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, such as antibody drug conjugates, having binding specificity for receptor tyrosine kinase orphan receptor 1 (ROR1) and isoforms and homologues thereof, and to compositions, including pharmaceutical compositions, comprising the antibodies or antibody conjugates. Also provided are 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.

Description

Cross - Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 357,442, filed Jun. 30, 2022; U.S. Provisional Application No. 63 / 389,741, filed Jul. 15, 2022; U.S. Provisional Application No. 63 / 382,262, filed Nov. 3, 2022; U.S. Provisional Application No. 63 / 487,706, filed Mar. 1, 2023; U.S. Provisional Application No. 63 / 489,926, filed Mar. 13, 2023; and U.S. Provisional Application No. 63 / 495,635, filed Apr. 12, 2023. Each of these applications is incorporated by reference in its entirety for all purposes. Technical Field

[0002] Provided herein are antibodies and antibody conjugates (e.g., antibody - drug conjugates) that have binding specificity for receptor tyrosine kinase orphan receptor 1 (ROR1), and compositions (including pharmaceutical compositions) comprising the antibody or antibody conjugate. Also provided herein are methods of generating the antibodies and conjugates, and methods of using the antibody or conjugate and compositions for therapy. The antibodies, conjugates, and compositions can be used in: methods of treating and preventing cell proliferation and cancer, e.g., by activating anti - tumor immunity; methods of detecting cell proliferation and cancer; and methods of diagnosing cell proliferation and cancer. The antibodies, conjugates, and compositions can also be used in methods of treating, preventing, detecting, and diagnosing autoimmune diseases, infectious diseases, and inflammatory disorders. Background Art

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

[0004] Recently, it has been shown that ROR1 is expressed on cancer cells, including ovarian cancer cells, and cancer stem cells. Zhang et al., 2014, Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America] 111:17266-71. Treatment with an ROR1-specific monoclonal antibody inhibits the development of ovarian cancer cells, and ROR1 has been considered as a target for cancer therapeutic agents. See ibid.

[0005] There is a need for improved methods of targeting and / or modulating ROR1 activity. Given the specific expression of ROR1 in cancer cells and tumor stem cells, there is a need for improved therapeutic agents that can specifically target cells and tissues that express or overexpress ROR1. Antibody conjugates against ROR1 can be used to deliver a therapeutically or diagnostically effective payload moiety to target cells expressing ROR1 for the treatment or diagnosis of such diseases. SUMMARY OF THE INVENTION

[0006] Provided herein are antibodies that selectively bind ROR1. In some embodiments, the antibody binds human ROR1. In some embodiments, the antibody also binds homologs of human ROR1.

[0007] In some embodiments, the antibody comprises the illustrative CDRs provided in this disclosure, V H or V L sequences, or variants thereof. In some aspects, the variant is a variant having one or more conservative amino acid substitutions. In some aspects, the variant has sequence identity with one or more of the illustrative sequences.

[0008] Compositions and kits comprising the antibody are also provided. In some embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition can be used. In some embodiments, the pharmaceutical composition is a composition for parenteral administration.

[0009] This 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 of purifying and / or quantifying ROR1.

[0010] In some embodiments, the antibody is used to treat a disease or disorder. In some aspects, the disease or disorder is selected from cancer, autoimmune diseases, and infections.

[0011] Antibody conjugates that selectively bind to the receptor tyrosine kinase orphan receptor 1 (ROR1) are also provided herein. The antibody conjugate comprises an antibody that binds to ROR1 linked to one or more payload moieties. The antibody can be directly linked to the payload by a covalent bond or indirectly linked to the payload through a linker. The ROR1 antibodies, as well as useful payload moieties and useful linkers, are described in detail herein.

[0012] In another aspect, a composition comprising the antibody conjugate is provided. In some embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition can be used. In some embodiments, the pharmaceutical composition is a composition for parenteral administration. In a further aspect, kits comprising the antibody conjugate or the pharmaceutical composition are provided herein.

[0013] In another aspect, methods of using the anti-ROR1 antibody conjugate are provided herein. 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 disorder. In some aspects, the disease or disorder is selected from cancer, autoimmune diseases, and infections. In certain embodiments, the anti-ROR1 antibody conjugate treats the disease or disorder, such as cancer, by activating anti-tumor immunity or protective immunity.

[0014] In some embodiments, the antibody conjugate binds to human ROR1. In some embodiments, the antibody conjugate also binds to homologs of human ROR1. In some aspects, the antibody conjugate also binds to homologs of cynomolgus monkey and / or mouse receptor ROR1.

[0015] These and other embodiments of the invention and many of its features are described in more detail in conjunction with the following text and the drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 A comparison of the Kabat and Chothia numbering systems for CDR-H1 is provided. Adapted from Martin A.C.R. (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In R. Kontermann and S. Dübel (Eds.), Antibody Engineering, Vol. 2 (pp. 33-51). Springer-Verlag, Berlin Heidelberg.

[0017] Figures 2 - 6 An alignment of VH sequences (SEQ ID NOs: 854-1020) from the variant antibodies provided herein is provided. CDRs according to Chothia are highlighted and CDRs according to Kabat are boxed.

[0018] Figure 7 An alignment of VL sequences (SEQ ID NOs: 1021-1026) from trastuzumab and the variant antibodies provided herein is provided. CDRs according to Chothia are highlighted and CDRs according to Kabat are underlined.

[0019] Figures 8A - 8C ELISA binding curves of selected heavy chains with three different light chains are provided.

[0020] Figures 9A - 9H Kinetic screening results of selected heavy chains with four different light chains are provided.

[0021] Figure 10A A comparison of formulation buffers for conjugate 46 at 4 °C is provided. Figure 10B A comparison of formulation buffers for conjugate 46 at 25 °C and 37 °C is provided. Figure 10C A comparison of formulation buffers for conjugate 47 at 4 °C is provided. Figure 10D A comparison of formulation buffers for conjugate 47 at 25 °C and 37 °C is provided.Figure 10E The HPLC-SEC results of conjugate 46 in 5x freeze / thaw cycles are provided. Figure 10F The HPLC-SEC results of conjugate 47 in 5x freeze / thaw cycles are provided. Figure 10G The protein concentration results of conjugate 46 in 5x freeze / thaw cycles are provided. Figure 10H The protein concentration results of conjugate 47 in 5x freeze / thaw cycles are provided. Figure 10I and Figure 10J The SEC monomer % maintained at 4 °C for 3 weeks with increasing protein concentration is provided.

[0022] Figure 11A The calculated DAR of conjugate 47 after 7 days is provided. Figure 11B The calculated DAR of conjugate 46 after 7 days is provided. Figure 11C The calculated DAR of conjugate 48 after 7 days is provided. Figure 11D The calculated DAR of conjugate 50 after 7 days is provided. Figure 11E The deconvoluted mass spectrometry of aROR1 ADC samples from the in vivo linker payload stability study of conjugate 46 is provided. Figure 11F The deconvoluted mass spectrometry of aROR1 ADC samples from the in vivo linker payload stability study of conjugate 47 is provided. Figure 11G The deconvoluted mass spectrometry of aROR1 ADC samples from the in vivo linker payload stability study of conjugate 48 is provided. Figure 11H The deconvoluted mass spectrometry of aROR1 ADC samples from the in vivo linker payload stability study of conjugate 50 is provided.

[0023] Figure 12A and Figure 12B It is shown that conjugates 46 and 47 show effective cell killing against ROR1-positive Ntera-2 cells, while the anti-GFP antibody conjugated with LP3 or LP4 shows no detectable cell killing against Ntera-2 cells. Figure 12C and Figure 12D It is shown that the cell killing activity of both conjugates 46 and 47 is inhibited in the presence of 1 μM unconjugated anti-ROR1 antibody 2188-D04.

[0024] Figure 13A-C provided the MDA-MB-231 tumor growth curves in response to treatment with four weekly doses (qwx4) of ROR1-targeting ADC, at doses ranging from (11A) 2 mg / kg to (11B) 5 mg / kg. (11C) Scatter plot of individual tumor volumes on day 42 post-treatment (when control tumors reached the study endpoint). Arrows indicate the days of dosing. On day 42, tumor volumes were statistically analyzed compared to the vehicle group using one-way ANOVA and Dunnett's multiple comparison test. 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.

[0025] Figure 14A -C provided the MDA-MB-231 tumor growth curves in response to treatment with four weekly doses (qwx4) of ROR1-targeting ADC, at doses ranging from (12A) 2 mg / kg to (12B) 5 mg / kg. (12C) Scatter plot of individual tumor volumes on day 43 post-treatment (when control tumors reached the study endpoint). Arrows indicate the days of dosing. On day 43, tumor volumes were statistically analyzed compared to the vehicle group using one-way ANOVA and Dunnett's multiple comparison test. 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.

[0026] Figure 15A -C provided the MDA-MB-231 tumor growth curves in response to treatment with three weekly doses (qwx3) of ROR1-targeting ADC, at doses ranging from (13A) 2 mg / kg to (13B) 5 mg / kg. (13C) Scatter plot of individual tumor volumes on day 37 post-treatment (when control tumors reached the study endpoint). Arrows indicate the days of dosing. On day 37, tumor volumes were statistically analyzed compared to the vehicle group using one-way ANOVA and Dunnett's multiple comparison test. 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.

[0027] Figure 16A-C provides tumor growth curves of MDA-MB-231 in response to treatment with ROR1-targeting ADC (14A) conjugate 49 and (14B) conjugate 46 at four weekly doses (qwx4), at dose ranges of 1 mg / kg to 5 mg / kg. (14C) Scatter plot of individual tumor volumes on Day 29 of the study (when control tumors reached the study endpoint). Arrows indicate days of dosing. On Day 29 of the study, tumor volumes were statistically analyzed compared to the vehicle group using one-way ANOVA and Dunnett's multiple comparison test. 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 plots are presented as individual values or mean ± SEM.

[0028] Figure 17A -D provides tumor growth curves of H1975 in response to treatment with ROR1-targeting ADC (15A) conjugate 46, (15B) conjugate 47, and (15C) conjugate 44 at two weekly doses (qwx2), at dose ranges of 1 mg / kg to 10 mg / kg. (15D) Scatter plot of individual tumor volumes on Day 14 of the study (when control tumors reached the study endpoint). Arrows indicate days of dosing. On Day 14 of the study, tumor volumes were statistically analyzed compared to the vehicle group using one-way ANOVA and Dunnett's multiple comparison test. A probability of less than 5% (p<0.05) was considered significant. **=p<0.01. All plots are presented as individual values or mean ± SEM.

[0029] Figure 18A -I provides PDX tumor growth curves in different NSCLC PDx models in response to treatment with up to five weekly doses (qwx5) of ROR1-targeting ADC conjugates 46, conjugate 47, and conjugate 49 dosed at 10 mg / kg. Arrows indicate days of dosing. All plots are presented as mean ± SEM.

[0030] Figure 19A -D provides PDX tumor growth curves in different TNBC PDx models in response to treatment with up to three weekly doses (qwx3) of conjugate 46 dosed at 5 mg / kg and twenty-eight daily doses (qdx28) of olaparib dosed at 50 mg / kg. Arrows indicate days of dosing of conjugate 46; dashed lines indicate days of dosing of olaparib. All plots are presented as mean ± SEM.

[0031] Figure 20A Provides calreticulin expression in Ntera-2 cells after treatment with conjugate 46 or irinotecan compared to isotype controls of the antibody alone and conjugate 46.

[0032] Figure 20B Provided is the release of HMGB1 in Ntera-2 cells after treatment with conjugate 46 or irinotecan, compared to isotype controls of the individual antibody and conjugate 46.

[0033] Figure 21A Provided is the percentage of viable target cells in Ntera-2 cells after treatment with conjugate 46 or irinotecan, compared to isotype controls of the individual antibody and conjugate 46.

[0034] Figure 21B The figure shows monocyte activation in Ntera-2 cells after treatment with conjugate 46 or irinotecan, compared to isotype controls of the individual antibody and conjugate 46.

[0035] Figure 21C The figure shows the percentage of calreticulin on the cell surface of Ntera-2 cells after treatment with conjugate 46 or irinotecan, compared to isotype controls of the individual antibody and conjugate 46. Calreticulin surface expression was measured as a percentage compared to untreated cells.

[0036] Figures 22A - 22F Provided is ( Figure 22A ) the proportion of total T cells, ( Figure 22B ) CD4 + T cells, ( Figure 22C ) CD8 + T cells, ( Figure 22D ) and tumor-associated macrophages (TAMs), ( Figure 22E ) the median fluorescence intensity (MFI) of CD80 on TAMs, and ( Figure 22F ) arginase 1 + (Arg1 + ) bar graphs of the proportion of TAMs in the tumors of mice treated with vehicle or 10 mg / kg conjugate 46 (qwx2) and / or 8 mg / kg anti-PD-1 (q3dx3). All figures are presented as individual values and mean ± SEM. Detailed Description 1. Definitions

[0037] Unless otherwise defined, all technical terms, symbols, and other scientific terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In some instances, for clarity and / or for ease of reference, terms with commonly understood meanings are defined herein, and the inclusion of these definitions herein should not be construed as representing a difference from that commonly understood in the art. The techniques and procedures described or cited herein are generally well known to those of ordinary skill in the art and are typically employed using conventional methods, such as, for example, the widely adopted molecular cloning methods described in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Procedures involving the use of commercially available kits and reagents are generally carried out according to the protocols and conditions defined by the manufacturer, unless otherwise noted, as appropriate.

[0038] As used herein, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural referents.

[0039] The term “about” indicates and encompasses the indicated value and ranges above and below that value. In certain embodiments, the term “about” indicates the specified value ±10%, ±5%, or ±1%. In certain embodiments, the term “about” indicates the specified value ± one standard deviation of that value.

[0040] The term “combinations thereof” includes every possible combination of the elements referred to by that term.

[0041] The terms “ROR1” and “receptor tyrosine kinase-like orphan receptor 1” are used interchangeably herein. ROR1 also has synonyms, including neurotrophic tyrosine kinase, receptor-related 1, and dJ537F10.1, such as NTRKR1. Unless otherwise noted, these terms include any variants, isotypes, and species homologs of human ROR1 that are naturally expressed by cells or expressed by cells transfected with ROR1 or the ROR1 gene. The ROR1 protein includes, for example, human ROR1 (SEQ ID NO:1). In some embodiments, the ROR1 protein includes cynomolgus monkey ROR1 (SEQ ID NO:2). In some embodiments, the ROR1 protein includes murine ROR1 (SEQ ID NO:3).

[0042] The term "immunoglobulin" refers to a class of structurally related proteins that typically comprise two pairs of polypeptide chains: one pair of light chains (L) and one pair of heavy chains (H). In a "complete immunoglobulin", all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology, 7th ed., Chapter 5 (2013), Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically has a heavy chain variable region (V H ) and a heavy chain constant region (C H ). The heavy chain constant region typically contains three domains, abbreviated as C H1 , C H2 , and C H3 . Each light chain typically has a light chain variable region (V L ) and a light chain constant region. The light chain constant region typically contains one domain, abbreviated as C L .

[0043] The term "antibody" describes a type of immunoglobulin molecule and is used herein in its broadest sense. Antibodies specifically include complete antibodies (e.g., complete immunoglobulins) and antibody fragments. An antibody contains at least one antigen-binding domain. An example of an antigen-binding domain is an antigen-binding domain formed by a V H -V L dimer. A "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", as described herein, is an antibody that specifically binds to ROR1 or ROR1. In some embodiments, the antibody binds to the extracellular domain of ROR1.

[0044] The V H and V L regions can be further subdivided into hypervariable regions ("hypervariable regions (HVR)"; also known as "complementary determining regions" (CDR)), which are interspersed with more conserved regions. The more conserved regions are called framework regions (FR). Each V H and V LGenerally includes three CDRs and four FRs, arranged in the following order (from the N-terminus to the C-terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The CDRs participate 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, Maryland, which is incorporated herein by reference in its entirety.

[0045] Based on the sequence of the constant domain, the light chain from any vertebrate species can be assigned to one of two types, which are called κ and λ.

[0046] The heavy chain 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 as α, δ, ε, γ, and μ, respectively. The IgG and IgA classes are further divided into subclasses based on differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0047] The amino acid sequence boundaries of the CDRs can be determined by those skilled in the art using any of a variety of known numbering schemes, including those described by: Kabat et al., supra ("Kabat" numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 ("Chothia" numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 ("Contact" numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 ("IMGT" numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 ("AHo" numbering scheme), each of which is incorporated herein by reference in its entirety.

[0048] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 identified by the Kabat and Chothia schemes. For CDR-H1, residue numbers are provided using the Kabat and Chothia numbering schemes. Table 1. Residues in CDRs according to the Kabat and Chothia numbering schemes. * When numbered using the Kabat numbering convention, the C-terminus of CDR-H1 varies between H32 and H34, depending on the length of the CDR, as Figure 1 shown.

[0049] Unless otherwise indicated, the numbering scheme used herein to identify a particular CDR is the Kabat / Chothia numbering scheme. When the residues covered by the two numbering schemes are different (e.g., CDR-H1 and / or CDR-H2), the numbering scheme is designated as Kabat or Chothia. For convenience, CDR-H3 is sometimes referred to as Kabat or Chothia herein. However, this does not imply that there are no differences in the sequences, and those skilled in the art can easily confirm whether the sequences are the same or different by examining the sequences.

[0050] CDRs can be specified, for example, using antibody numbering software such as Abnum, which is available at www.bioinf.org.uk / abs / abnum / and is described in Abhinandan and Martin, Immunology, 2008, 45:3832 - 3839, which is incorporated herein by reference in its entirety.

[0051] When referring to residues in the constant region of an antibody heavy chain, the "EU numbering scheme" is typically used (e.g., as reported in Kabat et al., supra). Unless otherwise indicated, the EU numbering scheme is used to refer to residues in the constant region of the antibody heavy chain described herein.

[0052] "Antibody fragment" includes a portion of a full antibody, such as the antigen-binding region or variable region of a full antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’) 2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0053] An "Fv" fragment contains a non-covalently linked dimer of a heavy chain variable domain and a light chain variable domain.

[0054] The "Fab" fragment contains, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (C H1 ) of the heavy chain. The Fab fragment can be produced, for example, by recombinant methods or by pepsin digestion of the full-length antibody.

[0055] The "F(ab’) 2 " fragment contains two Fab' fragments linked by a disulfide bond near the hinge region. The F(ab’) 2 fragment can be produced, for example, by recombinant methods or by pepsin digestion of the intact antibody. The F(ab’) fragment can be dissociated, for example, by treatment with β-mercaptoethanol.

[0056] The "single-chain Fv" or "sFv" or "scFv" antibody fragment contains the V H domain and the V L domain. The V H and V L are typically linked by a peptide linker. See Plückthun A. (1994). In some embodiments, the linker is SEQ ID NO:1034. In some embodiments, the linker is SEQ ID NO:1035. Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies [Pharmacology of Monoclonal Antibodies] Volume 113 (pp. 269-315). Springer-Verlag [Springer-Verlag], New York, incorporated herein by reference in its entirety.

[0057] The "scFv-Fc" fragment contains an scFv attached to an Fc domain. For example, the Fc domain can be linked to the C-terminus of the scFv. The Fc domain can be after V H or V L , depending on the orientation of the variable domains in the scFv (i.e., V H -V L or V L -V H ). Any suitable Fc domain known in the art or described herein can be used. In some cases, the Fc domain contains the IgG1 Fc domain. In some embodiments, the IgG1 Fc domain contains SEQ ID NO:1027 or a portion thereof. SEQ ID NO:1027 provides the C H1 , C H2 and C H3 sequences.

[0058] The term "monoclonal antibody" refers to an antibody derived from a substantially homogeneous population of antibodies. A substantially homogeneous population of antibodies comprises antibodies that are substantially similar and bind to one or more identical epitopes, except for variants that may typically arise during the production of monoclonal antibodies. Such variants generally occur only in minor amounts. Monoclonal antibodies are typically obtained by methods that include selecting a single antibody from a plurality of antibodies. For example, the selection process can be to select a unique clone from a plurality of clones (e.g., a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones). The selected antibody can be further modified, e.g., 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.

[0059] 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.

[0060] A "humanized" form of a non-human antibody is a chimeric antibody that contains the minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by 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 having the desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues of the donor antibody. A humanized antibody can also contain residues not found in the recipient antibody or the donor antibody. Such modifications can be made to further refine antibody function. For more 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 by reference in its entirety.

[0061] A "human antibody" is an antibody having an amino acid sequence corresponding to an amino acid sequence of an antibody produced by a human or a human cell, or an antibody derived from a non-human source that utilizes a human antibody library or human antibody-encoding sequences (e.g., obtained from a human source or redesigned). Human antibodies specifically exclude humanized antibodies.

