, PAY is a pyrrolobenzodiazepine. In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE. [ka] (30)

[0349] In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue of the unnatural amino acid represented by formula (56) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 404 of the heavy chain according to the EU numbering system of the unnatural amino acid represented by formula (56) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 180 of the heavy chain according to the EU numbering system of the unnatural amino acid represented by formula (56) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 241 of the heavy chain according to the EU numbering system of the unnatural amino acid represented by formula (56) below. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 222 of the heavy chain according to the EU numbering system of the unnatural amino acid shown below in formula (56). In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 7 of the light chain according to the Kabat or Chothia numbering system of the unnatural amino acid shown below in formula (56). In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, wherein COMP represents the residue at position 42 of the light chain according to the Kabat or Chothia numbering system of the unnatural amino acid shown below in formula (56).In certain embodiments, PAY is selected from the group consisting of maytansine, hemiasterlin, amanitin, camptothecan, exatecan, exatecan derivative (DXd), SN-38, anthracyclines, PNU-159682, PNU derivatives (PNU-EDA), pyrrolobenzodiazepines (PBD), MMAF, and MMAE. In certain embodiments, PAY is maytansine. In certain embodiments, PAY is hemiasterlin. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is exatecan. In certain embodiments, PAY is exatecan derivative (DXd). In certain embodiments, PAY is deruxtecan. In certain embodiments, PAY is an anthracycline. In certain embodiments, PAY is PNU-159682. In certain embodiments, PAY is a PNU derivative (PNU-EDA). In certain embodiments, PAY is a pyrrolobenzodiazepine. In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE. [ka] (56)

[0350] In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, in which COMP represents the non-natural amino acid residue of para-azido-L-phenylalanine. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, in which COMP represents the non-amino acid residue at position 404 of the heavy chain according to the EU numbering system of para-azido-L-phenylalanine. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, in which COMP represents the non-natural amino acid residue at position 180 of the heavy chain according to the EU numbering system of para-azido-L-phenylalanine. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate represented by any of the conjugates described herein, in which COMP represents the non-natural amino acid residue at position 241 of the heavy chain according to the EU numbering system of para-azido-L-phenylalanine. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate designated as any of the conjugates described herein, wherein COMP represents the non-natural amino acid residue at position 222 of the heavy chain according to the EU numbering system, para-azido-L-phenylalanine. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate designated as any of the conjugates described herein, wherein COMP represents the non-natural amino acid residue at position 7 of the light chain according to the Kabat or Chothia numbering system, para-azido-L-phenylalanine. In certain embodiments, provided herein is an anti-ROR1 antibody conjugate designated as any of the conjugates described herein, wherein COMP represents the non-natural amino acid residue at position 42 of the light chain according to the Kabat or Chothia numbering system, para-azido-L-phenylalanine.In certain embodiments, PAY is selected from the group consisting of maytansine, hemiasterlin, amanitin, camptothecan, exatecan, exatecan derivative (DXd), SN-38, anthracyclines, PNU-159682, pyrrolobenzodiazepines (PBD), MMAF, and MMAE. In certain embodiments, PAY is maytansine. In certain embodiments, PAY is hemiasterlin. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is exatecan. In certain embodiments, PAY is an exatecan derivative (DXd). In certain embodiments, PAY is an anthracycline. In certain embodiments, PAY is PNU-159682. In certain embodiments, PAY is a PNU derivative (PNU-EDA). In certain embodiments, PAY is a pyrrolobenzodiazepine. In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE.

[0351] 3. Payload In addition to the payloads described above, a molecular payload can be any molecular entity that one of skill in the art may desire to conjugate to a polypeptide. In certain embodiments, the payload is a therapeutic moiety. In such embodiments, an antibody conjugate can be used to target the therapeutic moiety to its molecular target. In certain embodiments, the payload is a labeling moiety. In such embodiments, the antibody conjugate can be used to detect binding of the polypeptide to its target. In certain embodiments, the payload is a cytotoxic moiety. In such embodiments, the antibody conjugate can be used to target the cytotoxic moiety to diseased cells, e.g., cancer cells, to initiate cell destruction or elimination. Conjugates containing other molecular payloads readily apparent to one of skill in the art are within the scope of the conjugates described herein.

[0352] In certain embodiments, the antibody conjugate is selected from the group consisting of a label, a dye, a polymer, a water soluble polymer, polyethylene glycol, a derivative of polyethylene glycol, a photocrosslinker, a cytotoxic compound, a radionuclide, a drug, an affinity label, a photoaffinity label, a reactive compound, a resin, a second protein or polypeptide or polypeptide analog, an antibody or antibody fragment, a metal chelator, a cofactor, a fatty acid, a carbohydrate, a polynucleotide, DNA, RNA, an antisense polynucleotide, a peptide, a water soluble dendrimer, a cyclodextrin, an inhibitory ribonucleic acid, a biomaterial, a nanoparticle, a spin label, a fluorophore, a metal containing moiety, The payload may be selected from the group consisting of a radioactive moiety, a novel functional group, a group that interacts covalently or non-covalently with other molecules, a photocaged moiety, a photoisomerizable moiety, biotin, a derivative of biotin, a biotin analog, a moiety containing a heavy atom, a chemically cleavable group, a photocleavable group, an extended side chain, a carbon-linked sugar, a redox-active agent, an aminothioacid, a toxic moiety, an isotopically labeled moiety, a biophysical probe, a phosphorescent group, a chemiluminescent group, an electron-dense group, a magnetic group, an intercalating group, a chromophore, an energy transfer agent, a bioactive agent, a detectable label, a small molecule, and any combination thereof. In some embodiments, the payload is a label, a dye, a cytotoxic compound, a radionuclide, a drug, an affinity label, a resin, a protein, a polypeptide, a polypeptide analog, an antibody, an antibody fragment, a metal chelator, a cofactor, a fatty acid, a carbohydrate, a polynucleotide, DNA, RNA, a peptide, a fluorophore, or a carbon-linked sugar. In another embodiment, the payload is a label, a dye, a polymer, a drug, an antibody, an antibody fragment, DNA, RNA, or a peptide.

[0353] Useful drug payloads include any cytotoxic or cytostatic agent. Useful classes of cytotoxic agents include, for example, antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes, e.g., cisplatin, monodentate, bidentate, and trinuclear platinum complexes, and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, calmodulin inhibitors, chemotherapy sensitizers, duocarmycins, etoposide, fluorinated pyrimidines, ionophores, lexitropsin, maytansinoids, nitrosoureas, platinol, pore-forming compounds, purine antimetabolites, puromycin, radiosensitizers, rapamycin, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, and the like.

[0354] Individual cytotoxic agents include, for example, androgens, anthracyclines (AMC), asparaginase, 5-azacytidine, azathioprine, bleomycin, busulfan, buthionine sulfoximine, calicheamicin, calicheamicin derivatives, camptothecin, carboplatin, carmustine (BSNU), CC-1065, chlorambucil, cisplatin, colchicine, cyclophosphamide, cytarabine, cytidine arabinoside, cytochalasin B, dacarbazine, dactinomycin (formerly actinomycin), daunorubicin, dacarbazine, DM1, DM4, docetaxel, doxorubicin, etoposide, estrogen, 5-fluorodeoxyuridine, fluordeoxyuridine, 5-fluorouracil, gemcitabine, gramicidin D, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine (CCNU), maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mithramycin, mitomycin C, mitoxantrone, nitroimidazole, paclitaxel, palytoxin, plicamycin, procarbizine, rhizoxin, streptozotocin, teniposide, 6-thioguanine, thioTEPA, topotecan, vinblastine, vincristine, vinorelbine, VP-16, and VM-26.

[0355] In some embodiments, suitable cytotoxic agents include, for example, DNA minor groove binders (e.g., enediynes and lexitropsins, CBI compounds; see also U.S. Pat. No. 6,130,237), duocarmycins, taxanes (e.g., paclitaxel and docetaxel), puromycin, vinca alkaloids, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, echinomycin, combretastatin, netropsin, epothilone A and B, estramustine, cryptophycin, cemadotin, maytansinoids, discodermolide, eleutherobin, and mitoxantrone.

[0356] In some embodiments, the payload is an antitubulin agent. Examples of antitubulin agents include, but are not limited to, taxanes (e.g., Taxol® (paclitaxel), Taxotere® (docetaxel)), T67 (Tularik), and vinca alkyloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine). Other antitubulin agents include, for example, baccatin derivatives, taxane analogs, epothilones (e.g., epothilone A and B), nocodazole, colchicine and colcemid, estramustine, cryptophycin, cemadotin, maytansinoids, combretastatins, discodermolide, and eleutherobin.

[0357] In certain embodiments, the cytotoxic agent is a maytansinoid, another group of antitubulin agents. For example, in certain embodiments, the maytansinoid can be maytansine or DM1 (ImmunoGen; see also Chari et al., 1992, Cancer Res. 52:127-131).

[0358] In some embodiments, the payload is an auristatin, such as auristatin E or a derivative thereof. For example, the auristatin E derivative can be an ester formed between auristatin E and a keto acid. For example, auristatin E can be reacted with paraacetylbenzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other exemplary auristatin derivatives include auristatin phenylalanine phenylenediamine (AFP), monomethyl auristatin F (MMAF), and monomethyl auristatin E (MMAE). The synthesis and structure of auristatin derivatives are described in U.S. Patent Application Publication Nos. 2003-0083263, 2005-0238649, and 2005-0009751, WO 04 / 010957, WO 02 / 088172, and U.S. Patent Nos. 6,323,315, 6,239,104, 6,034,065, 5,780,588, 5,665,860, and 5,663,149. , 5,635,483, 5,599,902, 5,554,725, 5,530,097, 5,521,284, 5,504,191, 5,410,024, 5,138,036, 5,076,973, 4,986,988, 4,978,744, 4,879,278, 4,816,444, and 4,486,414.

[0359] In some embodiments, the payload is hemiasterlin. Hemiasterlins suitable for use in the antibody-drug conjugates described herein are described, for example, in International Patent Publication No. 2016 / 2016 / 123582, which is incorporated herein by reference in its entirety.

[0360] In some embodiments, the payload is not a radioisotope. In some embodiments, the payload is not radioactive.

[0361] In some embodiments, the payload is an antimetabolite, which can be, for example, a purine antagonist (e.g., azathioprine or mycophenolate mofetil), a dihydrofolate reductase inhibitor (e.g., methotrexate), acyclovir, gancyclovir, zidovudine, vidarabine, ribavirin, azidothymidine, cytidine arabinoside, amantadine, dideoxyuridine, iododeoxyuridine, poscarnet, or trifluridine.

[0362] In other embodiments, the payload is tacrolimus, cyclosporine, FU506, or rapamycin. In further embodiments, the drug is aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, bexarotene, calusterone, capecitabine, celecoxib, cladribine, darbepoetin alfa, denileukin diftitox, dexrazoxane, dromostanolone propionate, epirubicin, epoetin alfa, estramustine, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gemcitabine, gemtuzumab ozogamicin (MYLOTARG), goserelin, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, irinotecan, letrozole, leucovorin, levamisole, mechlorethamine or nitrogen mustard, megestrol, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, nandrolone phenpropionate, oprelvekin, oxaliplatin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pentostatin, pipobroman, pladienolide, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, streptozocin, tamoxifen, temozolomide, teniposide, testolactone, thioguanine, toremifene, tositumomab, trastuzumab (HERCEPTIN), tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, or zoledronate.

[0363] Other useful drug payloads include chemicals useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), and PTK787 / ZK. 222584 (Novartis), oxaliplatin (Eloxatin®, Sanofi), 5-fluorouracil (5-FU, 5-fluorouracil), leucovorin, rapamycin (sinolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine. amines); acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictin;spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins, especially uncialamicin, calicheamicin gamma II, and calicheamicin omega II) (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicins, including dynemicin A; bisphosphonates, e.g., clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilins, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pladienolide B, pteropterin, trimetrexate;Purine analogues, for example, fludarabine, 6-mercaptopurine, thiamnipurine, thioguanine; pyrimidine analogues, for example, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, for example, calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; adrenocortical hormone synthesis inhibitors, for example, aminoglutethimide, mitotane, trilostane; folic acid supplements, for example, folinic acid acid); aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; eflornithine; elformithine acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL® (paclitaxel;Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor-free), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0364] Other useful payloads include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate). (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein (v) kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell growth, such as PKC-alpha, Ralf, and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitors, such as LURTOTECAN®; ABARELIX® rmRH; (ix) antiangiogenic agents, such as bevacizumab (AVASTIN®; Genentech);(x) agents that act to modulate or inhibit the activity of members of the poly(ADP-ribose) polymerase (PARP) family in tumors (e.g., talazoparib (BMN-673), iniparib (BSI 201), veliparib (ABT-888), olaparib (AZD-2281, trade name LYNPARZA™), rucaparib (AG 014699), BGB-290, E7016, E7449, and CEP-9722); (xi) agents that modulate or inhibit the activity of members of the poly(ADP-ribose) polymerase (PARP) family in tumors (e.g., talazoparib (BMN-673), iniparib (BSI 201), veliparib (ABT-888), olaparib (AZD-2281, trade name LYNPARZA™), rucaparib (AG 014699), BGB-290, E7016, E7449, and CEP-9722); (xii) agents that act to regulate or inhibit the activity of members of the mitochondrial isocitrate dehydrogenase family (e.g., abexinostat, entinostat, gavinostat, 4SC-202, ACY-241, AR-42, CG200745, CHR-2845, CHR-3996, CXD101, MPT0E028, OBP-801, SHP-141, CUDC-101, KA2507, panobinostat, pracinostat, xinostat, resminostat, ricolinostat); (xiii) agents that act to regulate or inhibit the activity of the mitochondrial enzyme isocitrate dehydrogenase type 2 (IDH2) in tumors (e.g., enasidenib mesylate (CC-90007), AG-221 mesylate);and (xiii) pharmaceutically acceptable salts, acids, and derivatives of any of the above. Other useful payloads include antiangiogenic agents, including, for example, matrix-metalloproteinase 2 (MMP-2) inhibitors, matrix-metalloproteinase 9 (MMP-9) inhibitors, cyclooxygenase II (COX-II) inhibitors, and VEGF receptor tyrosine kinase inhibitors. Examples of such useful matrix metalloproteinase inhibitors that may be used in combination with the present compounds / compositions are those described in WO 96 / 33172, WO 96 / 27583, EP 818442, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566 , EP 606,046, EP 931,788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 99 / 07675, EP 945864, U.S. Pat. No. 5,863,949, U.S. Pat. No. 5,861,510, and EP 780,386, all of which are incorporated herein by reference in their entirety. Examples of VEGF receptor tyrosine kinase inhibitors include 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 in WO 01 / 32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), vatalanib (PTK787;Compounds such as those disclosed in PCT Publication Nos. WO 98 / 35985 (Sunitinib) and SU11248 (Sunitinib; WO 01 / 60814), and PCT Publication Nos. 97 / 22596, 97 / 30035, 97 / 32856, and 98 / 13354;

[0365] In certain embodiments, the payload is selected from the group consisting of maytansine, hemiasterlin, amanitin, exatecan, deruxtecan (DXd), anthracyclines, PNU-159682, pyrrolobenzodiazepines (PBDs), MMAF, and MMAE. In certain embodiments, the payload is maytansine. In certain embodiments, the payload is hemiasterlin. In certain embodiments, the payload is amanitin. In certain embodiments, the payload is hemiasterlin. In certain embodiments, the payload is amanitin. In certain embodiments, the payload is hemiasterlin. In certain embodiments, the payload is deruxtecan. In certain embodiments, the payload is hemiasterlin. In certain embodiments, the payload is an anthracycline. In certain embodiments, the payload is hemiasterlin. In certain embodiments, the payload is PNU-159682. In certain embodiments, the payload is hemiasterlin. In certain embodiments, the payload is a pyrrolobenzodiazepine. In certain embodiments, the payload is MMAF. In certain embodiments, the payload is MMAE.

[0366] In certain embodiments, the payload is an antibody or antibody fragment. In certain embodiments, the payload antibody or fragment can be encoded by any of the immunoglobulin genes recognized by those of skill in the art. Immunoglobulin genes include, but are not limited to, kappa, lambda, alpha, gamma (IgG1, IgG2, IgG3, and IgG4), delta, epsilon, and mu constant region genes, and immunoglobulin variable region genes. The term encompasses full-length antibodies and antibody fragments, as well as variants thereof, recognized by those of skill in the art. Exemplary fragments include, but are not limited to, Fv, Fc, Fab, and (Fab')2, single-chain Fv (scFv), diabodies, triabodies, tetrabodies, bifunctional hybrid polypeptides, CDR1, CDR2, CDR3, CDR combinations, variable regions, framework regions, constant regions, etc.

[0367] In certain embodiments, the payload is one or more water-soluble polymers. A wide variety of large polymers and other molecules can be linked to the polypeptides described herein to modulate and / or confer new biological properties to the polypeptides. These large polymers can be linked to the polypeptides through naturally encoded amino acids, non-naturally encoded amino acids, or any functional substituent of a natural or modified amino acid, or any substituent or functional group added to a natural or modified amino acid. The molecular weight of the polymer can range over a wide range of molecular weights, including, but not limited to, from about 100 Da to about 100,000 Da, or 100,001 Da or more.

[0368] The polymer selected may be water soluble so that the protein to which it is attached does not precipitate in an aqueous environment, such as a physiological environment. The polymer may be branched or unbranched. Preferably, for therapeutic use in the final product preparation, the polymer will be pharmaceutically acceptable.

[0369] In certain embodiments, the ratio of polyethylene glycol molecules to polypeptide molecules will vary, as will their concentrations in the reaction mixture. Generally, the optimal ratio (the ratio at which excess unreacted protein or polymer is minimized in terms of reaction efficiency) can be determined by the molecular weight of the polyethylene glycol selected and by the number of available reactive groups available. With respect to molecular weight, typically, the higher the molecular weight of the polymer, the fewer the number of polymer molecules that can be attached to the protein. Similarly, polymer branching should be taken into consideration when optimizing these parameters. Generally, the higher the molecular weight (or the more branches), the higher the polymer:protein ratio.

[0370] The water-soluble polymer may be of any structural form, including, but not limited to, linear, forked, or branched. Typically, the water-soluble polymer is a poly(alkylene glycol) such as poly(ethylene glycol) (PEG), although other water-soluble polymers can also be utilized. As an example, PEG is used to illustrate certain embodiments.

[0371] PEG is a well-known water-soluble polymer that is commercially available or can be prepared by ring-opening polymerization of ethylene glycol according to methods well known in the art (Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol. 3, pages 138-161). The term "PEG" is used broadly to encompass any polyethylene glycol molecule, regardless of its size or modifications at its termini, and has the formula: XO-(CHCHO). n -CH2CH2-Y (wherein n is 2 to 10,000, and X is H or C 1-4 The amino acid may be represented as linked to the polypeptide by a terminal modification, including but not limited to alkyl, where Y is the point of attachment to the polypeptide.

[0372] In some cases, PEG is terminated at one end with hydroxy or methoxy, i.e., X is H or CH ("methoxy PEG"). Alternatively, PEG can be terminated with a reactive group, thereby forming a bifunctional polymer. Exemplary reactive groups include those commonly used to react with functional groups found on the 20 common amino acids (including, but not limited to, maleimide groups, activated carbonates (including, but not limited to, p-nitrophenyl esters), activated esters (including, but not limited to, N-hydroxysuccinimide, p-nitrophenyl esters, and aldehydes)), as well as functional groups that are inert toward the 20 common amino acids but specifically react with complementary functional groups present on non-naturally encoded amino acids (including, but not limited to, azide groups, alkyne groups). Note that the other end of PEG, designated Y in the above formula, will be attached to the polypeptide directly or indirectly through a naturally occurring or non-naturally encoded amino acid. For example, Y can be an amide, carbamate, or urea linkage to an amine group of a polypeptide (including, but not limited to, the epsilon amine of lysine or the N-terminus). Alternatively, Y can be a maleimide linkage to a thiol group (including, but not limited to, the thiol group of cysteine). Alternatively, Y can be a linkage to a residue not commonly available through the 20 common amino acids. For example, an azide group on PEG can be reacted with an alkyne group on a polypeptide to form a Huisgen [3+2] cycloaddition product. Alternatively, an alkyne group on PEG can be reacted with an azide group present in a non-naturally encoded amino acid, such as the modified amino acids described herein, to form a similar product. In some embodiments, strong nucleophiles (including, but not limited to, hydrazine, hydrazide, hydroxylamine, semicarbazide) can be reacted with an aldehyde or ketone group present in a non-naturally encoded amino acid to form a hydrazone, oxime, or semicarbazone, which, if applicable, can be further reduced in some cases by treatment with a suitable reducing agent.Alternatively, a strong nucleophile can be incorporated into the polypeptide via a non-naturally encoded amino acid and used to preferentially react with ketone or aldehyde groups present on the water-soluble polymer.

[0373] Any molecular mass of PEG can be used depending on the actual needs, including, but not limited to, from about 100 Daltons (Da) to 100,000 Da or 100,001 Da or more, as desired (sometimes including, but not limited to, 0.1 to 50 kDa or 10 to 40 kDa). Branched-chain PEGs can also be used, including, but not limited to, PEG molecules in which each chain has a MW ranging from 1 to 100 kDa (including, but not limited to, 1 to 50 kDa or 5 to 20 kDa). A wide variety of PEG molecules are described in, including, but not limited to, the Shearwater Polymers catalog and the Nektar Therapeutics catalog, both of which are incorporated herein by reference.

[0374] Generally, at least one terminus of the PEG molecule is available for reaction with the antibody. For example, PEG can be attached to the non-naturally encoded amino acids described herein using PEG derivatives bearing alkyne and azide moieties for reaction with amino acid side chains. If the non-naturally encoded amino acid contains an azide, the PEG will typically contain either an alkyne moiety to effect the formation of a [3 + 2] cycloaddition product, or an activated PEG species (i.e., ester, carbonate) containing a phosphine group to effect the formation of an amide linkage. Alternatively, if the non-naturally encoded amino acid contains an alkyne, the PEG will typically contain an azide moiety to effect the formation of a [3 + 2] Huisgen cycloaddition product. If the non-naturally encoded amino acid contains a carbonyl group, the PEG will typically contain a strong nucleophile (including, but not limited to, a hydrazide, hydrazine, hydroxylamine, or semicarbazide functional group) to effect the formation of the corresponding hydrazone, oxime, and semicarbazone linkages, respectively. In another alternative, the reverse of the orientation of the reactive groups described herein can be used, i.e., the azide moiety in the non-naturally encoded amino acid can be reacted with an alkyne-containing PEG derivative.

[0375] In some embodiments, the PEG-derivatized polypeptide variants contain chemical functional groups that are reactive with chemical functional groups present on the side chains of non-naturally encoded amino acids.

[0376] In certain embodiments, the payload is an azide- or acetylene-containing polymer comprising a water-soluble polymer backbone having an average molecular weight of about 800 Da to about 100,000 Da. The polymer backbone of the water-soluble polymer can be poly(ethylene glycol). However, it should be understood that a wide variety of water-soluble polymers are also suitable for use, including, but not limited to, poly(ethylene) glycol and other related polymers, including poly(dextran) and poly(propylene glycol), and that the use of the term PEG or poly(ethylene glycol) is intended to encompass and include all such molecules. The term PEG includes, but is not limited to, poly(ethylene glycol) in any of its forms, including bifunctional PEG, multi-armed PEG, derivatized PEG, forked PEG, branched PEG, pendant PEG (i.e., PEG or related polymers having one or more functional groups pendant from the polymer backbone), or PEG containing degradable linkages.

[0377] The polymer backbone can be linear or branched. Branched polymer backbones are generally known in the art. Typically, a branched polymer has a central branch core portion and multiple linear polymer chains connected to the central branch core. PEG is commonly used in branched forms, which can be prepared by the addition of ethylene oxide to various polyols, such as glycerol, glycerol oligomers, pentaerythritol, and sorbitol. The central branch portion can also be derived from several amino acids, such as lysine. Branched poly(ethylene glycol)s are generally represented by the formula R-(-PEG-OH) mwhere R is derived from the core moiety, e.g., glycerol, glycerol oligomer, or pentaerythritol, and m represents the number of arms. Multi-arm PEG molecules, such as those described in U.S. Pat. Nos. 5,932,462, 5,643,575, 5,229,490, and 4,289,872; U.S. Patent Application No. 2003 / 0143596; WO 96 / 21469, and WO 93 / 21259, each of which is incorporated herein by reference in its entirety, can also be used as the polymer backbone.

[0378] Branched PEG is PEG(-YCHZ2) n It may also be in the form of a forked PEG represented by the formula: where Y is a linking group and Z is an activated end group connected to CH by a chain of atoms of defined length.

[0379] Yet another branched form, pendant PEG, has reactive groups, such as carboxyl, along the PEG backbone rather than at the end of the PEG chain.

[0380] In addition to these forms of PEG, polymers can also be prepared with weak or degradable linkages in the backbone. For example, PEG can be prepared with ester linkages in the polymer backbone that undergo hydrolysis. As shown herein, this hydrolysis results in cleavage of the polymer into lower molecular weight fragments: -PEG-CO2-PEG-+HO→PEG-CO2H+HO-PEG-. Those of skill in the art will understand that the term poly(ethylene glycol) or PEG refers to or includes all forms known in the art, including, but not limited to, those disclosed herein.

[0381] Many other polymers are also suitable for use. In some embodiments, water-soluble polymer backbones having 2 to about 300 termini are particularly suitable. Examples of suitable polymers include, but are not limited to, other poly(alkylene glycols), such as poly(propylene glycol) ("PPG"), its copolymers (including, but not limited to, copolymers of ethylene glycol and propylene glycol), its terpolymers, mixtures thereof, and the like. The molecular weight of each chain of the polymer backbone can vary, but is typically in the range of about 800 Da to about 100,000 Da, often about 6,000 Da to about 80,000 Da.

[0382] Those skilled in the art will recognize that the foregoing list of substantially water soluble scaffolds is by no means exhaustive but merely illustrative, and that all polymeric materials having the qualities described herein are considered suitable for use.

[0383] In some embodiments, the polymer derivatives are "multifunctional," meaning that the polymer backbone has at least two termini functionalized or activated with functional groups, and possibly as many as about 300. Multifunctional polymer derivatives include, but are not limited to, linear polymers having two termini, each attached to a functional group, which may be the same or different.

[0384] 4. Linker In certain embodiments, the antibody may be linked to the payload by one or more linkers capable of reacting with the antibody amino acids and with the payload group. The one or more linkers may be any linker readily apparent to one of skill in the art.

[0385] The term "linker" is used herein to refer to a group or bond that is usually formed as a result of a chemical reaction and is typically a covalent linkage.

[0386] Useful linkers include those described herein. In certain embodiments, the linker is any bivalent or polyvalent linker known to those of skill in the art. Useful bivalent linkers include alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, arylene, substituted arylene, heteroarylene, and substituted heteroarylene. In certain embodiments, the linker is C 1-10 Alkylene or C 1-10 In some embodiments, C is heteroalkylene. 1-10 The heteroalkylene is PEG.

[0387] In certain embodiments, the linker is hydrolytically stable. Hydrolytically stable linkage means that the linkage is substantially stable in water and does not react with water at useful pH values, including, but not limited to, under physiological conditions for extended periods of time, perhaps even indefinitely. In certain embodiments, the linker is hydrolytically unstable. Hydrolytically unstable or hydrolytically degradable linkage means that the linkage is degradable in water or in aqueous solutions, including, for example, blood. Enzymatically unstable or enzymatically degradable linkage means that the linkage can be degraded by one or more enzymes.

[0388] As is understood in the art, PEG and related polymers may contain degradable linkages in the polymer backbone or in linker groups between the polymer backbone and one or more of the terminal functional groups of the polymer molecule. For example, ester linkages formed by reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on a bioactive agent generally hydrolyze under physiological conditions to release the agent.