[0062] "Isolated antibody" refers to an antibody that has been separated and / or recovered from the components of its natural environment. Components of the natural environment can include enzymes, hormones, and other protein or non-protein materials. In some embodiments, the isolated antibody is purified to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence, for example, by using a spinning cup sequencer. In some embodiments, the isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or non-reducing conditions, where detection is by Coomassie blue or silver staining. Isolated antibodies include in situ antibodies within recombinant cells because at least one component of the antibody's natural environment is absent. In some aspects, the isolated antibody is prepared by at least one purification step.

[0063] 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 as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight. In some embodiments, the isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by volume.

[0064] "Affinity" refers to the total strength of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity, which reflects the 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can be expressed by the dissociation constant (K D ). Affinity can be measured by conventional methods known in the art, including those described herein. For example, surface plasmon resonance (SPR) technology, such as an instrument, can be used to determine affinity. In some embodiments, the affinity is determined at 25°C.

[0065] With respect to the binding of an antibody to a target molecule, the terms "specifically bind," "specifically binds to," "specifically directed against," "selectively binds," and "selectively directed against" a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean a binding that is significantly different from non-specific or non-selective interactions. For example, specific binding can be measured by determining the binding of a molecule compared to its binding to a control molecule. Specific binding can also be determined by competition with a control molecule that mimics the antibody binding site on the target. In such a case, if the binding of the antibody to the target is competitively inhibited by the control molecule, specific binding is indicated.

[0066] As used herein, the term "kd ” (sec -1 ) refers to the dissociation rate constant of a specific antibody-antigen interaction. This value is also referred to as the k off value.

[0067] As used herein, the term "k a " (M -1 × sec -1 ) refers to the association rate constant of a specific antibody-antigen interaction. This value is also referred to as the k on value.

[0068] As used herein, the term "K D " (M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction. K D = k d / k a .

[0069] As used herein, the term "K A " (M -1 ) refers to the association equilibrium constant of a specific antibody-antigen interaction. K A = k a / k d .

[0070] An "affinity matured" antibody is an antibody that has one or more alterations in one or more CDRs or FRs, which result in an improvement in the affinity of the antibody for its antigen as compared to the parental antibody that does not have the one or more alterations. In one embodiment, the affinity matured antibody has a nanomolar or picomolar affinity for the target antigen. A variety of methods known in the art can be used to generate affinity matured antibodies. For example, Marks et al. (Bio / Technology, 1992, 10:779-783, incorporated herein by reference in its entirety) describe affinity maturation by V H and V L domain shuffling. Random mutagenesis of CDR and / or framework residues is described, for example, in Barbas et al. (Proc. Nat. Acad. Sci. U.S.A., 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.

[0071] When used in the context of two or more antibodies, the terms "compete" or "cross-compete" mean that the two or more antibodies compete to bind to an antigen (e.g., receptor tyrosine kinase orphan receptor 1, or ROR1). In one exemplary assay, ROR1 is coated on a plate and allowed to bind a first antibody, after which a second labeled antibody is added. If the presence of the first antibody reduces the binding of the second antibody, then the antibodies compete. In another exemplary assay, a first antibody is coated on a plate and allowed to bind to the antigen, and then a second antibody is added. The term "compete" also includes combinations of antibodies where one antibody reduces the 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 the binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0072] The term "epitope" refers to a portion of an antigen that is capable of specifically binding to an antibody. Epitopes typically consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural features as well as specific charge features. The difference between conformational and non-conformational epitopes is the loss of binding to the former but not the latter in the presence of a denaturing solvent. An epitope can include amino acid residues that directly participate in binding and other amino acid residues that do not directly participate in binding. Known techniques for epitope determination can be used to determine the epitope that binds to an antibody, such as testing the binding of an antibody to ROR1 variants with different point mutations.

[0073] The "identity" percentage 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 the amino acid residues in the reference sequence after sequence alignment and introduction of gaps (if necessary) to obtain the maximum percentage of sequence identity. Alignment for the purpose of determining the percentage amino acid sequence identity can be achieved in various ways within the skill in the art, e.g., 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 the appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment over the full length of the sequences being compared.

[0074] "Conservative substitution" or "conservative amino acid substitution" refers to the replacement of an amino acid with an amino acid that is chemically or functionally similar. Conservative substitution tables providing analogous amino acids are well known in the art. A polypeptide sequence having such substitutions is referred to as a "conservatively modified variant". Such conservatively modified variants are a complement of polymorphic variants, interspecies homologs, and alleles, and are not excluded therefrom. By way of example, the amino acid groups provided in Tables 2-4 are considered to be conservative substitutions for one another in some embodiments. Table 2. Selected amino acid groups that are considered to be conservative substitutions for one another in certain embodiments. Acidic residue D and E Basic residue K, R and H Hydrophilic uncharged residue S, T, N and Q Aliphatic uncharged residue G, A, V, L and I Non - polar uncharged residue C, M and P Aromatic residue F, Y and W Residue containing alcohol group S and T Aliphatic residue I, L, V and M Cycloalkenyl - related residue F, H, W and Y Hydrophobic residue A, C, F, G, H, I, L, M, R, T, V, W and Y Negatively charged residue D and E Polar residue C, D, E, H, K, N, Q, R, S and T Positively charged residue H, K and R Small residue A, C, D, G, N, P, S, T and V Very small residue A, G and S Residue involved in turn formation A, C, D, E, G, H, K, N, Q, R, S, P and T Flexible residue Q, T, K, S, G, P, D, E and R Table 3. Additional selected amino acid groups that are considered to be conservative substitutions for one another in certain embodiments. Group 1 A, S and T Group 2 D and E Group 3 N and Q Group 4 R and K Group 5 I, L and M Group 6 F, Y and W Table 4. Further selected amino acid groups that are considered to be conservative substitutions for one another in certain embodiments. Group A A and G Group B D and E Group C N and Q Group D R, K and H Group E I, L, M, V Group F F, Y and W Group G S and T Group H C and M

[0075] 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. An antibody produced by making one or more conservative substitutions of amino acid residues in a parental antibody is referred to as a "conservatively modified variant".

[0076] The term "payload" refers to the molecular moiety 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.

[0077] "Triple-negative breast cancer" (TNBC) refers to breast cancer characterized by negative estrogen receptor, negative progesterone receptor, and negative human epidermal growth factor receptor 2 (HER2-negative). TNBC can be BRCA1 / 2 wild-type or BRCA1 / 2 mutant. The determination of the negative status of estrogen, progesterone, and Her2 / neu expression can be readily determined by those skilled in the art, for example, according to currently accepted guidelines. For example, the guidelines developed by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) are widely accepted. ASCO / CAP recommends detection by immunohistochemistry (IHC) or in situ hybridization (ISH) techniques. In addition, if a single test (or all tests) performed on a tumor sample shows the following, the cancer is Her2-negative: (a) IHC negative, IHC 1+, or IHC 0, or (b) ISH negative using single-probe ISH or dual-probe ISH. Those skilled in the art will recognize that the triple-negative cancers described herein do not include any cancers with obvious histopathological inconsistencies as observed by pathologists. Wolff, A C et al J Clin Oncol. [Journal of Clinical Oncology] November 1, 2013: 31(31): 3997-4013. If, in the presence of evidence that the sample can express ER or PR (visible positive internal control), <1% of the tumor cell nuclei are immunoreactive, the cancer is ER-negative or PR-negative.

[0078] "PARP inhibitor resistance" refers to a decrease in the effectiveness of a PARP inhibitor in treating, curing, or improving triple-negative breast cancer in a subject. In certain embodiments, prolonged exposure to one or more PARP inhibitors results in PARP inhibitor resistance.

[0079] As used herein, the term "therapeutically effective amount" or "effective amount" refers to the amount of an antibody, antibody conjugate, or composition that is effective in treating a disease or disorder when administered to a subject. In some embodiments, the therapeutically effective amount or effective amount refers to the amount of an antibody, antibody conjugate, or composition that is effective in preventing or improving a disease or disease progression, or causing symptom improvement when administered to a subject. The "therapeutically effective amount" can vary depending in particular on the compound, the disease or disorder and its severity, and the age, weight, etc. of the subject being treated.

[0080] As used herein, the term "growth inhibition" (e.g., with respect to cells, such as tumor cells) is intended to include any measurable decrease in cell growth (e.g., tumor cell growth) when in contact with an anti-ROR1 antibody or antibody conjugate as described herein, compared to the growth of the same cells not in contact with the anti-ROR1 antibody. In some embodiments, growth can be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99% or 100%. The decrease in cell growth can occur through a variety of mechanisms, including but not limited to antibody internalization, apoptosis, necrosis, and / or effector function-mediated activity.

[0081] In some of the chemical structures shown herein, certain substituents, chemical groups, and atoms are depicted with a curved / wavy line intersecting one or more bonds (e.g., ) to indicate the atom through which the substituent, chemical group, and atom are bonded. For example, in some structures, such as but not limited to the curved / wavy line represents an atom in the backbone of the conjugate or linker-payload structure to which the depicted chemical entity is bonded. In some structures, such as but not limited to the curved / wavy line represents an atom in the antibody or antibody fragment and an atom in the backbone of the conjugate or linker-payload structure to which the depicted chemical entity is bonded.

[0082] Spiro compounds depicted with overlapping rings indicate that the rings can be bonded at any vertex. For example, in the spiro group the two rings can be bonded at any one of the three available vertex atoms in either ring.

[0083] When referring to the compounds provided herein, unless otherwise specified, the following terms have the following meanings. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. If a term in this document has more than one definition, the definition in this section shall prevail unless otherwise stated.

[0084] "Alkoxy" and "alkoxyl" refer to the group -OR″, where R″ is alkyl or cycloalkyl. In certain embodiments, alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.

[0085] As used herein, the term "alkoxyamine" refers to the group -alkylene-O-NH 2 , where alkylene is as defined herein. In some embodiments, the alkoxyamine group can react with an aldehyde to form an oxime residue. Examples of alkoxyamine groups include -CH2 CH 2 -O-NH 2 、 -CH 2 -O-NH 2 and -O-NH 2 。

[0086] As used herein, unless otherwise specified, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group contains from one to ten carbon atoms (i.e., C 1 to C 10 alkyl). In certain embodiments, the alkyl is a lower alkyl, such as C 1-6 alkyl, etc. In certain embodiments, the alkyl group is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-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 by, for example, one, two, or three groups independently selected from the following: halogen (e.g., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I)), alkyl, -CN, -NO 2 , amido, -C(O)-, -C(S)-, ester, carbamate, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, dialkylamino, haloalkyl, hydroxy, amino, alkylamino, and alkoxy. In some embodiments, the alkyl is unsubstituted.

[0087] As used herein, unless otherwise specified, the term "alkylene" refers to a divalent alkyl as defined herein. "Substituted alkylene" refers to a substituted alkylene as described herein for alkyl. In some embodiments, the alkylene is unsubstituted.

[0088] "Alkenyl" refers to an olefinically unsaturated hydrocarbon group which, in certain embodiments, has up to about 11 carbon atoms or 2 to 6 carbon atoms (e.g., "lower alkenyl"), the olefinically unsaturated hydrocarbon group may be straight-chain or branched, and has at least one or one to two olefinically unsaturated sites. "Substituted alkenyl" refers to a substituted alkenyl as described herein for alkyl.

[0089] "Alkenylene" refers to a divalent alkenyl as defined herein. Lower alkenylene is, for example, C 2 -C 6 -alkenylene.

[0090] "Alkynyl" refers to an alkynyl unsaturated hydrocarbon group. In certain embodiments, the alkynyl unsaturated hydrocarbon group has up to about 11 carbon atoms or 2 to 6 carbon atoms (e.g., "lower alkynyl"), and the alkynyl unsaturated hydrocarbon group can be straight-chain or branched-chain and has at least one or one to two alkynyl unsaturated sites. Non-limiting examples of alkynyl groups include acetylene (-C≡CH), propargyl (-CH 2 C≡CH), etc. "Substituted alkynyl" refers to a substituted alkynyl as described herein for alkyl.

[0091] "Alkynylene" refers to a divalent alkynyl as defined herein. Lower alkynylene is, for example, C 2 -C 6 -alkynylene.

[0092] "Amino" refers to -NH 2 2.

[0093] As used herein, the term "alkylamino", unless otherwise specified, refers to the group -NHR", where R" is, for example, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle, C 1-10 haloalkyl, etc. In certain embodiments, alkylamino is C 1-6 alkylamino.

[0094] As used herein, the term "dialkylamino" herein, unless otherwise specified, refers to the group -NR″R″, where each R″ is independently C 1-10 alkyl as defined herein. In certain embodiments, dialkylamino is, for example, di-C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle, C 1-10 haloalkyl, etc.

[0095] As used herein, the term "aryl", unless otherwise specified, refers to phenyl, biphenyl or naphthyl. The term includes substituted and unsubstituted moieties. An aryl group may be substituted with any of the moieties described, 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., fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate and phosphonate, where each moiety is independently unprotected or protected as needed, 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 where the aryl in arylamino and aryloxy substituents is not further substituted.

[0096] As used herein, the term "arylamino", unless otherwise specified, refers to an -NR′R″ group, where R′ is hydrogen or C 1 -C 6 -alkyl; and R″ is aryl as defined herein.

[0097] As used herein, the term "arylene", unless otherwise specified, refers to a divalent aryl group as defined herein.

[0098] As used herein, the term "aryloxy", unless otherwise specified, refers to an -OR group, where R is aryl as defined herein.

[0099] "Alkylarylene" refers to an arylene group as defined herein, where the aromatic ring is substituted with one or two alkyl groups. "Substituted alkylarylene" refers to an alkylarylene as defined herein, where the arylene group is further substituted as defined herein for aryl.

[0100] "Arylalkylene" refers to -CH 2 -arylene-, -arylene-CH 2 - or -CH 2 -arylene-CH 2 - groups, where arylene is as defined herein. "Substituted arylalkylene" refers to an arylalkylene as defined herein, where the arylalkylene group is substituted as defined herein for aryl.

[0101] "Carboxyl" or "carboxy" refers to -C(O)OH or -COOH.

[0102] As used herein, the term "cycloalkyl", unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group can be saturated, and / or bridged, and / or unbridged, and / or a fused bicyclic group and / or a spiro bicyclic group. In certain embodiments, the cycloalkyl group includes from three to ten carbon atoms (i.e., C 3 to C 10 cycloalkyl). In some embodiments, the cycloalkyl has from three to fifteen carbons (C 3-15 ), from three to ten carbons (C 3-10 ), from three to seven carbons (C 3-7 ), or from three to six carbons (C 3 -C 6 )(i.e., "lower cycloalkyl"). In certain embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, or adamantyl. Exemplary "cycloalkyl" or "carbocyclic" includes cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. "Cycloalkyl" or "carbocyclic" includes 3- to 10-membered monocycles, 6- to 12-membered bicycles, and 6- to 12-membered bridged rings. Each ring of a bicyclic cycloalkyl or carbocyclic can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Bicyclic cycloalkyl or carbocyclic includes any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic, provided that the valency permits. Bicyclic cycloalkyl or carbocyclic includes any combination of ring sizes, such as, for example, a 4-5 fused ring system, a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, a 5-7 fused ring system, a 6-7 fused ring system, a 5-8 fused ring system, and a 6-8 fused ring system. 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 spiro 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.

[0103] 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, where the two rings have at least one common atom (e.g., two common atoms). The bicyclic rings can be fused, bridged or spiro. Bicyclic ring systems include bicyclic aliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatic groups, bicyclic aryl and bicyclic heteroaryl.

[0104] The term "bridged bicyclic system" refers to a bicyclic heterocycloaliphatic ring system or a bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornyl, 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]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-dioxatricyclo[3.3.1.0 3,7 nonyl. The bridged bicyclic ring system can optionally be substituted with one or more substituents which are, for example, 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, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylthio, thioxo, urea, thiourea, sulfamoyl, sulfonamide, oxo or carbamoyl.

[0105] The term "spiro bicyclic ring system" refers to a bicyclic heterocycloaliphatic ring system or a bicyclic cycloaliphatic ring system in which two or three rings are joined together by a common atom. Spiro compounds depicted with overlapping rings indicate that the rings can be bonded at any vertex. For example, in a spiro ring group the two rings can be bonded at any one of the three available vertex atoms in either ring.

[0106] As used herein, the term "subcycloalkyl" refers to a divalent cycloalkyl as defined herein. In certain embodiments, the subcycloalkyl group is subcyclopropyl subcyclobutyl subcyclopentyl subcyclohexyl subcycloheptyl and the like. Lower subcycloalkyl refers to C 3 -C 6 -subcycloalkyl.

[0107] As used herein, the term "cycloalkylalkyl", unless otherwise specified, refers to an alkyl group as defined herein substituted with one or two cycloalkyls as defined herein.

[0108] As used herein, the term "ester" refers to -C(O)OR or -COOR, where R is an alkyl as defined herein.

[0109] As used herein, the term "fluorene" refers to where any one or more carbons bearing one or more hydrogens may be substituted with a chemical functional group as described herein.

[0110] As defined herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (e.g., in certain embodiments one, two, three, four or five) independently selected halogen atoms.

[0111] The term "heteroalkyl" refers to an alkyl as defined herein in which one or more carbon atoms are replaced by heteroatoms. As used herein, "heteroalkenyl" refers to an alkenyl as defined herein in which one or more carbon atoms are replaced by heteroatoms. As used herein, "heteroalkynyl" refers to an alkynyl as defined herein in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally 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., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino, and alkoxy. In some embodiments, the heteroalkyl group may contain one, two, three, or four heteroatoms. Those skilled in the art will recognize that 4-membered heteroalkyls typically may contain one or two heteroatoms, 5- or 6-membered heteroalkyls typically may contain one, two, or three heteroatoms, and 7- to 10-membered heteroalkyls typically may contain one, two, three, or four heteroatoms.

[0112] As used herein, the term "heteroalkylene" 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.

[0113] The term "heterocyclyl" refers to a monovalent, monocyclic or polycyclic non-aromatic ring system, wherein one or more of the ring atoms are heteroatoms independently selected from oxygen (O), sulfur (S) and nitrogen (N) (e.g., wherein the nitrogen or sulfur atom may optionally be oxidized and the nitrogen atom may optionally be quaternized) and the remaining ring atoms of the non-aromatic ring are carbon atoms. In certain embodiments, the heterocyclyl is a monovalent, monocyclic or polycyclic fully saturated ring system. In certain embodiments, the heterocyclyl group has three to twenty, three to fifteen, three to ten, three to eight, four to seven, four to eleven or five to six ring atoms. The heterocyclyl can be attached to the core structure at any heteroatom or carbon atom, thereby producing a stable compound. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused and / or bridged bicyclic groups and / or spiro bicyclic group ring systems, and wherein the nitrogen or sulfur atom may optionally be oxidized, and / or the nitrogen atom may optionally be quaternized. In some embodiments, the heterocyclyl radicals include but are not limited to 2,5-diazabicyclo[2.2.2]octyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, tetrahydroquinolinyl and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl may also be optionally substituted as described herein. In certain embodiments, the heterocyclyl is substituted with one, two or three groups independently selected from: halogen (e.g., fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)), alkyl, haloalkyl, hydroxy, amino, alkylamino and alkoxy. In some embodiments, the heterocyclyl group may contain one, two, three or four heteroatoms. Those skilled in the art will recognize that 4-membered heterocyclyl generally may contain one or two heteroatoms, 5- or 6-membered heterocyclyl generally may contain one, two or three heteroatoms, and 7- to 10-membered heterocyclyl generally may contain one, two, three or four heteroatoms.In some embodiments, the "heterocycloalkyl" or "heterocycle" radical includes, but is not limited to, 2,5-diazabicyclo[2.2.2]octyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. Non-limiting examples of bridged heterocycloalkyl or heterocyclic groups include, but are not limited to, 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-dioxatricyclo[3.3.1.0. 3,7 nonyl. Non-limiting examples of spiro 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.

[0114] "Heterocycloalkylidene" refers to a divalent heterocycloalkyl as defined herein.

[0115] The term "heteroaryl" refers to a monovalent, monocyclic aromatic group and / or a polycyclic aromatic group, wherein at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen within the ring. Each ring of the heteroaryl group may 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 each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has five to twenty, five to fifteen, or five to ten ring atoms. The 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, furyl, 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, benzofuryl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furanopyridyl, imidazopyridyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuryl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thiophenopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuryl, piperidinyl, phenanthrolinyl, phenanthridinyl, phenopyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl may also be optionally substituted as described herein. "Substituted heteroaryl" is a heteroaryl substituted as defined for aryl.

[0116] The term "heteroarylene" refers to a divalent heteroaryl as defined herein. "Substituted heteroarylene" is a heteroarylene substituted as defined for aryl.

[0117] As used herein, the term "protecting group", 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 or for other purposes. A 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).