[0389] hydrazone linkages, which are the reaction product of a hydrazide and an aldehyde; acetal linkages, which are the reaction product of an aldehyde and an alcohol; orthoester linkages, which are the reaction product of a formate and an alcohol; peptide linkages, which are formed between an amine group, including but not limited to, at the terminus of a polymer such as PEG, and a carboxyl group of a peptide; and oligonucleotide linkages, which are formed between a phosphoramidite group, including but not limited to, at the terminus of a polymer, and a 5' hydroxyl group of an oligonucleotide.

[0390] Several different cleavable linkers are known to those of skill in the art. See U.S. Pat. Nos. 4,618,492, 4,542,225, and 4,625,014. Mechanisms for drug release from these linker groups include, for example, irradiation of the photolabile bond and acid-catalyzed hydrolysis. For example, U.S. Pat. No. 4,671,958 describes immunoconjugates containing linkers that are cleaved at target sites in vivo by proteolytic enzymes of the patient's complement system. The length of the linker may be predetermined or may be selected depending on the desired spatial relationship between the polypeptide and the molecule to which it is linked. Given the numerous methods reported for attaching various radiodiagnostic compounds, radiotherapeutic compounds, drugs, toxins, and other agents to polypeptides, one of skill in the art will be able to determine the appropriate method for attaching a given agent to a polypeptide.

[0391] The linker may have a wide range of molecular weights or lengths. Linkers with larger or smaller molecular weights can be used to achieve the desired spatial relationship or conformation between the polypeptide and the linked entity. Linkers with longer or shorter molecular lengths can also be used to achieve the desired spacing or flexibility between the polypeptide and the linked entity. Similarly, linkers with specific shapes or conformations can be used to impart specific shapes or conformations to the polypeptide or the linked entity, either before or after the polypeptide reaches its target. Functional groups present on each end of the linker can be selected to modulate the release of the polypeptide or payload under desired conditions. Optimizing the spatial relationship between the polypeptide and the linked entity can provide the molecule with new, modulated, or desired properties.

[0392] In some embodiments, provided herein are water-soluble bifunctional linkers having a dumbbell structure, comprising: a) an azide, alkyne, hydrazine, hydrazide, hydroxylamine, or carbonyl-containing moiety on at least a first end of the polymer backbone; and b) at least a second functional group on a second end of the polymer backbone. The second functional group may be the same as or different from the first functional group. In some embodiments, the second functional group does not react with the first functional group. In some embodiments, provided are water-soluble compounds comprising at least one arm of a branched molecular structure. For example, the branched molecular structure may be a dendritic structure.

[0393] In some embodiments, the linker is selected from the group consisting of N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl-3-(2-pyridyldithio)propionate (SPP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)-2-sulfo-butanoate (sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl iodoacetate), N-succinimidyl(4-iodoacetyl)aminobenzoate (SIAB), maleimide PEG NHS, N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (sulfo-SMCC), N-sulfosuccinimidyl The linker precursor is derived from a linker precursor selected from the group consisting of 4-(maleimidomethyl)cyclohexanecarboxylate and 2,5-dioxopyrrolidin-1-yl 17-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-1-oate.In certain embodiments, the linker is derived from the linker precursor N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC).

[0394] In some embodiments, the linker is derived from a linker precursor selected from the group consisting of a dipeptide, a tripeptide, a tetrapeptide, and a pentapeptide. In such embodiments, the linker can be cleaved by a protease. Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe), phenylalanine-lysine (fk or phe-lys), phenylalanine-homolysine (phe-homolys), and N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit, glycine-valine-citrulline), glycine-glycine-glycine (gly-gly-gly, glycine-glycine-glycine), and glycine-methoxyethoxyethyl)serine-valine (gly-val-citalanine OMESerValAla, glycine- methoxyethoxyethyl)serine-valine).

[0395] In some embodiments, the linker comprises a self-immolative spacer. In certain embodiments, the self-immolative spacer comprises p-aminobenzyl. In some embodiments, p-aminobenzyl alcohol is attached to the amino acid unit via an amide bond, and a carbamate, methylcarbamate, or carbonate is created between the benzyl alcohol and the payload (Hamann et al. (2005) Expert Opin. Ther. Patents (2005) 15:1087-1103). In some embodiments, the linker comprises p-aminobenzyloxycarbonyl (PAB). Other examples of self-immolative spacers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group, such as 2-aminoimidazole-5-methanol derivatives (U.S. Pat. No. 7,375,078; Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho- or para-aminobenzyl acetals. In some embodiments, spacers that undergo cyclization by amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al. (1995) Chemistry Biology 2:223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al. (1972) J. Amer. Chem. Soc. 94:5815), and 2-aminophenylpropionic acid amide (Amsberry, et al. (1990) J. Org. Chem. 55:5867), can be used. Linking a drug to the α-carbon of a glycine residue is another example of a self-immolative spacer that can be useful in conjugates (Kingsbury et al. (1984) J. Med. Chem. 27:1447).

[0396] In certain embodiments, linker precursors can be combined to form larger linkers. For example, in certain embodiments, a linker comprises the dipeptide valine-citrulline and p-aminobenzyloxycarbonyl. These are also referred to as citValCit--PAB linkers.

[0397] In certain embodiments, the payload may be linked to a linker, referred to herein as a linker-payload, which has one or more linker groups capable of reacting with antibody amino acid groups. The one or more linkers may be any linker readily apparent to one of skill in the art or as described herein.

[0398] Additional linkers are disclosed herein, such as, for example, the linker precursors (A)-(L) described below.

[0399] 5. Antibodies and Antibody Specificity Provided herein are antibodies that selectively bind to human ROR1. In some aspects, the antibody selectively binds to the extracellular domain of human ROR1 (human ROR1).

[0400] Also provided herein is a conjugate comprising an antibody that selectively binds to human receptor tyrosine kinase orphan receptor 1. In some embodiments, the antibody of the conjugate selectively binds to the extracellular domain of human receptor tyrosine kinase orphan receptor 1 (human ROR1).

[0401] In some embodiments, the antibody binds to a homolog of human ROR1. In some aspects, the antibody binds to a homolog of human ROR1 from a species selected from monkey, mouse, dog, cat, rat, cow, horse, goat, and sheep. In some aspects, the homolog is a cynomolgus monkey homolog. In some aspects, the homolog is a mouse or murine analog.

[0402] In some embodiments, an antibody has one or more CDRs of a particular length, in terms of the number of amino acid residues. In some embodiments, the Chothia CDR-H1 of the antibody is 6, 7, or 8 residues in length. In some embodiments, the Kabat CDR-H1 of the antibody is 4, 5, or 6 residues in length. In some embodiments, the Chothia CDR-H2 of the antibody is 5, 6, or 7 residues in length. In some embodiments, the Kabat CDR-H2 of the antibody is 16, 17, or 18 residues in length. In some embodiments, the Kabat / Chothia CDR-H3 of the antibody is 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 residues in length.

[0403] In some aspects, the Kabat / Chothia CDR-L1 of the antibody is 10, 11, 12, 13, 14, 15, or 16 residues in length. In some aspects, the Kabat / Chothia CDR-L2 of the antibody is 6, 7, or 8 residues in length. In some aspects, the Kabat / Chothia CDR-L3 of the antibody is 8, 9, or 10 residues in length.

[0404] In some embodiments, the antibody comprises a light chain. In some aspects, the light chain is a kappa light chain. In some aspects, the light chain is a lambda light chain.

[0405] In some embodiments, the antibody comprises a heavy chain. In some aspects, the heavy chain is IgA. In some aspects, the heavy chain is IgD. In some aspects, the heavy chain is IgE. In some aspects, the heavy chain is IgG. In some aspects, the heavy chain is IgM. In some aspects, the heavy chain is IgG1. In some aspects, the heavy chain is IgG2. In some aspects, the heavy chain is IgG3. In some aspects, the heavy chain is IgG4. In some aspects, the heavy chain is IgA1. In some aspects, the heavy chain is IgA2.

[0406] In some embodiments, the antibody is an antibody fragment. In some aspects, the antibody fragment is an Fv fragment. In some aspects, the antibody fragment is a Fab fragment. In some aspects, the antibody fragment is a F(ab')2 fragment. In some aspects, the antibody fragment is a Fab' fragment. In some aspects, the antibody fragment is an scFv (sFv) fragment. In some aspects, the antibody fragment is an scFv-Fc fragment.

[0407] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.

[0408] In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

[0409] In some embodiments, the antibody is an affinity matured antibody. In some aspects, the antibody is an affinity matured antibody derived from the illustrative sequences provided in this disclosure.

[0410] The antibodies provided herein may be useful in the treatment of various diseases and conditions, including cancer. In some embodiments, the antibodies provided herein may be useful in the treatment of solid tumor cancer. For example, the antibodies provided herein may be useful in the treatment of colon cancer.

[0411] 5.1 CDR-H3 sequences In some embodiments, the antibody is an illustrative antibody or V H In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of the CDR-H3 sequence of SEQ ID NOs: 854-1020. H The sequence is the CDR-H3 sequence.

[0412] In some embodiments, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 672-838. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 672. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 673. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 674. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 675. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 676. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 677. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 678. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 679. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 680. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 681. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 682. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 683. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 684. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 685. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 686. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 687.In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 688. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 689. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 690. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 691. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 692. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 693. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 694. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 695. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 696. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 697. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 698. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 699.

[0413] In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 700. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 701. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 702. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 703. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 704. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 705. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 706. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 707. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 708. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 709. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 710. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 711. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 712. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 713. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 714. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 715. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 716.In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 717. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 718. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 719. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 720. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 721. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 722. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 723. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 724. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 725. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 726. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 727. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 728. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 729. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 730. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 731. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 732. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 733.In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 734. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 735. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 736. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 737. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 738. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 739. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 740. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 741. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 742. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 743. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 744. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 745. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 746. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 747. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 748. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 749.

[0414] In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 750. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 751. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 752. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 753. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 754. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 755. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 756. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 757. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 758. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 759. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 760. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 761. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 762. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 763. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 764. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 765. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 766.In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 767. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 768. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 769. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 770. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 771. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 772. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 773. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 774. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 775. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 776. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ...

Claims

1. 1. An antibody conjugate comprising an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1), site-specifically linked to at least one payload moiety, wherein the antibody comprises one or more unnatural amino acids.

2. 2. The antibody conjugate of claim 1, wherein the one or more unnatural amino acids are at an amino acid position of the antibody other than the amino terminus of the antibody.

3. 2. The antibody conjugate of claim 1, wherein the one or more unnatural amino acids are at an amino acid position of the antibody other than the carboxy terminus of the antibody.

4. 4. The antibody conjugate of any of claims 1 to 3, wherein the antibody comprises one or more unnatural amino acids selected from the group consisting of HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, and HC-S70 according to the Kabat, Chothia, or EU numbering scheme.

5. 5. The antibody conjugate of claim 4, wherein the antibody comprises one or more unnatural amino acids selected from the group consisting of HC-F404, HC-Y180, HC-F241, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering scheme.

6. 5. The antibody conjugate of claim 4, wherein the antibody comprises one or more unnatural amino acids at a site selected from the group consisting of HC-F404, HC-Y180, LC-K42, and LC-E161 according to the Kabat EU numbering scheme or the Kabat numbering scheme.

7. 5. The antibody conjugate of claim 4, wherein the antibody comprises one or more unnatural amino acids at a site selected from the group consisting of HC-F404, HC-Y180, HC-F241, and LC-K42 according to the Kabat EU numbering scheme or the Kabat numbering scheme.

8. The antibody conjugate of any one of claims 1 to 7, wherein the one or more unnatural amino acid residues are linked to the payload moiety via a hydrolytically stable linker.

9. The antibody conjugate of any one of claims 1 to 8, wherein the one or more unnatural amino acid residues are linked to the payload moiety via a cleavable linker.

10. 10. The antibody conjugate of any of claims 1 to 9, wherein the one or more unnatural amino acids are selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, -3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcβ-serine, L-dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-azido-methyl-L-phenylalanine, Compound 56, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and p-propargyloxy-phenylalanine.

11. The antibody conjugate of any one of claims 1 to 10, wherein the one or more unnatural amino acid residues are residues of compound (30) or compound (56).

12. The antibody conjugate of any one of claims 1 to 11, wherein the one or more unnatural amino acids is p-azidomethylphenylalanine.

13. The antibody conjugate of any one of claims 1 to 12, wherein the one or more unnatural amino acids is p-azido-methyl-L-phenylalanine.

14. 14. The antibody conjugate of any one of claims 1 to 13, wherein the payload moiety is selected from the group consisting of maytansine, hemiasterlin, amanitin, camptothecan, exatecan, anthracyclines, pyrrolobenzodiazepines, and auristatins.

15. 15. The antibody conjugate of any one of claims 1 to 14, wherein the payload moiety is selected from the group consisting of DM1, hemiasterlin, amanitin, camptothecan, exatecan, exatecan derivative (Dxd), SN-38, PNU-159862, PNU derivative (PNU-EDA), pyrrolobenzodiazepine, MMAF, and MMAE.

16. Formula I: 【Chemical 1】 (I) The structure of COMP is a residue of an anti-ROR1 antibody; L １ is -C １－６ alkylene-; Y is -X １ -C １－６ Alkylene-[X １ -C １－６ alkylene] ｎ -[X １ ] ｐ -, -X １ -C ２－６ Alkenylene-[X １ -C ２－６ alkenylene] ｎ -[X １ ] ｐ -, -X １ -C ２－６ Alkynylene-[X １ -C ２－６ alkynylene] ｎ -[X １ ] ｐ -, and at least one alkylene, alkenylene or alkynylene in Y is R ５０ and The alkylene, alkenylene, or alkynylene in Y is R ５１ and optionally substituted with one or more substituents selected from: R ５０ is -C １－６ Alkylene-X ２ -[C １－６ alkylene] ｍ -POLY, -C ２－６ Alkenylene-X ２ -[C ２－６ alkenylene] ｍ -POLY, or -C ２－６ Alkynylene-X ２ -[C ２－６ alkynylene] ｍ -POLY and R ５０ Each alkylene, alkenylene or alkynylene is selected from the group consisting of halogen, —CN, —NO ２ , —OH, —N(R １０ ) ２ , -C(O)N(R １０ ) ２ , -C(O)-, -C(S)-, -C(O)OCH ２ C ６ H ５ , -NHC(O)OCH ２ C ６ H ５ , C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycle, 3- to 12-membered heterocycle, and C １－１０ optionally substituted with one or more substituents selected from haloalkyl; R ５１ are independently halogen, —CN, —NO ２ , —OH, —N(R １０ ) ２ , -C(O)N(R １０ ) ２ , -C(O)-, C(S)-, C(O)OCH ２ C ６ H ５ , -NHC(O)OCH ２ C ６ H ５ , C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycle, 3- to 12-membered heterocycle, and C １－１０ haloalkyl; X １ and X ２ are independently —C(O)— and —N(R １０ )C(O)—; R １０ Each occurrence of represents hydrogen, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycle, 3- to 12-membered heterocycle, and C １－１０ independently selected from haloalkyl; POLY is a water-soluble polymer; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0 and 1; p is an integer selected from 0 and 1; Su is a hexose monosaccharide; D is a drug moiety; and RL is a reactive group residue 16. The antibody conjugate according to any one of claims 1 to 15, wherein:

17. Formula II: 【Chemistry 2】 The structure of COMP is a residue of the ROR1 antibody; L １ is -C １－６ alkylene-; Y is -X １ -C １－６ Alkylene-[X １ -C １－６ alkylene] ｎ -X １ -, -X １ -C ２－６ Alkenylene-[X １ -C ２－６ alkenylene] ｎ -X １ -, -X １ -C ２－６ Alkynylene-[X １ -C ２－６ alkynylene] ｎ -X １ -, and at least one alkylene, alkenylene or alkynylene in Y is R ５０ and is substituted with one or more substituents selected from: R ５０ is -C １－６ Alkylene-X ２ -[C １－６ alkylene] ｍ -POLY, -C ２－６ Alkenylene-X ２ -[C ２－６ alkenylene] ｍ -POLY, or -C ２－６ Alkynylene-X ２ -[C ２－６ alkynylene] ｍ -POLY and R ５０ Each alkylene, alkenylene or alkynylene is selected from the group consisting of halogen, —CN, —NO ２ , —OH, —N(R １０ ) ２ , -C(O)N(R １０ ) ２ , -C(O)-, -C(S)-, -C(O)OCH ２ C ６ H ５ , -NHC(O)OCH ２ C ６ H ５ , C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycle, 3- to 12-membered heterocycle, and C １－１０ optionally substituted with one or more substituents selected from haloalkyl; X １ and X ２ are independently —C(O)— and —N(R １０ )C(O)—; R １０ Each occurrence of represents hydrogen, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycle, 3- to 12-membered heterocycle, and C １－１０ independently selected from haloalkyl; POLY is a water-soluble polymer; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 0 and 1; Su is a hexose monosaccharide; D is a drug moiety; and RL is a reactive group residue.

17. The antibody conjugate according to any one of claims 1 to 16, wherein:

18. The compound of formula (II) is a compound of formula (IIA) 【Chemistry 3】 18. The conjugate of claim 17, wherein:

19. Su, 【Chemistry 4】 (In the formula, 【Chemistry 5】 represents the bond to the rest of the compound) The conjugate according to any one of claims 16 to 18, wherein

20. Su, 【Chemistry 6】 (In the formula, 【Chemistry 7】 represents the bond to the rest of the compound) The conjugate according to any one of claims 16 to 19, wherein

21. The conjugate of any one of claims 16 to 20, wherein D is a cytotoxic payload.

22. 22. The conjugate of claim 21, wherein the cytotoxic payload is a tubulin inhibitor, a DNA topoisomerase I inhibitor, or a DNA topoisomerase II inhibitor.

23. 21. The conjugate of any one of claims 16 to 20, wherein D is selected from the group consisting of hemiasterlin, camptothecin, anthracycline, PNU-159682, and EDA PNU-159682 derivatives.

24. 21. The conjugate of any one of claims 16 to 20, wherein D is hemiasterlin, exatecan, PNU-159682, or an EDA PNU-159682 derivative.

25. L １ But, -C １－３ The conjugate of any one of claims 16 to 24, which is alkylene-.

26. Y is -X １ -C １－６ Alkylene-[X １ -C １－６ alkylene] ｎ -X １ -, and at least one alkylene in Y is R ５０ The conjugate of any one of claims 16 to 25, substituted with one or more substituents selected from:

27. Y is -X １ -C １－４ Alkylene-X １ -C １－４ Alkylene-X １ -C １－４ Alkylene-X １ -, and at least one alkylene in Y is R ５０ The conjugate of any one of claims 16 to 26, substituted with one or more substituents selected from:

28. Y is -X １ -C １－４ Alkylene-X １ -C １－４ Alkylene-X １ -, and at least one alkylene in Y is R ５０ The conjugate of any one of claims 16 to 26, substituted with one or more substituents selected from:

29. R ５０ But, -C １－６ Alkylene-X ２ -[C １－６ alkylene] ｍ -POLY and R ５０ Each alkylene is halogen, —CN, —NO ２ , —OH, —N(R １０ ) ２ , -C(O)N(R １０ ) ２ , -C(O)-, -C(S)-, -C(O)OCH ２ C ６ H ５ , -NHC(O)OCH ２ C ６ H ５ , C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycle, 3- to 12-membered heterocycle, and C １－１０ The conjugate of any one of claims 16 to 28, which is optionally substituted with one or more substituents selected from haloalkyl.

30. The conjugate of any one of claims 16 to 29, wherein m is 1.

31. 31. The conjugate of any of claims 16-30, wherein POLY is polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), a copolymer of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), polysarcosine, or a combination thereof.

32. The conjugate of any one of claims 16 to 31, wherein POLY comprises polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG).

33. 33. The conjugate of any of claims 16-32, wherein RL comprises an alkyne, cyclooctyne, strained alkene, tetrazine, thiol, para-acetyl-phenylalanine residue, oxyamine, amine, maleimide, or azide.

34. RL is, 【Chemistry 8】 The conjugate of any one of claims 16 to 33, selected from the group consisting of:

35. Formula III: 【Chemistry 9】 (III) (In the formula, L １ａ teeth, 【Chemistry 10】 Selected from: Ring A is an optionally substituted bridged, fused, or spirocyclic bicyclic carbocycle, or an optionally substituted bridged, fused, or spirocyclic bicyclic heterocycle, and the carbocycle or heterocycle of Ring A is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO ２ , —OH, —N(R ２ R ３ ) ２ , -C(O)-, -C(O)N(R ２ R ３ ) ２ , -C(O)OR ２ , optionally substituted with one or more substituents selected from aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Ring B is an optionally substituted N-linked bridged, fused, or spirocyclic bicyclic heterocycle, wherein Ring B is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO ２ , —OH, —N(R ２ R ３ ) ２ , -C(O)-, -C(O)N(R ２ R ３ ) ２ , -C(O)OR ２ , optionally substituted with one or more substituents selected from aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R ａ and R ｂ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO ２ , —OH, —N(R ２ R ３ ) ２ , -C(O)N(R ２ R ３ ) ２ , -C(O)OR ２ , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; a is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; b is an integer selected from 0 or 1; R １ is hydrogen or cycloalkyl, halogen, alkoxy, —CN, —NO ２ , —OH, —N(R ２ R ３ ) ２ , -C(O)N(R ２ R ３ ) ２ , -C(O)OR ２ alkyl optionally substituted with one or more substituents selected from aryl, aryl, and heteroaryl; R ２ and R ３ is independently selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; Y ａ is *-C(O)-(CR ａ R ｂ ) ｃ -NH- or *-C(O)-(CR ａ R ｂ ) ｃ -, and * in these formulas represents Y ａ represents the point of attachment to RL; c is an integer selected from 1, 2, 3, 4, 5, or 6; RL is a reactive group residue; L ２ is a linker that is absent or comprises a hydrophilic polymer residue; L ３ does not exist ａ R ｂ ) ａ -Z-(CR) ａ R ｂ ) ａ -C(O)-、-C(O)-Z-(CR ａ R ｂ ) ａ -C(O)-Z-L ４ - ａ R ｂ ) ａ -、-AA-C(O)-、-C(O)-(CR ａ R ｂ ) ａ -Z-(CR) ａ R ｂ )-Z-AA-C(O)-、-C(O)O-L ４ -Z-C(O)-(CR ａ R ｂ ) ａ -Z-C(O)-、-AA-Z-、---(CR ａ R ｂ ) ａ -Z-AA-C(O)- ; Z is -NR ２ - and -O-; AA is an amino acid residue or a peptide residue; L ４ teeth, 【Chemistry 11】 where Su is a hexose monosaccharide; d is an integer independently selected from 1, 2, and 3; D is a drug moiety; COMP is a residue of the ROR1 antibody; and 【Chemistry 12】 represents the bond to the rest of the compound) The conjugate according to any one of claims 1 to 15, wherein:

36. Formula (V): 【Chemistry 13】 (V) (In the formula, L ５ is a linker comprising an unnatural amino acid; Y ａ is *-C(O)-(CR ａ R ｂ ) ｃ -NH- or *-C(O)-(CR ａ R ｂ ) ｃ -, and * in these formulas represents Y ａ represents the point of attachment to RL; c is an integer selected from 1, 2, 3, 4, 5, or 6; RL is a reactive group residue; L ２ is a linker that is absent or comprises a hydrophilic polymer residue; L ３ does not exist ａ R ｂ ) ａ -Z-(CR) ａ R ｂ ) ａ -C(O)-、-C(O)-Z-(CR ａ R ｂ ) ａ -C(O)-Z-L ４ - ａ R ｂ ) ａ - 、 -AA-C(O)-、-C(O)-(CR ａ R ｂ ) ａ -Z-(CR) ａ R ｂ )-Z-AA-C(O)-、-C(O)O-L ４ -Z-C(O)-(CR ａ R ｂ ) ａ -Z-C(O)-、-AA-Z-、---(CR ａ R ｂ ) ａ -Z-AA-C(O)- ; R ａ and R ｂ are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO ２ , —OH, —N(R ２ R ３ ) ２ , -C(O)N(R ２ R ３ ) ２ , -C(O)OR ２ , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; a is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6; Z is -NR ２ - and -O-; AA is an amino acid residue or a peptide residue; L ４ teeth, 【Chemistry 14】 where Su is a hexose monosaccharide; d is an integer independently selected from 1, 2, and 3; D is a drug moiety; COMP is a residue of the ROR1 antibody; and 【Chemistry 15】 represents the bond to the rest of the compound) The conjugate according to any one of claims 1 to 15, or a pharmaceutically acceptable salt and / or positional isomer thereof:

37. Ring B is 【Chemistry 16】 36. The conjugate of claim 35, selected from:

38. Ring B is 【Chemistry 17】 (In the formula, X １ａ , X ２ａ , X ３ , and X ４ are independently —C(R ４ ) ２ is selected from —, —NH—, —O—, and —S—; １ａ , X ２ａ and X ３ If there exists X １ａ ~X ３ At least one of the groups is -C(R ４ ) ２ - and X １ａ , X ２ａ , X ３ and X ４ If there exists X １ａ ~X ４ At least two of the ４ ) ２ Yes; and R ４ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, halogen, alkoxy, —CN, —NO ２ , —OH, —N(R ２ R ３ ) ２ , -C(O)N(R ２ R ３ ) ２ , -C(O)OR ２ , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or two R on the same carbon ４ groups together form an oxo group) 36. The conjugate of claim 35, selected from:

39. Ring B is 【Chemistry 18】 36. The conjugate of claim 35, selected from:

40. Ring A is 【Chemistry 19】 (In the formula, X １ａ , X ２ａ , X ３ , and X ４ are independently —C(R ４ ) ２ is selected from —, —NH—, —O—, and —S—; １ａ , X ２ａ and X ３ If there exists X １ａ ~X ３ At least one of the groups is -C(R ４ ) ２ - and X １ａ , X ２ａ , X ３ and X ４ If there exists X １ａ ~X ４ At least two of the ４ ) ２ and X ５ is N or CR ４ and R ４ are independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, halogen, alkoxy, —CN, —NO ２ , —OH, —N(R ２ R ３ ) ２ , -C(O)N(R ２ R ３ ) ２ , -C(O)OR ２ , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or two R on the same carbon ４ groups together form an oxo group) 36. The conjugate of claim 35, selected from:

41. L １ａ but, 【Chemistry 20】 The conjugate according to any one of claims 35 and 37 to 40,

42. L ２ But, -(CR ａ R ｂ ) ａ -POLY １ -, 【Chemical 21】 (In the formula, POLY １ - is the divalent residue of polyethylene glycol (PEG), poly(propylene glycol) (PPG), or a copolymer of ethylene glycol and propylene glycol; 【Chemical 22】 represents the bond to the rest of the compound) The conjugate according to any one of claims 35 to 41,

43. L ３ is -C(O)-AA-, -C(O)-AA-Z-(CR ａ R ｂ ) ａ -Z-(CR ａ R ｂ ) ａ The conjugate of any one of claims 35 to 42, which is -C(O)-, -Z-AA-, or -AA-.

44. Su, 【Chemical 23】 The conjugate according to any one of claims 35 to 43,

45. 45. The conjugate of any one of claims 35 to 44, wherein D is a drug moiety selected from a tubulin inhibitor, a DNA damaging agent, a DNA topoisomerase I inhibitor or a DNA topoisomerase II inhibitor, an RNA polymerase II inhibitor, a hemiasterlin residue, a camptothecin residue, a camptothexin derivative, an anthracycline residue, PNU-159682 and PNU-159682 derivatives, PBD, and a duocarmycin.

46. 【Catalog 24】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (wherein n2 is an integer from 1 to 10) 46. The antibody conjugate of any one of claims 1 to 45, having a structure selected from the group consisting of:

47. 【Catalog 25】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (wherein n2 is an integer from 1 to 10) 2. The antibody conjugate of claim 1, having a structure selected from the group consisting of:

48. 48. The antibody conjugate of claim 46 or 47, wherein n2 is an integer from 2 to 8, from 2 to 6, from 2 to 4, or n2 is 2, 4, 6, 8, or 10.

49. The antibody comprises a V selected from SEQ ID NOs: 854-1020. Ｈ Three heavy chain CDRs from the sequence, or variants thereof, and a V selected from SEQ ID NOs: 1021-1026. Ｌ 49. The antibody conjugate of any one of claims 1 to 48, comprising three light chain CDRs derived from the sequence:

50. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1021, 855 / 1021, 856 / 1021, 857 / 1021, 858 / 1021, 859 / 1021, 860 / 1021, 861 / 1021, 862 / 1021, 863 / 1021, 864 / 1021, 865 / 1021, 866 / 1021 , 867 / 1021, 868 / 1021, 869 / 1021, 870 / 1021, 871 / 1021, 872 / 1021, 873 / 1021, 874 / 1021, 875 / 1021, 876 / 1021, 877 / 1021, 878 / 1021, 879 / 1021, 880 / 1021 1, 881 / 1021, 882 / 1021, 883 / 1021, 884 / 1021, 885 / 1021, 886 / 1021, 887 / 1021, 888 / 1021, 889 / 1021, 890 / 1021, 891 / 1021, 892 / 1021, 893 / 1021, 894 / 1021 21, 895 / 1021, 896 / 1021, 897 / 1021, 898 / 1021, 899 / 1021, 900 / 1021, 901 / 1021, 902 / 1021, 903 / 1021, 904 / 1021, 905 / 1021, 906 / 1021, 907 / 1021, 908 / 1 021, 909 / 1021, 910 / 1021, 911 / 1021, 912 / 1021, 913 / 1021, 914 / 1021, 915 / 1021, 916 / 1021, 917 / 1021, 918 / 1021, 919 / 1021, 920 / 1021, 921 / 1021, 922 / 1021, 923 / 1021, 924 / 1021, 925 / 1021, 926 / 1021, 927 / 1021, 928 / 1021, 929 / 1021, 930 / 1021, 931 / 1021, 932 / 1021, 933 / 1021, 934 / 1021, 935 / 1021, 93 6 / 1021, 937 / 1021, 938 / 1021, 939 / 1021, 940 / 1021, 941 / 1021, 942 / 1021, 943 / 1021, 944 / 1021, 945 / 1021, 946 / 1021, 947 / 1021, 948 / 1021, 949 / 1021, 9 50 / 1021, 951 / 1021, 952 / 1021, 953 / 1021, 954 / 1021, 955 / 1021, 956 / 1021, 957 / 1021, 958 / 1021, 959 / 1021, 960 / 1021, 961 / 1021, 962 / 1021, 963 / 1021,964 / 1021, 965 / 1021, 966 / 1021, 967 / 1021, 968 / 1021, 969 / 1021, 970 / 1021, 971 / 1021, 972 / 1021, 973 / 1021, 974 / 1021, 975 / 1021, 976 / 1021, 977 / 1021, 978 / 1021, 97 9 / 1021, 980 / 1021, 981 / 1021, 982 / 1021, 983 / 1021, 984 / 1021, 985 / 1021, 986 / 1021, 987 / 1021, 988 / 1021, 989 / 1021, 990 / 1021, 991 / 1021, 992 / 1021, 993 / 1021, 994 / 1021, 995 / 1021, 996 / 1021, 997 / 1021, 998 / 1021, 999 / 1021, 1000 / 1021, 1001 / 1021, 1002 / 1021, 1003 / 1021, 1004 / 1021, 1005 / 1021, 1006 / 1021, 1007 / 1021, 1008 / 10 V selected from the group consisting of 21, 1009 / 1021, 1010 / 1021, 1011 / 1021, 1012 / 1021, 1013 / 1021, 1014 / 1021, 1015 / 1021, 1016 / 1021, 1017 / 1021, 1018 / 1021, 1019 / 1021, and 1020 / 1021; Ｈ / V Ｌ 50. The antibody conjugate of any one of claims 1 to 49, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from a pair.

51. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1022, 855 / 1022, 856 / 1022, 857 / 1022, 858 / 1022, 859 / 1022, 860 / 1022, 861 / 1022, 862 / 1022, 863 / 1022, 864 / 1022, 865 / 1022, 866 / 1022 , 867 / 1022, 868 / 1022, 869 / 1022, 870 / 1022, 871 / 1022, 872 / 1022, 873 / 1022, 874 / 1022, 875 / 1022, 876 / 1022, 877 / 1022, 878 / 1022, 879 / 1022, 880 / 1022 2, 881 / 1022, 882 / 1022, 883 / 1022, 884 / 1022, 885 / 1022, 886 / 1022, 887 / 1022, 888 / 1022, 889 / 1022, 890 / 1022, 891 / 1022, 892 / 1022, 893 / 1022, 894 / 10 22, 895 / 1022, 896 / 1022, 897 / 1022, 898 / 1022, 899 / 1022, 900 / 1022, 901 / 1022, 902 / 1022, 903 / 1022, 904 / 1022, 905 / 1022, 906 / 1022, 907 / 1022, 908 / 1 022, 909 / 1022, 910 / 1022, 911 / 1022, 912 / 1022, 913 / 1022, 914 / 1022, 915 / 1022, 916 / 1022, 917 / 1022, 918 / 1022, 919 / 1022, 920 / 1022, 921 / 1022, 922 / 1022, 923 / 1022, 924 / 1022, 925 / 1022, 926 / 1022, 927 / 1022, 928 / 1022, 929 / 1022, 930 / 1022, 931 / 1022, 932 / 1022, 933 / 1022, 934 / 1022, 935 / 1022, 93 6 / 1022, 937 / 1022, 938 / 1022, 939 / 1022, 940 / 1022, 941 / 1022, 942 / 1022, 943 / 1022, 944 / 1022, 945 / 1022, 946 / 1022, 947 / 1022, 948 / 1022, 949 / 1022, 9 50 / 1022, 951 / 1022, 952 / 1022, 953 / 1022, 954 / 1022, 955 / 1022, 956 / 1022, 957 / 1022, 958 / 1022, 959 / 1022, 960 / 1022, 961 / 1022, 962 / 1022, 963 / 1022,964 / 1022, 965 / 1022, 966 / 1022, 967 / 1022, 968 / 1022, 969 / 1022, 970 / 1022, 971 / 1022, 972 / 1022, 973 / 1022, 974 / 1022, 975 / 1022, 976 / 1022, 977 / 1022, 978 / 1022, 97 9 / 1022, 980 / 1022, 981 / 1022, 982 / 1022, 983 / 1022, 984 / 1022, 985 / 1022, 986 / 1022, 987 / 1022, 988 / 1022, 989 / 1022, 990 / 1022, 991 / 1022, 992 / 1022, 993 / 1022, 994 / 1022, 995 / 1022, 996 / 1022, 997 / 1022, 998 / 1022, 999 / 1022, 1000 / 1022, 1001 / 1022, 1002 / 1022, 1003 / 1022, 1004 / 1022, 1005 / 1022, 1006 / 1022, 1007 / 1022, 1008 / 10 V selected from the group consisting of 22, 1009 / 1022, 1010 / 1022, 1011 / 1022, 1012 / 1022, 1013 / 1022, 1014 / 1022, 1015 / 1022, 1016 / 1022, 1017 / 1022, 1018 / 1022, 1019 / 1022, and 1020 / 1022; Ｈ / V Ｌ 51. An antibody conjugate according to any preceding claim, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from a pair.

52. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1023, 855 / 1023, 856 / 1023, 857 / 1023, 858 / 1023, 859 / 1023, 860 / 1023, 861 / 1023, 862 / 1023, 863 / 1023, 864 / 1023, 865 / 1023, 866 / 1023 , 867 / 1023, 868 / 1023, 869 / 1023, 870 / 1023, 871 / 1023, 872 / 1023, 873 / 1023, 874 / 1023, 875 / 1023, 876 / 1023, 877 / 1023, 878 / 1023, 879 / 1023, 880 / 1023 3, 881 / 1023, 882 / 1023, 883 / 1023, 884 / 1023, 885 / 1023, 886 / 1023, 887 / 1023, 888 / 1023, 889 / 1023, 890 / 1023, 891 / 1023, 892 / 1023, 893 / 1023, 894 / 10 23, 895 / 1023, 896 / 1023, 897 / 1023, 898 / 1023, 899 / 1023, 900 / 1023, 901 / 1023, 902 / 1023, 903 / 1023, 904 / 1023, 905 / 1023, 906 / 1023, 907 / 1023, 908 / 1 023, 909 / 1023, 910 / 1023, 911 / 1023, 912 / 1023, 913 / 1023, 914 / 1023, 915 / 1023, 916 / 1023, 917 / 1023, 918 / 1023, 919 / 1023, 920 / 1023, 921 / 1023, 922 / 1023, 923 / 1023, 924 / 1023, 925 / 1023, 926 / 1023, 927 / 1023, 928 / 1023, 929 / 1023, 930 / 1023, 931 / 1023, 932 / 1023, 933 / 1023, 934 / 1023, 935 / 1023, 93 6 / 1023, 937 / 1023, 938 / 1023, 939 / 1023, 940 / 1023, 941 / 1023, 942 / 1023, 943 / 1023, 944 / 1023, 945 / 1023, 946 / 1023, 947 / 1023, 948 / 1023, 949 / 1023, 9 50 / 1023, 951 / 1023, 952 / 1023, 953 / 1023, 954 / 1023, 955 / 1023, 956 / 1023, 957 / 1023, 958 / 1023, 959 / 1023, 960 / 1023, 961 / 1023, 962 / 1023, 963 / 1023,964 / 1023, 965 / 1023, 966 / 1023, 967 / 1023, 968 / 1023, 969 / 1023, 970 / 1023, 971 / 1023, 972 / 1023, 973 / 1023, 974 / 1023, 975 / 1023, 976 / 1023, 977 / 1023, 978 / 1023, 97 9 / 1023, 980 / 1023, 981 / 1023, 982 / 1023, 983 / 1023, 984 / 1023, 985 / 1023, 986 / 1023, 987 / 1023, 988 / 1023, 989 / 1023, 990 / 1023, 991 / 1023, 992 / 1023, 993 / 1023, 994 / 1023, 995 / 1023, 996 / 1023, 997 / 1023, 998 / 1023, 999 / 1023, 1000 / 1023, 1001 / 1023, 1002 / 1023, 1003 / 1023, 1004 / 1023, 1005 / 1023, 1006 / 1023, 1007 / 1023, 1008 / 10 V selected from the group consisting of 1009 / 1023, 1010 / 1023, 1011 / 1023, 1012 / 1023, 1013 / 1023, 1014 / 1023, 1015 / 1023, 1016 / 1023, 1017 / 1023, 1018 / 1023, 1019 / 1023, and 1020 / 1023; Ｈ / V Ｌ 52. The antibody conjugate of any one of claims 1 to 51, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from a pair.

53. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1024, 855 / 1024, 856 / 1024, 857 / 1024, 858 / 1024, 859 / 1024, 860 / 1024, 861 / 1024, 862 / 1024, 863 / 1024, 864 / 1024, 865 / 1024, 866 / 1024 , 867 / 1024, 868 / 1024, 869 / 1024, 870 / 1024, 871 / 1024, 872 / 1024, 873 / 1024, 874 / 1024, 875 / 1024, 876 / 1024, 877 / 1024, 878 / 1024, 879 / 1024, 880 / 1024 4, 881 / 1024, 882 / 1024, 883 / 1024, 884 / 1024, 885 / 1024, 886 / 1024, 887 / 1024, 888 / 1024, 889 / 1024, 890 / 1024, 891 / 1024, 892 / 1024, 893 / 1024, 894 / 10 24, 895 / 1024, 896 / 1024, 897 / 1024, 898 / 1024, 899 / 1024, 900 / 1024, 901 / 1024, 902 / 1024, 903 / 1024, 904 / 1024, 905 / 1024, 906 / 1024, 907 / 1024, 908 / 1 024, 909 / 1024, 910 / 1024, 911 / 1024, 912 / 1024, 913 / 1024, 914 / 1024, 915 / 1024, 916 / 1024, 917 / 1024, 918 / 1024, 919 / 1024, 920 / 1024, 921 / 1024, 922 / 1024, 923 / 1024, 924 / 1024, 925 / 1024, 926 / 1024, 927 / 1024, 928 / 1024, 929 / 1024, 930 / 1024, 931 / 1024, 932 / 1024, 933 / 1024, 934 / 1024, 935 / 1024, 93 6 / 1024, 937 / 1024, 938 / 1024, 939 / 1024, 940 / 1024, 941 / 1024, 942 / 1024, 943 / 1024, 944 / 1024, 945 / 1024, 946 / 1024, 947 / 1024, 948 / 1024, 949 / 1024, 9 50 / 1024, 951 / 1024, 952 / 1024, 953 / 1024, 954 / 1024, 955 / 1024, 956 / 1024, 957 / 1024, 958 / 1024, 959 / 1024, 960 / 1024, 961 / 1024, 962 / 1024, 963 / 1024,964 / 1024, 965 / 1024, 966 / 1024, 967 / 1024, 968 / 1024, 969 / 1024, 970 / 1024, 971 / 1024, 972 / 1024, 973 / 1024, 974 / 1024, 975 / 1024, 976 / 1024, 977 / 1024, 978 / 1024, 97 9 / 1024, 980 / 1024, 981 / 1024, 982 / 1024, 983 / 1024, 984 / 1024, 985 / 1024, 986 / 1024, 987 / 1024, 988 / 1024, 989 / 1024, 990 / 1024, 991 / 1024, 992 / 1024, 993 / 1024, 994 / 1024, 995 / 1024, 996 / 1024, 997 / 1024, 998 / 1024, 999 / 1024, 1000 / 1024, 1001 / 1024, 1002 / 1024, 1003 / 1024, 1004 / 1024, 1005 / 1024, 1006 / 1024, 1007 / 1024, 1008 / 10 V selected from the group consisting of 1009 / 1024, 1010 / 1024, 1011 / 1024, 1012 / 1024, 1013 / 1024, 1014 / 1024, 1015 / 1024, 1016 / 1024, 1017 / 1024, 1018 / 1024, 1019 / 1024, and 1020 / 1024; Ｈ / V Ｌ 53. The antibody conjugate of any of claims 1 to 52, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from a pair.

54. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1025, 855 / 1025, 856 / 1025, 857 / 1025, 858 / 1025, 859 / 1025, 860 / 1025, 861 / 1025, 862 / 1025, 863 / 1025, 864 / 1025, 865 / 1025, 866 / 1025 , 867 / 1025, 868 / 1025, 869 / 1025, 870 / 1025, 871 / 1025, 872 / 1025, 873 / 1025, 874 / 1025, 875 / 1025, 876 / 1025, 877 / 1025, 878 / 1025, 879 / 1025, 880 / 1025 5, 881 / 1025, 882 / 1025, 883 / 1025, 884 / 1025, 885 / 1025, 886 / 1025, 887 / 1025, 888 / 1025, 889 / 1025, 890 / 1025, 891 / 1025, 892 / 1025, 893 / 1025, 894 / 10 25, 895 / 1025, 896 / 1025, 897 / 1025, 898 / 1025, 899 / 1025, 900 / 1025, 901 / 1025, 902 / 1025, 903 / 1025, 904 / 1025, 905 / 1025, 906 / 1025, 907 / 1025, 908 / 1 025, 909 / 1025, 910 / 1025, 911 / 1025, 912 / 1025, 913 / 1025, 914 / 1025, 915 / 1025, 916 / 1025, 917 / 1025, 918 / 1025, 919 / 1025, 920 / 1025, 921 / 1025, 922 / 1025, 923 / 1025, 924 / 1025, 925 / 1025, 926 / 1025, 927 / 1025, 928 / 1025, 929 / 1025, 930 / 1025, 931 / 1025, 932 / 1025, 933 / 1025, 934 / 1025, 935 / 1025, 93 6 / 1025, 937 / 1025, 938 / 1025, 939 / 1025, 940 / 1025, 941 / 1025, 942 / 1025, 943 / 1025, 944 / 1025, 945 / 1025, 946 / 1025, 947 / 1025, 948 / 1025, 949 / 1025, 9 50 / 1025, 951 / 1025, 952 / 1025, 953 / 1025, 954 / 1023, 955 / 1025, 956 / 1025, 957 / 1025, 958 / 1025, 959 / 1025, 960 / 1025, 961 / 1025, 962 / 1025, 963 / 1023,964 / 1025, 965 / 1025, 966 / 1025, 967 / 1025, 968 / 1025, 969 / 1025, 970 / 1025, 971 / 1025, 972 / 1025, 973 / 1025, 974 / 1025, 975 / 1025, 976 / 1025, 977 / 1025, 978 / 1025, 97 9 / 1025, 980 / 1025, 981 / 1025, 982 / 1025, 983 / 1025, 984 / 1025, 985 / 1025, 986 / 1025, 987 / 1025, 988 / 1025, 989 / 1025, 990 / 1025, 991 / 1025, 992 / 1025, 993 / 1025, 994 / 1025, 995 / 1025, 996 / 1025, 997 / 1025, 998 / 1025, 999 / 1025, 1000 / 1025, 1001 / 1025, 1002 / 1025, 1003 / 1025, 1004 / 1025, 1005 / 1025, 1006 / 1025, 1007 / 1025, 1008 / 10 V selected from the group consisting of 1009 / 1025, 1010 / 1025, 1011 / 1025, 1012 / 1025, 1013 / 1025, 1014 / 1025, 1015 / 1025, 1016 / 1025, 1017 / 1025, 1018 / 1025, 1019 / 1025, and 1020 / 1025; Ｈ / V Ｌ 54. An antibody conjugate according to any preceding claim, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from a pair.

55. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1026, 855 / 1026, 856 / 1026, 857 / 1026, 858 / 1026, 859 / 1026, 860 / 1026, 861 / 1026, 862 / 1026, 863 / 1026, 864 / 1026, 865 / 1026, 866 / 1026 , 867 / 1026, 868 / 1026, 869 / 1026, 870 / 1026, 871 / 1026, 872 / 1026, 873 / 1026, 874 / 1026, 875 / 1026, 876 / 1026, 877 / 1026, 878 / 1026, 879 / 1026, 880 / 1026 6, 881 / 1026, 882 / 1026, 883 / 1026, 884 / 1026, 885 / 1026, 886 / 1026, 887 / 1026, 888 / 1026, 889 / 1026, 890 / 1026, 891 / 1026, 892 / 1026, 893 / 1026, 894 / 10 26, 895 / 1026, 896 / 1026, 897 / 1026, 898 / 1026, 899 / 1026, 900 / 1026, 901 / 1026, 902 / 1026, 903 / 1026, 904 / 1026, 905 / 1026, 906 / 1026, 907 / 1026, 908 / 1 026, 909 / 1026, 910 / 1026, 911 / 1026, 912 / 1026, 913 / 1026, 914 / 1026, 915 / 1026, 916 / 1026, 917 / 1026, 918 / 1026, 919 / 1026, 920 / 1026, 921 / 1026, 922 / 1026, 923 / 1026, 924 / 1026, 925 / 1026, 926 / 1026, 927 / 1026, 928 / 1026, 929 / 1026, 930 / 1026, 931 / 1026, 932 / 1026, 933 / 1026, 934 / 1026, 935 / 1026, 93 6 / 1026, 937 / 1026, 938 / 1026, 939 / 1026, 940 / 1026, 941 / 1026, 942 / 1026, 943 / 1026, 944 / 1026, 945 / 1026, 946 / 1026, 947 / 1026, 948 / 1026, 949 / 1026, 9 50 / 1026, 951 / 1026, 952 / 1026, 953 / 1026, 954 / 1023, 955 / 1026, 956 / 1026, 957 / 1026, 958 / 1026, 959 / 1026, 960 / 1026, 961 / 1026, 962 / 1026, 963 / 1023,964 / 1026, 965 / 1026, 966 / 1026, 967 / 1026, 968 / 1026, 969 / 1026, 970 / 1026, 971 / 1026, 972 / 1026, 973 / 1026, 974 / 1026, 975 / 1026, 976 / 1026, 977 / 1026, 978 / 1026, 97 9 / 1026, 980 / 1026, 981 / 1026, 982 / 1026, 983 / 1026, 984 / 1026, 985 / 1026, 986 / 1026, 987 / 1026, 988 / 1026, 989 / 1026, 990 / 1026, 991 / 1026, 992 / 1026, 993 / 1026, 994 / 1026, 995 / 1026, 996 / 1026, 997 / 1026, 998 / 1026, 999 / 1026, 1000 / 1026, 1001 / 1026, 1002 / 1026, 1003 / 1026, 1004 / 1026, 1005 / 1026, 1006 / 1026, 1007 / 1026, 1008 / 10 V selected from the group consisting of 1009 / 1026, 1010 / 1026, 1011 / 1026, 1012 / 1026, 1013 / 1026, 1014 / 1026, 1015 / 1026, 1016 / 1026, 1017 / 1026, 1018 / 1026, 1019 / 1026, and 1020 / 1026; Ｈ / V Ｌ 55. An antibody conjugate according to any preceding claim, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from a pair.

56. The antibody comprises a V selected from SEQ ID NOs: 854-1020. Ｈ 56. The antibody conjugate of any one of claims 1 to 55, comprising:

57. The antibody comprises a V selected from SEQ ID NOs: 1021-1026. Ｌ 57. The antibody conjugate of any one of claims 1 to 56, comprising:

58. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1021, 855 / 1021, 856 / 1021, 857 / 1021, 858 / 1021, 859 / 1021, 860 / 1021, 861 / 1021, 862 / 1021, 863 / 1021, 864 / 1021, 865 / 1021, 866 / 1021 , 867 / 1021, 868 / 1021, 869 / 1021, 870 / 1021, 871 / 1021, 872 / 1021, 873 / 1021, 874 / 1021, 875 / 1021, 876 / 1021, 877 / 1021, 878 / 1021, 879 / 1021, 880 / 1021 1, 881 / 1021, 882 / 1021, 883 / 1021, 884 / 1021, 885 / 1021, 886 / 1021, 887 / 1021, 888 / 1021, 889 / 1021, 890 / 1021, 891 / 1021, 892 / 1021, 893 / 1021, 894 / 1021 21, 895 / 1021, 896 / 1021, 897 / 1021, 898 / 1021, 899 / 1021, 900 / 1021, 901 / 1021, 902 / 1021, 903 / 1021, 904 / 1021, 905 / 1021, 906 / 1021, 907 / 1021, 908 / 1 021, 909 / 1021, 910 / 1021, 911 / 1021, 912 / 1021, 913 / 1021, 914 / 1021, 915 / 1021, 916 / 1021, 917 / 1021, 918 / 1021, 919 / 1021, 920 / 1021, 921 / 1021, 922 / 1021, 923 / 1021, 924 / 1021, 925 / 1021, 926 / 1021, 927 / 1021, 928 / 1021, 929 / 1021, 930 / 1021, 931 / 1021, 932 / 1021, 933 / 1021, 934 / 1021, 935 / 1021, 93 6 / 1021, 937 / 1021, 938 / 1021, 939 / 1021, 940 / 1021, 941 / 1021, 942 / 1021, 943 / 1021, 944 / 1021, 945 / 1021, 946 / 1021, 947 / 1021, 948 / 1021, 949 / 1021, 9 50 / 1021, 951 / 1021, 952 / 1021, 953 / 1021, 954 / 1021, 955 / 1021, 956 / 1021, 957 / 1021, 958 / 1021, 959 / 1021, 960 / 1021, 961 / 1021, 962 / 1021, 963 / 1021,964 / 1021, 965 / 1021, 966 / 1021, 967 / 1021, 968 / 1021, 969 / 1021, 970 / 1021, 971 / 1021, 972 / 1021, 973 / 1021, 974 / 1021, 975 / 1021, 976 / 1021, 977 / 1021, 978 / 1021, 97 9 / 1021, 980 / 1021, 981 / 1021, 982 / 1021, 983 / 1021, 984 / 1021, 985 / 1021, 986 / 1021, 987 / 1021, 988 / 1021, 989 / 1021, 990 / 1021, 991 / 1021, 992 / 1021, 993 / 1021, 994 / 1021, 995 / 1021, 996 / 1021, 997 / 1021, 998 / 1021, 999 / 1021, 1000 / 1021, 1001 / 1021, 1002 / 1021, 1003 / 1021, 1004 / 1021, 1005 / 1021, 1006 / 1021, 1007 / 1021, 1008 / 10 V selected from the group consisting of 21, 1009 / 1021, 1010 / 1021, 1011 / 1021, 1012 / 1021, 1013 / 1021, 1014 / 1021, 1015 / 1021, 1016 / 1021, 1017 / 1021, 1018 / 1021, 1019 / 1021, and 1020 / 1021; Ｈ / V Ｌ 58. The antibody conjugate of any one of claims 1 to 57, comprising a pair, or a variant thereof.

59. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1022, 855 / 1022, 856 / 1022, 857 / 1022, 858 / 1022, 859 / 1022, 860 / 1022, 861 / 1022, 862 / 1022, 863 / 1022, 864 / 1022, 865 / 1022, 866 / 1022 , 867 / 1022, 868 / 1022, 869 / 1022, 870 / 1022, 871 / 1022, 872 / 1022, 873 / 1022, 874 / 1022, 875 / 1022, 876 / 1022, 877 / 1022, 878 / 1022, 879 / 1022, 880 / 1022 2, 881 / 1022, 882 / 1022, 883 / 1022, 884 / 1022, 885 / 1022, 886 / 1022, 887 / 1022, 888 / 1022, 889 / 1022, 890 / 1022, 891 / 1022, 892 / 1022, 893 / 1022, 894 / 10 22, 895 / 1022, 896 / 1022, 897 / 1022, 898 / 1022, 899 / 1022, 900 / 1022, 901 / 1022, 902 / 1022, 903 / 1022, 904 / 1022, 905 / 1022, 906 / 1022, 907 / 1022, 908 / 1 022, 909 / 1022, 910 / 1022, 911 / 1022, 912 / 1022, 913 / 1022, 914 / 1022, 915 / 1022, 916 / 1022, 917 / 1022, 918 / 1022, 919 / 1022, 920 / 1022, 921 / 1022, 922 / 1022, 923 / 1022, 924 / 1022, 925 / 1022, 926 / 1022, 927 / 1022, 928 / 1022, 929 / 1022, 930 / 1022, 931 / 1022, 932 / 1022, 933 / 1022, 934 / 1022, 935 / 1022, 93 6 / 1022, 937 / 1022, 938 / 1022, 939 / 1022, 940 / 1022, 941 / 1022, 942 / 1022, 943 / 1022, 944 / 1022, 945 / 1022, 946 / 1022, 947 / 1022, 948 / 1022, 949 / 1022, 9 50 / 1022, 951 / 1022, 952 / 1022, 953 / 1022, 954 / 1022, 955 / 1022, 956 / 1022, 957 / 1022, 958 / 1022, 959 / 1022, 960 / 1022, 961 / 1022, 962 / 1022, 963 / 1022,964 / 1022, 965 / 1022, 966 / 1022, 967 / 1022, 968 / 1022, 969 / 1022, 970 / 1022, 971 / 1022, 972 / 1022, 973 / 1022, 974 / 1022, 975 / 1022, 976 / 1022, 977 / 1022, 978 / 1022, 97 9 / 1022, 980 / 1022, 981 / 1022, 982 / 1022, 983 / 1022, 984 / 1022, 985 / 1022, 986 / 1022, 987 / 1022, 988 / 1022, 989 / 1022, 990 / 1022, 991 / 1022, 992 / 1022, 993 / 1022, 994 / 1022, 995 / 1022, 996 / 1022, 997 / 1022, 998 / 1022, 999 / 1022, 1000 / 1022, 1001 / 1022, 1002 / 1022, 1003 / 1022, 1004 / 1022, 1005 / 1022, 1006 / 1022, 1007 / 1022, 1008 / 10 V selected from the group consisting of 22, 1009 / 1022, 1010 / 1022, 1011 / 1022, 1012 / 1022, 1013 / 1022, 1014 / 1022, 1015 / 1022, 1016 / 1022, 1017 / 1022, 1018 / 1022, 1019 / 1022, and 1020 / 1022; Ｈ / V Ｌ 59. The antibody conjugate of any one of claims 1 to 58, comprising a pair, or a variant thereof.

60. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1023, 855 / 1023, 856 / 1023, 857 / 1023, 858 / 1023, 859 / 1023, 860 / 1023, 861 / 1023, 862 / 1023, 863 / 1023, 864 / 1023, 865 / 1023, 866 / 1023 , 867 / 1023, 868 / 1023, 869 / 1023, 870 / 1023, 871 / 1023, 872 / 1023, 873 / 1023, 874 / 1023, 875 / 1023, 876 / 1023, 877 / 1023, 878 / 1023, 879 / 1023, 880 / 1023 3, 881 / 1023, 882 / 1023, 883 / 1023, 884 / 1023, 885 / 1023, 886 / 1023, 887 / 1023, 888 / 1023, 889 / 1023, 890 / 1023, 891 / 1023, 892 / 1023, 893 / 1023, 894 / 10 23, 895 / 1023, 896 / 1023, 897 / 1023, 898 / 1023, 899 / 1023, 900 / 1023, 901 / 1023, 902 / 1023, 903 / 1023, 904 / 1023, 905 / 1023, 906 / 1023, 907 / 1023, 908 / 1 023, 909 / 1023, 910 / 1023, 911 / 1023, 912 / 1023, 913 / 1023, 914 / 1023, 915 / 1023, 916 / 1023, 917 / 1023, 918 / 1023, 919 / 1023, 920 / 1023, 921 / 1023, 922 / 1023, 923 / 1023, 924 / 1023, 925 / 1023, 926 / 1023, 927 / 1023, 928 / 1023, 929 / 1023, 930 / 1023, 931 / 1023, 932 / 1023, 933 / 1023, 934 / 1023, 935 / 1023, 93 6 / 1023, 937 / 1023, 938 / 1023, 939 / 1023, 940 / 1023, 941 / 1023, 942 / 1023, 943 / 1023, 944 / 1023, 945 / 1023, 946 / 1023, 947 / 1023, 948 / 1023, 949 / 1023, 9 50 / 1023, 951 / 1023, 952 / 1023, 953 / 1023, 954 / 1023, 955 / 1023, 956 / 1023, 957 / 1023, 958 / 1023, 959 / 1023, 960 / 1023, 961 / 1023, 962 / 1023, 963 / 1023,964 / 1023, 965 / 1023, 966 / 1023, 967 / 1023, 968 / 1023, 969 / 1023, 970 / 1023, 971 / 1023, 972 / 1023, 973 / 1023, 974 / 1023, 975 / 1023, 976 / 1023, 977 / 1023, 978 / 1023, 97 9 / 1023, 980 / 1023, 981 / 1023, 982 / 1023, 983 / 1023, 984 / 1023, 985 / 1023, 986 / 1023, 987 / 1023, 988 / 1023, 989 / 1023, 990 / 1023, 991 / 1023, 992 / 1023, 993 / 1023, 994 / 1023, 995 / 1023, 996 / 1023, 997 / 1023, 998 / 1023, 999 / 1023, 1000 / 1023, 1001 / 1023, 1002 / 1023, 1003 / 1023, 1004 / 1023, 1005 / 1023, 1006 / 1023, 1007 / 1023, 1008 / 10 V selected from the group consisting of 1009 / 1023, 1010 / 1023, 1011 / 1023, 1012 / 1023, 1013 / 1023, 1014 / 1023, 1015 / 1023, 1016 / 1023, 1017 / 1023, 1018 / 1023, 1019 / 1023, and 1020 / 1023; Ｈ / V Ｌ 60. The antibody conjugate of any one of claims 1 to 59, comprising a pair, or a variant thereof.

61. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1024, 855 / 1024, 856 / 1024, 857 / 1024, 858 / 1024, 859 / 1024, 860 / 1024, 861 / 1024, 862 / 1024, 863 / 1024, 864 / 1024, 865 / 1024, 866 / 1024 , 867 / 1024, 868 / 1024, 869 / 1024, 870 / 1024, 871 / 1024, 872 / 1024, 873 / 1024, 874 / 1024, 875 / 1024, 876 / 1024, 877 / 1024, 878 / 1024, 879 / 1024, 880 / 1024 4, 881 / 1024, 882 / 1024, 883 / 1024, 884 / 1024, 885 / 1024, 886 / 1024, 887 / 1024, 888 / 1024, 889 / 1024, 890 / 1024, 891 / 1024, 892 / 1024, 893 / 1024, 894 / 10 24, 895 / 1024, 896 / 1024, 897 / 1024, 898 / 1024, 899 / 1024, 900 / 1024, 901 / 1024, 902 / 1024, 903 / 1024, 904 / 1024, 905 / 1024, 906 / 1024, 907 / 1024, 908 / 1 024, 909 / 1024, 910 / 1024, 911 / 1024, 912 / 1024, 913 / 1024, 914 / 1024, 915 / 1024, 916 / 1024, 917 / 1024, 918 / 1024, 919 / 1024, 920 / 1024, 921 / 1024, 922 / 1024, 923 / 1024, 924 / 1024, 925 / 1024, 926 / 1024, 927 / 1024, 928 / 1024, 929 / 1024, 930 / 1024, 931 / 1024, 932 / 1024, 933 / 1024, 934 / 1024, 935 / 1024, 93 6 / 1024, 937 / 1024, 938 / 1024, 939 / 1024, 940 / 1024, 941 / 1024, 942 / 1024, 943 / 1024, 944 / 1024, 945 / 1024, 946 / 1024, 947 / 1024, 948 / 1024, 949 / 1024, 9 50 / 1024, 951 / 1024, 952 / 1024, 953 / 1024, 954 / 1024, 955 / 1024, 956 / 1024, 957 / 1024, 958 / 1024, 959 / 1024, 960 / 1024, 961 / 1024, 962 / 1024, 963 / 1024,964 / 1024, 965 / 1024, 966 / 1024, 967 / 1024, 968 / 1024, 969 / 1024, 970 / 1024, 971 / 1024, 972 / 1024, 973 / 1024, 974 / 1024, 975 / 1024, 976 / 1024, 977 / 1024, 978 / 1024, 97 9 / 1024, 980 / 1024, 981 / 1024, 982 / 1024, 983 / 1024, 984 / 1024, 985 / 1024, 986 / 1024, 987 / 1024, 988 / 1024, 989 / 1024, 990 / 1024, 991 / 1024, 992 / 1024, 993 / 1024, 994 / 1024, 995 / 1024, 996 / 1024, 997 / 1024, 998 / 1024, 999 / 1024, 1000 / 1024, 1001 / 1024, 1002 / 1024, 1003 / 1024, 1004 / 1024, 1005 / 1024, 1006 / 1024, 1007 / 1024, 1008 / 10 V selected from the group consisting of 1009 / 1024, 1010 / 1024, 1011 / 1024, 1012 / 1024, 1013 / 1024, 1014 / 1024, 1015 / 1024, 1016 / 1024, 1017 / 1024, 1018 / 1024, 1019 / 1024, and 1020 / 1024; Ｈ / V Ｌ 61. The antibody conjugate of any one of claims 1 to 60, comprising a pair, or a variant thereof.

62. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1025, 855 / 1025, 856 / 1025, 857 / 1025, 858 / 1025, 859 / 1025, 860 / 1025, 861 / 1025, 862 / 1025, 863 / 1025, 864 / 1025, 865 / 1025, 866 / 1025 , 867 / 1025, 868 / 1025, 869 / 1025, 870 / 1025, 871 / 1025, 872 / 1025, 873 / 1025, 874 / 1025, 875 / 1025, 876 / 1025, 877 / 1025, 878 / 1025, 879 / 1025, 880 / 1025 5, 881 / 1025, 882 / 1025, 883 / 1025, 884 / 1025, 885 / 1025, 886 / 1025, 887 / 1025, 888 / 1025, 889 / 1025, 890 / 1025, 891 / 1025, 892 / 1025, 893 / 1025, 894 / 10 25, 895 / 1025, 896 / 1025, 897 / 1025, 898 / 1025, 899 / 1025, 900 / 1025, 901 / 1025, 902 / 1025, 903 / 1025, 904 / 1025, 905 / 1025, 906 / 1025, 907 / 1025, 908 / 1 025, 909 / 1025, 910 / 1025, 911 / 1025, 912 / 1025, 913 / 1025, 914 / 1025, 915 / 1025, 916 / 1025, 917 / 1025, 918 / 1025, 919 / 1025, 920 / 1025, 921 / 1025, 922 / 1025, 923 / 1025, 924 / 1025, 925 / 1025, 926 / 1025, 927 / 1025, 928 / 1025, 929 / 1025, 930 / 1025, 931 / 1025, 932 / 1025, 933 / 1025, 934 / 1025, 935 / 1025, 93 6 / 1025, 937 / 1025, 938 / 1025, 939 / 1025, 940 / 1025, 941 / 1025, 942 / 1025, 943 / 1025, 944 / 1025, 945 / 1025, 946 / 1025, 947 / 1025, 948 / 1025, 949 / 1025, 9 50 / 1025, 951 / 1025, 952 / 1025, 953 / 1025, 954 / 1025, 955 / 1025, 956 / 1025, 957 / 1025, 958 / 1025, 959 / 1025, 960 / 1025, 961 / 1025, 962 / 1025, 963 / 1025,964 / 1025, 965 / 1025, 966 / 1025, 967 / 1025, 968 / 1025, 969 / 1025, 970 / 1025, 971 / 1025, 972 / 1025, 973 / 1025, 974 / 1025, 975 / 1025, 976 / 1025, 977 / 1025, 978 / 1025, 97 9 / 1025, 980 / 1025, 981 / 1025, 982 / 1025, 983 / 1025, 984 / 1025, 985 / 1025, 986 / 1025, 987 / 1025, 988 / 1025, 989 / 1025, 990 / 1025, 991 / 1025, 992 / 1025, 993 / 1025, 994 / 1025, 995 / 1025, 996 / 1025, 997 / 1025, 998 / 1025, 999 / 1025, 1000 / 1025, 1001 / 1025, 1002 / 1025, 1003 / 1025, 1004 / 1025, 1005 / 1025, 1006 / 1025, 1007 / 1025, 1008 / 10 V selected from the group consisting of 1009 / 1025, 1010 / 1025, 1011 / 1025, 1012 / 1025, 1013 / 1025, 1014 / 1025, 1015 / 1025, 1016 / 1025, 1017 / 1025, 1018 / 1025, 1019 / 1025, and 1020 / 1025; Ｈ / V Ｌ 62. The antibody conjugate of any one of claims 1 to 61, comprising a pair, or a variant thereof.

63. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1026, 855 / 1026, 856 / 1026, 857 / 1026, 858 / 1026, 859 / 1026, 860 / 1026, 861 / 1026, 862 / 1026, 863 / 1026, 864 / 1026, 865 / 1026, 866 / 1026 , 867 / 1026, 868 / 1026, 869 / 1026, 870 / 1026, 871 / 1026, 872 / 1026, 873 / 1026, 874 / 1026, 875 / 1026, 876 / 1026, 877 / 1026, 878 / 1026, 879 / 1026, 880 / 1026 6, 881 / 1026, 882 / 1026, 883 / 1026, 884 / 1026, 885 / 1026, 886 / 1026, 887 / 1026, 888 / 1026, 889 / 1026, 890 / 1026, 891 / 1026, 892 / 1026, 893 / 1026, 894 / 10 26, 895 / 1026, 896 / 1026, 897 / 1026, 898 / 1026, 899 / 1026, 900 / 1026, 901 / 1026, 902 / 1026, 903 / 1026, 904 / 1026, 905 / 1026, 906 / 1026, 907 / 1026, 908 / 1 026, 909 / 1026, 910 / 1026, 911 / 1026, 912 / 1026, 913 / 1026, 914 / 1026, 915 / 1026, 916 / 1026, 917 / 1026, 918 / 1026, 919 / 1026, 920 / 1026, 921 / 1026, 922 / 1026, 923 / 1026, 924 / 1026, 925 / 1026, 926 / 1026, 927 / 1026, 928 / 1026, 929 / 1026, 930 / 1026, 931 / 1026, 932 / 1026, 933 / 1026, 934 / 1026, 935 / 1026, 93 6 / 1026, 937 / 1026, 938 / 1026, 939 / 1026, 940 / 1026, 941 / 1026, 942 / 1026, 943 / 1026, 944 / 1026, 945 / 1026, 946 / 1026, 947 / 1026, 948 / 1026, 949 / 1026, 9 50 / 1026, 951 / 1026, 952 / 1026, 953 / 1026, 954 / 1026, 955 / 1026, 956 / 1026, 957 / 1026, 958 / 1026, 959 / 1026, 960 / 1026, 961 / 1026, 962 / 1026, 963 / 1026,964 / 1026, 965 / 1026, 966 / 1026, 967 / 1026, 968 / 1026, 969 / 1026, 970 / 1026, 971 / 1026, 972 / 1026, 973 / 1026, 974 / 1026, 975 / 1026, 976 / 1026, 977 / 1026, 978 / 1026, 97 9 / 1026, 980 / 1026, 981 / 1026, 982 / 1026, 983 / 1026, 984 / 1026, 985 / 1026, 986 / 1026, 987 / 1026, 988 / 1026, 989 / 1026, 990 / 1026, 991 / 1026, 992 / 1026, 993 / 1026, 994 / 1026, 995 / 1026, 996 / 1026, 997 / 1026, 998 / 1026, 999 / 1026, 1000 / 1026, 1001 / 1026, 1002 / 1026, 1003 / 1026, 1004 / 1026, 1005 / 1026, 1006 / 1026, 1007 / 1026, 1008 / 10 V selected from the group consisting of 1009 / 1026, 1010 / 1026, 1011 / 1026, 1012 / 1026, 1013 / 1026, 1014 / 1026, 1015 / 1026, 1016 / 1026, 1017 / 1026, 1018 / 1026, 1019 / 1026, and 1020 / 1026; Ｈ / V Ｌ 63. The antibody conjugate of any one of claims 1 to 62, comprising a pair, or a variant thereof.

64. The antibody is HC The following group of CDR SEQ ID NOs: 4 / 338 / 672; 5 / 339 / 673; 6 / 340 / 674; 7 / 341 / 675; 8 / 342 / 676; 9 / 343 / 677; 10 / 344 / 678; 11 / 345 / 679; 12 / 346 / 680; 13 / 347 / 681; 14 / 348 / 682; 15 / 349 / 683; 16 / 350 / 684; 17 / 351 / 685; 18 / 352 / 686; 19 / 353 / 687; 20 / 354 / 688; 21 / 355 / 689; 22 / 356 / 690; 23 / 357 / 691; 24 / 358 / 692; 25 / 359 / 69 3; 26 / 360 / 694; 27 / 361 / 695; 28 / 362 / 696; 29 / 363 / 697; 30 / 364 / 698; 31 / 365 / 699; 32 / 366 / 700; 33 / 367 / 701; 34 / 368 / 702; 35 / 369 / 703; 36 / 370 / 704; 37 / 371 / 705; 38 / 372 / 706; 39 / 373 / 707; 40 / 374 / 708; 41 / 375 / 709; 42 / 376 / 710; 43 / 377 / 711; 44 / 378 / 712; 45 / 379 / 713; 46 / 380 / 714; 47 / 381 / 715; 48 / 382 / 716; 49 / 383 / 717; 50 / 384 / 718; 51 / 385 / 719; 52 / 386 / 720; 53 / 387 / 721; 54 / 388 / 722; 55 / 389 / 723; 56 / 390 / 724; 57 / 391 / 725; 58 / 392 / 726; 59 / 3 93 / 727; 60 / 394 / 728; 61 / 395 / 729; 62 / 396 / 730; 63 / 397 / 731; 64 / 398 / 732; 65 / 399 / 733; 66 / 400 / 734; 67 / 401 / 735; 68 / 402 / 736; 69 / 403 / 737; 70 / 404 / 738; 71 / 405 / 739; 72 / 406 / 740; 73 / 407 / 741; 74 / 408 / 742; 75 / 409 / 743; 76 / 410 / 744; 77 / 411 / 745; 78 / 412 / 746; 79 / 413 / 747; 80 / 414 / 748; 81 / 415 / 7 49; 82 / 416 / 750; 83 / 417 / 751; 84 / 418 / 752; 85 / 419 / 753; 86 / 420 / 754; 87 / 421 / 755; 88 / 422 / 756; 89 / 423 / 757; 90 / 424 / 758; 91 / 425 / 759; 92 / 426 / 760;93 / 427 / 761; 94 / 428 / 762; 95 / 429 / 763; 96 / 430 / 764; 97 / 431 / 765; 98 / 432 / 766; 99 / 433 / 767; 100 / 434 / 768; 101 / 435 / 769; 102 / 436 / 770; 103 / 437 / 771; 104 / 438 / 772; 105 / 439 / 773; 106 / 440 / 774; 107 / 441 / 775; 108 / 442 / 776; 109 / 443 / 777; 110 / 444 / 778; 111 / 445 / 779; 112 / 446 / 780; 113 / 447 / 781; 114 / 448 / 782; 115 / 449 / 783; 116 / 450 / 784; 117 / 451 / 785; 118 / 452 / 786; 119 / 453 / 787; 120 / 454 / 788; 121 / 455 / 789; 122 / 456 / 790; 123 / 457 / 791; 124 / 458 / 792; 125 / 459 / 793; 126 / 460 / 794; 127 / 461 / 795; 128 / 462 / 796; 129 / 463 / 797; 130 / 464 / 798; 131 / 465 / 799; 132 / 466 / 800; 13 3 / 467 / 801; 134 / 468 / 802; 135 / 469 / 803; 136 / 470 / 804; 137 / 471 / 805; 138 / 472 / 806; 139 / 473 / 807; 140 / 474 / 808; 141 / 475 / 809; 142 / 476 / 810; 143 / 477 / 811; 144 / 478 / 812; 145 / 479 / 813; 146 / 480 / 814; 147 / 481 / 815; 148 / 482 / 816; 149 / 483 / 817; 150 / 484 / 818; 151 / 485 / 819; 152 / 486 / 820; Three Chothia species, designated as one of 153 / 487 / 821; 154 / 488 / 822; 155 / 489 / 823; 156 / 490 / 824; 157 / 491 / 825; 158 / 492 / 826; 159 / 493 / 827; 160 / 494 / 828; 161 / 495 / 829; 162 / 496 / 830; 163 / 497 / 831; 164 / 498 / 832; 165 / 499 / 833; 166 / 500 / 834; 167 / 501 / 835; 168 / 502 / 836; 169 / 503 / 837; and 170 / 504 / 838 The antibody conjugate of any one of claims 1 to 63, comprising HC CDRs.

65. The antibody may be selected from the following group of CDR SEQ ID NOs: 4 / 338 / 672 / 839 / 844 / 849; 5 / 339 / 673 / 839 / 844 / 849; 6 / 340 / 674 / 839 / 844 / 849; 7 / 341 / 675 / 839 / 844 / 849; 8 / 342 / 676 / 839 / 844 / 849; 9 / 343 / 677 / 839 / 844 / 849; 10 / 344 / 678 / 839 / 844 / 849; 11 / 345 / 679 / 839 / 844 / 849; 12 / 346 / 680 / 839 / 844 / 849; 13 / 347 / 681 / 839 / 844 / 849; 14 / 348 / 68 2 / 839 / 844 / 849; 15 / 349 / 683 / 839 / 844 / 849; 16 / 350 / 684 / 839 / 844 / 849; 17 / 351 / 685 / 839 / 844 / 849; 18 / 352 / 686 / 839 / 844 / 849; 19 / 353 / 687 / 839 / 844 / 849; 20 / 354 / 688 / 839 / 844 / 849; 21 / 355 / 689 / 839 / 844 / 849; 22 / 356 / 690 / 839 / 844 / 849; 23 / 357 / 691 / 839 / 844 / 849; 24 / 358 / 692 / 839 / 844 / 849; 25 / 359 / 693 / 839 / 844 / 849; 26 / 360 / 694 / 839 / 844 / 849; 27 / 361 / 695 / 839 / 844 / 849; 28 / 362 / 696 / 839 / 844 / 849; 29 / 363 / 697 / 839 / 844 / 849; 30 / 364 / 698 / 839 / 8 44 / 849; 31 / 365 / 699 / 839 / 844 / 849; 32 / 366 / 700 / 839 / 844 / 849; 33 / 367 / 701 / 839 / 844 / 849; 34 / 368 / 702 / 839 / 844 / 849; 35 / 369 / 703 / 839 / 844 / 849; 36 / 370 / 704 / 839 / 844 / 849; 37 / 371 / 705 / 839 / 844 / 849; 38 / 372 / 706 / 839 / 844 / 849; 39 / 373 / 707 / 839 / 844 / 849; 40 / 374 / 708 / 839 / 844 / 849; 41 / 375 / 709 / 83 9 / 844 / 849; 42 / 376 / 710 / 839 / 844 / 849; 43 / 377 / 711 / 839 / 844 / 849; 44 / 378 / 712 / 839 / 844 / 849; 45 / 379 / 713 / 839 / 844 / 849; 46 / 380 / 714 / 839 / 844 / 849;４７／３８１／７１５／８３９／８４４／８４９；４８／３８２／７１６／８３９／８４４／８４９；４９／３８３／７１７／８３９／８４４／８４９；５０／３８４／７１８／８３９／８４４／８４９；５１／３８５／７１９／８３９／８４４／８４９；５２／３８６／７２０／８３９／８４４／８４９；５３／３８７／７２１／８３９／８４４／８４９；５４／３８８／７２２／８３９／８４４／８４９；５５／３８９／７２３／８３９／８４４／８４９；５６／３９０／７２４／８３９／８４４／８４９；５７／３９１／７２５／８３９／８４４／８４９；５８／３９２／７２６／８３９／８４４／８４９；５９／３９３／７２７／８３９／８４４／８４９；６０／３９４／７２８／８３９／８４４／８４９；６１／３９５／７２９／８３９／８４４／８４９；６２／３９６／７３０／８３９／８４４／８４９；６３／３９７／７３１／８３９／８４４／８４９；６４／３９８／７３２／８３９／８４４／８４９；６５／３９９／７３３／８３９／８４４／８４９；６６／４００／７３４／８３９／８４４／８４９；６７／４０１／７３５／８３９／８４４／８４９；６８／４０２／７３６／８３９／８４４／８４９；６９／４０３／７３７／８３９／８４４／８４９；７０／４０４／７３８／８３９／８４４／８４９；７１／４０５／７３９／８３９／８４４／８４９；７２／４０６／７４０／８３９／８４４／８４９；７３／４０７／７４１／８３９／８４４／８４９；７４／４０８／７４２／８３９／８４４／８４９；７５／４０９／７４３／８３９／８４４／８４９；７６／４１０／７４４／８３９／８４４／８４９；７７／４１１／７４５／８３９／８４４／８４９；７８／４１２／７４６／８３９／８４４／８４９；７９／４１３／７４７／８３９／８４４／８４９；８０／４１４／７４８／８３９／８４４／８４９；８１／４１５／７４９／８３９／８４４／８４９；８２／４１６／７５０／８３９／８４４／８４９；８３／４１７／７５１／８３９／８４４／８４９；８４／４１８／７５２／８３９／８４４／８４９；８５／４１９／７５３／８３９／８４４／８４９；８６／４２０／７５４／８３９／８４４／８４９；８７／４２１／７５５／８３９／８４４／８４９；８８／４２２／７５６／８３９／８４４／８４９；８９／４２３／７５７／８３９／８４４／８４９；９０／４２４／７５８／８３９／８４４／８４９；９１／４２５／７５９／８３９／８４４／８４９；９２／４２６／７６０／８３９／８４４／８４９；９３／４２７／７６１／８３９／８４４／８４９；９４／４２８／７６２／８３９／８４４／８４９；９５／４２９／７６３／８３９／８４４／８４９；９６／４３０／７６４／８３９／８４４／８４９；９７／４３１／７６５／８３９／８４４／８４９；９８／４３２／７６６／８３９／８４４／８４９；９９／４３３／７６７／８３９／８４４／８４９；１００／４３４／７６８／８３９／８４４／８４９；１０１／４３５／７６９／８３９／８４４／８４９；１０２／４３６／７７０／８３９／８４４／８４９；１０３／４３７／７７１／８３９／８４４／８４９；１０４／４３８／７７２／８３９／８４４／８４９；１０５／４３９／７７３／８３９／８４４／８４９；１０６／４４０／７７４／８３９／８４４／８４９；１０７／４４１／７７５／８３９／８４４／８４９；１０８／４４２／７７６／８３９／８４４／８４９；１０９／４４３／７７７／８３９／８４４／８４９；１１０／４４４／７７８／８３９／８４４／８４９；１１１／４４５／７７９／８３９／８４４／８４９；１１２／４４６／７８０／８３９／８４４／８４９；１１３／４４７／７８１／８３９／８４４／８４９；１１４／４４８／７８２／８３９／８４４／８４９；１１５／４４９／７８３／８３９／８４４／８４９；１１６／４５０／７８４／８３９／８４４／８４９；１１７／４５１／７８５／８３９／８４４／８４９；１１８／４５２／７８６／８３９／８４４／８４９；１１９／４５３／７８７／８３９／８４４／８４９；１２０／４５４／７８８／８３９／８４４／８４９；１２１／４５５／７８９／８３９／８４４／８４９；１２２／４５６／７９０／８３９／８４４／８４９；１２３／４５７／７９１／８３９／８４４／８４９；１２４／４５８／７９２／８３９／８４４／８４９；１２５／４５９／７９３／８３９／８４４／８４９；１２６／４６０／７９４／８３９／８４４／８４９；１２７／４６１／７９５／８３９／８４４／８４９；１２８／４６２／７９６／８３９／８４４／８４９；１２９／４６３／７９７／８３９／８４４／８４９；１３０／４６４／７９８／８３９／８４４／８４９；１３１／４６５／７９９／８３９／８４４／８４９；１３２／４６６／８００／８３９／８４４／８４９；１３３／４６７／８０１／８３９／８４４／８４９；１３４／４６８／８０２／８３９／８４４／８４９；１３５／４６９／８０３／８３９／８４４／８４９；１３６／４７０／８０４／８３９／８４４／８４９；１３７／４７１／８０５／８３９／８４４／８４９；１３８／４７２／８０６／８３９／８４４／８４９；１３９／４７３／８０７／８３９／８４４／８４９；１４０／４７４／８０８／８３９／８４４／８４９；１４１／４７５／８０９／８３９／８４４／８４９；１４２／４７６／８１０／８３９／８４４／８４９；１４３／４７７／８１１／８３９／８４４／８４９；１４４／４７８／８１２／８３９／８４４／８４９；１４５／４７９／８１３／８４０／８４５／８５０；１４６／４８０／８１４／８４０／８４５／８５０；１４７／４８１／８１５／８４０／８４５／８５０；１４８／４８２／８１６／８４０／８４５／８５０；１４９／４８３／８１７／８４０／８４５／８５０；１５０／４８４／８１８／８４０／８４５／８５０；１５１／４８５／８１９／８４０／８４５／８５０；１５２／４８６／８２０／８４０／８４５／８５０；１５３／４８７／８２１／８４０／８４５／８５０；１５４／４８８／８２２／８４０／８４５／８５０；１５５／４８９／８２３／８４０／８４５／８５０；１５６／４９０／８２４／８４０／８４５／８５０；１５７／４９１／８２５／８４０／８４５／８５０；１５８／４９２／８２６／８４０／８４５／８５０；１５９／４９３／８２７／８４０／８４５／８５０；１６０／４９４／８２８／８４０／８４５／８５０；１６１／４９５／８２９／８４０／８４５／８５０；１６２／４９６／８３０／８４０／８４５／８５０；１６３／４９７／８３１／８４０／８４５／８５０；１６４／４９８／８３２／８４０／８４５／８５０；１６５／４９９／８３３／８４０／８４５／８５０；１６６／５００／８３４／８４０／８４５／８５０；１６７／５０１／８３５／８４０／８４５／８５０；１６８／５０２／８３６／８４０／８４５／８５０；１６９／５０３／８３７／８４０／８４５／８５０；１７０／５０４／８３８／８４０／８４５／８５０；１４５／４７９／８１３／８４１／８４６／８５１；１４６／４８０／８１４／８４１／８４６／８５１；147 / 481 / 815 / 841 / 846 / 851; 148 / 482 / 816 / 841 / 846 / 851; 149 / 483 / 817 / 841 / 846 / 851; 150 / 484 / 818 / 841 / 846 / 851; 151 / 485 / 819 / 841 / 846 / 851; 152 / 486 / 820 / 841 / 846 / 851; 153 / 487 / 821 / 841 / 846 / 851; 154 / 488 / 822 / 841 / 846 / 851; 155 / 489 / 823 / 841 / 846 / 851; 156 / 490 / 824 / 841 / 846 / 851; 157 / 491 / 825 / 841 / 846 / 851; 158 / 492 / 826 / 841 / 846 / 851; 159 / 493 / 827 / 841 / 846 / 851; 160 / 494 / 828 / 841 / 846 / 851; 161 / 495 / 829 / 841 / 846 / 851; 162 / 496 / 830 / 841 / 846 / 851; 163 / 497 / 831 / 841 / 846 / 851; 164 / 498 / 832 / 841 / 846 / 851; 165 / 499 / 833 / 841 / 846 / 851; 166 / 500 / 834 / 65. The antibody conjugate of any one of claims 1 to 64, comprising six CDRs designated as one of: 841 / 846 / 851; 167 / 501 / 835 / 841 / 846 / 851; 168 / 502 / 836 / 841 / 846 / 851; 169 / 503 / 837 / 841 / 846 / 851; and 170 / 504 / 838 / 841 / 846 / 851.