[0118] "Pharmaceutically acceptable salts" refers to any salts of the compounds provided herein which retain their biological properties and are non-toxic or otherwise not undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counterions well known in the art. Such salts include, but are not limited to, (1) acid addition salts formed with 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, cyclopentanepropionic 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, ethanesulfonic acid, 1,2-ethanedisulfonic 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, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is either (a) replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion), or an alkali metal or alkaline earth metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide or ammonia); or (b) coordinated with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, including but not limited to ammonia, methylamine, dimethylamine, diethylamine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, etc.

[0119] Pharmaceutically acceptable salts further include, for example but not limited to, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, etc., and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, such as hydrochloride and hydrobromide salts, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentanepropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, 1,2-ethanedisulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (besylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-toluenesulfonates, camphorates, camphorsulfonates, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylates, glucoheptonates, 3-phenylpropionates, trimethylacetates, tert-butylacetates, dodecylsulfates, glucuronates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexylsulfamates, quininates, muconates, etc.

[0120] The terms “substantially free of” or “substantially absent from” with respect to a composition mean that the composition contains at least 85% or 90% by weight, in certain embodiments 95%, 98%, 99% or 100% by weight; or in certain embodiments, 95%, 98%, 99% or 100% of the designated enantiomer or diastereomer of the compound. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of one of the two enantiomers. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of one of the two diastereomers. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of enantiomers (i.e., the compound is not a racemic or 50:50 mixture of the compound).

[0121] Similarly, the term “isolated” with respect to a composition means that the composition comprises at least 85%, 90%, 95%, 98% or 99% to 100% by weight of the compound, the remainder comprising other chemical species, enantiomers or diastereomers.

[0122] “Solvate” means a compound or a salt thereof provided herein, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0123] "Isotopic composition" refers to the amounts of each isotope present for a given atom, and "natural isotopic composition" refers to the isotopic composition or abundance of the naturally occurring isotopes of a given atom. Atoms having their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise indicated, atoms of a compound described herein are intended to represent any stable isotope of that atom. For example, unless otherwise indicated, when a position is specifically designated as hydrogen (H), that position is understood to have hydrogen in its natural isotopic composition.

[0124] "Isotope enrichment" refers to the percentage of incorporation of a specific isotope that replaces the natural isotope abundance at a given atom in a molecule. For example, 1% deuterium (D) enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the designated position. Since the natural abundance of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotope enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0125] "Isotope enrichment" refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. "Isotope enrichment" can also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom.

[0126] As used herein, "alkyl", "alkylene", "alkylamino", "dialkylamino", "cycloalkyl", "aryl", "arylene", "alkoxy", "amino", "carboxyl", "heterocycloalkyl", "heteroaryl", "heteroarylene", "carboxyl", and "amino acid" groups optionally contain deuterium (D) at one or more positions where a hydrogen (H) atom is present, and wherein the deuterium composition of the one or more atoms is different from the natural isotopic composition.

[0127] Also as used herein, "alkyl", "alkylene", "alkylamino", "dialkylamino", "cycloalkyl", "aryl", "arylene", "alkoxy", "amino", "carboxyl", "heterocycloalkyl", "heteroaryl", "heteroarylene", "carboxyl", and "amino acid" groups optionally contain carbon-13 ( 13 C) in an amount different from the natural isotopic composition.

[0128] The term "macromolecule" or "macromolecular moiety" refers to a protein, peptide, antibody, nucleic acid, carbohydrate, or other macromolecule composed of polymeric monomers. They include peptides having two or more residues, or ten or more residues. In certain embodiments, the macromolecule has a mass of at least 1000 Da. In certain embodiments, the macromolecule has at least 1000 atoms. In certain embodiments, the macromolecule can be modified. For example, a protein, peptide, or antibody can be modified with one or more carbohydrates and / or small molecule therapeutic compounds.

[0129] The term "amino acid" refers to the twenty 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. Natural amino acids also include citrulline. Naturally encoded amino acids include post-translational variants of the twenty-two 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 unnatural (or non-natural) or synthetic α-, β-, γ-, or δ-amino acids, and includes, but is not limited to, the amino acids found in proteins, namely, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, and histidine. In certain embodiments, the amino acid is in the L-configuration. In certain embodiments, the amino acid is in the D-configuration. Alternatively, the amino acid can be alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, threonyl, cysteyl, tyrosyl, asparaginyl, glutaminyl, aspartyl, glutaryl, lysyl, arginyl, histidyl, β-alanyl, β-valyl, β-leucyl, β-isoleucyl, β-prolyl, β-phenylalanyl, β-tryptophanyl, β-methionyl, β-glycyl, β-seryl, β-threonyl, β-cysteyl, β-tyrosyl, β-asparaginyl, β-glutaminyl, β-aspartyl, β-glutaryl, β-lysyl, β-arginyl, or β-histidyl. Unnatural amino acids are not protein amino acids or their post-translationally modified variants. Specifically, the term unnatural amino acid refers to an amino acid that is not one of the twenty common amino acids or pyrrolysine or selenocysteine, or a post-translationally modified variant thereof.

[0130] The term "conjugate" or "antibody conjugate" refers to a compound or drug moiety linked to one or more macromolecular moieties as described herein. The macromolecular moiety is as defined herein or any macromolecule considered suitable by one of ordinary 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 macromolecular moiety via a covalent bond, or the compound or drug moiety can be indirectly linked to the macromolecular moiety via a linker. Typically, the linker is covalently bonded to the macromolecular moiety and also covalently bonded to the compound or drug moiety.

[0131] "pAMF", "pAMF residue", or "pAMF mutation" refers to a variant phenylalanine residue added or substituted into a polypeptide (i.e., para-azidomethyl-L-phenylalanine).

[0132] The term "linker" refers to a molecular moiety capable of forming at least two covalent bonds. Typically, the linker is capable of forming at least one covalent bond with a macromolecular moiety and at least another covalent bond with a compound or drug moiety. In certain embodiments, the linker can form more than one covalent bond with the macromolecular moiety. In certain embodiments, the linker can form more than one covalent bond with the compound or drug moiety, or can form covalent bonds with more than one compound or drug moiety. After the linker forms a bond with the macromolecular moiety, the compound or drug moiety, or both, the remaining structure (i.e., the linker residue(s) after one or more covalent bonds are formed ("linker residue")) can still be referred to herein as the "linker". The term "linker precursor" refers to a linker having one or more reactive groups capable of forming covalent bonds with a macromolecule, or a compound or drug moiety, or both. In the context of giving how the term linker is used, one of ordinary skill in the art will understand whether "linker" means a linker precursor having one reactive group, a linker precursor having more than one reactive group, a linker residue covalently bonded to a macromolecule, a linker residue covalently bonded to a compound or drug moiety, and / or a linker residue covalently bonded to a macromolecule and covalently bonded to a compound or drug moiety. In some embodiments, the linker is a cleavable linker. For example, a cleavable linker can be a linker released by a bio-unstable or enzymatic function, which can be or can not be engineered. In some embodiments, the linker is a non-cleavable linker. For example, a non-cleavable linker can be a linker released after degradation of the macromolecular moiety.

[0133] As used herein, the term "EC 50 " refers to the dose, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximum expression of a particular response induced, stimulated, or enhanced by the particular test compound.

[0134] As used herein, and unless otherwise specified, the term "IC 50"refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximum such response in the determination of a measurement response.

[0135] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "subjects" refer to animals, such as mammals, including non - primates (e.g., cows, pigs, horses, cats, dogs, rats, mice, camels, birds, goats and sheep) and primates (e.g., monkeys, such as cynomolgus monkeys, chimpanzees and humans), and in certain embodiments, refer to humans. In certain embodiments, the subject is a farm animal (e.g., horse, cow, pig, etc.) or a pet (e.g., 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 with an antibody or antibody conjugate provided herein. In some embodiments, the disease is gastric cancer, colorectal 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.

[0136] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any one or more agents that can be used in the treatment or prevention of a disorder or one or more of its symptoms. In certain embodiments, the term "therapeutic agent" includes an antibody or antibody conjugate provided herein. In certain embodiments, a therapeutic agent is an agent known to be useful for, or that has been or is currently being used for, the treatment or prevention of a disorder or one or more of its symptoms.

[0137] "Treating" or "treatment" of any disease or disorder in certain embodiments refers to ameliorating the disease or disorder present in a subject. In another embodiment, "treating" or "treatment" includes ameliorating at least one physical parameter that may not be perceptible to the subject. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or both. In yet another embodiment, "treating" or "treatment" includes delaying or preventing the onset of a disease or disorder, or delaying or preventing the recurrence of a disease or disorder. In yet another embodiment, "treating" or "treatment" includes reducing or eliminating a disease or disorder, or delaying the progression of a disease or disorder or one or more of its symptoms, or reducing the severity of a disease or disorder or one or more of its symptoms.

[0138] As used herein, the terms "preventive agent" and "plural preventive agents" refer to any one or more agents that can be used in the prevention of a disorder or one or more of its symptoms. In certain embodiments, the term "preventive agent" includes the compounds, drug moieties or conjugates provided herein. In certain other embodiments, the term "preventive agent" does not refer to the compounds, drug moieties or conjugates provided herein. For example, a preventive agent is an agent known to be useful for, or that has been or is currently being used for, preventing or impeding the onset, development, progression and / or severity of a disorder.

[0139] As used herein, the phrase "preventive effective amount" refers to an amount of a therapy (e.g., a preventive agent) that is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a disorder or to enhance or improve one or more preventive effects of another therapy (e.g., another preventive agent).

[0140] In some of the chemical structures shown herein, certain substituents, chemical groups and atoms are depicted with a curve / wavy line / wavy dash (e.g., ) that intersects with one or more bonds to indicate the atom through which the substituent, chemical group and atom are bonded. For example, in some structures, such as but not limited to the curve / wavy line / wavy dash represents an atom in the backbone of the conjugate, compound or drug moiety structure to which the depicted chemical entity is bonded. In some structures, such as but not limited to the curve / wavy line / wavy dash represents an atom in a macromolecule as well as an atom in the backbone of the conjugate, compound or drug moiety structure to which the depicted chemical entity is bonded.

[0141] As used herein, an illustration showing a substituent bonded to a cyclic group (e.g., an aromatic, heteroaromatic, fused ring and saturated or unsaturated cycloalkyl or heterocycloalkyl) via a bond between ring atoms is intended to mean that, unless otherwise specified, the cyclic group can be substituted with the substituent at any ring position in the cyclic group or on any ring in a fused ring group according to the techniques set forth herein or known in the art to which this disclosure pertains. For example, the group wherein the subscript q is an integer from 0 to 4 and wherein the position of the substituent R 1 is generally described, i.e., not directly attached to any vertex of the bond-line structure, i.e., a particular ring carbon atom, including among others where the substituent R 1 is bonded to a particular ring carbon atom, non-limiting examples of the group:

[0142] As used herein, the term "carbocyclic" herein, unless otherwise specified, refers to a saturated, unsaturated or aromatic ring in which the ring atoms are carbon. In certain embodiments, the carbocyclic group can be saturated, and / or bridged, and / or unbridged, and / or a fused bicyclic group and / or a spiro bicyclic group. In certain embodiments, the carbocyclic group comprises from three to ten carbon atoms (i.e., C 3 to C 10 carbocyclic). In some embodiments, the carboalkyl has from three to fifteen carbons (C 3-15 ), from three to ten carbons (C 3-10 ), from three to seven carbons (C 3-7 ), or from three to six carbons (C 3 -C 6 ). In certain embodiments, the carbocyclic group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl or adamantyl.

[0143] The term "heterocyclic" 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 can optionally be oxidized, and the nitrogen atom can optionally be quaternized and the remaining ring atoms of the non-aromatic ring are carbon atoms. Heterocycles include 3- to 10-membered monocycles, 6- to 12-membered bicycles and 6- to 12-membered bridged rings. In certain embodiments, the heterocycle is a monovalent, monocyclic or polycyclic fully saturated ring system. In certain embodiments, the heterocycloalkyl or "heterocyclic" group can be unsaturated, and / or bridged, and / or unbridged, and / or a fused bicyclic group, and / or a spiro bicyclic group.

[0144] The term "site-specific" refers to the modification of a polypeptide at a predetermined sequence position in the polypeptide. The modification is at a single, predictable residue of the polypeptide, with little or no variation. In certain embodiments, a modified amino acid is introduced at that sequence position, for example recombinantly or synthetically. Similarly, a moiety can be "site-specifically" linked to a residue at a specific sequence position in the polypeptide. In certain embodiments, the polypeptide can comprise more than one site-specific modification. 2. Conjugates

[0145] The present disclosure provides conjugates of antibodies against receptor tyrosine kinase orphan receptor 1 (ROR1). The conjugate comprises an ROR1 antibody covalently linked directly or indirectly through a linker to a payload. In some embodiments, the conjugate comprises an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1), the antibody is site-specifically linked to at least one payload moiety, and 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 two, three, four, five, six, seven, eight, nine, ten or more payloads.

[0146] The payload can be any payload that is considered useful by a person skilled in the art. 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 following sections and examples.

[0147] The linker can be any linker capable of forming at least one bond with the antibody and at least one bond with the payload. Useful linkers are described in the following sections and examples.

[0148] In the conjugates provided herein, the antibody can be any antibody that has binding specificity for ROR1. ROR1 can be from any species. In certain embodiments, ROR1 is a vertebrate ROR1. In certain embodiments, ROR1 is a mammalian ROR1. In certain embodiments, ROR1 is a human ROR1. In certain embodiments, ROR1 is a murine ROR1. In certain embodiments, ROR1 is a cynomolgus monkey ROR1.

[0149] In certain embodiments, the antibody against ROR1 competes for binding with the antibodies described herein. In certain embodiments, the antibody against ROR1 binds to the same epitope as the antibodies described herein.

[0150] Antibodies are typically proteins that comprise multiple polypeptide chains. In certain embodiments, the antibody is a heterotetramer comprising two identical light (L) chains and two identical heavy (H) chains. Each light chain can be linked to a heavy chain by one covalent disulfide bond. Each heavy chain can be linked to another heavy chain by one or more covalent disulfide bonds. Each heavy chain and each light chain can also have one or more intrachain disulfide bonds. As is known to those skilled in the art, each heavy chain typically comprises a variable domain (V H ), followed by a plurality of constant domains. Each light chain typically comprises a variable domain (V L ) at one end, and a constant domain. As is known to those skilled in the art, antibodies typically have selective affinity for their target molecule, i.e., an antigen.

[0151] The antibodies provided herein can have any antibody form known to those skilled in the art. They can 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.

[0152] 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 the heavy chain variable domain (V H ) described below. In certain embodiments, the antibody of the conjugate comprises the light chain variable domain (V L ) described herein. In certain embodiments, the antibody of the conjugate comprises the heavy chain variable domain (V H ) and the light chain variable domain (V L ) described herein. In certain embodiments, the antibody of the conjugate comprises the paired heavy chain variable domain and light chain variable domain (V H -V L pair).

[0153] In certain embodiments, the antibody of the conjugate comprises any of the amino acid sequences of the above-mentioned antibodies. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 10 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 9 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 8 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 7 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 6 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 5 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 4 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 3 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 2 amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned 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-mentioned amino acid sequences with up to 10 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 9 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 8 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 7 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 6 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 5 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 4 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 3 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 2 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the above-mentioned amino acid sequences with up to 1 conservative amino acid substitution.

[0154] In certain embodiments, an antibody conjugate can be formed from an antibody comprising one or more reactive groups. In certain embodiments, an antibody conjugate can be formed from an antibody comprising all naturally encoded amino acids. Those skilled in the art will recognize that several naturally encoded amino acids include reactive groups capable of conjugating to a payload or linker. These reactive groups include cysteine side chains, lysine side chains, and amino-terminal groups. In these embodiments, the antibody conjugate can comprise a payload or linker linked to a residue of the antibody reactive group. In these embodiments, the payload precursor or linker precursor comprises a reactive group capable of forming a bond with the antibody reactive group. Exemplary reactive groups include 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). Particularly useful reactive groups include maleimide and succinimide, such as N-hydroxysuccinimide, for forming bonds with cysteine and lysine side chains. Additional reactive groups include alkynes, such as strained alkynes, and azides, for forming bonds with non-natural amino acids incorporated into the antibody polypeptide chain. Other reactive groups are described in the sections and examples below.

[0155] In certain embodiments, the antibody comprises one or more modified amino acids having reactive groups as described herein. Generally, the modified amino acids are not naturally encoded amino acids. These modified amino acids can comprise reactive groups that can be used to form covalent bonds with a linker precursor or payload precursor. Those skilled in the art can use the reactive groups to link a polypeptide to any molecular entity capable of forming a covalent bond with the modified amino acid. Accordingly, provided herein are conjugates comprising an antibody comprising modified amino acid residues directly or indirectly linked to a payload through a linker. Exemplary modified amino acids are described in the sections below. Generally, the modified amino acids have reactive groups capable of forming a bond between the linker or payload and a complementary reactive group.

[0156] The non-natural amino acids are located at selected positions in the polypeptide chain of the antibody. These positions are determined to provide optimal sites for non-natural amino acid substitution. Each site is capable of bearing a non-natural amino acid with optimal structure, function, and / or method of generating the antibody.

[0157] In certain embodiments, the site-specific positions for substitution provide a stable antibody. Stability can be measured by any technique obvious to those skilled in the art.

[0158] In certain embodiments, the site-specific positions for substitution provide antibodies with optimal functional properties. For example, the antibodies may show little or no loss in binding affinity to their target antigen compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may show enhanced binding compared to antibodies without site-specific unnatural amino acids.

[0159] In certain embodiments, the site-specific positions for substitution provide antibodies that can be advantageously prepared. For example, in certain embodiments, the antibodies show advantageous properties in their synthesis methods, as described below. In certain embodiments, the antibodies may show little or no loss in yield during production compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may show enhanced yield compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may show little or no loss in tRNA repression compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may show enhanced tRNA repression during production compared to antibodies without site-specific unnatural amino acids.

[0160] In certain embodiments, the site-specific positions for substitution provide antibodies with favorable solubility. In certain embodiments, the antibodies may show little or no loss in solubility compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may show enhanced solubility compared to antibodies without site-specific unnatural amino acids.

[0161] In certain embodiments, the site-specific positions for substitution provide antibodies with favorable expression. In certain embodiments, the antibodies may show little or no loss in expression compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may show enhanced expression compared to antibodies without site-specific unnatural amino acids.

[0162] In certain embodiments, the site-specific positions for substitution provide antibodies with favorable folding. In certain embodiments, the antibodies may show little or no loss in correct folding compared to antibodies without site-specific unnatural amino acids. In certain embodiments, the antibodies may show enhanced folding compared to antibodies without site-specific unnatural amino acids.

[0163] In certain embodiments, the site-specific positions for substitution provide antibodies that can be advantageously conjugated. As described below, several unnatural amino acids have side chains or functional groups that facilitate the conjugation of the antibody to a second agent, either directly or via a linker. In certain embodiments, the antibody may exhibit enhanced conjugation efficiency compared to an antibody that does not have the same or other unnatural amino acids at other positions. In certain embodiments, the antibody may exhibit enhanced conjugation yield compared to an antibody that does not have the same or other unnatural amino acids at other positions. In certain embodiments, the antibody may exhibit enhanced conjugation specificity compared to an antibody that does not have the same or other unnatural amino acids at other positions.

[0164] 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, but is not limited thereto, including the light chain or the heavy chain. The site-specific position can be in any domain of the antibody, including any variable domain and any constant domain.

[0165] In certain embodiments, the antibodies provided herein contain one unnatural amino acid at the site-specific position. In certain embodiments, the antibodies provided herein contain two unnatural amino acids at the site-specific position. In certain embodiments, the antibodies provided herein contain three unnatural amino acids at the site-specific position. In certain embodiments, the antibodies provided herein contain more than three unnatural amino acids at the site-specific position. In certain embodiments, the antibodies provided herein contain four unnatural amino acids at the site-specific position.

[0166] In certain embodiments, each of the antibodies provided herein comprises one or more unnatural amino acids or post-translationally modified variants thereof at positions selected from the group consisting of heavy chain 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, or HC-S70 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, each of the antibodies provided herein comprises one or more unnatural amino acids or post-translationally modified variants thereof at positions selected from the group consisting of heavy chain or light chain residues HC-F404, HC-Y180, HC-F241, LC-K42, and LC-E161 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise an unnatural amino acid, or a post-translationally modified variant thereof, at position HC-F404 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise an unnatural amino acid, or a post-translationally modified variant thereof, at position HC-Y180 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise unnatural amino acids, or post-translationally modified variants thereof, at positions HC-F404 and HC-Y180 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise an unnatural amino acid, or a post-translationally modified variant thereof, at position HC-F241 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise an unnatural amino acid, or a post-translationally modified variant thereof, at position LC-K42 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise an unnatural amino acid, or a post-translationally modified variant thereof, at position LC-E161 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise unnatural amino acids, or post-translationally modified variants thereof, at positions HC-F404, HC-Y180, and LC-K42 (according to the Kabat or Chothia or EU numbering scheme). In certain embodiments, the antibodies provided herein comprise unnatural amino acids, or post-translationally modified variants thereof, at positions HC-F404, HC-Y180, LC-K42, and LC-E161 (according to the Kabat or Chothia or EU numbering scheme).In certain embodiments, the antibodies provided herein contain unnatural amino acids at positions HC-F404, HC-Y180, and HC-F241 (according to the Kabat or Chothia or EU numbering scheme), or post-translationally modified variants thereof. In certain embodiments, the antibodies provided herein contain unnatural amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42 (according to the Kabat or Chothia or EU numbering scheme), or post-translationally modified variants thereof. In certain embodiments, the antibodies provided herein contain unnatural amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42 (according to the Kabat or Chothia or EU numbering scheme), or post-translationally modified variants thereof. In these designations, HC represents a heavy chain residue and LC represents a light chain residue.