66. The antibody is HC The following group of CDR SEQ ID NOs: 171 / 505 / 672; 172 / 506 / 673; 173 / 507 / 674; 174 / 508 / 675; 175 / 509 / 676; 176 / 510 / 677; 177 / 511 / 678; 178 / 512 / 679; 179 / 513 / 680; 180 / 514 / 681; 181 / 515 / 682; 182 / 516 / 683; 183 / 517 / 684; 184 / 518 / 685; 185 / 519 / 686; 186 / 520 / 687; 187 / 521 / 688; 188 / 522 / 689; 189 / 523 / 690; 190 / 52 4 / 691; 191 / 525 / 692; 192 / 526 / 693; 193 / 527 / 694; 194 / 528 / 695; 195 / 529 / 696; 196 / 530 / 697; 197 / 531 / 698; 198 / 532 / 699; 199 / 533 / 700; 200 / 534 / 7 01; 201 / 535 / 702; 202 / 536 / 703; 203 / 537 / 704; 204 / 538 / 705; 205 / 539 / 706; 206 / 540 / 707; 207 / 541 / 708; 208 / 542 / 709; 209 / 543 / 710; 210 / 544 / 711; 211 / 545 / 712; 212 / 546 / 713; 213 / 547 / 714; 214 / 548 / 715; 215 / 549 / 716; 216 / 550 / 717; 217 / 551 / 718; 218 / 552 / 719; 219 / 553 / 720; 220 / 554 / 721; 221 / 555 / 722; 222 / 556 / 723; 223 / 557 / 724; 224 / 558 / 725; 225 / 559 / 726; 226 / 560 / 727; 227 / 561 / 728; 228 / 562 / 729; 229 / 563 / 730; 230 / 564 / 731; 231 / 56 5 / 732; 232 / 566 / 733; 233 / 567 / 734; 234 / 568 / 735; 235 / 569 / 736; 236 / 570 / 737; 237 / 571 / 738; 238 / 572 / 739; 239 / 573 / 740; 240 / 574 / 741; 241 / 575 / 7 42; 242 / 576 / 743; 243 / 577 / 744; 244 / 578 / 745; 245 / 579 / 746; 246 / 580 / 747; 247 / 581 / 748; 248 / 582 / 749; 249 / 583 / 750; 250 / 584 / 751; 251 / 585 / 752;２５２／５８６／７５３；２５３／５８７／７５４；２５４／５８８／７５５；２５５／５８９／７５６；２５６／５９０／７５７；２５７／５９１／７５８；２５８／５９２／７５９；２５９／５９３／７６０；２６０／５９４／７６１；２６１／５９５／７６２；２６２／５９６／７６３；２６３／５９７／７６４；２６４／５９８／７６５；２６５／５９９／７６６；２６６／６００／７６７；２６７／６０１／７６８；２６８／６０２／７６９；２６９／６０３／７７０；２７０／６０４／７７１；２７１／６０５／７７２；２７２／６０６／７７３；２７３／６０７／７７４；２７４／６０８／７７５；２７５／６０９／７７６；２７６／６１０／７７７；２７７／６１１／７７８；２７８／６１２／７７９；２７９／６１３／７８０；２８０／６１４／７８１；２８１／６１５／７８２；２８２／６１６／７８３；２８３／６１７／７８４；２８４／６１８／７８５；２８５／６１９／７８６；２８６／６２０／７８７；２８７／６２１／７８８；２８８／６２２／７８９；２８９／６２３／７９０；２９０／６２４／７９１；２９１／６２５／７９２；２９２／６２６／７９３；２９３／６２７／７９４；２９４／６２８／７９５；２９５／６２９／７９６；２９６／６３０／７９７；２９７／６３１／７９８；２９８／６３２／７９９；２９９／６３３／８００；３００／６３４／８０１；３０１／６３５／８０２；３０２／６３６／８０３；３０３／６３７／８０４；３０４／６３８／８０５；３０５／６３９／８０６；３０６／６４０／８０７；３０７／６４１／８０８；３０８／６４２／８０９；３０９／６４３／８１０；３１０／６４４／８１１；３１１／６４５／８１２；３１２／６４６／８１３；３１３／６４７／８１４；３１４／６４８／８１５；３１５／６４９／８１６；３１６／６５０／８１７；３１７／６５１／８１８；３１８／６５２／８１９；３１９／６５３／８２０；３２０／６５４／８２１；３２１／６５５／８２２；３２２／６５６／８２３；３２３／６５７／８２４；３２４／６５８／８２５；３２５／６５９／８２６；３２６／６６０／８２７；３２７／６６１／８２８；３２８／６６２／８２９；３２９／６６３／８３０；３３０／６６４／８３１；３３１／６６５／８３２；３３２／６６６／８３３；３３３／６６７／８３４；３３４／６６８／８３５；66. The antibody conjugate of any one of claims 1 to 65, comprising three Kabat HC CDRs designated as one of 335 / 669 / 836; 336 / 670 / 837; and 337 / 671 / 838.

67. The antibody may comprise one of the following groups of CDR SEQ ID NOs: 171 / 505 / 672 / 839 / 844 / 849; 172 / 506 / 673 / 839 / 844 / 849; 173 / 507 / 674 / 839 / 844 / 849; 174 / 508 / 675 / 839 / 844 / 849; 175 / 509 / 676 / 839 / 844 / 849; 176 / 510 / 677 / 839 / 844 / 849; 177 / 511 / 678 / 839 / 844 / 849; 178 / 512 / 679 / 839 / 844 / 849; 179 / 513 / 680 / 839 / 844 / 849; 180 / 514 / 681 / 839 / 84 4 / 849; 181 / 515 / 682 / 839 / 844 / 849; 182 / 516 / 683 / 839 / 844 / 849; 183 / 517 / 684 / 839 / 844 / 849; 184 / 518 / 685 / 839 / 844 / 849; 185 / 519 / 686 / 839 / 844 / 849 ;186 / 520 / 687 / 839 / 844 / 849;187 / 521 / 688 / 839 / 844 / 849;188 / 522 / 689 / 839 / 844 / 849;189 / 523 / 690 / 839 / 844 / 849;190 / 524 / 691 / 839 / 844 / 849;191 / 525 / 692 / 839 / 844 / 849; 192 / 526 / 693 / 839 / 844 / 849; 193 / 527 / 694 / 839 / 844 / 849; 194 / 528 / 695 / 839 / 844 / 849; 195 / 529 / 696 / 839 / 844 / 849; 196 / 530 / 6 97 / 839 / 844 / 849; 197 / 531 / 698 / 839 / 844 / 849; 198 / 532 / 699 / 839 / 844 / 849; 199 / 533 / 700 / 839 / 844 / 849; 200 / 534 / 701 / 839 / 844 / 849; 201 / 535 / 702 / 83 9 / 844 / 849; 202 / 536 / 703 / 839 / 844 / 849; 203 / 537 / 704 / 839 / 844 / 849; 204 / 538 / 705 / 839 / 844 / 849; 205 / 539 / 706 / 839 / 844 / 849; 206 / 540 / 707 / 839 / 844 / 849; 207 / 541 / 708 / 839 / 844 / 849; 208 / 542 / 709 / 839 / 844 / 849; 209 / 543 / 710 / 839 / 844 / 849; 210 / 544 / 711 / 839 / 844 / 849; 211 / 545 / 712 / 839 / 844 / 849;２１２／５４６／７１３／８３９／８４４／８４９；２１３／５４７／７１４／８３９／８４４／８４９；２１４／５４８／７１５／８３９／８４４／８４９；２１５／５４９／７１６／８３９／８４４／８４９；２１６／５５０／７１７／８３９／８４４／８４９；２１７／５５１／７１８／８３９／８４４／８４９；２１８／５５２／７１９／８３９／８４４／８４９；２１９／５５３／７２０／８３９／８４４／８４９；２２０／５５４／７２１／８３９／８４４／８４９；２２１／５５５／７２２／８３９／８４４／８４９；２２２／５５６／７２３／８３９／８４４／８４９；２２３／５５７／７２４／８３９／８４４／８４９；２２４／５５８／７２５／８３９／８４４／８４９；２２５／５５９／７２６／８３９／８４４／８４９；２２６／５６０／７２７／８３９／８４４／８４９；２２７／５６１／７２８／８３９／８４４／８４９；２２８／５６２／７２９／８３９／８４４／８４９；２２９／５６３／７３０／８３９／８４４／８４９；２３０／５６４／７３１／８３９／８４４／８４９；２３１／５６５／７３２／８３９／８４４／８４９；２３２／５６６／７３３／８３９／８４４／８４９；２３３／５６７／７３４／８３９／８４４／８４９；２３４／５６８／７３５／８３９／８４４／８４９；２３５／５６９／７３６／８３９／８４４／８４９；２３６／５７０／７３７／８３９／８４４／８４９；２３７／５７１／７３８／８３９／８４４／８４９；２３８／５７２／７３９／８３９／８４４／８４９；２３９／５７３／７４０／８３９／８４４／８４９；２４０／５７４／７４１／８３９／８４４／８４９；２４１／５７５／７４２／８３９／８４４／８４９；２４２／５７６／７４３／８３９／８４４／８４９；２４３／５７７／７４４／８３９／８４４／８４９；２４４／５７８／７４５／８３９／８４４／８４９；２４５／５７９／７４６／８３９／８４４／８４９；２４６／５８０／７４７／８３９／８４４／８４９；２４７／５８１／７４８／８３９／８４４／８４９；２４８／５８２／７４９／８３９／８４４／８４９；２４９／５８３／７５０／８３９／８４４／８４９；２５０／５８４／７５１／８３９／８４４／８４９；２５１／５８５／７５２／８３９／８４４／８４９；２５２／５８６／７５３／８３９／８４４／８４９；２５３／５８７／７５４／８３９／８４４／８４９；２５４／５８８／７５５／８３９／８４４／８４９；２５５／５８９／７５６／８３９／８４４／８４９；２５６／５９０／７５７／８３９／８４４／８４９；２５７／５９１／７５８／８３９／８４４／８４９；２５８／５９２／７５９／８３９／８４４／８４９；２５９／５９３／７６０／８３９／８４４／８４９；２６０／５９４／７６１／８３９／８４４／８４９；２６１／５９５／７６２／８３９／８４４／８４９；２６２／５９６／７６３／８３９／８４４／８４９；２６３／５９７／７６４／８３９／８４４／８４９；２６４／５９８／７６５／８３９／８４４／８４９；２６５／５９９／７６６／８３９／８４４／８４９；２６６／６００／７６７／８３９／８４４／８４９；２６７／６０１／７６８／８３９／８４４／８４９；２６８／６０２／７６９／８３９／８４４／８４９；２６９／６０３／７７０／８３９／８４４／８４９；２７０／６０４／７７１／８３９／８４４／８４９；２７１／６０５／７７２／８３９／８４４／８４９；２７２／６０６／７７３／８３９／８４４／８４９；２７３／６０７／７７４／８３９／８４４／８４９；２７４／６０８／７７５／８３９／８４４／８４９；２７５／６０９／７７６／８３９／８４４／８４９；２７６／６１０／７７７／８３９／８４４／８４９；２７７／６１１／７７８／８３９／８４４／８４９；２７８／６１２／７７９／８３９／８４４／８４９；２７９／６１３／７８０／８３９／８４４／８４９；２８０／６１４／７８１／８３９／８４４／８４９；２８１／６１５／７８２／８３９／８４４／８４９；２８２／６１６／７８３／８３９／８４４／８４９；２８３／６１７／７８４／８３９／８４４／８４９；２８４／６１８／７８５／８３９／８４４／８４９；２８５／６１９／７８６／８３９／８４４／８４９；２８６／６２０／７８７／８３９／８４４／８４９；２８７／６２１／７８８／８３９／８４４／８４９；２８８／６２２／７８９／８３９／８４４／８４９；２８９／６２３／７９０／８３９／８４４／８４９；２９０／６２４／７９１／８３９／８４４／８４９；２９１／６２５／７９２／８３９／８４４／８４９；２９２／６２６／７９３／８３９／８４４／８４９；２９３／６２７／７９４／８３９／８４４／８４９；２９４／６２８／７９５／８３９／８４４／８４９；２９５／６２９／７９６／８３９／８４４／８４９；２９６／６３０／７９７／８３９／８４４／８４９；２９７／６３１／７９８／８３９／８４４／８４９；２９８／６３２／７９９／８３９／８４４／８４９；２９９／６３３／８００／８３９／８４４／８４９；３００／６３４／８０１／８３９／８４４／８４９；３０１／６３５／８０２／８３９／８４４／８４９；３０２／６３６／８０３／８３９／８４４／８４９；３０３／６３７／８０４／８３９／８４４／８４９；３０４／６３８／８０５／８３９／８４４／８４９；３０５／６３９／８０６／８３９／８４４／８４９；３０６／６４０／８０７／８３９／８４４／８４９；３０７／６４１／８０８／８３９／８４４／８４９；３０８／６４２／８０９／８３９／８４４／８４９；３０９／６４３／８１０／８３９／８４４／８４９；３１０／６４４／８１１／８３９／８４４／８４９；３１１／６４５／８１２／８４０／８４５／８５０；３１２／６４６／８１３／８４０／８４５／８５０；３１３／６４７／８１４／８４０／８４５／８５０；３１４／６４８／８１５／８４０／８４５／８５０；３１５／６４９／８１６／８４０／８４５／８５０；３１６／６５０／８１７／８４０／８４５／８５０；３１７／６５１／８１８／８４０／８４５／８５０；３１８／６５２／８１９／８４０／８４５／８５０；３１９／６５３／８２０／８４０／８４５／８５０；３２０／６５４／８２１／８４０／８４５／８５０；３２１／６５５／８２２／８４０／８４５／８５０；３２２／６５６／８２３／８４０／８４５／８５０；３２３／６５７／８２４／８４０／８４５／８５０；３２４／６５８／８２５／８４０／８４５／８５０；３２５／６５９／８２６／８４０／８４５／８５０；３２６／６６０／８２７／８４０／８４５／８５０；３２７／６６１／８２８／８４０／８４５／８５０；３２８／６６２／８２９／８４０／８４５／８５０；３２９／６６３／８３０／８４０／８４５／８５０；３３０／６６４／８３１／８４０／８４５／８５０；３３１／６６５／８３２／８４０／８４５／８５０；３３２／６６６／８３３／８４０／８４５／８５０；３３３／６６７／８３４／８４０／８４５／８５０；３３４／６６８／８３５／８４０／８４５／８５０；335 / 669 / 836 / 840 / 845 / 850; 336 / 670 / 837 / 840 / 845 / 850; 337 / 671 / 838 / 840 / 845 / 850; 311 / 645 / 812 / 841 / 846 / 851; 312 / 646 / 813 / 841 / 846 / 851; 313 / 647 / 814 / 841 / 846 / 851; 314 / 648 / 815 / 841 / 846 / 851; 315 / 649 / 816 / 841 / 846 / 851; 316 / 650 / 817 / 841 / 846 / 851; 317 / 651 / 818 / 841 / 846 / 851; 318 / 652 / 819 / 841 / 846 / 851; 319 / 653 / 820 / 841 / 846 / 851; 320 / 654 / 821 / 841 / 846 / 851; 321 / 655 / 822 / 841 / 846 / 851; 322 / 656 / 823 / 841 / 846 / 851; 323 / 657 / 824 / 841 / 846 / 851; 324 / 658 / 825 / 841 / 846 / 851; 325 / 659 / 826 / 841 / 846 / 851; 326 / 660 / 827 / 841 / 846 / 851; 327 / 661 / 828 / 841 / 846 / 851; 328 / 662 / 829 / 841 / 846 / 851; 329 / 663 / 830 / 841 / 846 / 851; 330 / 664 / 831 / 841 / 846 / 851; 331 / 665 / 832 / 841 / 846 / 851; 67. The antibody conjugate of any one of claims 1 to 66, comprising six CDRs designated as one of: 332 / 666 / 833 / 841 / 846 / 851; 333 / 667 / 834 / 841 / 846 / 851; 334 / 668 / 835 / 841 / 846 / 851; 335 / 669 / 836 / 841 / 846 / 851; 336 / 670 / 837 / 841 / 846 / 851; and 337 / 671 / 838 / 841 / 846 / 851.

68. The antibody, (a) V Ｈ Region SEQ ID NO: 854 and V Ｌ three heavy chain CDRs and three light chain CDRs of region SEQ ID NO: 1021; (b) V Ｈ Region SEQ ID NO: 859 and V Ｌ the three heavy chain CDRs and the three light chain CDRs of region SEQ ID NO: 1021; or (c) V Ｈ Region SEQ ID NO: 895 and V Ｌ Three heavy chain CDRs and three light chain CDRs of region SEQ ID NO: 1021 68. The antibody conjugate of any one of claims 1 to 67, comprising:

69. The antibody is V Ｈ Region SEQ ID NO: 854 and V Ｌ 69. The antibody conjugate of any of claims 1 to 68, comprising three heavy chain CDRs and three light chain CDRs of the region SEQ ID NO: 1021.

70. The antibody, (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 4 and 171, a CDR-H2 comprising at least one of SEQ ID NOs: 338 and 505, and a CDR-H3 comprising SEQ ID NO: 672; Ｈ and V comprising CDR-L1 comprising SEQ ID NO:839, CDR-L2 comprising SEQ ID NO:844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ ; (b) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 9 and 176, a CDR-H2 comprising at least one of SEQ ID NOs: 343 and 510, and a CDR-H3 comprising SEQ ID NO: 677; Ｈ and V comprising CDR-L1 comprising SEQ ID NO:839, CDR-L2 comprising SEQ ID NO:844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ or (c) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO:839, CDR-L2 comprising SEQ ID NO:844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ 70. The antibody conjugate of any one of claims 1 to 69, comprising:

71. 71. The antibody conjugate of any of claims 49 to 70, wherein the variant has 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitution.

72. 72. The antibody conjugate of claim 71, wherein the amino acid substitutions are conservative amino acid substitutions.

73. 73. The antibody conjugate of any of claims 49 to 72, wherein the variant has 90%, 95%, 96%, 97%, 98%, or 99% sequence identity.

74. (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO: 839, CDR-L2 comprising SEQ ID NO: 844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ an antibody comprising: (b) a para-azidomethylphenylalanine residue at antibody site HC404; and (c) the following linker-payload structure: 【Chemical formula 26】 where n2 is 2 and each linker-payload is attached to one of the para-azidomethylphenylalanine residue side chains.

74. The antibody conjugate of any one of claims 1 to 73, comprising:

75. (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO: 839, CDR-L2 comprising SEQ ID NO: 844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ an antibody comprising: (b) para-azidomethylphenylalanine residues at antibody sites HC180 and HC404; (c) the following linker-payload structure: 【Chemical 27】 where n2 is 4 and each linker-payload is attached to one of the para-azidomethylphenylalanine residue side chains.

75. The antibody conjugate of any one of claims 1 to 74, comprising:

76. (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO: 839, CDR-L2 comprising SEQ ID NO: 844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ an antibody comprising: (b) para-azidomethylphenylalanine residues in antibody sites HC180, HC241, HC404, and LC42; and (c) the following linker-payload structure: 【Chemical Formula 28】 where n2 is 8 and each linker-payload is attached to one of the para-azidomethylphenylalanine residue side chains.

76. The antibody conjugate of any one of claims 1 to 75, comprising:

77. (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO: 839, CDR-L2 comprising SEQ ID NO: 844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ an antibody comprising: (b) para-azidomethylphenylalanine residues in antibody sites HC180, HC241, HC404, and LC42; and (c) the following linker-payload structure: 【Chemical 29】 where n2 is 8 and each linker-payload is attached to one of the para-azidomethylphenylalanine residue side chains.

77. The antibody conjugate of any one of claims 1 to 76, comprising:

78. (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO: 839, CDR-L2 comprising SEQ ID NO: 844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ an antibody comprising: (b) para-azidomethylphenylalanine residues in antibody sites HC180, HC241, HC404, and LC42; and (c) the following linker-payload structure: 【Chemistry 30】 where n2 is 8 and each linker-payload is attached to one of the para-azidomethylphenylalanine residue side chains.

78. The antibody conjugate of any one of claims 1 to 77, comprising:

79. (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO: 839, CDR-L2 comprising SEQ ID NO: 844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ an antibody comprising: (b) para-azidomethylphenylalanine residues at antibody sites HC180, HC241, and HC404; and (c) the following linker-payload structure: 【Chemical 31】 where n2 is 8 and each linker-payload is attached to one of the para-azidomethylphenylalanine residue side chains.

79. The antibody conjugate of any one of claims 1 to 78, comprising:

80. The antibody is V Ｈ / V Ｌ 80. The antibody conjugate of any of claims 74 to 79, comprising the pair SEQ ID NO: 895 / 1021.

81. The antibody comprises a V selected from SEQ ID NOs: 854-1020. Ｈ region and a V selected from SEQ ID NOs: 1021 to 1026 Ｌ 81. The antibody conjugate of any one of claims 1 to 80, which binds to the same epitope as a second antibody having a region.

82. 82. The antibody conjugate of claim 81, wherein the antibody inhibits binding of the second antibody to ROR1 by at least 50%, or the second antibody inhibits binding of the isolated antibody to ROR1 by at least 50%.

83. When the antibody associates with human ROR1 at 25°C, it binds approximately 9.17 x 10 ４ M －１ × seconds －１ ~Approx. 5.94×10 ６ M －１ × seconds －１ No.K ａ 83. The antibody conjugate of any one of claims 1 to 82, having:

84. When the antibody dissociates from human ROR1 at 25°C, it has a binding affinity of approximately 1.01 x 10 －４ seconds －１ ~about 0.05 seconds －１ No.K ｄ 84. The antibody conjugate of any one of claims 1 to 83, having:

85. When the antibody binds to human ROR1 at 25°C, it has a binding activity of approximately 1.39 x 10 －１０ M ~ approx. 1.01 x 10 －７ K of M Ｄ 85. The antibody conjugate of any one of claims 1 to 84, having the formula:

86. 86. The antibody conjugate of any preceding claim, wherein the antibody comprises at least one constant region domain.

87. 87. The antibody conjugate of claim 86, wherein the constant region comprises a sequence selected from SEQ ID NOs: 1027-1029.

88. The antibody conjugate of any one of claims 1 to 87, wherein the antibody is a monoclonal antibody.

89. 89. The antibody conjugate of any one of claims 1 to 88, wherein the antibody is IgA, IgD, IgE, IgG, or IgM.

90. The antibody conjugate of any one of claims 1 to 89, wherein the antibody is a humanized antibody or a human antibody.

91. The antibody conjugate of any one of claims 1 to 90, wherein the antibody is glycosylated.

92. The antibody conjugate of any one of claims 1 to 91, wherein the antibody is an antibody fragment.

93. The antibody fragment may be an Fv fragment, an Fab fragment, or an F(ab') ２ 93. The antibody conjugate of claim 92, wherein the antibody conjugate is selected from a Fab' fragment, a scFv (sFv) fragment, and a scFv-Fc fragment.

94. 93. The antibody conjugate of claim 92, wherein the antibody is an scFv fragment.

95. An isolated antibody that specifically binds to ROR1, comprising a V selected from SEQ ID NOs: 854-1020. Ｈ Three heavy chain CDRs or variants thereof from the sequence and a V selected from SEQ ID NOs: 1021-1026 Ｌ and three light chain CDRs derived from the sequence or variants thereof.

96. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1021, 855 / 1021, 856 / 1021, 857 / 1021, 858 / 1021, 859 / 1021, 860 / 1021, 861 / 1021, 862 / 1021, 863 / 1021, 864 / 1021, 865 / 1021, 866 / 1021 , 867 / 1021, 868 / 1021, 869 / 1021, 870 / 1021, 871 / 1021, 872 / 1021, 873 / 1021, 874 / 1021, 875 / 1021, 876 / 1021, 877 / 1021, 878 / 1021, 879 / 1021, 880 / 1021 1, 881 / 1021, 882 / 1021, 883 / 1021, 884 / 1021, 885 / 1021, 886 / 1021, 887 / 1021, 888 / 1021, 889 / 1021, 890 / 1021, 891 / 1021, 892 / 1021, 893 / 1021, 894 / 1021 21, 895 / 1021, 896 / 1021, 897 / 1021, 898 / 1021, 899 / 1021, 900 / 1021, 901 / 1021, 902 / 1021, 903 / 1021, 904 / 1021, 905 / 1021, 906 / 1021, 907 / 1021, 908 / 1 021, 909 / 1021, 910 / 1021, 911 / 1021, 912 / 1021, 913 / 1021, 914 / 1021, 915 / 1021, 916 / 1021, 917 / 1021, 918 / 1021, 919 / 1021, 920 / 1021, 921 / 1021, 922 / 1021, 923 / 1021, 924 / 1021, 925 / 1021, 926 / 1021, 927 / 1021, 928 / 1021, 929 / 1021, 930 / 1021, 931 / 1021, 932 / 1021, 933 / 1021, 934 / 1021, 935 / 1021, 93 6 / 1021, 937 / 1021, 938 / 1021, 939 / 1021, 940 / 1021, 941 / 1021, 942 / 1021, 943 / 1021, 944 / 1021, 945 / 1021, 946 / 1021, 947 / 1021, 948 / 1021, 949 / 1021, 9 50 / 1021, 951 / 1021, 952 / 1021, 953 / 1021, 954 / 1021, 955 / 1021, 956 / 1021, 957 / 1021, 958 / 1021, 959 / 1021, 960 / 1021, 961 / 1021, 962 / 1021, 963 / 1021,964 / 1021, 965 / 1021, 966 / 1021, 967 / 1021, 968 / 1021, 969 / 1021, 970 / 1021, 971 / 1021, 972 / 1021, 973 / 1021, 974 / 1021, 975 / 1021, 976 / 1021, 977 / 1021, 978 / 1021, 97 9 / 1021, 980 / 1021, 981 / 1021, 982 / 1021, 983 / 1021, 984 / 1021, 985 / 1021, 986 / 1021, 987 / 1021, 988 / 1021, 989 / 1021, 990 / 1021, 991 / 1021, 992 / 1021, 993 / 1021, 994 / 1021, 995 / 1021, 996 / 1021, 997 / 1021, 998 / 1021, 999 / 1021, 1000 / 1021, 1001 / 1021, 1002 / 1021, 1003 / 1021, 1004 / 1021, 1005 / 1021, 1006 / 1021, 1007 / 1021, 1008 / 10 V selected from the group consisting of 21, 1009 / 1021, 1010 / 1021, 1011 / 1021, 1012 / 1021, 1013 / 1021, 1014 / 1021, 1015 / 1021, 1016 / 1021, 1017 / 1021, 1018 / 1021, 1019 / 1021, and 1020 / 1021; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from the pair.

97. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1022, 855 / 1022, 856 / 1022, 857 / 1022, 858 / 1022, 859 / 1022, 860 / 1022, 861 / 1022, 862 / 1022, 863 / 1022, 864 / 1022, 865 / 1022, 866 / 1022 , 867 / 1022, 868 / 1022, 869 / 1022, 870 / 1022, 871 / 1022, 872 / 1022, 873 / 1022, 874 / 1022, 875 / 1022, 876 / 1022, 877 / 1022, 878 / 1022, 879 / 1022, 880 / 1022 2, 881 / 1022, 882 / 1022, 883 / 1022, 884 / 1022, 885 / 1022, 886 / 1022, 887 / 1022, 888 / 1022, 889 / 1022, 890 / 1022, 891 / 1022, 892 / 1022, 893 / 1022, 894 / 10 22, 895 / 1022, 896 / 1022, 897 / 1022, 898 / 1022, 899 / 1022, 900 / 1022, 901 / 1022, 902 / 1022, 903 / 1022, 904 / 1022, 905 / 1022, 906 / 1022, 907 / 1022, 908 / 1 022, 909 / 1022, 910 / 1022, 911 / 1022, 912 / 1022, 913 / 1022, 914 / 1022, 915 / 1022, 916 / 1022, 917 / 1022, 918 / 1022, 919 / 1022, 920 / 1022, 921 / 1022, 922 / 1022, 923 / 1022, 924 / 1022, 925 / 1022, 926 / 1022, 927 / 1022, 928 / 1022, 929 / 1022, 930 / 1022, 931 / 1022, 932 / 1022, 933 / 1022, 934 / 1022, 935 / 1022, 93 6 / 1022, 937 / 1022, 938 / 1022, 939 / 1022, 940 / 1022, 941 / 1022, 942 / 1022, 943 / 1022, 944 / 1022, 945 / 1022, 946 / 1022, 947 / 1022, 948 / 1022, 949 / 1022, 9 50 / 1022, 951 / 1022, 952 / 1022, 953 / 1022, 954 / 1022, 955 / 1022, 956 / 1022, 957 / 1022, 958 / 1022, 959 / 1022, 960 / 1022, 961 / 1022, 962 / 1022, 963 / 1022,964 / 1022, 965 / 1022, 966 / 1022, 967 / 1022, 968 / 1022, 969 / 1022, 970 / 1022, 971 / 1022, 972 / 1022, 973 / 1022, 974 / 1022, 975 / 1022, 976 / 1022, 977 / 1022, 978 / 1022, 97 9 / 1022, 980 / 1022, 981 / 1022, 982 / 1022, 983 / 1022, 984 / 1022, 985 / 1022, 986 / 1022, 987 / 1022, 988 / 1022, 989 / 1022, 990 / 1022, 991 / 1022, 992 / 1022, 993 / 1022, 994 / 1022, 995 / 1022, 996 / 1022, 997 / 1022, 998 / 1022, 999 / 1022, 1000 / 1022, 1001 / 1022, 1002 / 1022, 1003 / 1022, 1004 / 1022, 1005 / 1022, 1006 / 1022, 1007 / 1022, 1008 / 10 V selected from the group consisting of 22, 1009 / 1022, 1010 / 1022, 1011 / 1022, 1012 / 1022, 1013 / 1022, 1014 / 1022, 1015 / 1022, 1016 / 1022, 1017 / 1022, 1018 / 1022, 1019 / 1022, and 1020 / 1022; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from the pair.

98. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1023, 855 / 1023, 856 / 1023, 857 / 1023, 858 / 1023, 859 / 1023, 860 / 1023, 861 / 1023, 862 / 1023, 863 / 1023, 864 / 1023, 865 / 1023, 866 / 1023 , 867 / 1023, 868 / 1023, 869 / 1023, 870 / 1023, 871 / 1023, 872 / 1023, 873 / 1023, 874 / 1023, 875 / 1023, 876 / 1023, 877 / 1023, 878 / 1023, 879 / 1023, 880 / 1023 3, 881 / 1023, 882 / 1023, 883 / 1023, 884 / 1023, 885 / 1023, 886 / 1023, 887 / 1023, 888 / 1023, 889 / 1023, 890 / 1023, 891 / 1023, 892 / 1023, 893 / 1023, 894 / 10 23, 895 / 1023, 896 / 1023, 897 / 1023, 898 / 1023, 899 / 1023, 900 / 1023, 901 / 1023, 902 / 1023, 903 / 1023, 904 / 1023, 905 / 1023, 906 / 1023, 907 / 1023, 908 / 1 023, 909 / 1023, 910 / 1023, 911 / 1023, 912 / 1023, 913 / 1023, 914 / 1023, 915 / 1023, 916 / 1023, 917 / 1023, 918 / 1023, 919 / 1023, 920 / 1023, 921 / 1023, 922 / 1023, 923 / 1023, 924 / 1023, 925 / 1023, 926 / 1023, 927 / 1023, 928 / 1023, 929 / 1023, 930 / 1023, 931 / 1023, 932 / 1023, 933 / 1023, 934 / 1023, 935 / 1023, 93 6 / 1023, 937 / 1023, 938 / 1023, 939 / 1023, 940 / 1023, 941 / 1023, 942 / 1023, 943 / 1023, 944 / 1023, 945 / 1023, 946 / 1023, 947 / 1023, 948 / 1023, 949 / 1023, 9 50 / 1023, 951 / 1023, 952 / 1023, 953 / 1023, 954 / 1023, 955 / 1023, 956 / 1023, 957 / 1023, 958 / 1023, 959 / 1023, 960 / 1023, 961 / 1023, 962 / 1023, 963 / 1023,964 / 1023, 965 / 1023, 966 / 1023, 967 / 1023, 968 / 1023, 969 / 1023, 970 / 1023, 971 / 1023, 972 / 1023, 973 / 1023, 974 / 1023, 975 / 1023, 976 / 1023, 977 / 1023, 978 / 1023, 97 9 / 1023, 980 / 1023, 981 / 1023, 982 / 1023, 983 / 1023, 984 / 1023, 985 / 1023, 986 / 1023, 987 / 1023, 988 / 1023, 989 / 1023, 990 / 1023, 991 / 1023, 992 / 1023, 993 / 1023, 994 / 1023, 995 / 1023, 996 / 1023, 997 / 1023, 998 / 1023, 999 / 1023, 1000 / 1023, 1001 / 1023, 1002 / 1023, 1003 / 1023, 1004 / 1023, 1005 / 1023, 1006 / 1023, 1007 / 1023, 1008 / 10 V selected from the group consisting of 1009 / 1023, 1010 / 1023, 1011 / 1023, 1012 / 1023, 1013 / 1023, 1014 / 1023, 1015 / 1023, 1016 / 1023, 1017 / 1023, 1018 / 1023, 1019 / 1023, and 1020 / 1023; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from the pair.

99. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1024, 855 / 1024, 856 / 1024, 857 / 1024, 858 / 1024, 859 / 1024, 860 / 1024, 861 / 1024, 862 / 1024, 863 / 1024, 864 / 1024, 865 / 1024, 866 / 1024 , 867 / 1024, 868 / 1024, 869 / 1024, 870 / 1024, 871 / 1024, 872 / 1024, 873 / 1024, 874 / 1024, 875 / 1024, 876 / 1024, 877 / 1024, 878 / 1024, 879 / 1024, 880 / 1024 4, 881 / 1024, 882 / 1024, 883 / 1024, 884 / 1024, 885 / 1024, 886 / 1024, 887 / 1024, 888 / 1024, 889 / 1024, 890 / 1024, 891 / 1024, 892 / 1024, 893 / 1024, 894 / 10 24, 895 / 1024, 896 / 1024, 897 / 1024, 898 / 1024, 899 / 1024, 900 / 1024, 901 / 1024, 902 / 1024, 903 / 1024, 904 / 1024, 905 / 1024, 906 / 1024, 907 / 1024, 908 / 1 024, 909 / 1024, 910 / 1024, 911 / 1024, 912 / 1024, 913 / 1024, 914 / 1024, 915 / 1024, 916 / 1024, 917 / 1024, 918 / 1024, 919 / 1024, 920 / 1024, 921 / 1024, 922 / 1024, 923 / 1024, 924 / 1024, 925 / 1024, 926 / 1024, 927 / 1024, 928 / 1024, 929 / 1024, 930 / 1024, 931 / 1024, 932 / 1024, 933 / 1024, 934 / 1024, 935 / 1024, 93 6 / 1024, 937 / 1024, 938 / 1024, 939 / 1024, 940 / 1024, 941 / 1024, 942 / 1024, 943 / 1024, 944 / 1024, 945 / 1024, 946 / 1024, 947 / 1024, 948 / 1024, 949 / 1024, 9 50 / 1024, 951 / 1024, 952 / 1024, 953 / 1024, 954 / 1024, 955 / 1024, 956 / 1024, 957 / 1024, 958 / 1024, 959 / 1024, 960 / 1024, 961 / 1024, 962 / 1024, 963 / 1024,964 / 1024, 965 / 1024, 966 / 1024, 967 / 1024, 968 / 1024, 969 / 1024, 970 / 1024, 971 / 1024, 972 / 1024, 973 / 1024, 974 / 1024, 975 / 1024, 976 / 1024, 977 / 1024, 978 / 1024, 97 9 / 1024, 980 / 1024, 981 / 1024, 982 / 1024, 983 / 1024, 984 / 1024, 985 / 1024, 986 / 1024, 987 / 1024, 988 / 1024, 989 / 1024, 990 / 1024, 991 / 1024, 992 / 1024, 993 / 1024, 994 / 1024, 995 / 1024, 996 / 1024, 997 / 1024, 998 / 1024, 999 / 1024, 1000 / 1024, 1001 / 1024, 1002 / 1024, 1003 / 1024, 1004 / 1024, 1005 / 1024, 1006 / 1024, 1007 / 1024, 1008 / 10 V selected from the group consisting of 1009 / 1024, 1010 / 1024, 1011 / 1024, 1012 / 1024, 1013 / 1024, 1014 / 1024, 1015 / 1024, 1016 / 1024, 1017 / 1024, 1018 / 1024, 1019 / 1024, and 1020 / 1024; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from the pair.

100. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1025, 855 / 1025, 856 / 1025, 857 / 1025, 858 / 1025, 859 / 1025, 860 / 1025, 861 / 1025, 862 / 1025, 863 / 1025, 864 / 1025, 865 / 1025, 866 / 1025 , 867 / 1025, 868 / 1025, 869 / 1025, 870 / 1025, 871 / 1025, 872 / 1025, 873 / 1025, 874 / 1025, 875 / 1025, 876 / 1025, 877 / 1025, 878 / 1025, 879 / 1025, 880 / 1025 5, 881 / 1025, 882 / 1025, 883 / 1025, 884 / 1025, 885 / 1025, 886 / 1025, 887 / 1025, 888 / 1025, 889 / 1025, 890 / 1025, 891 / 1025, 892 / 1025, 893 / 1025, 894 / 10 25, 895 / 1025, 896 / 1025, 897 / 1025, 898 / 1025, 899 / 1025, 900 / 1025, 901 / 1025, 902 / 1025, 903 / 1025, 904 / 1025, 905 / 1025, 906 / 1025, 907 / 1025, 908 / 1 025, 909 / 1025, 910 / 1025, 911 / 1025, 912 / 1025, 913 / 1025, 914 / 1025, 915 / 1025, 916 / 1025, 917 / 1025, 918 / 1025, 919 / 1025, 920 / 1025, 921 / 1025, 922 / 1025, 923 / 1025, 924 / 1025, 925 / 1025, 926 / 1025, 927 / 1025, 928 / 1025, 929 / 1025, 930 / 1025, 931 / 1025, 932 / 1025, 933 / 1025, 934 / 1025, 935 / 1025, 93 6 / 1025, 937 / 1025, 938 / 1025, 939 / 1025, 940 / 1025, 941 / 1025, 942 / 1025, 943 / 1025, 944 / 1025, 945 / 1025, 946 / 1025, 947 / 1025, 948 / 1025, 949 / 1025, 9 50 / 1025, 951 / 1025, 952 / 1025, 953 / 1025, 954 / 1025, 955 / 1025, 956 / 1025, 957 / 1025, 958 / 1025, 959 / 1025, 960 / 1025, 961 / 1025, 962 / 1025, 963 / 1025,964 / 1025, 965 / 1025, 966 / 1025, 967 / 1025, 968 / 1025, 969 / 1025, 970 / 1025, 971 / 1025, 972 / 1025, 973 / 1025, 974 / 1025, 975 / 1025, 976 / 1025, 977 / 1025, 978 / 1025, 97 9 / 1025, 980 / 1025, 981 / 1025, 982 / 1025, 983 / 1025, 984 / 1025, 985 / 1025, 986 / 1025, 987 / 1025, 988 / 1025, 989 / 1025, 990 / 1025, 991 / 1025, 992 / 1025, 993 / 1025, 994 / 1025, 995 / 1025, 996 / 1025, 997 / 1025, 998 / 1025, 999 / 1025, 1000 / 1025, 1001 / 1025, 1002 / 1025, 1003 / 1025, 1004 / 1025, 1005 / 1025, 1006 / 1025, 1007 / 1025, 1008 / 10 V selected from the group consisting of 1009 / 1025, 1010 / 1025, 1011 / 1025, 1012 / 1025, 1013 / 1025, 1014 / 1025, 1015 / 1025, 1016 / 1025, 1017 / 1025, 1018 / 1025, 1019 / 1025, and 1020 / 1025; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from the pair.

101. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1026, 855 / 1026, 856 / 1026, 857 / 1026, 858 / 1026, 859 / 1026, 860 / 1026, 861 / 1026, 862 / 1026, 863 / 1026, 864 / 1026, 865 / 1026, 866 / 1026 , 867 / 1026, 868 / 1026, 869 / 1026, 870 / 1026, 871 / 1026, 872 / 1026, 873 / 1026, 874 / 1026, 875 / 1026, 876 / 1026, 877 / 1026, 878 / 1026, 879 / 1026, 880 / 1026 6, 881 / 1026, 882 / 1026, 883 / 1026, 884 / 1026, 885 / 1026, 886 / 1026, 887 / 1026, 888 / 1026, 889 / 1026, 890 / 1026, 891 / 1026, 892 / 1026, 893 / 1026, 894 / 10 26, 895 / 1026, 896 / 1026, 897 / 1026, 898 / 1026, 899 / 1026, 900 / 1026, 901 / 1026, 902 / 1026, 903 / 1026, 904 / 1026, 905 / 1026, 906 / 1026, 907 / 1026, 908 / 1 026, 909 / 1026, 910 / 1026, 911 / 1026, 912 / 1026, 913 / 1026, 914 / 1026, 915 / 1026, 916 / 1026, 917 / 1026, 918 / 1026, 919 / 1026, 920 / 1026, 921 / 1026, 922 / 1026, 923 / 1026, 924 / 1026, 925 / 1026, 926 / 1026, 927 / 1026, 928 / 1026, 929 / 1026, 930 / 1026, 931 / 1026, 932 / 1026, 933 / 1026, 934 / 1026, 935 / 1026, 93 6 / 1026, 937 / 1026, 938 / 1026, 939 / 1026, 940 / 1026, 941 / 1026, 942 / 1026, 943 / 1026, 944 / 1026, 945 / 1026, 946 / 1026, 947 / 1026, 948 / 1026, 949 / 1026, 9 50 / 1026, 951 / 1026, 952 / 1026, 953 / 1026, 954 / 1026, 955 / 1026, 956 / 1026, 957 / 1026, 958 / 1026, 959 / 1026, 960 / 1026, 961 / 1026, 962 / 1026, 963 / 1026,964 / 1026, 965 / 1026, 966 / 1026, 967 / 1026, 968 / 1026, 969 / 1026, 970 / 1026, 971 / 1026, 972 / 1026, 973 / 1026, 974 / 1026, 975 / 1026, 976 / 1026, 977 / 1026, 978 / 1026, 97 9 / 1026, 980 / 1026, 981 / 1026, 982 / 1026, 983 / 1026, 984 / 1026, 985 / 1026, 986 / 1026, 987 / 1026, 988 / 1026, 989 / 1026, 990 / 1026, 991 / 1026, 992 / 1026, 993 / 1026, 994 / 1026, 995 / 1026, 996 / 1026, 997 / 1026, 998 / 1026, 999 / 1026, 1000 / 1026, 1001 / 1026, 1002 / 1026, 1003 / 1026, 1004 / 1026, 1005 / 1026, 1006 / 1026, 1007 / 1026, 1008 / 10 V selected from the group consisting of 1009 / 1026, 1010 / 1026, 1011 / 1026, 1012 / 1026, 1013 / 1026, 1014 / 1026, 1015 / 1026, 1016 / 1026, 1017 / 1026, 1018 / 1026, 1019 / 1026, and 1020 / 1026; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof from the pair.

102. The antibody comprises a V selected from SEQ ID NOs: 854-1020. Ｈ 96. The isolated antibody of claim 95, comprising:

103. The antibody comprises a V selected from SEQ ID NOs: 1021-1026. Ｌ 96. The isolated antibody of claim 95, comprising:

104. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1021, 855 / 1021, 856 / 1021, 857 / 1021, 858 / 1021, 859 / 1021, 860 / 1021, 861 / 1021, 862 / 1021, 863 / 1021, 864 / 1021, 865 / 1021, 866 / 1021 , 867 / 1021, 868 / 1021, 869 / 1021, 870 / 1021, 871 / 1021, 872 / 1021, 873 / 1021, 874 / 1021, 875 / 1021, 876 / 1021, 877 / 1021, 878 / 1021, 879 / 1021, 880 / 1021 1, 881 / 1021, 882 / 1021, 883 / 1021, 884 / 1021, 885 / 1021, 886 / 1021, 887 / 1021, 888 / 1021, 889 / 1021, 890 / 1021, 891 / 1021, 892 / 1021, 893 / 1021, 894 / 1021 21, 895 / 1021, 896 / 1021, 897 / 1021, 898 / 1021, 899 / 1021, 900 / 1021, 901 / 1021, 902 / 1021, 903 / 1021, 904 / 1021, 905 / 1021, 906 / 1021, 907 / 1021, 908 / 1 021, 909 / 1021, 910 / 1021, 911 / 1021, 912 / 1021, 913 / 1021, 914 / 1021, 915 / 1021, 916 / 1021, 917 / 1021, 918 / 1021, 919 / 1021, 920 / 1021, 921 / 1021, 922 / 1021, 923 / 1021, 924 / 1021, 925 / 1021, 926 / 1021, 927 / 1021, 928 / 1021, 929 / 1021, 930 / 1021, 931 / 1021, 932 / 1021, 933 / 1021, 934 / 1021, 935 / 1021, 93 6 / 1021, 937 / 1021, 938 / 1021, 939 / 1021, 940 / 1021, 941 / 1021, 942 / 1021, 943 / 1021, 944 / 1021, 945 / 1021, 946 / 1021, 947 / 1021, 948 / 1021, 949 / 1021, 9 50 / 1021, 951 / 1021, 952 / 1021, 953 / 1021, 954 / 1021, 955 / 1021, 956 / 1021, 957 / 1021, 958 / 1021, 959 / 1021, 960 / 1021, 961 / 1021, 962 / 1021, 963 / 1021,964 / 1021, 965 / 1021, 966 / 1021, 967 / 1021, 968 / 1021, 969 / 1021, 970 / 1021, 971 / 1021, 972 / 1021, 973 / 1021, 974 / 1021, 975 / 1021, 976 / 1021, 977 / 1021, 978 / 1021, 97 9 / 1021, 980 / 1021, 981 / 1021, 982 / 1021, 983 / 1021, 984 / 1021, 985 / 1021, 986 / 1021, 987 / 1021, 988 / 1021, 989 / 1021, 990 / 1021, 991 / 1021, 992 / 1021, 993 / 1021, 994 / 1021, 995 / 1021, 996 / 1021, 997 / 1021, 998 / 1021, 999 / 1021, 1000 / 1021, 1001 / 1021, 1002 / 1021, 1003 / 1021, 1004 / 1021, 1005 / 1021, 1006 / 1021, 1007 / 1021, 1008 / 10 V selected from the group consisting of 21, 1009 / 1021, 1010 / 1021, 1011 / 1021, 1012 / 1021, 1013 / 1021, 1014 / 1021, 1015 / 1021, 1016 / 1021, 1017 / 1021, 1018 / 1021, 1019 / 1021, and 1020 / 1021; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising a pair, or a variant thereof.

105. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1022, 855 / 1022, 856 / 1022, 857 / 1022, 858 / 1022, 859 / 1022, 860 / 1022, 861 / 1022, 862 / 1022, 863 / 1022, 864 / 1022, 865 / 1022, 866 / 1022 , 867 / 1022, 868 / 1022, 869 / 1022, 870 / 1022, 871 / 1022, 872 / 1022, 873 / 1022, 874 / 1022, 875 / 1022, 876 / 1022, 877 / 1022, 878 / 1022, 879 / 1022, 880 / 1022 2, 881 / 1022, 882 / 1022, 883 / 1022, 884 / 1022, 885 / 1022, 886 / 1022, 887 / 1022, 888 / 1022, 889 / 1022, 890 / 1022, 891 / 1022, 892 / 1022, 893 / 1022, 894 / 10 22, 895 / 1022, 896 / 1022, 897 / 1022, 898 / 1022, 899 / 1022, 900 / 1022, 901 / 1022, 902 / 1022, 903 / 1022, 904 / 1022, 905 / 1022, 906 / 1022, 907 / 1022, 908 / 1 022, 909 / 1022, 910 / 1022, 911 / 1022, 912 / 1022, 913 / 1022, 914 / 1022, 915 / 1022, 916 / 1022, 917 / 1022, 918 / 1022, 919 / 1022, 920 / 1022, 921 / 1022, 922 / 1022, 923 / 1022, 924 / 1022, 925 / 1022, 926 / 1022, 927 / 1022, 928 / 1022, 929 / 1022, 930 / 1022, 931 / 1022, 932 / 1022, 933 / 1022, 934 / 1022, 935 / 1022, 93 6 / 1022, 937 / 1022, 938 / 1022, 939 / 1022, 940 / 1022, 941 / 1022, 942 / 1022, 943 / 1022, 944 / 1022, 945 / 1022, 946 / 1022, 947 / 1022, 948 / 1022, 949 / 1022, 9 50 / 1022, 951 / 1022, 952 / 1022, 953 / 1022, 954 / 1022, 955 / 1022, 956 / 1022, 957 / 1022, 958 / 1022, 959 / 1022, 960 / 1022, 961 / 1022, 962 / 1022, 963 / 1022,964 / 1022, 965 / 1022, 966 / 1022, 967 / 1022, 968 / 1022, 969 / 1022, 970 / 1022, 971 / 1022, 972 / 1022, 973 / 1022, 974 / 1022, 975 / 1022, 976 / 1022, 977 / 1022, 978 / 1022, 97 9 / 1022, 980 / 1022, 981 / 1022, 982 / 1022, 983 / 1022, 984 / 1022, 985 / 1022, 986 / 1022, 987 / 1022, 988 / 1022, 989 / 1022, 990 / 1022, 991 / 1022, 992 / 1022, 993 / 1022, 994 / 1022, 995 / 1022, 996 / 1022, 997 / 1022, 998 / 1022, 999 / 1022, 1000 / 1022, 1001 / 1022, 1002 / 1022, 1003 / 1022, 1004 / 1022, 1005 / 1022, 1006 / 1022, 1007 / 1022, 1008 / 10 V selected from the group consisting of 22, 1009 / 1022, 1010 / 1022, 1011 / 1022, 1012 / 1022, 1013 / 1022, 1014 / 1022, 1015 / 1022, 1016 / 1022, 1017 / 1022, 1018 / 1022, 1019 / 1022, and 1020 / 1022; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising a pair, or a variant thereof.

106. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1023, 855 / 1023, 856 / 1023, 857 / 1023, 858 / 1023, 859 / 1023, 860 / 1023, 861 / 1023, 862 / 1023, 863 / 1023, 864 / 1023, 865 / 1023, 866 / 1023 , 867 / 1023, 868 / 1023, 869 / 1023, 870 / 1023, 871 / 1023, 872 / 1023, 873 / 1023, 874 / 1023, 875 / 1023, 876 / 1023, 877 / 1023, 878 / 1023, 879 / 1023, 880 / 1023 3, 881 / 1023, 882 / 1023, 883 / 1023, 884 / 1023, 885 / 1023, 886 / 1023, 887 / 1023, 888 / 1023, 889 / 1023, 890 / 1023, 891 / 1023, 892 / 1023, 893 / 1023, 894 / 10 23, 895 / 1023, 896 / 1023, 897 / 1023, 898 / 1023, 899 / 1023, 900 / 1023, 901 / 1023, 902 / 1023, 903 / 1023, 904 / 1023, 905 / 1023, 906 / 1023, 907 / 1023, 908 / 1 023, 909 / 1023, 910 / 1023, 911 / 1023, 912 / 1023, 913 / 1023, 914 / 1023, 915 / 1023, 916 / 1023, 917 / 1023, 918 / 1023, 919 / 1023, 920 / 1023, 921 / 1023, 922 / 1023, 923 / 1023, 924 / 1023, 925 / 1023, 926 / 1023, 927 / 1023, 928 / 1023, 929 / 1023, 930 / 1023, 931 / 1023, 932 / 1023, 933 / 1023, 934 / 1023, 935 / 1023, 93 6 / 1023, 937 / 1023, 938 / 1023, 939 / 1023, 940 / 1023, 941 / 1023, 942 / 1023, 943 / 1023, 944 / 1023, 945 / 1023, 946 / 1023, 947 / 1023, 948 / 1023, 949 / 1023, 9 50 / 1023, 951 / 1023, 952 / 1023, 953 / 1023, 954 / 1023, 955 / 1023, 956 / 1023, 957 / 1023, 958 / 1023, 959 / 1023, 960 / 1023, 961 / 1023, 962 / 1023, 963 / 1023,964 / 1023, 965 / 1023, 966 / 1023, 967 / 1023, 968 / 1023, 969 / 1023, 970 / 1023, 971 / 1023, 972 / 1023, 973 / 1023, 974 / 1023, 975 / 1023, 976 / 1023, 977 / 1023, 978 / 1023, 97 9 / 1023, 980 / 1023, 981 / 1023, 982 / 1023, 983 / 1023, 984 / 1023, 985 / 1023, 986 / 1023, 987 / 1023, 988 / 1023, 989 / 1023, 990 / 1023, 991 / 1023, 992 / 1023, 993 / 1023, 994 / 1023, 995 / 1023, 996 / 1023, 997 / 1023, 998 / 1023, 999 / 1023, 1000 / 1023, 1001 / 1023, 1002 / 1023, 1003 / 1023, 1004 / 1023, 1005 / 1023, 1006 / 1023, 1007 / 1023, 1008 / 10 V selected from the group consisting of 1009 / 1023, 1010 / 1023, 1011 / 1023, 1012 / 1023, 1013 / 1023, 1014 / 1023, 1015 / 1023, 1016 / 1023, 1017 / 1023, 1018 / 1023, 1019 / 1023, and 1020 / 1023; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising a pair, or a variant thereof.

107. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1024, 855 / 1024, 856 / 1024, 857 / 1024, 858 / 1024, 859 / 1024, 860 / 1024, 861 / 1024, 862 / 1024, 863 / 1024, 864 / 1024, 865 / 1024, 866 / 1024 , 867 / 1024, 868 / 1024, 869 / 1024, 870 / 1024, 871 / 1024, 872 / 1024, 873 / 1024, 874 / 1024, 875 / 1024, 876 / 1024, 877 / 1024, 878 / 1024, 879 / 1024, 880 / 1024 4, 881 / 1024, 882 / 1024, 883 / 1024, 884 / 1024, 885 / 1024, 886 / 1024, 887 / 1024, 888 / 1024, 889 / 1024, 890 / 1024, 891 / 1024, 892 / 1024, 893 / 1024, 894 / 10 24, 895 / 1024, 896 / 1024, 897 / 1024, 898 / 1024, 899 / 1024, 900 / 1024, 901 / 1024, 902 / 1024, 903 / 1024, 904 / 1024, 905 / 1024, 906 / 1024, 907 / 1024, 908 / 1 024, 909 / 1024, 910 / 1024, 911 / 1024, 912 / 1024, 913 / 1024, 914 / 1024, 915 / 1024, 916 / 1024, 917 / 1024, 918 / 1024, 919 / 1024, 920 / 1024, 921 / 1024, 922 / 1024, 923 / 1024, 924 / 1024, 925 / 1024, 926 / 1024, 927 / 1024, 928 / 1024, 929 / 1024, 930 / 1024, 931 / 1024, 932 / 1024, 933 / 1024, 934 / 1024, 935 / 1024, 93 6 / 1024, 937 / 1024, 938 / 1024, 939 / 1024, 940 / 1024, 941 / 1024, 942 / 1024, 943 / 1024, 944 / 1024, 945 / 1024, 946 / 1024, 947 / 1024, 948 / 1024, 949 / 1024, 9 50 / 1024, 951 / 1024, 952 / 1024, 953 / 1024, 954 / 1024, 955 / 1024, 956 / 1024, 957 / 1024, 958 / 1024, 959 / 1024, 960 / 1024, 961 / 1024, 962 / 1024, 963 / 1024,964 / 1024, 965 / 1024, 966 / 1024, 967 / 1024, 968 / 1024, 969 / 1024, 970 / 1024, 971 / 1024, 972 / 1024, 973 / 1024, 974 / 1024, 975 / 1024, 976 / 1024, 977 / 1024, 978 / 1024, 97 9 / 1024, 980 / 1024, 981 / 1024, 982 / 1024, 983 / 1024, 984 / 1024, 985 / 1024, 986 / 1024, 987 / 1024, 988 / 1024, 989 / 1024, 990 / 1024, 991 / 1024, 992 / 1024, 993 / 1024, 994 / 1024, 995 / 1024, 996 / 1024, 997 / 1024, 998 / 1024, 999 / 1024, 1000 / 1024, 1001 / 1024, 1002 / 1024, 1003 / 1024, 1004 / 1024, 1005 / 1024, 1006 / 1024, 1007 / 1024, 1008 / 10 V selected from the group consisting of 1009 / 1024, 1010 / 1024, 1011 / 1024, 1012 / 1024, 1013 / 1024, 1014 / 1024, 1015 / 1024, 1016 / 1024, 1017 / 1024, 1018 / 1024, 1019 / 1024, and 1020 / 1024; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising a pair, or a variant thereof.

108. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1025, 855 / 1025, 856 / 1025, 857 / 1025, 858 / 1025, 859 / 1025, 860 / 1025, 861 / 1025, 862 / 1025, 863 / 1025, 864 / 1025, 865 / 1025, 866 / 1025 , 867 / 1025, 868 / 1025, 869 / 1025, 870 / 1025, 871 / 1025, 872 / 1025, 873 / 1025, 874 / 1025, 875 / 1025, 876 / 1025, 877 / 1025, 878 / 1025, 879 / 1025, 880 / 1025 5, 881 / 1025, 882 / 1025, 883 / 1025, 884 / 1025, 885 / 1025, 886 / 1025, 887 / 1025, 888 / 1025, 889 / 1025, 890 / 1025, 891 / 1025, 892 / 1025, 893 / 1025, 894 / 10 25, 895 / 1025, 896 / 1025, 897 / 1025, 898 / 1025, 899 / 1025, 900 / 1025, 901 / 1025, 902 / 1025, 903 / 1025, 904 / 1025, 905 / 1025, 906 / 1025, 907 / 1025, 908 / 1 025, 909 / 1025, 910 / 1025, 911 / 1025, 912 / 1025, 913 / 1025, 914 / 1025, 915 / 1025, 916 / 1025, 917 / 1025, 918 / 1025, 919 / 1025, 920 / 1025, 921 / 1025, 922 / 1025, 923 / 1025, 924 / 1025, 925 / 1025, 926 / 1025, 927 / 1025, 928 / 1025, 929 / 1025, 930 / 1025, 931 / 1025, 932 / 1025, 933 / 1025, 934 / 1025, 935 / 1025, 93 6 / 1025, 937 / 1025, 938 / 1025, 939 / 1025, 940 / 1025, 941 / 1025, 942 / 1025, 943 / 1025, 944 / 1025, 945 / 1025, 946 / 1025, 947 / 1025, 948 / 1025, 949 / 1025, 9 50 / 1025, 951 / 1025, 952 / 1025, 953 / 1025, 954 / 1025, 955 / 1025, 956 / 1025, 957 / 1025, 958 / 1025, 959 / 1025, 960 / 1025, 961 / 1025, 962 / 1025, 963 / 1025,964 / 1025, 965 / 1025, 966 / 1025, 967 / 1025, 968 / 1025, 969 / 1025, 970 / 1025, 971 / 1025, 972 / 1025, 973 / 1025, 974 / 1025, 975 / 1025, 976 / 1025, 977 / 1025, 978 / 1025, 97 9 / 1025, 980 / 1025, 981 / 1025, 982 / 1025, 983 / 1025, 984 / 1025, 985 / 1025, 986 / 1025, 987 / 1025, 988 / 1025, 989 / 1025, 990 / 1025, 991 / 1025, 992 / 1025, 993 / 1025, 994 / 1025, 995 / 1025, 996 / 1025, 997 / 1025, 998 / 1025, 999 / 1025, 1000 / 1025, 1001 / 1025, 1002 / 1025, 1003 / 1025, 1004 / 1025, 1005 / 1025, 1006 / 1025, 1007 / 1025, 1008 / 10 V selected from the group consisting of 1009 / 1025, 1010 / 1025, 1011 / 1025, 1012 / 1025, 1013 / 1025, 1014 / 1025, 1015 / 1025, 1016 / 1025, 1017 / 1025, 1018 / 1025, 1019 / 1025, and 1020 / 1025; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising a pair, or a variant thereof.

109. The antibody is selected from the group consisting of SEQ ID NOs: 854 / 1026, 855 / 1026, 856 / 1026, 857 / 1026, 858 / 1026, 859 / 1026, 860 / 1026, 861 / 1026, 862 / 1026, 863 / 1026, 864 / 1026, 865 / 1026, 866 / 1026 , 867 / 1026, 868 / 1026, 869 / 1026, 870 / 1026, 871 / 1026, 872 / 1026, 873 / 1026, 874 / 1026, 875 / 1026, 876 / 1026, 877 / 1026, 878 / 1026, 879 / 1026, 880 / 1026 6, 881 / 1026, 882 / 1026, 883 / 1026, 884 / 1026, 885 / 1026, 886 / 1026, 887 / 1026, 888 / 1026, 889 / 1026, 890 / 1026, 891 / 1026, 892 / 1026, 893 / 1026, 894 / 10 26, 895 / 1026, 896 / 1026, 897 / 1026, 898 / 1026, 899 / 1026, 900 / 1026, 901 / 1026, 902 / 1026, 903 / 1026, 904 / 1026, 905 / 1026, 906 / 1026, 907 / 1026, 908 / 1 026, 909 / 1026, 910 / 1026, 911 / 1026, 912 / 1026, 913 / 1026, 914 / 1026, 915 / 1026, 916 / 1026, 917 / 1026, 918 / 1026, 919 / 1026, 920 / 1026, 921 / 1026, 922 / 1026, 923 / 1026, 924 / 1026, 925 / 1026, 926 / 1026, 927 / 1026, 928 / 1026, 929 / 1026, 930 / 1026, 931 / 1026, 932 / 1026, 933 / 1026, 934 / 1026, 935 / 1026, 93 6 / 1026, 937 / 1026, 938 / 1026, 939 / 1026, 940 / 1026, 941 / 1026, 942 / 1026, 943 / 1026, 944 / 1026, 945 / 1026, 946 / 1026, 947 / 1026, 948 / 1026, 949 / 1026, 9 50 / 1026, 951 / 1026, 952 / 1026, 953 / 1026, 954 / 1026, 955 / 1026, 956 / 1026, 957 / 1026, 958 / 1026, 959 / 1026, 960 / 1026, 961 / 1026, 962 / 1026, 963 / 1026,964 / 1026, 965 / 1026, 966 / 1026, 967 / 1026, 968 / 1026, 969 / 1026, 970 / 1026, 971 / 1026, 972 / 1026, 973 / 1026, 974 / 1026, 975 / 1026, 976 / 1026, 977 / 1026, 978 / 1026, 97 9 / 1026, 980 / 1026, 981 / 1026, 982 / 1026, 983 / 1026, 984 / 1026, 985 / 1026, 986 / 1026, 987 / 1026, 988 / 1026, 989 / 1026, 990 / 1026, 991 / 1026, 992 / 1026, 993 / 1026, 994 / 1026, 995 / 1026, 996 / 1026, 997 / 1026, 998 / 1026, 999 / 1026, 1000 / 1026, 1001 / 1026, 1002 / 1026, 1003 / 1026, 1004 / 1026, 1005 / 1026, 1006 / 1026, 1007 / 1026, 1008 / 10 V selected from the group consisting of 1009 / 1026, 1010 / 1026, 1011 / 1026, 1012 / 1026, 1013 / 1026, 1014 / 1026, 1015 / 1026, 1016 / 1026, 1017 / 1026, 1018 / 1026, 1019 / 1026, and 1020 / 1026; Ｈ / V Ｌ 96. The isolated antibody of claim 95, comprising a pair, or a variant thereof.

110. The antibody is HC The following group of CDR SEQ ID NOs: 4 / 338 / 672; 5 / 339 / 673; 6 / 340 / 674; 7 / 341 / 675; 8 / 342 / 676; 9 / 343 / 677; 10 / 344 / 678; 11 / 345 / 679; 12 / 346 / 680; 13 / 347 / 681; 14 / 348 / 682; 15 / 349 / 683; 16 / 350 / 684; 17 / 351 / 685; 18 / 352 / 686; 19 / 353 / 687; 20 / 354 / 688; 21 / 355 / 689; 22 / 356 / 690; 23 / 357 / 691; 24 / 358 / 692; 25 / 359 / 69 3; 26 / 360 / 694; 27 / 361 / 695; 28 / 362 / 696; 29 / 363 / 697; 30 / 364 / 698; 31 / 365 / 699; 32 / 366 / 700; 33 / 367 / 701; 34 / 368 / 702; 35 / 369 / 703; 36 / 370 / 704; 37 / 371 / 705; 38 / 372 / 706; 39 / 373 / 707; 40 / 374 / 708; 41 / 375 / 709; 42 / 376 / 710; 43 / 377 / 711; 44 / 378 / 712; 45 / 379 / 713; 46 / 380 / 714; 47 / 381 / 715; 48 / 382 / 716; 49 / 383 / 717; 50 / 384 / 718; 51 / 385 / 719; 52 / 386 / 720; 53 / 387 / 721; 54 / 388 / 722; 55 / 389 / 723; 56 / 390 / 724; 57 / 391 / 725; 58 / 392 / 726; 59 / 3 93 / 727; 60 / 394 / 728; 61 / 395 / 729; 62 / 396 / 730; 63 / 397 / 731; 64 / 398 / 732; 65 / 399 / 733; 66 / 400 / 734; 67 / 401 / 735; 68 / 402 / 736; 69 / 403 / 737; 70 / 404 / 738; 71 / 405 / 739; 72 / 406 / 740; 73 / 407 / 741; 74 / 408 / 742; 75 / 409 / 743; 76 / 410 / 744; 77 / 411 / 745; 78 / 412 / 746; 79 / 413 / 747; 80 / 414 / 748; 81 / 415 / 7 49; 82 / 416 / 750; 83 / 417 / 751; 84 / 418 / 752; 85 / 419 / 753; 86 / 420 / 754; 87 / 421 / 755; 88 / 422 / 756; 89 / 423 / 757; 90 / 424 / 758; 91 / 425 / 759; 92 / 426 / 760;93 / 427 / 761; 94 / 428 / 762; 95 / 429 / 763; 96 / 430 / 764; 97 / 431 / 765; 98 / 432 / 766; 99 / 433 / 767; 100 / 434 / 768; 101 / 435 / 769; 102 / 436 / 770; 103 / 437 / 771; 104 / 438 / 772; 105 / 439 / 773; 106 / 440 / 774; 107 / 441 / 775; 108 / 442 / 776; 109 / 443 / 777; 110 / 444 / 778; 111 / 445 / 779; 112 / 446 / 780; 113 / 447 / 781; 114 / 448 / 782; 115 / 449 / 783; 116 / 450 / 784; 117 / 451 / 785; 118 / 452 / 786; 119 / 453 / 787; 120 / 454 / 788; 121 / 455 / 789; 122 / 456 / 790; 123 / 457 / 791; 124 / 458 / 792; 125 / 459 / 793; 126 / 460 / 794; 127 / 461 / 795; 128 / 462 / 796; 129 / 463 / 797; 130 / 464 / 798; 131 / 465 / 799; 132 / 466 / 800; 13 3 / 467 / 801; 134 / 468 / 802; 135 / 469 / 803; 136 / 470 / 804; 137 / 471 / 805; 138 / 472 / 806; 139 / 473 / 807; 140 / 474 / 808; 141 / 475 / 809; 142 / 476 / 810; 143 / 477 / 811; 144 / 478 / 812; 145 / 479 / 813; 146 / 480 / 814; 147 / 481 / 815; 148 / 482 / 816; 149 / 483 / 817; 150 / 484 / 818; 151 / 485 / 819; 152 / 486 / 820; 96. The isolated antibody of claim 95, comprising three Chothia HC CDRs designated as one of 153 / 487 / 821; 154 / 488 / 822; 155 / 489 / 823; 156 / 490 / 824; 157 / 491 / 825; 158 / 492 / 826; 159 / 493 / 827; 160 / 494 / 828; 161 / 495 / 829; 162 / 496 / 830; 163 / 497 / 831; 164 / 498 / 832; 165 / 499 / 833; 166 / 500 / 834; 167 / 501 / 835; 168 / 502 / 836; 169 / 503 / 837; and 170 / 504 / 838. ;

111. The antibody may be selected from the following group of CDR SEQ ID NOs: 4 / 338 / 672 / 839 / 844 / 849; 5 / 339 / 673 / 839 / 844 / 849; 6 / 340 / 674 / 839 / 844 / 849; 7 / 341 / 675 / 839 / 844 / 849; 8 / 342 / 676 / 839 / 844 / 849; 9 / 343 / 677 / 839 / 844 / 849; 10 / 344 / 678 / 839 / 844 / 849; 11 / 345 / 679 / 839 / 844 / 849; 12 / 346 / 680 / 839 / 844 / 849; 13 / 347 / 681 / 839 / 844 / 849; 14 / 348 / 68 2 / 839 / 844 / 849; 15 / 349 / 683 / 839 / 844 / 849; 16 / 350 / 684 / 839 / 844 / 849; 17 / 351 / 685 / 839 / 844 / 849; 18 / 352 / 686 / 839 / 844 / 849; 19 / 353 / 687 / 839 / 844 / 849; 20 / 354 / 688 / 839 / 844 / 849; 21 / 355 / 689 / 839 / 844 / 849; 22 / 356 / 690 / 839 / 844 / 849; 23 / 357 / 691 / 839 / 844 / 849; 24 / 358 / 692 / 839 / 844 / 849; 25 / 359 / 693 / 839 / 844 / 849; 26 / 360 / 694 / 839 / 844 / 849; 27 / 361 / 695 / 839 / 844 / 849; 28 / 362 / 696 / 839 / 844 / 849; 29 / 363 / 697 / 839 / 844 / 849; 30 / 364 / 698 / 839 / 8 44 / 849; 31 / 365 / 699 / 839 / 844 / 849; 32 / 366 / 700 / 839 / 844 / 849; 33 / 367 / 701 / 839 / 844 / 849; 34 / 368 / 702 / 839 / 844 / 849; 35 / 369 / 703 / 839 / 844 / 849; 36 / 370 / 704 / 839 / 844 / 849; 37 / 371 / 705 / 839 / 844 / 849; 38 / 372 / 706 / 839 / 844 / 849; 39 / 373 / 707 / 839 / 844 / 849; 40 / 374 / 708 / 839 / 844 / 849; 41 / 375 / 709 / 83 9 / 844 / 849; 42 / 376 / 710 / 839 / 844 / 849; 43 / 377 / 711 / 839 / 844 / 849; 44 / 378 / 712 / 839 / 844 / 849; 45 / 379 / 713 / 839 / 844 / 849; 46 / 380 / 714 / 839 / 844 / 849;４７／３８１／７１５／８３９／８４４／８４９；４８／３８２／７１６／８３９／８４４／８４９；４９／３８３／７１７／８３９／８４４／８４９；５０／３８４／７１８／８３９／８４４／８４９；５１／３８５／７１９／８３９／８４４／８４９；５２／３８６／７２０／８３９／８４４／８４９；５３／３８７／７２１／８３９／８４４／８４９；５４／３８８／７２２／８３９／８４４／８４９；５５／３８９／７２３／８３９／８４４／８４９；５６／３９０／７２４／８３９／８４４／８４９；５７／３９１／７２５／８３９／８４４／８４９；５８／３９２／７２６／８３９／８４４／８４９；５９／３９３／７２７／８３９／８４４／８４９；６０／３９４／７２８／８３９／８４４／８４９；６１／３９５／７２９／８３９／８４４／８４９；６２／３９６／７３０／８３９／８４４／８４９；６３／３９７／７３１／８３９／８４４／８４９；６４／３９８／７３２／８３９／８４４／８４９；６５／３９９／７３３／８３９／８４４／８４９；６６／４００／７３４／８３９／８４４／８４９；６７／４０１／７３５／８３９／８４４／８４９；６８／４０２／７３６／８３９／８４４／８４９；６９／４０３／７３７／８３９／８４４／８４９；７０／４０４／７３８／８３９／８４４／８４９；７１／４０５／７３９／８３９／８４４／８４９；７２／４０６／７４０／８３９／８４４／８４９；７３／４０７／７４１／８３９／８４４／８４９；７４／４０８／７４２／８３９／８４４／８４９；７５／４０９／７４３／８３９／８４４／８４９；７６／４１０／７４４／８３９／８４４／８４９；７７／４１１／７４５／８３９／８４４／８４９；７８／４１２／７４６／８３９／８４４／８４９；７９／４１３／７４７／８３９／８４４／８４９；８０／４１４／７４８／８３９／８４４／８４９；８１／４１５／７４９／８３９／８４４／８４９；８２／４１６／７５０／８３９／８４４／８４９；８３／４１７／７５１／８３９／８４４／８４９；８４／４１８／７５２／８３９／８４４／８４９；８５／４１９／７５３／８３９／８４４／８４９；８６／４２０／７５４／８３９／８４４／８４９；８７／４２１／７５５／８３９／８４４／８４９；８８／４２２／７５６／８３９／８４４／８４９；８９／４２３／７５７／８３９／８４４／８４９；９０／４２４／７５８／８３９／８４４／８４９；９１／４２５／７５９／８３９／８４４／８４９；９２／４２６／７６０／８３９／８４４／８４９；９３／４２７／７６１／８３９／８４４／８４９；９４／４２８／７６２／８３９／８４４／８４９；９５／４２９／７６３／８３９／８４４／８４９；９６／４３０／７６４／８３９／８４４／８４９；９７／４３１／７６５／８３９／８４４／８４９；９８／４３２／７６６／８３９／８４４／８４９；９９／４３３／７６７／８３９／８４４／８４９；１００／４３４／７６８／８３９／８４４／８４９；１０１／４３５／７６９／８３９／８４４／８４９；１０２／４３６／７７０／８３９／８４４／８４９；１０３／４３７／７７１／８３９／８４４／８４９；１０４／４３８／７７２／８３９／８４４／８４９；１０５／４３９／７７３／８３９／８４４／８４９；１０６／４４０／７７４／８３９／８４４／８４９；１０７／４４１／７７５／８３９／８４４／８４９；１０８／４４２／７７６／８３９／８４４／８４９；１０９／４４３／７７７／８３９／８４４／８４９；１１０／４４４／７７８／８３９／８４４／８４９；１１１／４４５／７７９／８３９／８４４／８４９；１１２／４４６／７８０／８３９／８４４／８４９；１１３／４４７／７８１／８３９／８４４／８４９；１１４／４４８／７８２／８３９／８４４／８４９；１１５／４４９／７８３／８３９／８４４／８４９；１１６／４５０／７８４／８３９／８４４／８４９；１１７／４５１／７８５／８３９／８４４／８４９；１１８／４５２／７８６／８３９／８４４／８４９；１１９／４５３／７８７／８３９／８４４／８４９；１２０／４５４／７８８／８３９／８４４／８４９；１２１／４５５／７８９／８３９／８４４／８４９；１２２／４５６／７９０／８３９／８４４／８４９；１２３／４５７／７９１／８３９／８４４／８４９；１２４／４５８／７９２／８３９／８４４／８４９；１２５／４５９／７９３／８３９／８４４／８４９；１２６／４６０／７９４／８３９／８４４／８４９；１２７／４６１／７９５／８３９／８４４／８４９；１２８／４６２／７９６／８３９／８４４／８４９；１２９／４６３／７９７／８３９／８４４／８４９；１３０／４６４／７９８／８３９／８４４／８４９；１３１／４６５／７９９／８３９／８４４／８４９；１３２／４６６／８００／８３９／８４４／８４９；１３３／４６７／８０１／８３９／８４４／８４９；１３４／４６８／８０２／８３９／８４４／８４９；１３５／４６９／８０３／８３９／８４４／８４９；１３６／４７０／８０４／８３９／８４４／８４９；１３７／４７１／８０５／８３９／８４４／８４９；１３８／４７２／８０６／８３９／８４４／８４９；１３９／４７３／８０７／８３９／８４４／８４９；１４０／４７４／８０８／８３９／８４４／８４９；１４１／４７５／８０９／８３９／８４４／８４９；１４２／４７６／８１０／８３９／８４４／８４９；１４３／４７７／８１１／８３９／８４４／８４９；１４４／４７８／８１２／８３９／８４４／８４９；１４５／４７９／８１３／８４０／８４５／８５０；１４６／４８０／８１４／８４０／８４５／８５０；１４７／４８１／８１５／８４０／８４５／８５０；１４８／４８２／８１６／８４０／８４５／８５０；１４９／４８３／８１７／８４０／８４５／８５０；１５０／４８４／８１８／８４０／８４５／８５０；１５１／４８５／８１９／８４０／８４５／８５０；１５２／４８６／８２０／８４０／８４５／８５０；１５３／４８７／８２１／８４０／８４５／８５０；１５４／４８８／８２２／８４０／８４５／８５０；１５５／４８９／８２３／８４０／８４５／８５０；１５６／４９０／８２４／８４０／８４５／８５０；１５７／４９１／８２５／８４０／８４５／８５０；１５８／４９２／８２６／８４０／８４５／８５０；１５９／４９３／８２７／８４０／８４５／８５０；１６０／４９４／８２８／８４０／８４５／８５０；１６１／４９５／８２９／８４０／８４５／８５０；１６２／４９６／８３０／８４０／８４５／８５０；１６３／４９７／８３１／８４０／８４５／８５０；１６４／４９８／８３２／８４０／８４５／８５０；１６５／４９９／８３３／８４０／８４５／８５０；１６６／５００／８３４／８４０／８４５／８５０；１６７／５０１／８３５／８４０／８４５／８５０；１６８／５０２／８３６／８４０／８４５／８５０；１６９／５０３／８３７／８４０／８４５／８５０；１７０／５０４／８３８／８４０／８４５／８５０；１４５／４７９／８１３／８４１／８４６／８５１；１４６／４８０／８１４／８４１／８４６／８５１；147 / 481 / 815 / 841 / 846 / 851; 148 / 482 / 816 / 841 / 846 / 851; 149 / 483 / 817 / 841 / 846 / 851; 150 / 484 / 818 / 841 / 846 / 851; 151 / 485 / 819 / 841 / 846 / 851; 152 / 486 / 820 / 841 / 846 / 851; 153 / 487 / 8 21 / 841 / 846 / 851; 154 / 488 / 822 / 841 / 846 / 851; 155 / 489 / 823 / 841 / 846 / 851; 156 / 490 / 824 / 841 / 846 / 851; 157 / 491 / 825 / 841 / 846 / 851; 158 / 492 / 826 / 841 / 846 / 851; 159 / 493 / 827 / 841 / 846 / 851; 160 / 494 / 828 / 841 / 846 / 851; 161 / 495 / 829 / 841 / 846 / 851; 162 / 496 / 830 / 841 / 846 / 851; 163 / 497 / 831 / 841 / 846 / 851; 164 / 498 / 832 / 841 / 846 / 851; 165 / 499 / 833 / 841 / 846 / 851; 166 / 5 96. The isolated antibody of claim 95, comprising six CDRs set forth in one of: 00 / 834 / 841 / 846 / 851; 167 / 501 / 835 / 841 / 846 / 851; 168 / 502 / 836 / 841 / 846 / 851; 169 / 503 / 837 / 841 / 846 / 851; and 170 / 504 / 838 / 841 / 846 / 851.

112. The antibody is HC The following group of CDR SEQ ID NOs: 171 / 505 / 672; 172 / 506 / 673; 173 / 507 / 674; 174 / 508 / 675; 175 / 509 / 676; 176 / 510 / 677; 177 / 511 / 678; 178 / 512 / 679; 179 / 513 / 680; 180 / 514 / 681; 181 / 515 / 682; 182 / 516 / 683; 183 / 517 / 684; 184 / 518 / 685; 185 / 519 / 686; 186 / 520 / 687; 187 / 521 / 688; 188 / 522 / 689; 189 / 523 / 690; 190 / 52 4 / 691; 191 / 525 / 692; 192 / 526 / 693; 193 / 527 / 694; 194 / 528 / 695; 195 / 529 / 696; 196 / 530 / 697; 197 / 531 / 698; 198 / 532 / 699; 199 / 533 / 700; 200 / 534 / 7 01; 201 / 535 / 702; 202 / 536 / 703; 203 / 537 / 704; 204 / 538 / 705; 205 / 539 / 706; 206 / 540 / 707; 207 / 541 / 708; 208 / 542 / 709; 209 / 543 / 710; 210 / 544 / 711; 211 / 545 / 712; 212 / 546 / 713; 213 / 547 / 714; 214 / 548 / 715; 215 / 549 / 716; 216 / 550 / 717; 217 / 551 / 718; 218 / 552 / 719; 219 / 553 / 720; 220 / 554 / 721; 221 / 555 / 722; 222 / 556 / 723; 223 / 557 / 724; 224 / 558 / 725; 225 / 559 / 726; 226 / 560 / 727; 227 / 561 / 728; 228 / 562 / 729; 229 / 563 / 730; 230 / 564 / 731; 231 / 56 5 / 732; 232 / 566 / 733; 233 / 567 / 734; 234 / 568 / 735; 235 / 569 / 736; 236 / 570 / 737; 237 / 571 / 738; 238 / 572 / 739; 239 / 573 / 740; 240 / 574 / 741; 241 / 575 / 7 42; 242 / 576 / 743; 243 / 577 / 744; 244 / 578 / 745; 245 / 579 / 746; 246 / 580 / 747; 247 / 581 / 748; 248 / 582 / 749; 249 / 583 / 750; 250 / 584 / 751; 251 / 585 / 752;２５２／５８６／７５３；２５３／５８７／７５４；２５４／５８８／７５５；２５５／５８９／７５６；２５６／５９０／７５７；２５７／５９１／７５８；２５８／５９２／７５９；２５９／５９３／７６０；２６０／５９４／７６１；２６１／５９５／７６２；２６２／５９６／７６３；２６３／５９７／７６４；２６４／５９８／７６５；２６５／５９９／７６６；２６６／６００／７６７；２６７／６０１／７６８；２６８／６０２／７６９；２６９／６０３／７７０；２７０／６０４／７７１；２７１／６０５／７７２；２７２／６０６／７７３；２７３／６０７／７７４；２７４／６０８／７７５；２７５／６０９／７７６；２７６／６１０／７７７；２７７／６１１／７７８；２７８／６１２／７７９；２７９／６１３／７８０；２８０／６１４／７８１；２８１／６１５／７８２；２８２／６１６／７８３；２８３／６１７／７８４；２８４／６１８／７８５；２８５／６１９／７８６；２８６／６２０／７８７；２８７／６２１／７８８；２８８／６２２／７８９；２８９／６２３／７９０；２９０／６２４／７９１；２９１／６２５／７９２；２９２／６２６／７９３；２９３／６２７／７９４；２９４／６２８／７９５；２９５／６２９／７９６；２９６／６３０／７９７；２９７／６３１／７９８；２９８／６３２／７９９；２９９／６３３／８００；３００／６３４／８０１；３０１／６３５／８０２；３０２／６３６／８０３；３０３／６３７／８０４；３０４／６３８／８０５；３０５／６３９／８０６；３０６／６４０／８０７；３０７／６４１／８０８；３０８／６４２／８０９；３０９／６４３／８１０；３１０／６４４／８１１；３１１／６４５／８１２；３１２／６４６／８１３；３１３／６４７／８１４；３１４／６４８／８１５；３１５／６４９／８１６；３１６／６５０／８１７；３１７／６５１／８１８；３１８／６５２／８１９；３１９／６５３／８２０；３２０／６５４／８２１；３２１／６５５／８２２；３２２／６５６／８２３；３２３／６５７／８２４；３２４／６５８／８２５；３２５／６５９／８２６；３２６／６６０／８２７；３２７／６６１／８２８；３２８／６６２／８２９；３２９／６６３／８３０；３３０／６６４／８３１；３３１／６６５／８３２；３３２／６６６／８３３；３３３／６６７／８３４；３３４／６６８／８３５；96. The isolated antibody of claim 95, comprising three Kabat HC CDRs designated as one of 335 / 669 / 836; 336 / 670 / 837; and 337 / 671 / 838.