[0167] In some aspects, the present disclosure provides conjugates according to the following formula: or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or tautomer thereof, wherein: COMP is a residue of an anti-ROR1 antibody; PAY is a payload moiety; LINK is a linker; and n2 is an integer from 1 to 10, wherein COMP comprises one or more unnatural amino acids.

[0168] In certain embodiments, the present disclosure provides conjugates according to formula (C1) or (C2): or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or tautomer thereof, wherein: COMP is a residue of an anti-ROR1 antibody; PAY is a payload moiety; W 1 、W 2 、W 3 、W 4 and W 5 are each independently a single bond, absent, or a divalent attachment group; EG is absent, or is an elimination group; each RT is a release trigger group, in the backbone of formula (C1) or (C2) or bonded to EG, wherein each RT is optional; HP is a single bond, absent, or a divalent hydrophilic group; each SG is a single bond, absent, or a divalent spacer group; R is hydrogen, a terminal conjugating group, or a divalent residue of a terminal conjugating group; and n2 is an integer from 1 to 10.

[0169] In some embodiments, the conjugate according to 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. Attachment group

[0170] The attachment group facilitates the incorporation of an elimination group, a release trigger group, a hydrophobic group, a spacer group, and / or a conjugating group into the compound. Useful attachment groups are known and obvious to those skilled in the art. Examples of useful attachment groups are provided herein. In certain embodiments, the attachment group is designated as W 1 , W 2 , W 3 , W 4 or W 5 . In certain embodiments, the attachment group can comprise a divalent ketone, a divalent ester, a divalent ether, a divalent amide, a divalent amine, an alkylene, an arylene, a thioether, a disulfide, a carbonyl or a combination thereof. In certain embodiments, the attachment group can comprise -C(O)-, -O-, -C(O)NH-, -C(O)NH-alkyl-, –OC(O)NH–, –SC(O)NH–, –NH–, –NH-alkyl–, –N(CH 3 )CH 2 CH 2 N(CH 3 )–, –S–, –S-S–, –OCH 2 CH 2 O– or its reverse form (e.g., –NHC(O)–), or a combination thereof. Elimination group

[0171] The elimination group facilitates the in vivo and / or in vitro separation of the bioactive moiety of the compounds or conjugates described herein from the remainder of the compound or conjugate. The elimination group can also facilitate the separation of the bioactive moiety of the compounds or conjugates described herein that is bound to a release trigger group. For example, the elimination group and the release trigger group can react in a release reaction to release the bioactive moiety of the compounds or conjugates described herein in vivo and / or in vitro. After the release reaction is triggered by a release trigger, the elimination group cleaves the bioactive moiety or a prodrug form of the bioactive moiety and forms a stable, non-toxic entity that has no further effect on the activity of the bioactive moiety.

[0172] In certain embodiments, the elimination group is designated herein as EG. Useful elimination groups include those described above. In certain embodiments, the elimination group is: wherein R EG is selected from the group consisting of: hydrogen, alkyl, biphenyl, -CF 3 , -NO 2 , -CN, fluorine, bromine, chlorine, alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-. In each structure, the phenyl ring may be bonded to one, two, three, or in some cases four R EG groups. In the second and third structures, one of ordinary skill in the art will recognize that EG is bonded to 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, -CF 3 , alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-. In further embodiments, R EG is selected from the group consisting of: hydrogen, -NO 2 , -CN, fluorine, bromine, and chlorine. In certain embodiments, the elimination group is In certain embodiments, the elimination group is In certain embodiments, the elimination group is

[0173] In some embodiments, provided herein are conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof; wherein EG comprises a phenylene, carboxy, amine, or combinations thereof. In some embodiments, the elimination group is: wherein Z can be CH or N, and R EG is selected from the group consisting of: hydrogen, alkyl, biphenyl, -CF 3 , -NO 2 , -CN, fluorine, bromine, chlorine, alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-. In each structure, the phenyl ring may be bonded to one, two, three, or in some cases four R EGGroup binding. In the first and second structures, one of ordinary skill in the art will recognize that the EG is bonded 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, -CF 3 , alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino C(O)-. In further embodiments, R EG is selected from the group consisting of: hydrogen, -NO 2 , -CN, fluorine, bromine, and chlorine. In some embodiments, each R EG in the EG is hydrogen. In certain embodiments, the eliminator group is In certain embodiments, the eliminator group is In certain embodiments, the eliminator group is Release trigger group

[0174] The release trigger group facilitates the in vivo and / or in vitro separation of the bioactive moiety of the compounds or conjugates described herein from the remainder of the compound or conjugate. The release trigger group can also facilitate the separation of the bioactive moiety of the compounds or conjugates described herein that is bound to the eliminator group. For example, the eliminator group and the release trigger group can react in a release reaction to release the bioactive moiety of the compounds or conjugates described herein from the compound or conjugate in vivo and / or in vitro. In certain embodiments, the release trigger can act through a bio-driven reaction having high tumor:non-tumor specificity (e.g., proteolysis by an enzyme overexpressed in the tumor environment).

[0175] In certain embodiments, the release trigger group is designated herein as RT. In certain embodiments, RT is divalent and is bonded within the backbone of formula (C1). In other embodiments, RT is monovalent and is bonded to the EG as depicted above. Useful release trigger groups include those described herein. In certain embodiments, the release trigger group comprises residues of natural or unnatural amino acids or residues of sugar rings. In certain embodiments, the release trigger group is: One of ordinary skill in the art will recognize that the first structure is divalent and can be bonded within the backbone of formula (C1) or as depicted in formula (C2), and the second structure is monovalent and can be bonded to the EG as depicted in formula (C1) above. In certain embodiments, the release trigger group is In certain embodiments, the release trigger group is

[0176] In some embodiments, the release trigger group is a protease-cleavable R 1 -Val-X peptide having the following structure: wherein R 1 is H or and R 2 is CH 3 、CH 2 CH 2 CO 2 H, or (CH 2 ) 3 NHCONH 2 ; a legumain-cleavable Ala-Ala-Asn or Ala-Ala-Asp peptide having the following structure: wherein Z is OH or NH 2 ; or a β-glucuronidase-cleavable β-glucuronide having the following structure: or a Val-Lys-Gly peptide having the following structure: Those skilled in the art will recognize that is a divalent structure and can be bonded within the backbone of formula (C1) or as depicted in formula (C2). Structure is monovalent and can be bonded to EG, as depicted in formula (C1) above.

[0177] 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 group further comprises unnatural amino acids. In certain embodiments, the unnatural amino acid is according to where POLY is a polymer, such as a hydrophilic polymer. In certain embodiments, the unnatural amino acid is according to where m1 is an integer from 1 to 25, such as 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25. Hydrophilic group

[0178] Hydrophilic groups are beneficial for increasing the hydrophilicity of the compounds described herein. It is believed that the increased hydrophilicity allows for greater solubility in aqueous solutions (such as those found in biological systems). Hydrophilic groups can also act as spacer groups described in further detail herein.

[0179] In certain embodiments, the hydrophilic group is designated as HP herein. 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 is a divalent poly(ethylene glycol) according to the following formula: wherein m1 is an integer from 1 to 13, optionally from 1 to 4, optionally from 2 to 4, or optionally from 4 to 8. In certain embodiments, m1 is 4. In certain embodiments, m1 is 12. In certain embodiments, m1 is 13.

[0180] In some embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the following formula:

[0181] In some other embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the following formula:

[0182] In other embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the following formula:

[0183] In other embodiments, the hydrophilic group is a divalent poly(ethylene glycol) having the following formula:

[0184] In some embodiments, the hydrophilic group is a sulfonic acid. In some embodiments, the hydrophilic group is the side chain of sulfopropylalanine. In some embodiments, the hydrophilic group can carry a sulfonic acid presented with a chain having the following formula: In certain embodiments, the hydrophilic group is the side chain of a non-natural amino acid according to wherein m1 is an integer from 1 to 25, such as 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25. Spacer group

[0185] Spacer groups are beneficial for spacing the conjugate group from other groups of the compounds described herein. Such spacing can enable the compounds described herein to conjugate more effectively with antibodies, as well as cleave active catabolites more effectively. Spacer groups can also stabilize the conjugate group and improve the overall antibody-drug conjugate properties.

[0186] 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: In certain embodiments, the spacer group W 4 and the hydrophilic group combine to form a divalent poly(ethylene glycol) according to the following formula: wherein m1 is an integer from 1 to 13, optionally from 1 to 4, optionally from 2 to 4, or optionally from 4 to 8.

[0187] In some embodiments, SP is

[0188] In some embodiments, the divalent poly(ethylene glycol) has the following formula:

[0189] In some other embodiments, the divalent poly(ethylene glycol) has the following formula:

[0190] In other embodiments, the divalent poly(ethylene glycol) has the following formula:

[0191] In other embodiments, the divalent poly(ethylene glycol) has the following formula:

[0192] In some embodiments, the spacer group may carry a sulfonic acid presented by a chain having the following formula:

[0193] In some embodiments, the spacer group is a diamine. In some embodiments, the spacer group is according to

[0194] In some embodiments, the spacer group includes a fused ring or a spiro ring. In some embodiments, the spacer group is according to where each n a , m a , o a and p a is independently an integer selected from 1, 2, 3, 4, and 5. In some embodiments, the spacer group is according to where each n a , m a , o a and p ais an integer independently selected from 1, 2, 3, 4, and 5. In some embodiments, the spacer group is selected from the group consisting of: a conjugate group and its residue

[0195] The conjugate group facilitates the conjugation of the payloads described herein with a second compound (such as an antibody described herein). In certain embodiments, the conjugate group is designated as R herein. The conjugate group can react through any suitable reaction mechanism known to those skilled in the art. In certain embodiments, the conjugate group reacts through a [3+2] alkyne-azide cycloaddition reaction, a reverse electron demand Diels-Alder ligation reaction, a thiol-electrophile reaction, or a carbonyl-oxyamine reaction, as described in detail herein. In certain embodiments, the conjugate group includes an alkyne, a strained alkyne, a tetrazine, a thiol, a p-acetyl-phenylalanine residue, an oxyamine, a maleimide, or an azide. In certain embodiments, the conjugate group is: –N 3 or –SH; wherein R 201 is a lower alkyl. In an embodiment, R 201 is methyl, ethyl, or propyl. In an embodiment, R 201 is methyl. Additional conjugate groups are described, for example, in U.S. Patent Publication No. 2014 / 0356385, U.S. Patent Publication No. 2013 / 0189287, U.S. Patent Publication No. 2013 / 0251783, U.S. Patent No. 8,703,936, U.S. Patent No. 9,145,361, U.S. Patent No. 9,222,940, and U.S. Patent No. 8,431,558.

[0196] After conjugation, a divalent residue of the conjugate group is formed and bonded 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.

[0197] In certain embodiments, when the conjugate is formed through a [3+2] alkyne-azide cycloaddition reaction, the divalent residue of the conjugate group contains a triazole ring or a fused cyclic group containing a triazole ring. In certain embodiments, when the conjugate is formed through a strain-promoted [3+2] alkyne-azide cycloaddition (SPAAC) reaction, the divalent residue of the conjugate group is:

[0198] In certain embodiments, when forming a conjugate by a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the conjugating group comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In certain embodiments, when forming a conjugate by a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the conjugating group is:

[0199] In certain embodiments, when forming a conjugate by a thiol-maleimide reaction, the divalent residue of the conjugating group comprises a succinimidyl group and a sulfur linkage. In certain embodiments, when forming a conjugate by a thiol-maleimide reaction, the divalent residue of the conjugating group is:

[0200] In certain embodiments, the following groups are used to form a conjugate by a thiol-N-hydroxysuccinimide reaction: The reactions involved in forming the conjugate include the following steps: And the divalent residue of the resulting conjugating group is:

[0201] In certain embodiments, when forming a conjugate by a carbonyl-oxyamine reaction, the divalent residue of the conjugating group comprises the divalent residue of a non-natural amino acid. In certain embodiments, when forming a conjugate by a carbonyl-oxyamine reaction, the divalent residue of the conjugating group is:

[0202] In certain embodiments, when forming a conjugate by a carbonyl-oxyamine reaction, the divalent residue of the conjugating group comprises an oxime linkage. In certain embodiments, when forming a conjugate by a carbonyl-oxyamine reaction, the divalent residue of the conjugating group is:

[0203] In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R comprises a triazole ring. In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; R is a triazole ring or a fused cyclic group comprising a triazole ring. In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R is:

[0204] In embodiments, provided herein are conjugates according to 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 in the ring. In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R is:

[0205] In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R comprises a sulfur linkage. In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R is:

[0206] In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R comprises a divalent residue of a non-natural amino acid. In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R is:

[0207] In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein comprises an amide linkage. In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R is:

[0208] In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein comprises an oxime linkage. In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R is:

[0209] In embodiments, provided herein are conjugates according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof; wherein R is:

[0210] In embodiments, provided herein are compounds according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof; wherein COMP is a residue of any compound known to be useful for conjugation to a payload described herein and an optional linker described herein. In embodiments, provided herein are compounds according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof; wherein COMP is a residue of an antibody chain.

[0211] In one aspect, provided herein are antibody-drug conjugates comprising a payload described herein and an optional linker described herein attached to an anti-ROR1 antibody, wherein COMP is a residue of the antibody. In embodiments, provided herein are antibody-drug conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody; and R comprises a triazole ring or a fused cyclic group containing a triazole ring. In embodiments, provided herein are antibody-drug conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody; and R is:

[0212] In embodiments, provided herein are antibody-drug conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody; and R comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In embodiments, provided herein are antibody-drug conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody; and R is:

[0213] In embodiments, provided herein are antibody-drug conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R comprises a sulfur linkage. In embodiments, provided herein are antibody-drug conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R is:

[0214] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R comprises a divalent residue of a non-natural amino acid. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R is:

[0215] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R comprises an amide linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R is:

[0216] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R comprises an amide linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of a polypeptide; and R is:

[0217] In one aspect, provided herein are antibody conjugates comprising a payload described herein and optionally a linker described herein attached to an antibody according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein COMP is a residue of the antibody. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody; and R comprises a triazole ring or a fused cyclic group containing a triazole ring. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody; and R is:

[0218] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R is:

[0219] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R comprises a sulfur linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R is:

[0220] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R comprises a divalent residue of a non-natural amino acid. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R is:

[0221] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R comprises an amide linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R is:

[0222] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R comprises an oxime linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody; and R is:

[0223] In one aspect, provided herein are antibody conjugates comprising a payload described herein and optionally a linker described herein attached to an antibody chain according to formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein COMP is a residue of the antibody chain. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody chain; and R comprises a triazole ring or a fused cyclic group containing a triazole ring. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody chain; and R is:

[0224] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody chain; and R comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody chain; and R is:

[0225] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody chain; and R comprises a sulfur linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2), or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of the antibody chain; and R is:

[0226] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody chain; and R comprises a divalent residue of a non-natural amino acid. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody chain; and R is:

[0227] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody chain; and R comprises an amide linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody chain; and R is:

[0228] In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody chain; and R comprises an amide linkage. In embodiments, provided herein are antibody conjugates according to formula (C1) or (C2) or pharmaceutically acceptable salts, solvates, stereoisomers or tautomers thereof, wherein: COMP is a residue of an antibody chain; and R is: Conjugate

[0229] In embodiments, provided herein are conjugates according to any of the following formulas, wherein COMP represents a residue of an anti-ROR1 antibody and PAY represents a payload moiety:

[0230] In embodiments, provided herein are conjugates according to any of the following formulas, wherein COMP represents a residue of an anti-ROR1 antibody and PAY represents a payload moiety:

[0231] In embodiments, provided herein are conjugates according to any of the following formulas, wherein COMP represents a residue of an anti-ROR1 antibody and PAY represents a payload moiety:

[0232] In an embodiment, provided herein is a conjugate according to any one of Formulas 101a - 104b, wherein COMP represents a residue of an anti - ROR1 antibody and PAY represents a payload moiety:

[0233] In any of the foregoing 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.

[0234] In some embodiments, provided herein is an anti - ROR1 conjugate comprising a modified hemiasterlin and a linker, as described, for example, in PCT Publication No. WO 2016 / 123582. For example, the conjugate can have a structure comprising any one of Formulas 1000 - 1000b, 1001 - 1001b, 1002 - 1002b, and I - XIXb - 2, 101 - 111b, or 1 - 8b as described in PCT Publication No. WO 2016 / 123582. Examples of conjugates comprising a modified hemiasterlin and a linker are provided below.

[0235] In some embodiments, provided is a conjugate of Formula (I) or a pharmaceutically acceptable salt thereof, wherein COMP is a residue of an anti - ROR1 antibody provided herein; 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 –, where at least one of the alkylene, alkenylene or alkynylene groups in Y is substituted with one or more substituents selected from R 50 ; and where the alkylene, alkenylene or alkynylene groups in Y are optionally substituted with one or more substituents selected from R 51 ; 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, where each alkylene, alkenylene or alkynylene group in R 50 is optionally substituted with one or more substituents selected from the following: 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; R 51 is independently selected from 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 selected from -C(O)- and –N(R 10 )C(O)–; R 10 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3 - 12 - membered heterocycle, and C 1-10 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 the hexose form of a monosaccharide; D is a drug moiety; and RL is a reactive group residue.

[0236] In some embodiments, there is provided a conjugate of formula (II) or a pharmaceutically acceptable salt thereof, wherein COMP is a residue of an anti - ROR1 antibody provided herein; 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 — provided that at least one of the alkylene, alkenylene or alkynylene groups in Y is substituted by one or more substituents selected from R 50 ; 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, where each alkylene, alkenylene or alkynylene group in R 50 is optionally substituted by one or more substituents selected from: 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 selected from -C(O)- and –N(R 10 )C(O)–; R 10 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3-12 membered heterocycle and C 1-10 haloalkyl each time it appears; 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 form of a monosaccharide; D is a drug moiety; and RL is a reactive group residue.

[0237] In some embodiments, a conjugate of formula (IIA) is provided or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compound of formula (II) is according to formula (IIB) or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments of formula (I), (II), (IIA) or (IIB), L 1 is -C 1-3 alkylene-. In some embodiments, L 1 is -CH 2 -. In some embodiments of formula (I), (II), (IIA) or (IIB), L 1 is -CH 2 CH 2 -. In some embodiments, L 1 is -CH 2 CH 2 CH 2 -.

[0240] In some embodiments of formula (I), including any of the foregoing, p is 0. In some embodiments of formula (I), including any of the foregoing, p is 1.

[0241] In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 1-6 alkylene-[X 1 -C 1-6 alkylene]] n -X 1 –, wherein at least one alkylene in Y is substituted with one or more substituents selected from R 50 . In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 1-6 alkylene-[X 1 -C 1-6 alkylene]] n -, wherein at least one alkylene in Y is substituted with one or more substituents selected from R 50substituted by substituents. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 2-6 alkenylene-[X 1 -C 2-6 alkenylene] n -X 1 –, wherein at least one alkenylene in Y is substituted by one or more substituents selected from R 50 substituted by substituents. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 2-6 alkenylene-[X 1 -C 2-6 alkenylene] n -, wherein at least one alkenylene in Y is substituted by one or more substituents selected from R 50 substituted by substituents. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 2-6 alkynylene-[X 1 -C 2-6 alkynylene] n -X 1 –, wherein at least one alkynylene in Y is substituted by one or more substituents selected from R 50 substituted by substituents. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 2-6 alkynylene-[X 1 -C 2-6 alkynylene] n -, wherein at least one alkynylene in Y is substituted by one or more substituents selected from R 50 substituted by substituents. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n is 0. In some embodiments of formula (I), (II), (IIA) or (IIB), n is one. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n is two. In some embodiments, including any of the foregoing, n is three.

[0242] In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 1-4 alkylene-[X 1 -C 1-4 alkylene] n -X1 –, wherein at least one alkylene in Y is substituted by one or more substituents selected from R 50 In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n is 0. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n is one. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n is two. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n is three.