113. The antibody may comprise one of the following groups of CDR SEQ ID NOs: 171 / 505 / 672 / 839 / 844 / 849; 172 / 506 / 673 / 839 / 844 / 849; 173 / 507 / 674 / 839 / 844 / 849; 174 / 508 / 675 / 839 / 844 / 849; 175 / 509 / 676 / 839 / 844 / 849; 176 / 510 / 677 / 839 / 844 / 849; 177 / 511 / 678 / 839 / 844 / 849; 178 / 512 / 679 / 839 / 844 / 849; 179 / 513 / 680 / 839 / 844 / 849; 180 / 514 / 681 / 839 / 84 4 / 849; 181 / 515 / 682 / 839 / 844 / 849; 182 / 516 / 683 / 839 / 844 / 849; 183 / 517 / 684 / 839 / 844 / 849; 184 / 518 / 685 / 839 / 844 / 849; 185 / 519 / 686 / 839 / 844 / 849 ;186 / 520 / 687 / 839 / 844 / 849;187 / 521 / 688 / 839 / 844 / 849;188 / 522 / 689 / 839 / 844 / 849;189 / 523 / 690 / 839 / 844 / 849;190 / 524 / 691 / 839 / 844 / 849;191 / 525 / 692 / 839 / 844 / 849; 192 / 526 / 693 / 839 / 844 / 849; 193 / 527 / 694 / 839 / 844 / 849; 194 / 528 / 695 / 839 / 844 / 849; 195 / 529 / 696 / 839 / 844 / 849; 196 / 530 / 6 97 / 839 / 844 / 849; 197 / 531 / 698 / 839 / 844 / 849; 198 / 532 / 699 / 839 / 844 / 849; 199 / 533 / 700 / 839 / 844 / 849; 200 / 534 / 701 / 839 / 844 / 849; 201 / 535 / 702 / 83 9 / 844 / 849; 202 / 536 / 703 / 839 / 844 / 849; 203 / 537 / 704 / 839 / 844 / 849; 204 / 538 / 705 / 839 / 844 / 849; 205 / 539 / 706 / 839 / 844 / 849; 206 / 540 / 707 / 839 / 844 / 849; 207 / 541 / 708 / 839 / 844 / 849; 208 / 542 / 709 / 839 / 844 / 849; 209 / 543 / 710 / 839 / 844 / 849; 210 / 544 / 711 / 839 / 844 / 849; 211 / 545 / 712 / 839 / 844 / 849;２１２／５４６／７１３／８３９／８４４／８４９；２１３／５４７／７１４／８３９／８４４／８４９；２１４／５４８／７１５／８３９／８４４／８４９；２１５／５４９／７１６／８３９／８４４／８４９；２１６／５５０／７１７／８３９／８４４／８４９；２１７／５５１／７１８／８３９／８４４／８４９；２１８／５５２／７１９／８３９／８４４／８４９；２１９／５５３／７２０／８３９／８４４／８４９；２２０／５５４／７２１／８３９／８４４／８４９；２２１／５５５／７２２／８３９／８４４／８４９；２２２／５５６／７２３／８３９／８４４／８４９；２２３／５５７／７２４／８３９／８４４／８４９；２２４／５５８／７２５／８３９／８４４／８４９；２２５／５５９／７２６／８３９／８４４／８４９；２２６／５６０／７２７／８３９／８４４／８４９；２２７／５６１／７２８／８３９／８４４／８４９；２２８／５６２／７２９／８３９／８４４／８４９；２２９／５６３／７３０／８３９／８４４／８４９；２３０／５６４／７３１／８３９／８４４／８４９；２３１／５６５／７３２／８３９／８４４／８４９；２３２／５６６／７３３／８３９／８４４／８４９；２３３／５６７／７３４／８３９／８４４／８４９；２３４／５６８／７３５／８３９／８４４／８４９；２３５／５６９／７３６／８３９／８４４／８４９；２３６／５７０／７３７／８３９／８４４／８４９；２３７／５７１／７３８／８３９／８４４／８４９；２３８／５７２／７３９／８３９／８４４／８４９；２３９／５７３／７４０／８３９／８４４／８４９；２４０／５７４／７４１／８３９／８４４／８４９；２４１／５７５／７４２／８３９／８４４／８４９；２４２／５７６／７４３／８３９／８４４／８４９；２４３／５７７／７４４／８３９／８４４／８４９；２４４／５７８／７４５／８３９／８４４／８４９；２４５／５７９／７４６／８３９／８４４／８４９；２４６／５８０／７４７／８３９／８４４／８４９；２４７／５８１／７４８／８３９／８４４／８４９；２４８／５８２／７４９／８３９／８４４／８４９；２４９／５８３／７５０／８３９／８４４／８４９；２５０／５８４／７５１／８３９／８４４／８４９；２５１／５８５／７５２／８３９／８４４／８４９；２５２／５８６／７５３／８３９／８４４／８４９；２５３／５８７／７５４／８３９／８４４／８４９；２５４／５８８／７５５／８３９／８４４／８４９；２５５／５８９／７５６／８３９／８４４／８４９；２５６／５９０／７５７／８３９／８４４／８４９；２５７／５９１／７５８／８３９／８４４／８４９；２５８／５９２／７５９／８３９／８４４／８４９；２５９／５９３／７６０／８３９／８４４／８４９；２６０／５９４／７６１／８３９／８４４／８４９；２６１／５９５／７６２／８３９／８４４／８４９；２６２／５９６／７６３／８３９／８４４／８４９；２６３／５９７／７６４／８３９／８４４／８４９；２６４／５９８／７６５／８３９／８４４／８４９；２６５／５９９／７６６／８３９／８４４／８４９；２６６／６００／７６７／８３９／８４４／８４９；２６７／６０１／７６８／８３９／８４４／８４９；２６８／６０２／７６９／８３９／８４４／８４９；２６９／６０３／７７０／８３９／８４４／８４９；２７０／６０４／７７１／８３９／８４４／８４９；２７１／６０５／７７２／８３９／８４４／８４９；２７２／６０６／７７３／８３９／８４４／８４９；２７３／６０７／７７４／８３９／８４４／８４９；２７４／６０８／７７５／８３９／８４４／８４９；２７５／６０９／７７６／８３９／８４４／８４９；２７６／６１０／７７７／８３９／８４４／８４９；２７７／６１１／７７８／８３９／８４４／８４９；２７８／６１２／７７９／８３９／８４４／８４９；２７９／６１３／７８０／８３９／８４４／８４９；２８０／６１４／７８１／８３９／８４４／８４９；２８１／６１５／７８２／８３９／８４４／８４９；２８２／６１６／７８３／８３９／８４４／８４９；２８３／６１７／７８４／８３９／８４４／８４９；２８４／６１８／７８５／８３９／８４４／８４９；２８５／６１９／７８６／８３９／８４４／８４９；２８６／６２０／７８７／８３９／８４４／８４９；２８７／６２１／７８８／８３９／８４４／８４９；２８８／６２２／７８９／８３９／８４４／８４９；２８９／６２３／７９０／８３９／８４４／８４９；２９０／６２４／７９１／８３９／８４４／８４９；２９１／６２５／７９２／８３９／８４４／８４９；２９２／６２６／７９３／８３９／８４４／８４９；２９３／６２７／７９４／８３９／８４４／８４９；２９４／６２８／７９５／８３９／８４４／８４９；２９５／６２９／７９６／８３９／８４４／８４９；２９６／６３０／７９７／８３９／８４４／８４９；２９７／６３１／７９８／８３９／８４４／８４９；２９８／６３２／７９９／８３９／８４４／８４９；２９９／６３３／８００／８３９／８４４／８４９；３００／６３４／８０１／８３９／８４４／８４９；３０１／６３５／８０２／８３９／８４４／８４９；３０２／６３６／８０３／８３９／８４４／８４９；３０３／６３７／８０４／８３９／８４４／８４９；３０４／６３８／８０５／８３９／８４４／８４９；３０５／６３９／８０６／８３９／８４４／８４９；３０６／６４０／８０７／８３９／８４４／８４９；３０７／６４１／８０８／８３９／８４４／８４９；３０８／６４２／８０９／８３９／８４４／８４９；３０９／６４３／８１０／８３９／８４４／８４９；３１０／６４４／８１１／８３９／８４４／８４９；３１１／６４５／８１２／８４０／８４５／８５０；３１２／６４６／８１３／８４０／８４５／８５０；３１３／６４７／８１４／８４０／８４５／８５０；３１４／６４８／８１５／８４０／８４５／８５０；３１５／６４９／８１６／８４０／８４５／８５０；３１６／６５０／８１７／８４０／８４５／８５０；３１７／６５１／８１８／８４０／８４５／８５０；３１８／６５２／８１９／８４０／８４５／８５０；３１９／６５３／８２０／８４０／８４５／８５０；３２０／６５４／８２１／８４０／８４５／８５０；３２１／６５５／８２２／８４０／８４５／８５０；３２２／６５６／８２３／８４０／８４５／８５０；３２３／６５７／８２４／８４０／８４５／８５０；３２４／６５８／８２５／８４０／８４５／８５０；３２５／６５９／８２６／８４０／８４５／８５０；３２６／６６０／８２７／８４０／８４５／８５０；３２７／６６１／８２８／８４０／８４５／８５０；３２８／６６２／８２９／８４０／８４５／８５０；３２９／６６３／８３０／８４０／８４５／８５０；３３０／６６４／８３１／８４０／８４５／８５０；３３１／６６５／８３２／８４０／８４５／８５０；３３２／６６６／８３３／８４０／８４５／８５０；３３３／６６７／８３４／８４０／８４５／８５０；３３４／６６８／８３５／８４０／８４５／８５０；335 / 669 / 836 / 840 / 845 / 850; 336 / 670 / 837 / 840 / 845 / 850; 337 / 671 / 838 / 840 / 845 / 850; 311 / 645 / 812 / 841 / 846 / 851; 312 / 646 / 813 / 841 / 846 / 851; 313 / 647 / 814 / 841 / 846 / 851; 314 / 648 / 815 / 841 / 846 / 851; 315 / 649 / 816 / 841 / 846 / 8 51; 316 / 650 / 817 / 841 / 846 / 851; 317 / 651 / 818 / 841 / 846 / 851; 318 / 652 / 819 / 841 / 846 / 851; 319 / 653 / 820 / 841 / 846 / 851; 320 / 654 / 821 / 841 / 846 / 851; 321 / 655 / 822 / 841 / 846 / 851; 322 / 656 / 823 / 841 / 846 / 851; 323 / 657 / 824 / 841 / 846 / 851; 324 / 658 / 825 / 841 / 846 / 851; 325 / 659 / 826 / 841 / 846 / 851; 326 / 660 / 827 / 841 / 846 / 851; 327 / 661 / 828 / 841 / 846 / 851; 328 / 662 / 829 / 841 / 846 / 851; 329 / 663 / 830 / 841 / 846 / 851; 330 / 664 / 831 / 841 / 846 / 851; 331 / 665 / 832 / 841 / 8 96. The isolated antibody of claim 95, comprising six CDRs designated as one of: 46 / 851; 332 / 666 / 833 / 841 / 846 / 851; 333 / 667 / 834 / 841 / 846 / 851; 334 / 668 / 835 / 841 / 846 / 851; 335 / 669 / 836 / 841 / 846 / 851; 336 / 670 / 837 / 841 / 846 / 851; and 337 / 671 / 838 / 841 / 846 / 851.

114. The antibody, (a) V Ｈ Region SEQ ID NO: 854 and V Ｌ three heavy chain CDRs and three light chain CDRs of region SEQ ID NO: 1021; (b) V Ｈ Region SEQ ID NO: 859 and V Ｌ the three heavy chain CDRs and the three light chain CDRs of region SEQ ID NO: 1021; or (c) V Ｈ Region SEQ ID NO: 895 and V Ｌ Three heavy chain CDRs and three light chain CDRs of region SEQ ID NO: 1021 110. The isolated antibody of any of claims 95 to 109, comprising:

115. The antibody is V Ｈ Region SEQ ID NO: 854 and V Ｌ 115. The isolated antibody of claim 114, comprising three heavy chain CDRs and three light chain CDRs of region SEQ ID NO: 1021.

116. The antibody, (a) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 4 and 171, a CDR-H2 comprising at least one of SEQ ID NOs: 338 and 505, and a CDR-H3 comprising SEQ ID NO: 672; Ｈ and V comprising CDR-L1 comprising SEQ ID NO:839, CDR-L2 comprising SEQ ID NO:844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ ; (b) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 9 and 176, a CDR-H2 comprising at least one of SEQ ID NOs: 343 and 510, and a CDR-H3 comprising SEQ ID NO: 677; Ｈ and V comprising CDR-L1 comprising SEQ ID NO:839, CDR-L2 comprising SEQ ID NO:844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ or (c) a V comprising a CDR-H1 comprising at least one of SEQ ID NOs: 45 and 212, a CDR-H2 comprising at least one of SEQ ID NOs: 379 and 546, and a CDR-H3 comprising SEQ ID NO: 713; Ｈ and V comprising CDR-L1 comprising SEQ ID NO:839, CDR-L2 comprising SEQ ID NO:844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ 116. The isolated antibody of any of claims 95 to 115, comprising:

117. the antibody comprises a CDR-H1 comprising at least one of SEQ ID NOs: 4 and 171, a CDR-H2 comprising at least one of SEQ ID NOs: 338 and 505, and a CDR-H3 comprising SEQ ID NO: 672; Ｈ and V comprising CDR-L1 comprising SEQ ID NO: 839, CDR-L2 comprising SEQ ID NO: 844, and CDR-L3 comprising SEQ ID NO:

849. Ｌ 117. The isolated antibody of any of claims 95 to 116, comprising:

118. 118. The isolated antibody of any of claims 95-117, wherein the variant has 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitution.

119. 119. The isolated antibody of claim 118, wherein the amino acid substitutions are conservative amino acid substitutions.

120. 118. The isolated antibody of any of claims 95-117, wherein the variant has 90%, 95%, 96%, 97%, 98%, or 99% sequence identity.

121. An isolated antibody that specifically binds to ROR1, comprising a V selected from SEQ ID NOs: 854-1020. Ｈ region and a V selected from SEQ ID NOs: 1021 to 1026 Ｌ and a second antibody having a region and a region corresponding to said first antibody.

122. 122. The isolated antibody of claim 121, wherein the isolated antibody inhibits binding of a second antibody to ROR1 by at least 50%, or the second antibody inhibits binding of the isolated antibody to ROR1 by at least 50%.

123. When the antibody associates with human ROR1 at 25°C, it binds approximately 9.17 x 10 ４ M －１ × seconds －１ ~Approx. 5.94×10 ６ M －１ × seconds －１ No.K ａ 123. The isolated antibody of any of claims 95 to 122, having the following structure:

124. When the antibody dissociates from human ROR1 at 25°C, it has a binding affinity of approximately 1.01 x 10 －４ seconds －１ ~about 0.05 seconds －１ No.K ｄ 124. The isolated antibody of any one of claims 95 to 123, having the following structure:

125. When the antibody binds to human ROR1 at 25°C, it has a binding activity of approximately 1.39 x 10 －１０ M ~ approx. 1.01 x 10 －７ K of M Ｄ 125. The isolated antibody of any of claims 95 to 124, having the following structure:

126. 126. The isolated antibody of any of claims 95-125, wherein the antibody comprises at least one constant region domain.

127. 127. The isolated antibody of claim 126, wherein the constant region comprises a sequence selected from SEQ ID NOs: 1027-1029.

128. 128. The isolated antibody of any of claims 95 to 127, wherein the antibody is a monoclonal antibody.

129. 129. The isolated antibody of any of claims 95-128, wherein the antibody is IgA, IgD, IgE, IgG, or IgM.

130. 130. The isolated antibody of any of claims 95-129, wherein the antibody is a humanized antibody or a human antibody.

131. 131. The isolated antibody of any of claims 95-130, wherein the antibody is aglycosylated.

132. 132. The isolated antibody of any one of claims 95 to 131, wherein the antibody is an antibody fragment.

133. The antibody fragment may be an Fv fragment, an Fab fragment, or an F(ab') ２ 133. The isolated antibody of claim 132, wherein the antibody is selected from a Fab' fragment, a scFv (sFv) fragment, and a scFv-Fc fragment.

134. 134. The isolated antibody of claim 133, wherein the antibody is an scFv fragment.

135. A kit comprising an antibody conjugate according to any one of claims 1 to 94 or an isolated antibody according to any one of claims 95 to 134, and instructions for use.

136. 136. The kit of claim 135, wherein the antibody conjugate or isolated antibody is lyophilized.

137. 137. The kit of claim 136, further comprising a liquid for reconstitution of the lyophilized antibody conjugate or isolated antibody.

138. A polynucleotide encoding the antibody of any one of claims 95 to 134.

139. A vector comprising the polynucleotide of claim 138.

140. A recombinant host cell comprising the vector of claim 139.

141. 141. The host cell of claim 140, selected from a bacterial cell, a fungal cell, and a mammalian cell.

142. 142. The host cell of claim 141, wherein the host cell is selected from an E. coli cell, a Saccharomyces cerevisiae cell, and a CHO cell.

143. 140. A cell-free expression reaction comprising the vector of claim 139.

144. A pharmaceutical composition comprising the antibody conjugate of any of claims 1 to 94 or the isolated antibody of any of claims 95 to 134, and a pharmaceutically acceptable carrier.

145. 134. A pharmaceutical composition comprising: (a) the antibody conjugate of any one of claims 1 to 94 or the isolated antibody of any one of claims 95 to 134; (b) one or more additional active agents; and (c) a pharmaceutically acceptable carrier.

146. 146. The pharmaceutical composition of claim 145, wherein the one or more additional active agents are one or more checkpoint inhibitors.

147. 147. The pharmaceutical composition of claim 146, wherein the one or more checkpoint inhibitors are a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, or a TIM-3 inhibitor.

148. The pharmaceutical composition of claim 147, wherein the one or more checkpoint inhibitors are a PD-1 inhibitor or a PD-L1 inhibitor.

149. 149. The pharmaceutical composition of claim 148, wherein the one or more PD-1 or PD-L1 inhibitors are small molecule blockers of the PD-1 or PD-L1 pathway.

150. The pharmaceutical composition of claim 148, wherein the one or more PD-1 or PD-L1 inhibitors are antibodies that inhibit PD-1 or PD-L1 activity.

151. The one or more PD-1 or PD-L1 inhibitors are selected from the group consisting of CA-170, BMS-8, BMS-202, BMS-936558, CK-301, AUNP12, avelumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, AMP-224, MEDI0680 / AMP-514, PDR001, and semi- Primab, TSR-042, tislelizumab / BGB-A317, CK-301, BMS-936559, camrelizumab, sintilimab, toripalimab, genolimuzumab, A167, MGA012, PF-06801591, LY3300054, FAZ053, PD-11, CX-072, BGB-A333, BI 754091, JNJ-63723283, AGEN2034, CA-327, CX-188, STI-A1110, JTX-4014, (LLY)AM0001, CBT-502, FS118, XmAb20717, XmAb23104, AB122, KY1003, RXI-762, PRS-33, ALPN-202, TSR-075, MCLA-145, MGD013, and MGD019.

152. 146. The pharmaceutical composition of claim 145, wherein the one or more additional active agents are one or more PARP inhibitors.

153. 153. The pharmaceutical composition of claim 152, wherein the one or more PARP inhibitors are selected from olaparib, rucaparib, niraparib, and talazoparib.

154. 154. The pharmaceutical composition of claim 153, wherein the one or more PARP inhibitors is olaparib.

155. 154. A method of reducing cell proliferation in a subject in need thereof, comprising administering to said subject an effective amount of the antibody conjugate of any of claims 1-94, or the isolated antibody of any of claims 95-134, or the pharmaceutical composition of any of claims 144-154.

156. 154. A method of treating or preventing a disease or condition in a subject in need thereof, said method comprising administering to said subject an effective amount of the antibody conjugate of any of claims 1-94, or the isolated antibody of any of claims 95-134, or the pharmaceutical composition of any of claims 144-154.

157. 154. A method of diagnosing a disease or condition in a subject in need thereof, said method comprising administering to said subject an effective amount of the antibody conjugate of any of claims 1-94, or the isolated antibody of any of claims 95-134, or the pharmaceutical composition of any of claims 144-154.

158. 154。 A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of an antibody conjugate of any of claims 1-94, or an isolated antibody of any of claims 95-134, or a pharmaceutical composition of any of claims 144-154, and administering to the subject one or more additional active agents.

159. 159. The method of claim 158, wherein an effective amount of the antibody conjugate of any of claims 1 to 94, or the isolated antibody of any of claims 95 to 134, or the pharmaceutical composition of any of claims 144 to 154, and one or more additional active agents are administered sequentially.

160. 159. The method of claim 158, wherein an effective amount of the antibody conjugate of any of claims 1 to 94, or the isolated antibody of any of claims 95 to 134, or the pharmaceutical composition of any of claims 144 to 154, and one or more additional active agents are administered simultaneously.

161. 161. The method of any of claims 158-160, wherein the one or more additional active agents are one or more checkpoint inhibitors.

162. 162. The method of claim 161, wherein the one or more checkpoint inhibitors are a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, or a TIM-3 inhibitor.

163. 163. The method of claim 162, wherein the one or more checkpoint inhibitors is a PD-1 inhibitor or a PD-L1 inhibitor.

164. 164. The method of claim 163, wherein the one or more PD-1 or PD-L1 inhibitors are small molecule blockers of the PD-1 or PD-L1 pathway.

165. 164. The method of claim 163, wherein the one or more PD-1 or PD-L1 inhibitors are antibodies that inhibit PD-1 or PD-L1 activity.

166. The one or more PD-1 or PD-L1 inhibitors are selected from the group consisting of CA-170, BMS-8, BMS-202, BMS-936558, CK-301, AUNP12, avelumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, AMP-224, MEDI0680 / AMP-514, PDR001, and semi- Primab, TSR-042, tislelizumab / BGB-A317, CK-301, BMS-936559, camrelizumab, sintilimab, toripalimab, genolimuzumab, A167, MGA012, PF-06801591, LY3300054, FAZ053, PD-11, CX-072, BGB-A333, BI 754091, JNJ-63723283, AGEN2034, CA-327, CX-188, STI-A1110, JTX-4014, (LLY)AM0001, CBT-502, FS118, XmAb20717, XmAb23104, AB122, KY1003, RXI-762, PRS-33, ALPN-202, TSR-075, MCLA-145, MGD013, and MGD019.

167. 161. The method of any of claims 158-160, wherein the one or more additional active agents are one or more PARP inhibitors.

168. 168. The method of claim 167, wherein the one or more PARP inhibitors are selected from olaparib, rucaparib, niraparib, and talazoparib.

169. 169. The method of claim 168, wherein the one or more PARP inhibitors is olaparib.

170. 170. The method of any one of claims 155 to 169, wherein the disease or condition is cancer.

171. 170. The method of any one of claims 155 to 169, wherein the disease or condition is a blood cancer.

172. 170. The method of any one of claims 155 to 169, wherein the disease or condition is solid tumor cancer.

173. 170. The method of any one of claims 155 to 169, wherein the disease or condition is colon cancer.

174. 170. The method of any one of claims 155 to 169, wherein the disease or condition is breast cancer.

175. The method of claim 174, wherein the breast cancer is triple-negative breast cancer.

176. The method of claim 175, wherein the triple-negative breast cancer is resistant to a PARP inhibitor.

177. The method of claim 175 or 176, wherein the triple-negative breast cancer is BRCA1 / 2 wild-type triple-negative breast cancer.

178. The method of claim 175 or 176, wherein the triple-negative breast cancer is BRCA1 / 2 mutant triple-negative breast cancer.

179. 170. The method of any one of claims 155 to 169, wherein the disease or condition is ovarian cancer.

180. 170. The method of any one of claims 155 to 169, wherein the disease or condition is cervical cancer.

181. 170. The method of any one of claims 155 to 169, wherein the disease or condition is lung cancer.

182. 170. The method of any one of claims 155 to 169, wherein the disease or condition is head and neck cancer.

183. 170. The method of any one of claims 155 to 169, wherein the disease or condition is renal cell carcinoma.

184. 170. The method of any one of claims 155 to 169, wherein the disease or condition is endometrial cancer.

185. The method of any one of claims 155 to 169, wherein the disease or condition is a ROR1-expressing cancer.

186. 154。 A method of treating or alleviating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the antibody conjugate of any of claims 1-94 or the isolated antibody of any of claims 95-134, or the pharmaceutical composition of any of claims 144-154, wherein the effective amount of the antibody conjugate of any of claims 1-94 or the isolated antibody of any of claims 95-134, or the pharmaceutical composition of any of claims 144-154 treats cancer by activating anti-tumor or protective immunity.

187. 154. A method of reducing the size of a tumor in a subject in need thereof, comprising administering to said subject an effective amount of the antibody conjugate of any of claims 1-94, or the isolated antibody of any of claims 95-134, or the pharmaceutical composition of any of claims 144-154.

188. 188. The method of claim 187, wherein the size of the tumor is reduced by at least 25%.

189. 188. The method of claim 187, wherein the size of the tumor is reduced by at least 50%.

190. 1. A method for diagnosing cancer in a subject in need thereof, comprising: a) administering to said subject an effective amount of an antibody conjugate according to any of claims 1 to 94 or an isolated antibody according to any of claims 95 to 134, or a pharmaceutical composition according to any of claims 144 to 154, wherein the antibody drug conjugate according to any of claims 1 to 94, the isolated antibody according to any of claims 95 to 134, or the antibody drug conjugate comprised in the pharmaceutical composition according to any of claims 144 to 154 optionally comprises a label; and b) detecting the antibody drug conjugate or detecting the label contained in the antibody drug conjugate The method comprising:

191. 1. A method of diagnosing cancer in a subject in need thereof, comprising detecting expression of ROR1 in a cell or tissue, a) administering to said subject an effective amount of an antibody conjugate according to any of claims 1 to 94 or an isolated antibody according to any of claims 95 to 134, or a pharmaceutical composition according to any of claims 144 to 154, wherein the antibody drug conjugate according to any of claims 1 to 94, the isolated antibody according to any of claims 95 to 134, or the antibody drug conjugate comprised in the pharmaceutical composition according to any of claims 144 to 154 optionally comprises a label; and b) detecting the antibody drug conjugate or detecting the label contained in the antibody drug conjugate The method comprising:

192. 1. A method for diagnosing cancer in a subject in need thereof, comprising: a) detecting the expression of ROR1 in cells or tissues of the subject; and b) administering to said subject an effective amount of an antibody conjugate according to any of claims 1 to 94 or an isolated antibody according to any of claims 95 to 134, or a pharmaceutical composition according to any of claims 144 to 154. The method comprising:

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