[0243] In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, 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 –, wherein at least one alkylene in Y is substituted by one or more substituents selected from R 50 In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 1-4 alkylene-X 1 -C 1-4 alkylene-X 1 -C 1-4 alkylene-X 1 -, wherein at least one alkylene in Y is substituted by one or more substituents selected from R 50 In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, Y is –X 1 -C 1-4 alkylene-X 1 -C 1-4 alkylene-X 1 –, wherein at least one alkylene in Y is substituted by one or more substituents selected from R 50 of the substituents.

[0244] In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, R 50 is –C 1-6 alkylene-X 2 -[C 1-6 alkylene] m-POLY, where R 50 Each alkylene of is optionally substituted with one or more substituents selected from the following: 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. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, R 50 is –C 1-4 alkylene-X 2 -[C 1-4 alkylene] m -POLY, where R 50 Each alkylene of is optionally substituted with one or more substituents selected from the following: 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. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, R 50 Each alkylene of is optionally substituted with one or more substituents selected from the following: halogen, -OH, -N(R 10 ), 2 , -C(O)N(R 10 ), 2 , -C(O)-, C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycle, 3- to 12-membered heterocycle, and C 1-10 Haloalkyl. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing, m is 0. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing, m is one.

[0245] In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing, R 50 is –C 2-6 Alkenylene-X 2 -[C 2-6 Alkenylene] m -POLY, wherein each alkenylene of R 50 is optionally substituted with one or more substituents selected from the following: 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. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing, m is 0. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing, m is one.

[0246] In certain embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing, R 50 is –C 2-6 Alkynylene-X 2 -[C 2-6 Alkynylene] m -POLY, wherein each alkynylene of R 50 is optionally substituted with one or more substituents selected from the following: halogen, -CN, -NO 2 , -OH, -N(R10 ) 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,a 3- to 12-membered heterocycle,and C 1-10 haloalkyl.In some embodiments of formula (I),(II),(IIA),or (IIB),including any of the foregoing,m is 0.In some embodiments of formula (I),(II),(IIA),or (IIB),including any of the foregoing,m is one.

[0247] In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), a copolymer of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(alkenyl alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), poly(sarcosine) or a combination thereof. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is polyethylene glycol (PEG). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is methoxypolyethylene glycol (mPEG). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, 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 the foregoing, POLY is poly(oxyethylated polyol). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(alkenyl alcohol). In some embodiments, including any of the foregoing, POLY is poly(vinylpyrrolidone). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(hydroxyalkyl methacrylamide). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(hydroxyalkyl methacrylate). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(saccharide). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(α-hydroxy acid). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(vinyl alcohol). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is polyphosphazene. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is polyoxazoline (POZ). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(N-acryloylmorpholine).In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is poly(sarcosine). In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is a non-peptide water-soluble polymer. In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY comprises polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG). In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, POLY is. wherein represents attachment to the remainder of the compound, and wherein n1 is an integer from 1 to 20. In certain embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is an integer between five and fifteen. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is one. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is two. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is three. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is four. In some embodiments of formula (II), (IIA) or (IIB), including any of the foregoing, n1 is five. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is six. In some embodiments of formula (I), (II), (IIA) or (IIB), n1 is seven. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is eight. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is nine. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is ten. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is eleven. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twelve. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is thirteen. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is fourteen. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is fifteen. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is sixteen. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is seventeen. In some embodiments of formula (I), (II), (IIA) or (IIB), n1 is eighteen. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is nineteen. In some embodiments of formula (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty.In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-one. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-two. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-three. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-four. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-five. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-six. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-seven. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-eight. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is twenty-nine. In some embodiments of formula (I), (II), (IIA) or (IIB), including any of the foregoing, n1 is thirty.

[0248] In certain embodiments, RL includes an alkyne, cyclooctyne, strained olefin, tetrazine, amine, methylcyclopropene, thiol, p-acetyl-phenylalanine residue, oxime, maleimide or azide. In some embodiments, RL includes an alkyne. In some embodiments, RL includes cyclooctyne. In some embodiments, RL includes a strained olefin. In some embodiments, RL includes tetrazine. In some embodiments, RL includes an amine. In some embodiments, RL includes methylcyclopropene. In some embodiments, RL includes a thiol. In some embodiments, RL includes a p-acetyl-phenylalanine residue. In some embodiments, RL includes an oxime. In some embodiments, RL includes maleimide. In some embodiments, RL includes azide. In certain embodiments, RL is selected from the group consisting of: and represents attachment to the remainder of the compound. In some embodiments, RL is and represents attachment to the remainder of the compound. In some embodiments, RL is and represents attachment to the remainder of the compound. In some embodiments, RL is and Denotes attachment to the remainder of the compound. In some embodiments, RL is and Denotes attachment to the remainder of the compound. In some embodiments, RL is and Denotes attachment to the remainder of the compound. In some embodiments, RL is wherein Denotes attachment to the remainder of the compound. In some embodiments, RL is and Denotes attachment to the remainder of the compound. In some embodiments, RL is and Denotes attachment to the remainder of the compound. In some embodiments, RL is and Denotes attachment to the remainder of the compound. In some embodiments, Su is a sugar moiety. In some embodiments, Su is a hexose form of a monosaccharide. Su can be a glucuronic acid or mannose residue. In certain embodiments, Su is wherein Denotes attachment to the remainder of the compound. In certain embodiments, Su is wherein Denotes attachment to the remainder of the compound.

[0249] In one aspect, provided herein is a conjugate of formula (III): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein L 1a is selected from Ring A is an optionally substituted bridged, fused or spiro bicyclic carbocycle, or an optionally substituted bridged, fused or spiro bicyclic heterocycle, wherein the carbocycle or heterocycle of Ring A is optionally substituted with one or more substituents selected from: 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 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Ring B is an optionally substituted N-linked bridged, fused or spiro bicyclic heterocycle, wherein ring B is optionally substituted with one or more substituents selected from the following: 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 、aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; R a and R b are independently selected from 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 an integer independently selected from 0, 1, 2, 3, 4, 5 and 6; R 1 is hydrogen or alkyl optionally substituted with one or more substituents selected from the following: 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 、aryl and heteroaryl; R 2 and R 3 are 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 -, where * represents the position where Y a is bound to RL; c is an integer selected from 1, 2, 3, 4, 5 or 6; RL is a reactive group residue; L 2 is absent or is a linker comprising a hydrophilic polymer residue; L 3 is absent, is -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)-Z-L 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)O-L 4 -Z-C(O)-(CR a R b ) a -Z-C(O)-, -AA-Z- or –(CR a R b ) a -Z-AA-C(O)-; Z is selected from -NR 2 - and -O-; AA is an amino acid residue or a peptide residue; L 4 is wherein Su is the hexose form of a monosaccharide; d is an integer independently selected from 1, 2 and 3; D is a drug moiety; COMP is a residue of an anti-ROR1 antibody; and represents attachment to the remainder of the compound.

[0250] In certain embodiments, the compound of formula (III) is the compound of formula (IIIA): or a pharmaceutically acceptable salt and / or regioisomer thereof; where the integers c, RL, R a , R b , ring B, L 2 , L 3 , D and COMP are as defined herein.

[0251] In certain embodiments, the compounds of formula (IIIA) are selected from the following: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0252] In certain embodiments, the compound of formula (III) is a compound of formula (IIIB): or a pharmaceutically acceptable salt and / or regioisomer thereof; where the integers c, RL, R a , R b , ring B, L 2 , L 3 , D and COMP are as defined herein.

[0253] In certain embodiments, the compounds of formula (IIIB) are selected from the following: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0254] In certain embodiments, the compound of formula (III) is a compound of formula (IIIC): or a pharmaceutically acceptable salt and / or regioisomer thereof; where the integer a, the integer c, RL, R a , R b , ring A, L 2 , L 3 , D, and COMP are as defined herein.

[0255] In certain embodiments, the compounds of formula (IIIC) are selected from the following: and or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0256] In certain embodiments, the compound of formula (III) is a compound of formula (IIID): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein integer a, integer c, RL, R a , R b , ring A, L 2 , L 3 , D, and COMP are as defined herein.

[0257] In certain embodiments, the compound of formula (IIID) is selected from the following: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0258] In certain embodiments, the compound of formula (III) is a compound of formula (IIIE): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein integer a, integer c, RL, R a , R b , ring B, L 3 , POLY 2 , D, and COMP are as defined herein.

[0259] In certain embodiments, the compound of formula (IIIE) is selected from the following: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0260] In certain embodiments, the compound of formula (III) is a compound of formula (IIIF): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein integer a, integer c, RL, R a , R b , ring B, L 3 , POLY 2 , D, and COMP are as defined herein.

[0261] In certain embodiments, the compound of formula (IIIF) is selected from the following: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0262] In certain embodiments, the compound of formula (III) is a compound of formula (IIIG): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein integer a, integer c, RL, R a , R b , ring A, L 3 , POLY 2 , D, and COMP are as defined herein.

[0263] In certain embodiments, the compound of formula (IIIG) is selected from the following: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0264] In certain embodiments, the compound of formula (III) is a compound of formula (IIIH): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein integer a, integer c, RL, R a , R b , ring A, L 3 , POLY 2 , D, and COMP are as defined herein.

[0265] In certain embodiments, the compound of formula (IIIH) is selected from the following: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0266] In one aspect, provided herein is a conjugate of formula (V): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein L 5 is a linker comprising a non-natural amino acid; and RL, COMP, Y a , L 2 , L 3 , and D are as defined herein.

[0267] In certain embodiments, the compound of formula (V) is a compound of formula (VA): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein RL, COMP, Y a , L 2 , L 3 and D are as defined herein.

[0268] In certain embodiments, the compound of formula (V) is a compound of formula (VB): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein integer a, integer c, RL, COMP, R a , R b , POLY 1 , AA and D are as defined herein.

[0269] In certain embodiments, the compound of formula (VB) is a compound of the following formula: or a pharmaceutically acceptable salt and / or regioisomer thereof.

[0270] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is

[0271] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is

[0272] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of is an optionally substituted 5- to 12-membered N-linked bridged, fused or spiro bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S (including N attached to the ring), where ring B is optionally substituted with one or more substituents selected from: 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 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl. In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of is an optionally substituted 5- to 12-membered N-linked spiro bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S (including N attached to the ring).

[0273] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of is selected from where m a is an integer selected from 1, 2, 3, 4 and 5; and na and o a Each is independently an integer selected from 1, 2, and 3.

[0274] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of In certain embodiments of formulas (III)-(VB), is selected from In certain embodiments of formulas (III)-(VB), is selected from In certain embodiments of formulas (III)-(VB), L 1a ring B of In certain embodiments, ring B is

[0275] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of In certain embodiments of formulas (III)-(VB), is selected from In certain embodiments of formulas (III)-(VB), is selected from In certain embodiments of formulas (III)-(VB), L 1a ring B of In certain embodiments of formulas (III)-(VB), L 1a ring B of

[0276] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of In certain embodiments of formulas (III)-(VB), is where m a is 1, 2, or 3. In certain embodiments of formulas (III)-(VB), is where m a is 1, 2, or 3. In certain embodiments of formulas (III)-(VB), is where m a is 1, 2, or 3. In certain embodiments of formulas (III)-(VB), is where m ais 1, 2 or 3.

[0277] In certain embodiments of formulas (III)-(VB), is In certain embodiments of formulas (III)-(VB), is In certain embodiments of formulas (III)-(VB), is In certain embodiments of formulas (III)-(VB), is In certain embodiments of formulas (III)-(VB), is

[0278] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a of ring B is In certain embodiments of formulas (III)-(VB), is where m a is 1, 2 or 3. In certain embodiments of formulas (III)-(VB), is where m a is 1, 2 or 3. In certain embodiments of formulas (III)-(VB), is where m a is 1, 2 or 3. In certain embodiments of formulas (III)-(VB), is where m a is 1, 2 or 3.

[0279] In certain embodiments of formulas (III)-(VB), is In certain embodiments of formulas (III)-(VB), is In certain embodiments of formulas (III)-(VB), is In certain embodiments, is In certain embodiments of formulas (III)-(VB), is

[0280] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a of ring B is

[0281] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of is selected from

[0282] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of is selected from

[0283] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is selected from where m a is an integer selected from 1, 2, 3, 4, and 5; and n a and o a are each independently an integer selected from 1, 2, and 3.

[0284] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is selected from

[0285] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring B of is selected from where X 1a , X 2a , X 3 and X 4 are independently selected from -C(R 4 ) 2 -, -NH-, -O-, and -S-, where when X 1a , X 2a and X 3 are present, at least one of X 1a -X 3 is -C(R 4 ) 2 - and when X 1a , X 2a , X 3 and X 4 are present, at least two of X 1a -X 4 are -C(R 4 ) 2 -; and R 4Independently selected from 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 4 groups on the same carbon together form an oxo group

[0286] In certain embodiments of formulas (III)-(VB), including any of the foregoing, ring B of L 1a is selected from wherein X 1a , X 2a , X 3 and X 4 are independently selected from -C(R 4 ) 2 -, -NH-, -O- and -S-, where when X 1a , X 2a and X 3 are present, at least one of X 1a -X 3 is -C(R 4 ) 2 - and when X 1a , X 2a , X 3 and X 4 are present, at least two of X 1a -X 4 are -C(R 4 ) 2 -; and R 4 is independently selected from 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 R3 ) 2 、 -C(O)OR 2 、 aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; or two R groups on the same carbon together form an oxo group. 4 Group together form an oxo group.

[0287] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a Ring A is an optionally substituted bridged, fused or spiro bicyclic carbocycle, wherein the carbocycle or heterocycle of ring A is optionally substituted with one or more substituents selected from the following: 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 、 aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl. In certain embodiments, including any of the foregoing, L 1a Ring A of is an optionally substituted C 4-12 Bridged, fused or spiro bicyclic carbocycle. In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a Ring A of is an optionally substituted C 4-12 Bridged bicyclic carbocycle. In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a Ring A of is an optionally substituted C 4-8 Bridged bicyclic carbocycle.

[0288] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a Ring A of is selected from Wherein X 1a 、 X 2a 、 X 3 And X 4 Are independently selected from -C(R 4 ) 2 -, -NH-, -O- and -S-, wherein when X 1a 、 X 2a And X 3 Are present, X 1a -X 3at least one of which is -C(R 4 ) 2 - and when X 1a 、X 2a 、X 3 and X 4 are present, at least two of X 1a -X 4 are -C(R 4 ) 2 -; X 5 is CR 4 or N; and R 4 is independently selected from 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 4 groups on the same carbon together form an oxo group.

[0289] In certain embodiments of formulas (III)-(VB), including any of the foregoing, ring A of L 1a is selected from

[0290] In certain embodiments of formulas (III)-(VB), including any of the foregoing, ring A of L 1a is selected from

[0291] In certain embodiments of formulas (III)-(VB), including any of the foregoing, ring A of L 1a is selected from

[0292] In certain embodiments of formulas (III)-(VB), including any of the foregoing, ring A of L 1a is selected from

[0293] In certain embodiments of formulas (III)-(VB), including any of the foregoing, ring A of L 1a is In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a ring A of is

[0294] In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 1a 、X 2a 、X 3 and / or X 4 is -C(R 4 ) 2 -. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 1a and X 2a are -C(R 4 ) 2 -. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 1a 、X 2a and X 3 are -C(R 4 ) 2 -. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 1a 、X 2a 、X 3 and X 4 are -C(R 4 ) 2 -. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 1a is -NH-. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 2a is NH-. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 3 is -NH-. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 4 is NH-. In certain embodiments, including any of the foregoing, X 1a is -O-. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 2a is -O-. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 3 is -O-. In certain embodiments of formulas (III)-(VB), including any of the foregoing, X 4 is -O-.

[0295] In certain embodiments of formulas (III)-(VB), including any of the foregoing, L 1a is In certain embodiments, L 1a is

[0296] In certain embodiments, including any of the foregoing, a is 0. In certain embodiments, including any of the foregoing, a is 1. In certain embodiments, including any of the foregoing, a is 2. In certain embodiments, including any of the foregoing, a is 3. In certain embodiments, including any of the foregoing, a is 4. In certain embodiments, including any of the foregoing, a is 5. In certain embodiments, including any of the foregoing, a is 6.

[0297] In certain embodiments of formulae (III)-(VB), b is 0. In certain embodiments, b is 1.

[0298] In certain embodiments of formulae (III)-(VB), b is 0 and a is 0. In certain embodiments of formulae (III)-(VB), b is 0 and a is 1. In certain embodiments of formulae (III)-(VB), b is 0 and a is 2. In certain embodiments of formulae (III)-(VB), b is 0 and a is 3. In certain embodiments of formulae (III)-(VB), b is 0 and a is 4. In certain embodiments of formulae (III)-(VB), b is 0 and a is 5. In certain embodiments of formulae (III)-(VB), b is 0 and a is 6. In certain embodiments of formulae (III)-(VB), b is 1 and a is 1. In certain embodiments of formulae (III)-(VB), b is 1 and a is 2. In certain embodiments of formulae (III)-(VB), b is 1 and a is 3. In certain embodiments of formulae (III)-(VB), b is 1 and a is 4. In certain embodiments of formulae (III)-(VB), b is 1 and a is 5. In certain embodiments of formulae (III)-(VB), b is 1 and a is 6.

[0299] In certain embodiments of formulae (III)-(VB), including any of the foregoing, R 1 is hydrogen. In certain embodiments of formulae (III)-(VB), including any of the foregoing, R 1 is unsubstituted alkyl. In certain embodiments of formulae (III)-(VB), including any of the foregoing, R 1 is methyl. In certain embodiments of formulae (III)-(VB), including any of the foregoing, R 1 is alkyl optionally substituted with one or more substituents selected from cycloalkyl, halogen, alkoxy, -CN, -NO 2 and -OH.

[0300] In certain embodiments of formulae (III)-(IVB), L5 is a linker comprising at least one amino acid selected from the group consisting of: thiopropionic acid, hydroxyproline (Hyp), β-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 is a linker comprising . In certain embodiments of formulas (III)-(IVB), L 5 is a linker comprising . In certain embodiments of formulas (III)-(IVB), L 5 is In certain embodiments of formulas (III)-(IVB), L 5 is

[0301] In certain embodiments, including any of the foregoing, R a is hydrogen and R b is selected from the group consisting of 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. In certain embodiments, including any of the foregoing, R a is hydrogen and R b is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO 2 , -OH, NH 2 , -C(O)NH 2 , -C(O)OH, aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. In certain embodiments, including any of the foregoing, R a is hydrogen and R b is selected from the group consisting of hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, NH 2 , -C(O)NH 2 , and -C(O)OH. In certain embodiments, including any of the foregoing, R a and R b are both hydrogen.

[0302] In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a is hydrogen; R b is selected from hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, -NH 2 , -C(O)NH 2 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 the foregoing, R a is hydrogen; R b is selected from hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, -NH 2 , -C(O)NH 2 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 the foregoing, R a is hydrogen; R b is selected from hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, -NH 2 , -C(O)NH 2 and -C(O)OH; R 1 is hydrogen; a is 3; and b is 1.

[0303] In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a is hydrogen; 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 1; and b is 0. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a is hydrogen; 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 2, and b is 0. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a is hydrogen; R b is selected from hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, -NH 2 , -C(O)NH2 and -C(O)OH; a is 3, and b is 0.

[0304] In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a is hydrogen; R b is selected from hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, -NH 2 , -C(O)NH 2 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 the foregoing, R a is hydrogen; R b is selected from hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, -NH 2 , -C(O)NH 2 and -C(O)OH; R 1 is methyl; a is 2; and b is 1. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a is hydrogen; R b is selected from hydrogen, alkyl, halogen, alkoxy, -CN, -NO 2 , -OH, -NH 2 , -C(O)NH 2 and -C(O)OH; R 1 is methyl; a is 3, and b is 1.

[0305] In certain embodiments, including any of the foregoing of formulas (III)-(VB), R a and R b are both hydrogen; R 1 is hydrogen; a is 1, and b is 1. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is hydrogen; a is 2, and b is 1. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is hydrogen; a is 3, and b is 1. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is hydrogen; a is 4, and b is 1. In certain embodiments of formulas (III)-(VB), including any of the foregoing, Ra and R b are both hydrogen; R 1 is hydrogen; a is 5, and b is 1. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is hydrogen; a is 6, and b is 1.

[0306] In certain embodiments of formulas (III)-(VB), including any of the foregoing, 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 the foregoing, 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 the foregoing, 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 the foregoing, 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 the foregoing, 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 the foregoing, R a and R b are both hydrogen; a is 6; and b is 0.

[0307] In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is methyl; a is 1; and b is 0. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is methyl; a is 2; and b is 0. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is methyl; a is 3; and b is 0. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1is methyl; a is 4; and b is 0. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is methyl; a is 5; and b is 0. In certain embodiments of formulas (III)-(VB), including any of the foregoing, R a and R b are both hydrogen; R 1 is methyl; a is 6; and b is 0.

[0308] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, R a is hydrogen; 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 1; and c is 1. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, R a is hydrogen; 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 2; and c is 1. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, R a is hydrogen; 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.

[0309] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) c -NH-, where * indicates where Y a is bonded to RL. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) c -NH-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH2 ) -NH-. In certain embodiments, including any of the foregoing, Y a is *-C(O)-(CH 2 ) 2 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 3 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 4 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 5 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 6 -NH-.

[0310] In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b )-NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 2 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 3 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 4 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 5 -NH-. In certain embodiments of formulae (III)-(IVB), including any of the foregoing, Ya is *-C(O)-(CR a R b ) 6 -NH-.

[0311] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) c -NH-, where R a is hydrogen and R b is selected from 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. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y 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-, where R a is hydrogen and R b is selected from 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.

[0312] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) c-, where * indicates that Y a is combined with RL. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) c -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 )-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 2 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 3 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 4 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing of formulas (III)-(IVB), Y a is *-C(O)-(CH 2 ) 5 -. In certain embodiments, including any of the foregoing, Y a is *-C(O)-(CH 2 ) 6 -.

[0313] In certain embodiments, including any of the foregoing of formulas (III)-(IVB), Y a is *-C(O)-(CR a R b )-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 2 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 3 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a Rb ) 4 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 5 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 6 -.

[0314] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) c -, where R a is hydrogen and R b is selected from 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. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CR a R b ) 2 -, *-C(O)-(CR a R b ) 3 - or *-C(O)-(CR a R b ) 4 -, where R a is hydrogen and R b is selected from 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.

[0315] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Y a is *-C(O)-(CH 2 ) 2 -NH- or *-C(O)-(CH 2 ) 4 -.

[0316] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is absent. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is a linker comprising a hydrophilic polymer residue.

[0317] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -CH 2 -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 3 -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 4 -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) 5 -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 )6 -POLY 1 -。In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -CR a R b -POLY 1 -。In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CR a R b ) 2 -POLY 1 -。In certain embodiments, including any of the foregoing, L 2 is –(CR a R b ) 3 -POLY 1 -。In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CR a R b ) 4 -POLY 1 -。

[0318] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -POLY 1 -。

[0319] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, 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 the foregoing, 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)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) a -POLY 1 -(CH2 ) a -, wherein a is independently selected from 0, 1, 2, 3, 4, 5 or 6. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) a -POLY 1 -(CR a R b ) a -, wherein a is selected from 1, 2, 3, 4, 5 or 6. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CR a R b ) a -POLY 1 -(CH 2 ) a -, wherein a is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0320] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of a non-peptide hydrophilic polymer. In certain embodiments of formulas (III)-(IVB), POLY 1 is a divalent residue of: polyethylene glycol (PEG), poly(propylene glycol) (PPG), a copolymer of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(alkenyl alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), poly(sarcosine) or a combination thereof. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of polyethylene glycol (PEG), poly(propylene glycol) (PPG) or a copolymer of ethylene glycol and propylene glycol.

[0321] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of polyethylene glycol (PEG). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(propylene glycol) (PPG). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of a copolymer of ethylene glycol and propylene glycol. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY1 is a divalent residue of poly(oxyethylated polyol). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(alkenyl alcohol). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(vinylpyrrolidone). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(hydroxyalkyl methacrylamide). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(hydroxyalkyl methacrylate). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(saccharide). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(α-hydroxy acid). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(vinyl alcohol). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of polyphosphazene. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of polyoxazoline (POZ). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(N-acryloylmorpholine). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is a divalent residue of poly(sarcosine).

[0322] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 1 is wherein R 5 is hydrogen or methyl, x is an integer from 1 to 100 (inclusive), and Denotes attachment to the remainder of the compound or conjugate. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 1 and 25. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 5 and 15. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 1. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 2. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 3. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 4. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 5. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 6. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 7. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 8. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 9. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 10. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 11. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 12. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 13. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 14. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 15. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 16. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 17. In some embodiments, including any of the foregoing, x is 18. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 19. In some embodiments of formulas (III)-(IVB), including any of the foregoing, x is 20. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 25 and 50. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 35 and 45. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 50 and 75. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 55 and 65.In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 75 and 100. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 85 and 95. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer in the range of 1 and 25, 20 and 45, 40 and 65, 60 and 85, 70 and 95, or 75 and 100.

[0323] In some embodiments of formulas (III)-(IVB), including any of the foregoing, R 5 is hydrogen. In some embodiments, including any of the foregoing, R 5 is methyl.

[0324] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CR a R b ) a -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CR a R b ) a -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) a -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) 2 -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CR a R b ) a -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CR a R b ) a -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) 2 -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) 2 -POLY 1 -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is –(CH 2 ) 2 -POLY 1 -, where POLY 1 is

[0325] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments, including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a -, where POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 -(CR a R b ) a -, where POLY 1 is

[0326] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is selected from In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is

[0327] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is

[0328] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of a non-peptide 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), a copolymer of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(alkenyl alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), poly(sarcosine), or a combination thereof. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, 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 foregoing, POLY 2 is a residue of methoxypolyethylene glycol (mPEG).

[0329] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of polyethylene glycol (PEG). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(propylene glycol) (PPG). In certain embodiments, including any of the foregoing, POLY 2 is a residue of a copolymer of ethylene glycol and propylene glycol. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(oxyethylated polyol). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(alkenyl alcohol). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2is a residue of poly(vinylpyrrolidone). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(hydroxyalkyl methacrylamide). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(hydroxyalkyl methacrylate). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(saccharide). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(α-hydroxy acid). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(vinyl alcohol). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of polyphosphazene. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of polyoxazoline (POZ). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(N-acryloylmorpholine). In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is a residue of poly(sarcosine).

[0330] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, POLY 2 is wherein R 5 is hydrogen or methyl, x is an integer from 1 to 100 (inclusive), and Denotes attachment to the remainder of the compound or conjugate. In certain embodiments of Formulas (III)-(IVB), including any of the foregoing, x is an integer between 1 and 25. In certain embodiments of Formulas (III)-(IVB), including any of the foregoing, x is an integer between 5 and 15. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 1. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 2. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 3. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 4. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 5. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 6. In some embodiments, including any of the foregoing, x is 7. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 8. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 9. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 10. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 11. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 12. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 13. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 14. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 15. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 16. In some embodiments of Formulas (III)-(IVB), including any of the foregoing of Formulas (III)-(IVB), x is 17. In some embodiments, including any of the foregoing of Formulas (III)-(IVB), x is 18. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 19. In some embodiments of Formulas (III)-(IVB), including any of the foregoing, x is 20. In certain embodiments of Formulas (III)-(IVB), including any of the foregoing, x is an integer between 25 and 50. In certain embodiments of Formulas (III)-(IVB), including any of the foregoing, x is an integer between 35 and 45. In certain embodiments of Formulas (III)-(IVB), including any of the foregoing, x is an integer between 50 and 75. In certain embodiments of Formulas (III)-(IVB), including any of the foregoing, x is an integer between 55 and 65.In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 75 and 100. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer between 85 and 95. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, x is an integer in the range of 1 and 25, 20 and 45, 40 and 65, 60 and 85, 70 and 95, or 75 and 100.

[0331] In some embodiments of formulas (III)-(IVB), including any of the foregoing, R 5 is hydrogen. In some embodiments of formulas (III)-(IVB), including any of the foregoing, R 5 is methyl.

[0332] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is selected from the group consisting of:

[0333] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is selected from the group consisting of:

[0334] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is

[0335] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is

[0336] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-AA-.

[0337] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-AA-Z-(CR a R b ) a-Z-(CR a R b ) a -C(O)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-AA-NR 2 -(CR a R b ) a -NR 2 -(CR a R b ) a -C(O)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-AA-NH-(CR a R b ) a -NH-(CR a R b ) a -C(O)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-AA-NH-(CH 2 ) a -NH-(CH 2 ) a -C(O)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-AA-NH-(CH 2 ) a -NH-(CH 2 ) a -C(O)-, where a is selected from 1, 2, and 3. In certain embodiments, including any of the foregoing, L 3 is -C(O)-AA-NH-CH 2 -NH-CH 2 -C(O)-

[0338] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-AA-Z-(CR a R b ) a . In certain embodiments, including any of the foregoing, L 3 is -C(O)-AA-NR 2 -(CH 2 ) a . In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L3 is -C(O)-AA-NH-(CH 2 ) 2 .

[0339] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -AA-. In certain embodiments, including any of the foregoing, L 3 is

[0340] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, -AA- is an amino acid residue. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, -AA- is a peptide residue. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, -AA- is a dipeptide residue, a tripeptide residue, a tetrapeptide residue, or a pentapeptide residue. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, -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 the foregoing, -AA- comprises at least one amino acid residue selected from alanine and glycine. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, -AA- is selected from the group consisting of:

[0341] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, -AA- is selected from the group consisting of:

[0342] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-.

[0343] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-Z-(CR a R b ) a -C(O)-Z-L 4 -OC(O)-, where L 4 is and Su is the hexose form of a monosaccharide and d is an integer independently selected from 1, 2, and 3. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-NR2 -(CR a R b ) a -C(O)-NR 2 -L 4 -OC(O)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-NR 2 -(CH 2 ) 2 -C(O)-NR 2 -L 4 -OC(O)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-NH-(CR a R b ) a -C(O)-NH-L 4 -OC(O)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-NH-(CH 2 ) 2 -C(O)-NH-L 4 -OC(O)-.

[0344] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 4 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 4 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 4 is

[0345] In some embodiments of formulas (III)-(IVB), including any of the foregoing, Su is a sugar moiety. In some embodiments, Su is the hexose form of a monosaccharide. Su can be a glucuronic acid or mannose residue. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Su is wherein represents attachment to the remainder of the compound. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, Su is wherein represents attachment to the remainder of the compound.

[0346] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 4 is

[0347] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-NH-(CH 2 ) 2 -C(O)-NH-L 4 -OC(O)-, where L 4 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 3 is -C(O)-NH-(CH 2 ) 2 -C(O)-NH-L 4 -OC(O)-, where L 4 is

[0348] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, 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 the foregoing, L 2 is -(CR a R b ) a -POLY 1 -; L 3 is -C(O)-AA-; and, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) a -POLY 1 -; L 3 is -C(O)-AA-; POLY 1 is and x is an integer between 10 and 15. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3is -C(O)-AA-; and, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3 is -C(O)-AA-; POLY 1 is and AA is a dipeptide residue, tripeptide residue, tetrapeptide residue or pentapeptide residue.

[0349] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, 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)-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 -; L 3 is -C(O)-AA-Z-(CR a R b ) a -Z-(CR a R b ) a -C(O)-; POLY 1 is and Z is -NH-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) a -POLY 1 -; L 3 is -C(O)-AA-NH-(CH 2 ) a -NH-(CH 2 ) a -C(O)-; POLY 1 is And x is an integer between 10 and 15. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3 is -C(O)-AA-NH-CH 2 -NH-CH 2 -C(O)-; And, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3 is -C(O)-AA-NH-CH 2 -NH-CH 2 -C(O)-; POLY 1 is And AA is a dipeptide residue, a tripeptide residue, a tetrapeptide residue or a pentapeptide residue.

[0350] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, 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 the foregoing, L 2 is -(CR a R b ) a -POLY 1 -; L 3 is -C(O); And, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) a -POLY 1 -; L 3 is -C(O); POLY 1 is And x is an integer between 10 and 15. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2-POLY 1 -; L 3 is -C(O); and, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3 is -C(O); POLY 1 is and AA is a dipeptide residue, tripeptide residue, tetrapeptide residue or pentapeptide residue.

[0351] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 - and L 3 is absent. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CR a R b ) a -POLY 1 -; L 3 is absent; and, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) a -POLY 1 -; L 3 is absent; POLY 1 is and x is an integer between 10 and 15. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3 is absent; and, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3 is absent; POLY1 is and AA is a dipeptide residue, a tripeptide residue, a tetrapeptide residue or a pentapeptide residue.

[0352] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, 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 the foregoing, L 2 is -(CR a R b ) a -POLY 1 -; L 3 is -C(O)-AA-Z-(CR a R b ) a -; and, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) a -POLY 1 -; -C(O)-AA-NR 2 -(CR a R b ) a -; POLY 1 is and x is an integer between 10 and 15. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L 3 is -C(O)-AA-NH-(CR a R b ) a -; and, POLY 1 is In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is -(CH 2 ) 2 -POLY 1 -; L3 is -C(O)-AA-NH-(CR a R b ) a -; POLY 1 is and AA is a dipeptide residue, tripeptide residue, tetrapeptide residue or pentapeptide residue.

[0353] -L 2 -L 3 - non-limiting examples of which include:

[0354] -L 2 -L 3 Additional non-limiting examples of which include:

[0355] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is and L 3 is -C(O)-Z-(CR a R b ) a -C(O)-Z-L 4 -OC(O)-, where L 4 is and Su is the hexose form of a monosaccharide and d is an integer independently selected from 1, 2, and 3. In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is and L 3 is -C(O)-Z-(CR a R b ) a -C(O)-Z-L 4 -OC(O)-.

[0356] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is and L 3 is -C(O). In certain embodiments, including any of the foregoing, L 2 is and L 3 is absent.

[0357] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is selected from the group consisting of: and L 3 is -C(O)-NH-(CR a R b ) a -C(O)-NH-L 4 -OC(O)-.

[0358] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is selected from the group consisting of: and L 3 is -C(O)-NH-(CR a R b ) a -C(O)-NH-L 4 -OC(O)-.

[0359] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is selected from the group consisting of: and L 3 is -C(O)-NH-(CH 2 ) 2 -C(O)-NH-L 4 -OC(O)-, wherein L 4 is

[0360] In certain embodiments of formulas (III)-(IVB), including any of the foregoing, L 2 is selected from the group consisting of: and L 3 is -C(O).

[0361] In certain embodiments, including any of the foregoing, D is a cytotoxic payload selected from tubulin inhibitors, DNA topoisomerase I inhibitors, and DNA topoisomerase II inhibitors. In some embodiments, including any of the foregoing, D is a tubulin inhibitor. In some embodiments, including any of the foregoing, D is a DNA topoisomerase I inhibitor. In some embodiments, including any of the foregoing, 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 foregoing, D is irinotecan. In some embodiments, including any of the foregoing, D is SN-38. In some embodiments, including any of the foregoing, D is topotecan. In some embodiments, including any of the foregoing, D is exatecan. In some embodiments, including any of the foregoing, D is a DNA topoisomerase II inhibitor. In some embodiments, including any of the foregoing, D is a DNA topoisomerase II inhibitor selected from the group consisting of etoposide, teniposide, and talaporfin. In some embodiments, including any of the foregoing, D is etoposide. In some embodiments, including any of the foregoing, D is teniposide. In some embodiments, including any of the foregoing, D is talaporfin. In some embodiments, including any of the foregoing, D is selected from the group consisting of hamigerans, camptothecins, and anthracyclines. Anthracyclines may include PNU-159682 and EDA PNU-159682 derivatives. In some embodiments, including any of the foregoing, D is an anthracycline selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin. In some embodiments, including any of the foregoing, D is daunorubicin. In some embodiments, including any of the foregoing, D is doxorubicin. In some embodiments, including any of the foregoing, D is epirubicin. In some embodiments, including any of the foregoing, D is idarubicin. In some embodiments, including any of the foregoing, D is mitoxantrone. In some embodiments, including any of the foregoing, D is valrubicin. In some embodiments, including any of the foregoing, D is hamigeran. In some embodiments, including any of the foregoing, D is a camptothecin. In some embodiments, including any of the foregoing, D is an anthracycline. In some embodiments, including any of the foregoing, D is PNU-159682. In some embodiments, including any of the foregoing, D is an EDA PNU compound. In some embodiments, including any of the foregoing, D is an EDA PNU-159682 derivative. In some embodiments, including any of the foregoing, D is hamigeran, exatecan, PNU-159682, or an EDA PNU-159682 derivative. In some embodiments, including any of the foregoing, D is hamigeran.In some embodiments, including any of the foregoing, D is irinotecan. In some embodiments, including any of the foregoing, D is PNU-159682. In some embodiments, including any of the foregoing, D is the EDA PNU-159682 compound or derivative. In some embodiments, including any of the foregoing, D is not an immunostimulatory compound.

[0362] In some embodiments, including any of the foregoing, D is an alkylating agent. In some embodiments, including any of the foregoing, D is a bifunctional alkylating agent. In some embodiments, including any of the foregoing, D is a bifunctional alkylating agent selected from the group consisting of cyclophosphamide, mechlorethamine, chlorambucil, and melphalan. In some embodiments, including any of the foregoing, D is cyclophosphamide. In some embodiments, including any of the foregoing, D is mechlorethamine. In some embodiments, including any of the foregoing, D is chlorambucil. In some embodiments, including any of the foregoing, D is melphalan. In some embodiments, including any of the foregoing, D is a monofunctional alkylating agent. In some embodiments, including any of the foregoing, D is a monofunctional alkylating agent selected from the group consisting of dacarbazine, nitrosourea, and temozolomide. In some embodiments, including any of the foregoing, D is dacarbazine. In some embodiments, including any of the foregoing, D is nitrosourea. In some embodiments, including any of the foregoing, D is temozolomide. In some embodiments, including any of the foregoing, D is a cytoskeleton disruptor (e.g., taxane). In some embodiments, including any of the foregoing, D is a cytoskeleton disruptor selected from the group consisting of paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, including any of the foregoing, D is paclitaxel. In some embodiments, including any of the foregoing, D is docetaxel. In some embodiments, including any of the foregoing, D is abraxane. In some embodiments, including any of the foregoing, D is taxotere. In some embodiments, including any of the foregoing, D is epothilone. In some embodiments, including any of the foregoing, 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 the foregoing, D is epothilone A. In some embodiments, including any of the foregoing, D is epothilone B. In some embodiments, including any of the foregoing, D is epothilone C. In some embodiments, including any of the foregoing, D is epothilone D. In some embodiments, including any of the foregoing, D is ixabepilone. In some embodiments, including any of the foregoing, D is a histone deacetylase inhibitor. In some embodiments, including any of the foregoing, D is a histone deacetylase inhibitor selected from the group consisting of vorinostat and romidepsin. In some embodiments, including any of the foregoing, D is vorinostat. In some embodiments, including any of the foregoing, D is romidepsin. In some embodiments, including any of the foregoing, D is a kinase inhibitor.In some embodiments, including any of the foregoing, 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 foregoing, D is bortezomib. In some embodiments, including any of the foregoing, D is erlotinib. In some embodiments, including any of the foregoing, D is gefitinib. In some embodiments, including any of the foregoing, D is imatinib. In some embodiments, including any of the foregoing, D is vemurafenib. In some embodiments, including any of the foregoing, D is vismodegib. In some embodiments, including any of the foregoing, D is a nucleotide analogue and / or a precursor analogue. In some embodiments, including any of the foregoing, D is a nucleotide analogue and / or a precursor analogue selected from the group consisting of azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and thioguanine (formerly known as thioguanine). In some embodiments, including any of the foregoing, D is azacitidine. In some embodiments, including any of the foregoing, D is azathioprine. In some embodiments, including any of the foregoing, D is capecitabine. In some embodiments, including any of the foregoing, D is cytarabine. In some embodiments, including any of the foregoing, D is doxifluridine. In some embodiments, including any of the foregoing, D is fluorouracil. In some embodiments, including any of the foregoing, D is gemcitabine. In some embodiments, including any of the foregoing, D is hydroxyurea. In some embodiments, including any of the foregoing, D is mercaptopurine. In some embodiments, including any of the foregoing, D is methotrexate. In some embodiments, including any of the foregoing, D is thioguanine (formerly known as thioguanine). In some embodiments, including any of the foregoing, D is a peptide antibiotic. In some embodiments, including any of the foregoing, D is a peptide antibiotic selected from the group consisting of bleomycin and actinomycin. In some embodiments, including any of the foregoing, D is bleomycin. In some embodiments, including any of the foregoing, D is actinomycin. In some embodiments, including any of the foregoing, D is a platinum-based agent. In some embodiments, including any of the foregoing, D is a platinum-based agent selected from the group consisting of carboplatin, cisplatin, and oxaliplatin. In some embodiments, including any of the foregoing, D is carboplatin. In some embodiments, including any of the foregoing, D is cisplatin. In some embodiments, including any of the foregoing, D is oxaliplatin. In some embodiments, including any of the foregoing, D is a retinoid. In some embodiments, including any of the foregoing, D is a retinoid selected from the group consisting of tretinoin, alitretinoin, and bexarotene.In some embodiments, including any of the foregoing, D is retinoic acid. In some embodiments, including any of the foregoing, D is alitretinoin. In some embodiments, including any of the foregoing, D is bexarotene. In some embodiments, including any of the foregoing, D is vinca alkaloid and its derivatives. In some embodiments, including any of the foregoing, D is vinca alkaloid and its derivatives selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine. In some embodiments, including any of the foregoing, D is a residue of vinblastine. In some embodiments, including any of the foregoing, D is vincristine. In some embodiments, including any of the foregoing, D is vindesine.

[0363] In any of the foregoing 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.

[0364] In some embodiments, provided herein are anti-ROR1 conjugates having the structure of any of conjugates A-MM in the following table. 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. This disclosure encompasses each and every regioisomer of the conjugate structures depicted below.

[0365] In some embodiments, provided herein are anti-ROR1 conjugates having the structure of any of Conjugate 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. This disclosure encompasses each and every regioisomer of the conjugate structures depicted below.

[0366] In any of the foregoing embodiments, wherein the anti-ROR1 conjugate has a structure according to any of Conjugates A-GG, the structure in parentheses may be covalently bonded to one or more unnatural amino acids of the antibody, wherein the one or more unnatural amino acids are located at sites selected from the group consisting of: HC-F404, HC-Y180, HC-F241, LC-K42, and LC-E161, according to the Kabat or Kabat's EU numbering scheme. In some embodiments, the structure in parentheses is covalently bonded to one or more unnatural amino acids at the site HC-F404 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to one or more unnatural amino acids at the site HC-Y180 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to one or more unnatural amino acids at the site HC-F241 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to one or more unnatural amino acids at the site LC-K42 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to one or more unnatural amino acids at the site LC-E161 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to unnatural amino acids at the sites HC-F404 and HC-Y180 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to unnatural amino acids at the sites HC-F404, HC-Y180, and LC-K42 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to unnatural amino acids at the sites HC-F404, HC-Y180, LC-K42, and LC-E161 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to unnatural amino acids at the sites HC-F404, HC-Y180, and HC-F241 of the antibody. In some embodiments, the structure in parentheses is covalently bonded to unnatural amino acids at the sites HC-F404, HC-Y180, HC-F241, and LC-K42 of the antibody.

[0367] In certain embodiments, provided herein are anti-ROR1 conjugates according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (30). In certain embodiments, provided herein are anti-ROR1 conjugates according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (30) at heavy chain position 404 according to the EU numbering system. In certain embodiments, provided herein are anti-ROR1 conjugates according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (30) at heavy chain position 180 according to the EU numbering system. In certain embodiments, provided herein are anti-ROR1 conjugates according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (30) at heavy chain position 241 according to the EU numbering system. In certain embodiments, provided herein are anti-ROR1 conjugates according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (30) at heavy chain position 222 according to the EU numbering system. In certain embodiments, provided herein are anti-ROR1 conjugates according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (30) at light chain position 7 according to the Kabat or Chothia numbering systems. In certain embodiments, provided herein are anti-ROR1 conjugates according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (30) at light chain position 42 according to the Kabat or Chothia numbering systems. In certain embodiments, PAY is selected from the group consisting of: maytansine, hamiltine, amanitin, camptothecin, 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 hamiltine. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is camptothecin. In certain embodiments, PAY is exatecan derivative Dxd. In certain embodiments, PAY is anthracyclines. In certain embodiments, PAY is PNU-159682. In certain embodiments, PAY is PNU derivative (PNU-EDA). In certain embodiments, PAY is pyrrolobenzodiazepine In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE.

[0368] In certain embodiments, provided herein is an anti-ROR1 conjugate according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (56). In certain embodiments, provided herein is an anti-ROR1 conjugate according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (56) at heavy chain position 404 according to the EU numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (56) at heavy chain position 180 according to the EU numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (56) at heavy chain position 241 according to the EU numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (56) at heavy chain position 222 according to the EU numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (56) at light chain position 7 according to the Kabat or Chothia numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any of the conjugates described herein, wherein COMP represents a residue of an unnatural amino acid according to formula (56) at light chain position 42 according to the Kabat or Chothia numbering system. In certain embodiments, PAY is selected from the group consisting of: maytansine, hamiltine, amanitin, camptothecin, 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 hamiltine. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is camptothecin. 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 anthracyclines. In certain embodiments, PAY is PNU-159682. In certain embodiments, PAY is PNU derivative (PNU-EDA). In certain embodiments, PAY is pyrrolobenzodiazepine In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE.

[0369] In certain embodiments, provided herein is an anti-ROR1 conjugate according to any one of the conjugates described herein, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any one of the conjugates described herein, wherein COMP represents an unnatural amino acid residue of para-azido-phenylalanine at heavy chain position 404 according to the EU numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any conjugate described herein, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine at heavy chain position 180 (according to the EU numbering system). In certain embodiments, provided herein is an anti-ROR1 conjugate according to any conjugate described herein, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine at heavy chain position 241 according to the EU numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any conjugate described herein, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine at heavy chain position 222 according to the EU numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any conjugate described herein, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine at light chain position 7 according to the Kabat or Chothia numbering system. In certain embodiments, provided herein is an anti-ROR1 conjugate according to any conjugate described herein, wherein COMP represents an unnatural amino acid residue of para-azido-L-phenylalanine at light chain position 42 according to the Kabat or Chothia numbering system. In certain embodiments, PAY is selected from the group consisting of maytansine, haematopodin, amanitin, camptothecin, exatecan, exatecan derivative (DXd), SN-38, anthracyclines, PNU-159682, pyrrolobenzodiazepine (PBD), MMAF, and MMAE. In certain embodiments, PAY is maytansine. In certain embodiments, PAY is haematopodin. In certain embodiments, PAY is amanitin. In certain embodiments, PAY is camptothecin. In certain embodiments, PAY is exatecan. In certain embodiments, PAY is exatecan derivative (DXd). In certain embodiments, PAY is anthracyclines. In certain embodiments, PAY is PNU-159682. In certain embodiments, PAY is PNU derivative (PNU-EDA). In certain embodiments, PAY is pyrrolobenzodiazepine In certain embodiments, PAY is MMAF. In certain embodiments, PAY is MMAE. 3. Payload

[0370] In addition to the foregoing payloads, the molecular payload can be any molecular entity that one of ordinary skill in the art may desire to conjugate to a polypeptide. In certain embodiments, the payload is a therapeutic moiety. In such embodiments, the 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 the 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 effect the destruction or elimination of the cells. Conjugates containing other molecular payloads that would be apparent to one of ordinary skill in the art are within the scope of the conjugates described herein.

[0371] In certain embodiments, the antibody conjugate can have a payload selected from the group consisting of: a label, a dye, a polymer, a water-soluble polymer, polyethylene glycol, a derivative of polyethylene glycol, a photo-crosslinker, 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 analogue, 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, a radioactive moiety, a novel functional group, a group that interacts covalently or non-covalently with other molecules, a photocage moiety, a photo-isomerizable moiety, biotin, a derivative of biotin, a biotin analogue, 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 aminothio acid, a toxic moiety, an isotope-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, or any combination thereof. In an embodiment, the payload is a label, a dye, a polymer, a cytotoxic compound, a radionuclide, a drug, an affinity label, a resin, a protein, a polypeptide, a polypeptide analogue, 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.

[0372] Useful drug payloads include any cytotoxic agent or cell growth inhibitor. Useful classes of cytotoxic agents include, for example, anti-tubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes (e.g., cisplatin, mono(platinum), bis(platinum), and trinuclear platinum complexes and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, calmodulin inhibitors, chemosensitizers, esperamicins, etoposides, fluoropyrimidines, ionophores, lexitropsins, maytansine alkaloids, nitrosoureas, cisplatin, pore-forming compounds, purine antimetabolites, puromycin, radiosensitizers, rapamycins, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, or analogs thereof.

[0373] Individual cytotoxic agents include, for example, androgen, anthramycin (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, decarbazine, DM1, DM4, docetaxel, doxorubicin, etoposide, estrogen, 5-fluorodeoxyuridine, 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, procarbazine, rhizoxin, streptozocin, teniposide, 6-thioguanine, thiotepa, topotecan, vinblastine, vincristine, vinorelbine, VP-16, and VM-26.

[0374] In some embodiments, suitable cytotoxic agents include, for example, DNA minor groove binders (e.g., enediynes and lexitropsins, CBI compounds; see also U.S. Patent No. 6,130,237), esperamicins, taxanes (e.g., paclitaxel and docetaxel), puromycin, vinca alkaloids, CC-1065, SN-38, topotecan, morpholino doxorubicin, rhizoxin, cyanomorpholino doxorubicin, echinosporin, combretastatin, netropsin, epothilones A and B, estramustine, nostocarbolines, simadotin, maytansine alkaloids, discodermolide, acanthifolicin, and mitoxantrone.

[0375] In some embodiments, the payload is a tubulin agent. Examples of tubulin agents include, but are not limited to, taxanes (e.g., (paclitaxel), (docetaxel)), T67 (Tularik), and vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine). Other tubulin agents include, for example, baccatin derivatives, taxane analogs, epothilones (e.g., epothilone A and B), nocodazole, colchicine and colchiceine, estramustine, nostocarbolines, zimadoline, maytansinoids, combretastatins, discodermolide, and acanthifolicin.

[0376] In certain embodiments, the cytotoxic agent is a maytansinoid, which is another group of tubulin agents. For example, in a particular embodiment, the maytansinoid can be maytansine or DM1 (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res. [Genetic Research] 52:127-131).

[0377] In some embodiments, the payload is an auristatin, such as auristatin E or a derivative thereof. For example, an auristatin E derivative can be an ester formed between auristatin E and a keto acid. For example, auristatin E can react with p-acetylbenzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other typical auristatin derivatives include AFP (auristatin phenylalanine phenylene diamine), MMAF (monomethyl auristatin F), and MMAE (monomethyl auristatin E). The synthesis and structure of auristatin derivatives are described in U.S. Patent Application Publication Nos. 2003-0083263, 2005-0238649, and 2005-0009751; International Patent Publication Nos. 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; 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.

[0378] In certain embodiments, the payload is hamiterbine. Hamiterbine classes suitable for use in the antibody-drug conjugates described herein are described, for example, in International Patent Publication No. WO 2016 / 123582, which is incorporated herein by reference in its entirety.

[0379] In certain embodiments, the payload is not a radioisotope. In certain embodiments, the payload is not radioactive.

[0380] In certain embodiments, the payload is an antimetabolite. Antimetabolites can be, for example, purine antagonists (e.g., azathioprine or mycophenolate mofetil), dihydrofolate reductase inhibitors (e.g., methotrexate), acyclovir, ganciclovir, zidovudine, vidarabine, ribavirin, azidothymidine, cytarabine, amantadine, didanosine, idoxuridine, foscarnet, or trifluridine.

[0381] 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, bexarotene, calusterone, capecitabine, celecoxib, cladribine, darbepoetin alfa, denileukin diftitox, dexrazoxane, drostanolone propionate, epirubicin, epoetin alfa, estramustine, exemestane, filgrastine, floxuridine, fludarabine, fulvestrant, gemcitabine, gemtuzumab ozogamicin (MYLOTARG), goserelin, idarubicin, ifosfamide, imatinib mesylate, interferon α-2a, irinotecan, letrozole, leucovorin, levamisole, mechlorethamine or nitrogen mustard, megestrol acetate, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, nandrolone phenylpropionate, oprelvekin, oxaliplatin, pamidronate disodium, pegaspargase, pegaspargase, pegfilgrastine, pentostatin, pipobroman, 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.

[0382] Other useful drug payloads include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSI Pharm.), bortezomib ( Millennium Pharm., fulvestrant AstraZeneca, SU11248 (Pfizer), letrozole Novartis, imatinib mesylate Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin Sanofi, 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, Wyeth, lapatinib GSK572016, Glaxo Smith Kline, lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs) and gefitinib AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and Cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triaziquone, thiotepa, and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including synthetic analogues such as topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycins (specifically cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, for example enediyne antibiotics (for example, calicheamicin, especially uncialamycin, calicheamicin γ11, and calicheamicin ω11 (Angew Chem.Intl.Ed.Engl.[Journal of Applied Chemistry International Edition](1994) 33: 183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,. Doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinyl-doxorubicin, and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, 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 analogs such as fludarabine, 6-mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, cyclopenthiazide, metandienone, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as leucovorin; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; ametantrone; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; epothilones; etoglucid; gallium nitrate;Hydroxyurea; Lentinan; Lonidainine; Maytansine alkaloids such as Maytansine and Ansamitocins; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Phenamet; Pirarubicin; Losoxantrone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, Oreg); Razoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2”-Trichloroethylamine; Trichothecenes (especially T-2 toxin, Verracurin A, Roridin A and Anguidine); Urethan; Vinzolidine; Dacarbazine; Mannomustine; Dibromomannitol; Dibromodulcitol; Pipobroman; Gacytosine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Taxanes, such as (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (without hydrogenated castor oil), Albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, IL), and (Docetaxel; Rhone-Poulenc Rorer, Antony, France); Chlorambucil; (Gemcitabine); 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum analogs such as Cisplatin and Carboplatin; Vinblastine; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; (Vinorelbine); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Capecitabine Ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

[0383] Other useful payloads include: (i) antihormonal agents for modulating or inhibiting the action of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including for example tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and (toremifene citrate); (ii) aromatase inhibitors that inhibit aromatase (which regulates estrogen production in the adrenal gland), such as for example 4(5)-imidazole, aminoglutethimide, (megestrol acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis), and (anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; and troxacitabine (1,3-dioxolane nucleoside cytosine analogue); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes (such as PKC-α, Ralf and H-Ras) in signal transduction pathways associated with abnormal cell proliferation; (vii) ribozymes such as VEGF expression inhibitors (for example, ), and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, such as and rIL-2; topoisomerase 1 inhibitors such as rmRH; (ix) antiangiogenic agents such as bevacizumab ( Genentech); (x) agents for modulating or inhibiting the activity of members of the poly(ADP-ribose) polymerase (PARP) family in tumors (for example, talazoparib (BMN-673), iniparib (BSI 201), veliparib (ABT-888), olaparib (AZD-2281, trade name LYNPARZA TM), olaparib (AG 014699), BGB-290, E7016, E7449, and CEP-9722); (xi) agents for modulating or inhibiting the activity of members of the histone deacetylase (HDAC) family in tumors (e.g., abexinostat, entinostat, givinostat, 4SC-202, ACY-241, AR-42, CG200745, CHR-2845, CHR-3996, CXD101, MPT0E028, OBP-801, SHP-141, CUDC-101, KA2507, panobinostat, pracinostat, quisinostat, resminostat, ricolinostat); (xii) agents that act to modulate or inhibit the activity of 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 foregoing substances. Other useful payloads include anti-angiogenic agents, including, for example, MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, COX-II (cyclooxygenase II) inhibitors, and VEGF receptor tyrosine kinase inhibitors. Examples of such useful matrix metalloproteinase inhibitors that can be used in combination with the compounds / compositions of the present invention are 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. Patent No. 5,863,949, U.S. Patent 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; WO 98 / 35985), and SU11248 (sunitinib; WO 01 / 60814), and those compounds disclosed, for example, in PCT Publication Nos. WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, and WO 98 / 13354.

[0384] In certain embodiments, the payload is selected from the group consisting of maytansinoid, halichomycin, amanitin, irinotecan, deruxtecan (DXd), anthracyclines, PNU-159682, pyrrolobenzodiazepine (PBD), MMAF, and MMAE. In certain embodiments, the payload is maytansinoid. In certain embodiments, the payload is halichomycin. In certain embodiments, the payload is amanitin. In certain embodiments, the payload is halichomycin. In certain embodiments, the payload is amanitin. In certain embodiments, the payload is halichomycin. In certain embodiments, the payload is deruxtecan. In certain embodiments, the payload is halichomycin. In certain embodiments, the payload is anthracyclines. In certain embodiments, the payload is halichomycin. In certain embodiments, the payload is PNU-159682. In certain embodiments, the payload is halichomycin. In certain embodiments, the payload is pyrrolobenzodiazepine In certain embodiments, the payload is MMAF. In certain embodiments, the payload is MMAE.

[0385] In certain embodiments, the payload is an antibody or an antibody fragment. In certain embodiments, the payload antibody or fragment may be encoded by any of the immunoglobulin genes known to those skilled in the art. Immunoglobulin genes include, but are not limited to, κ, λ, α, γ (IgG1, IgG2, IgG3, and IgG4), δ, ε, and μ constant region genes, and immunoglobulin variable region genes. The term includes full-length antibodies and antibody fragments known to those skilled in the art, and variants thereof. Exemplary fragments include, but are not limited to, Fv, Fc, Fab, and (Fab') 2 2, single-chain Fv (scFv), diabody, triabody, tetrabody, bifunctional hybrid polypeptides, CDR1, CDR2, CDR3, combinations of CDRs, variable regions, framework regions, constant regions, etc.

[0386] In certain embodiments, the payload is one or more water-soluble polymers. A variety of macromolecular polymers and other molecules can be linked to the polypeptides described herein to modulate the biological properties of the polypeptides and / or to confer new biological properties to the polypeptides. These macromolecular polymers can be linked to the polypeptides via naturally encoded amino acids, via non-naturally encoded amino acids, or any functional substituents of natural or modified amino acids, or any substituents or functional groups added to natural or modified amino acids. The molecular weight of the polymer can be in a wide range, including but not limited to between about 100 Da and about 100,000 Da or greater.

[0387] The selected polymer can be water-soluble such that the attached protein does not precipitate in an aqueous environment such as a physiological environment. The polymer can be branched or unbranched. Preferably, for therapeutic use of the final product formulation, the polymer will be pharmaceutically acceptable.

[0388] In certain embodiments, the ratio of polyethylene glycol molecules to polypeptide molecules varies, as does their concentration in the reaction mixture. Generally, the optimal ratio (in terms of reaction efficiency, with a minimum excess of unreacted protein or polymer) can be determined by the molecular weight of the selected polyethylene glycol and the number of available reactive groups. In terms of 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, the branching of the polymer should be considered when optimizing these parameters. Generally, the higher the molecular weight (or the more branched), the higher the polymer:protein ratio.

[0389] The water-soluble polymer can 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), but other water-soluble polymers can also be used. For example, PEG is used to describe certain embodiments.

[0390] PEG is a well-known water-soluble polymer that is commercially available or can be prepared by ring-opening polymerization of ethylene glycol by methods well known in the art (Sandler and Karo, Polymer Synthesis, Academic Press, New York, Volume 3, pages 138 - 161). Without considering the size or modification of the PEG termini, the term "PEG" is used broadly to encompass any polyethylene glycol molecule and can be represented as linked to a polypeptide by the formula: XO–(CH 2 CH 2 O) n –CH 2 CH 2–Y, where n is from 2 to 10,000, X is H or a terminal modification including but not limited to C 1-4 alkyl, and Y is the attachment point to the polypeptide.

[0391] In some cases, PEG is terminated at one end with a hydroxyl or methoxy group, i.e., X is H or CH 3 ("methoxy PEG"). Alternatively, PEG can be capped with a reactive group to form a bifunctional polymer. Typical reactive groups can include those commonly used to react with functional groups found in 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)) and functional groups that are inert to the 20 common amino acids but react specifically with complementary functional groups present in non-naturally encoded amino acids (including but not limited to azide groups, alkyne groups). It should be noted that the other end of the PEG represented by Y in the above formula will be attached directly or indirectly via a naturally occurring or non-naturally encoded amino acid to the polypeptide. For example, Y can be an amide, carbamate, or urea linked to an amine group of the polypeptide (including but not limited to the ε-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 that is not normally accessible through the 20 common amino acids. For example, an azide group on PEG can react with an alkyne group on the polypeptide to form a Huisgen [3+2] cycloaddition product. Alternatively, an alkyne group on PEG can react 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 react with aldehyde or ketone groups present in non-naturally encoded amino acids to form hydrazones, oximes, or semicarbazones (where applicable), which in some cases can be further reduced by treatment with an appropriate reducing agent. Alternatively, strong nucleophiles can be incorporated into the polypeptide via non-naturally encoded amino acids and used to preferentially react with ketone or aldehyde groups present in the water-soluble polymer.

[0392] Any molecular weight of PEG can be used according to the actual expectation, including but not limited to from about 100 Daltons (Da) to 100,000 Da or higher according to the expectation (including but not limited to sometimes 0.1 - 50 kDa or 10 - 40 kDa). Branched PEG, including but not limited to PEG molecules having an MW range of 1 - 100 kDa (including but not limited to 1 - 50 kDa or 5 - 20 kDa) per chain. A variety of PEG molecules are described in, including but not limited to the catalogs of Shearwater Polymers, Inc. and Nektar Therapeutics, which are incorporated herein by reference.

[0393] Generally, at least one end of the PEG molecule can be used to react with an antibody. For example, PEG derivatives with alkyne and azide moieties for reacting with amino acid side chains can be used to attach PEG to non - naturally encoded amino acids as described herein. If the non - naturally encoded amino acid contains an azide, the PEG will typically contain an alkyne moiety to affect the formation of [3 + 2] cycloaddition products or an activated PEG species containing a phosphine group (i.e., ester, carbonate) to affect the formation of amide linkages. Alternatively, if the non - naturally encoded amino acid contains an alkyne, the PEG will typically contain an azide moiety to affect the formation of [3 + 2] Huisgen cycloaddition products. If the non - naturally encoded amino acid contains a carbonyl group, the PEG will typically contain an effective nucleophile (including but not limited to hydrazide, hydrazine, hydroxylamine or semicarbazide functional groups) to affect the formation of the corresponding hydrazone, oxime and semicarbazone linkages respectively. In other alternatives, the opposite orientation of the reactive groups described herein can be used, i.e., the azide moiety in the non - naturally encoded amino acid can react with a PEG derivative containing an alkyne.

[0394] In some embodiments, the polypeptide variant having a PEG derivative contains a chemical functional group that reacts with a chemical functional group present on the side chain of a non - naturally encoded amino acid.

[0395] In certain embodiments, the payload is an azide- or acetylene-containing polymer comprising a water-soluble polymer backbone having an average molecular weight of from 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 variety of water-soluble polymers (including but not limited to poly(ethylene glycol) and other related polymers (including dextran and poly(propylene glycol))) are also suitable for use, and 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 any form of poly(ethylene glycol), including bifunctional PEG, multi-arm PEG, derivatized PEG, branched PEG, branched PEG, pendant PEG (i.e., PEG or related polymer having one or more functional groups pendant from the polymer backbone), or PEG having a degradable linkage therein.

[0396] The polymer backbone can be linear or branched. Branched polymer backbones are well known in the art. Generally, a branched polymer has a central branched core portion and a plurality of linear polymer chains attached to the central branched core. PEG is commonly used in a branched form, which can be prepared by adding ethylene oxide to various polyols (such as glycerol, glycerol oligomers, pentaerythritol, and sorbitol). The central branched portion can also be derived from several amino acids, such as lysine. Branched poly(ethylene glycol) can be represented in a general form as R(-PEG-OH) m , where R is derived from the core portion, such as glycerol, glycerol oligomer, or pentaerythritol, and m represents the number of arms. Multi-arm PEG molecules, such as those described in U.S. Patent Nos. 5,932,462, 5,643,575; 5,229,490; 4,289,872; U.S. Patent Application 2003 / 0143596; WO 96 / 21469; WO 93 / 21259 (each of which is incorporated herein by reference in its entirety), can also be used as the polymer backbone.

[0397] Branched PEG can also be in the form of a branched PEG represented by PEG(YCHZ 2 ) n , where Y is a linking group and Z is an activated terminal group attached to CH through an atomic chain of a specified length.

[0398] Another branched form, namely pendant PEG, has reactive groups, such as carboxyl groups, along the PEG backbone rather than at the ends of the PEG chains.

[0399] In addition to these forms of PEG, polymers having weak or degradable linkages in the backbone can also be prepared. For example, PEG can be prepared with an ester linkage in the polymer backbone that is subject to hydrolysis. As shown herein, such hydrolysis results in cleavage of the polymer into lower molecular weight fragments: -PEG-CO 2 -PEG- + H 2 O → PEG-CO 2 H + HO-PEG-. Those skilled in the art will understand that the term poly(ethylene glycol) or PEG denotes or includes all forms known in the art, including but not limited to those disclosed herein.

[0400] Many other polymers are also suitable for use. In some embodiments, a water-soluble polymer backbone having from 2 to about 300 termini is 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. Although the molecular weight of each chain of the polymer backbone can vary, it is typically in the range of about 800 Da to about 100,000 Da, often in the range of about 6,000 Da to about 80,000 Da.

[0401] One of ordinary skill in the art will recognize that the foregoing list of basic water-soluble backbones is in no way exhaustive but merely illustrative, and all polymer materials having the qualities described herein are considered suitable for use.

[0402] In some embodiments, the polymer derivative is "multifunctional", meaning that the polymer backbone has at least two termini, and possibly up to about 300 termini, which are functionalized or activated with functional groups. Multifunctional polymer derivatives include but are not limited to linear polymers having two termini, each terminus bonded to a functional group that can be the same or different. 4. Linker

[0403] In certain embodiments, the antibody can be linked to the payload through one or more linkers capable of reacting with antibody amino acids and with the payload group. One or more linkers can be any linker that would be apparent to one of ordinary skill in the art.

[0404] As used herein, the term "linker" refers to a group or bond that is typically formed as a result of a chemical reaction and is typically a covalent linkage.

[0405] Useful linkers include those described herein. In certain embodiments, the linker is any divalent or multivalent linker known to those skilled in the art. Useful divalent 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 heteroalkylene. In some embodiments, the C 1-10 heteroalkylene is PEG.

[0406] 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 a long time, and possibly indefinitely. In certain embodiments, the linker is hydrolytically unstable. Hydrolytically unstable or degradable linkage means that the linkage is degradable in water or an aqueous solution (including, for example, blood). Enzymatically unstable or degradable linkage means that the linkage can be degraded by one or more enzymes.

[0407] As understood in the art, PEG and related polymers can include degradable linkages in the polymer backbone or in the linker groups between the polymer backbone and one or more terminal functional groups of the polymer molecule. For example, an ester linkage formed by the reaction of PEG carboxylic acid or activated PEG carboxylic acid with an alcohol group on a bioactive agent is typically hydrolyzed under physiological conditions to release the agent.

[0408] Other hydrolytically degradable linkages include but are not limited to carbonate linkages; imine linkages produced by the reaction of an amine and an aldehyde; phosphate ester linkages formed by the reaction of an alcohol with a phosphate group; hydrazone linkages, which are reaction products of an acylhydrazine and an aldehyde; acetal linkages, which are reaction products of an aldehyde and an alcohol; orthoester linkages, which are reaction products of a formate ester and an alcohol; peptide linkages formed by an amine group (including but not limited to at the end of a polymer such as PEG) and a carboxyl group of a peptide; and oligonucleotide linkages formed by a phosphoramidite group (including but not limited to at the end of a polymer) and a 5'-hydroxy group of an oligonucleotide.

[0409] Many different cleavable linkers are known to those skilled in the art. See U.S. Patent Nos. 4,618,492; 4,542,225 and 4,625,014. Mechanisms for releasing agents from these linker groups include, for example, irradiation of a photo-labile bond and acid-catalyzed hydrolysis. For example, U.S. Patent No. 4,671,958 includes a description of an immunoconjugate that contains a linker that is cleaved by proteolytic enzymes of the patient's complement system at the in vivo target site. The length of the linker can be predetermined or selected based on the desired spatial relationship between the polypeptide and the molecule to which it is attached. Given the many methods reported for attaching various radiodiagnostic compounds, radiotherapeutic compounds, drugs, toxins, and other agents to polypeptides, those skilled in the art will be able to determine a suitable method for attaching a given agent to a polypeptide.

[0410] Linkers can have a wide range of molecular weights or molecular lengths. Larger or smaller molecular weight linkers can be used to provide a desired spatial relationship or conformation between the polypeptide and the attached entity. Linkers with longer or shorter molecular lengths can also be used to provide a desired space or flexibility between the polypeptide and the attached entity. Similarly, before or after the polypeptide reaches its target, linkers with a specific shape or conformation can be utilized to impart a specific shape or conformation to the polypeptide or the attached entity. The functional groups present at each end of the linker can be selected to modulate the release of the polypeptide or payload under the desired conditions. This optimization of the spatial relationship between the polypeptide and the attached entity can provide new, regulated, or desired properties to the molecule.

[0411] In some embodiments, provided herein are water-soluble bifunctional linkers having a dumbbell structure that includes: a) an azide, alkyne, hydrazine, hydrazide, hydroxylamine, or carbonyl-containing moiety at at least a first end of a polymer backbone; and b) at least a second functional group at a second end of the polymer backbone. The second functional group can be the same as or different from the first functional group. In certain embodiments, the second functional group does not react with the first functional group. In some embodiments, provided are water-soluble compounds that include at least one arm of a branched molecular structure. For example, the branched molecular structure can be a dendrimeric structure.

[0412] In some embodiments, the linker is derived from a linker precursor selected from the group consisting of N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)-2-sulfo-butanoate (sulfosuccinimidyl-4-(2-pyridyldithio)butanoate or sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl (4-iodoacetyl)aminobenzoate (SIAB), maleimide PEG NHS, N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), N-sulfo-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (sulfo-SMCC), or 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-tetraazadecane-1-carboxylate (CX1-1). In a particular embodiment, the linker is derived from the linker precursor N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC).

[0413] In some embodiments, the linker is derived from a linker precursor selected from the group consisting of dipeptides, tripeptides, tetrapeptides, and pentapeptides. In such embodiments, the linker may 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-glycine-glycine (gly-gly-gly), and glycine-(2-methoxyethoxyethyl)serine-valine (gly-val-citalanine OMESerValAla).

[0414] In some embodiments, the linker comprises a self-cleaving spacer. In certain embodiments, the self-cleaving 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 formed between the benzyl alcohol and the payload (Hamann et al. (2005) Expert Opin. Ther. Patents 15:1087-1103). In some embodiments, the linker comprises p-aminobenzyloxycarbonyl (PAB). Other examples of self-cleaving spacers include, but are not limited to, aromatic compounds electronically similar to the PAB group, such as 2-aminoimidazole-5-methanol derivatives (U.S. Patent No. 7,375,078; Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and o-aminobenzyl acetals or p-aminobenzyl acetals. In some embodiments, a spacer that undergoes cyclization after amide bond hydrolysis can be used, such as substituted and unsubstituted 4-aminobutyramide (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-aminophenylpropionamide (Amsberry, et al. (1990) J. Org. Chem. 55:5867). The attachment of the drug to the α-carbon of the glycine residue is another example of a self-cleaving spacer that can be used in the conjugate (Kingsbury et al. (1984) J. Med. Chem. 27:1447).

[0415] In certain embodiments, linker precursors can combine to form larger linkers. For example, in certain embodiments, the linker comprises the dipeptide valine-citrulline and p-aminobenzyloxycarbonyl. These linkers are also referred to as citValCit--PAB linkers.

[0416] In certain embodiments, the payload can be attached to the linker, herein referred to as a linker-payload, wherein there is one or more linker groups capable of reacting with the antibody amino acid groups. One or more linkers can be any linker obvious to those skilled in the art or those linkers described herein.

[0417] Additional linkers are disclosed herein, such as linker precursors (A)-(L) described below. 5. Antibodies and Antibody Specificity

[0418] The present disclosure provides antibodies that selectively bind to human ROR1. In some aspects, the antibodies selectively bind to the extracellular domain of human ROR1 (hROR1).

[0419] The present disclosure also provides conjugates comprising an antibody that selectively binds to human receptor tyrosine kinase orphan receptor 1. In some aspects, the antibody of the conjugate selectively binds to the extracellular domain of human receptor tyrosine kinase orphan receptor 1 (hROR1).

[0420] In some embodiments, the antibody binds to a homolog of human ROR1. In some aspects, the antibody binds to a human ROR1 homolog from a species selected from: monkey, mouse, dog, cat, rat, bovine, 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.

[0421] In some embodiments, the antibody has one or more CDRs of a specific length in terms of the number of amino acid residues. In some embodiments, the length of the Chothia CDR-H1 of the antibody is 6, 7, or 8 residues. In some embodiments, the length of the Kabat CDR-H1 of the antibody is 4, 5, or 6 residues. In some embodiments, the length of the Chothia CDR-H2 of the antibody is 5, 6, or 7 residues. In some embodiments, the length of the Kabat CDR-H2 of the antibody is 16, 17, or 18 residues. In some embodiments, the length of the Kabat / Chothia CDR-H3 of the antibody is 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 residues.

[0422] In some aspects, the length of the Kabat / Chothia CDR-L1 of the antibody is 10, 11, 12, 13, 14, 15, or 16 residues. In some aspects, the length of the Kabat / Chothia CDR-L2 of the antibody is 6, 7, or 8 residues. In some aspects, the length of the Kabat / Chothia CDR-L3 of the antibody is 8, 9, or 10 residues.

[0423] In some embodiments, the antibody comprises a light chain. In some aspects, the light chain is a κ light chain. In some aspects, the light chain is a λ light chain.

[0424] 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.

[0425] 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 F(ab’) 2 fragment. In some aspects, the antibody fragment is a Fab’ fragment. In some aspects, the antibody fragment is a scFv (sFv) fragment. In some aspects, the antibody fragment is a scFv-Fc fragment.

[0426] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.

[0427] 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.

[0428] 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.

[0429] The antibodies provided herein can be used to treat a variety of diseases and disorders, including cancer. In some embodiments, the antibodies provided herein can be used to treat cancers of solid tumors. For example, the antibodies provided herein can be used to treat colorectal cancer. 5.1 CDR-H3 Sequence

[0430] In some embodiments, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: the CDR-H3 sequence of the illustrative antibodies or V H sequences provided herein. In some aspects, the CDR-H3 sequence is the CDR-H3 sequence of the V H sequences provided in SEQ ID NO: 854-1020.

[0431] In some embodiments, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of a sequence selected from SEQ ID NOs: 672-838. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 672. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 673. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 674. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 675. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 676. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 677. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 678. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 679. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 680. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 681. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 682. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 683. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 684. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 685. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 686. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 687. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of SEQ ID NO: 688.In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 689. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 690. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 691. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 692. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 693. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 694. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 695. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 696. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 697. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 698. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO: 699.

[0432] In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:700. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:701. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:702. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:703. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:704. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:705. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:706. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:707. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:708. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:709. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:710. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:711. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:712. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:713. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:714. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:715. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:716. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:717.In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:718. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:719. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:720. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:721. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:722. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:723. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:724. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:725. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:726. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:727. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:728. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:729. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:730. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:731. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:732. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:733. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:734. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:735.In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:736. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:737. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:738. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:739. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:740. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:741. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:742. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:743. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:744. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:745. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:746. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:747. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:748. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:749.

[0433] In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:750. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:751. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:752. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:753. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:754. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:755. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:756. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:757. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:758. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:759. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:760. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:761. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:762. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:763. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:764. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:765. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:766. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:767.In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:768. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:769. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:770. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:771. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:772. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:773. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:774. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:775. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:776. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:777. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:778. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:779. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:780. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:781. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:782. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:783. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:784. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:785.In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:786. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:787. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:788. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:789. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:790. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:791. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:792. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:793. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:794. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:795. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:796. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:797. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:798. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:799.

[0434] In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:800. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:801. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:802. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:803. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:804. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:805. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:806. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:807. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:808. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:809. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:810. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:811. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:812. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:813. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:814. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:815. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:816. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:817.In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:818. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:819. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:820. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:821. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:822. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:823. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:824. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:825. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:826. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:827. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:828. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:829. In some aspects, the antibody comprises a CDR-H3 sequence that comprises, consists of, or consists essentially of: SEQ ID NO:830. In s...

Claims

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

2. The antibody conjugate according to claim 1, wherein the one or more unnatural amino acids are located at antibody amino acid sites other than the amino - terminus of the antibody.

3. The antibody conjugate according to claim 1, wherein the one or more unnatural amino acids are located at antibody amino acid sites other than the carboxy - terminus of the antibody.

4. The antibody conjugate according to any one of claims 1 - 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. The antibody conjugate according to 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. The antibody conjugate according to claim 4, wherein the antibody comprises one or more unnatural amino acids at sites selected from the group consisting of: HC - F404, HC - Y180, LC - K42, and LC - E161, according to the Kabat or EU numbering scheme of Kabat.

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

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

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

10. The antibody conjugate according to any one of the preceding claims, 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, phosphonylserine, phosphonyltyrosine, p-iodophenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and p-propargyloxy-phenylalanine.

11. The antibody conjugate according to any one of the preceding claims, wherein the residue of the one or more unnatural amino acids is the residue of compound (30) or compound (56).

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

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

14. The antibody conjugate according to any one of the preceding claims, wherein the payload moiety is selected from the group consisting of maytansinoids, calicheamicins, amanitins, camptothecins, exatecan, anthracyclines, pyrrolobenzodiazepines and auristatins.

15. The antibody conjugate according to any one of the preceding claims, wherein the payload moiety is selected from the group consisting of: DM1, calicheamicin, α-amanitin, camptothecin, irinotecan, irinotecan derivative (Dxd), SN-38, PNU-159862, PNU derivative (PNU-EDA), pyrrolobenzodiazepine , MMAF, and MMAE.

16. The antibody conjugate according to any one of the preceding claims, having the structure according to formula I: or a pharmaceutically acceptable salt thereof, wherein COMP is the 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 -, where at least one of the alkylene, alkenylene or alkynylene groups in Y is substituted with one or more substituents selected from R 50 ; and​​​ wherein the alkylene, alkenylene or alkynylene in Y is optionally substituted by one or more substituents selected from R 51 ; 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, where each alkylene, alkenylene or alkynylene of R 50 is optionally substituted with one or more substituents selected from: 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; R 51 independently selected from 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 selected from -C(O)- and –N(R 10 )C(O)–; R 10 independently selected from 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 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 the hexose form of a monosaccharide; D is a drug moiety; and RL is a reactive group residue.

17. The antibody conjugate according to any one of the preceding claims, having the structure according to formula II: or a pharmaceutically acceptable salt thereof, wherein COMP is the residue of an 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 –, wherein at least one of the alkylene, alkenylene or alkynylene groups in Y is substituted with one or more substituents selected from R 50 ; 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, wherein each alkylene, alkenylene or alkynylene of R 50 is optionally substituted with one or more substituents selected from: 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 selected from -C(O)- and –N(R 10 )C(O)–; R 10 independently selected from 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 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 the hexose form of a monosaccharide; D is a drug moiety; and RL is a reactive group residue.

18. The conjugate according to claim 17, wherein the compound of formula (II) is according to formula (IIA) 19. The conjugate according to any one of claims 16 to 18, wherein Su is wherein represents attachment to the remainder of the compound.

20. The conjugate according to any one of claims 16 to 19, wherein Su is wherein represents attachment to the remainder of the compound.

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

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

23. The conjugate according to any one of claims 16 to 20, wherein D is selected from the group consisting of: halichondrins, camptothecins, anthracyclines, PNU-159682, and EDA PNU-159682 derivatives.

24. The conjugate according to any one of claims 16 to 20, wherein D is hamitrine, irinotecan, PNU-159682 or an EDA PNU-159682 derivative.

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

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

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

28. The conjugate according to any one of claims 16 to 26, wherein Y is –X 1 -C 1-4 alkylene-X 1 -C 1-4 alkylene-X 1 –, wherein at least one alkylene in Y is substituted with one or more substituents selected from R 50 and 29. The conjugate according to any one of claims 16 to 28, wherein R 50 is –C 1-6 alkylene-X 2 -[C 1-6 alkylene] m -POLY, wherein each alkylene of R 50 is optionally substituted with one or more substituents selected from the following: 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.

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

31. The conjugate according to any one of claims 16 to 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(alkenyl alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly(N-acryloylmorpholine), poly(sarcosine) or a combination thereof.

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

33. The conjugate according to any one of claims 16 to 32, wherein RL comprises an alkyne, cyclooctyne, strained olefin, tetrazine, thiol, p-acetyl-phenylalanine residue, oxime, amine, maleimide or azide.

34. The conjugate according to any one of claims 16 to 33, wherein RL is selected from the group consisting of:

35. The conjugate according to any one of claims 1-15, which is according to formula III: or a pharmaceutically acceptable salt thereof; wherein L 1a selected from Ring A is an optionally substituted bridged, fused or spiro bicyclic carbocycle, or an optionally substituted bridged, fused or spiro bicyclic heterocycle, wherein said carbocycle or said heterocycle of Ring A is optionally substituted with one or more substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO 2 2, -OH, -N(R 2 R 3 ) 2 2), -C(O)-, -C(O)N(R 2 R 3 ) 2 , -C(O)OR 2 , aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; Ring B is an optionally substituted N-linked bridged, fused or spiro bicyclic heterocycle, wherein Ring B is optionally substituted with one or more substituents 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 、aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; R a and R b are independently selected from 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 an integer independently selected from 0, 1, 2, 3, 4, 5 and 6; b is an integer selected from 0 or 1; R 1 is hydrogen or an alkyl group optionally substituted with one or more substituents selected from the following: 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 , aryl, and heteroaryl; R 2 and R 3 are 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 -, where * indicates that Y a is combined with RL; c is an integer selected from 1, 2, 3, 4, 5 or 6; RL is a reactive group residue; L 2 is absent or is a linker containing hydrophilic polymer residues; L 3 is absent, -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)-Z-L 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)O-L 4 -Z-C(O)-(CR a R b ) a -Z-C(O)-, -AA-Z-; and –(CR a R b ) a -Z-AA-C(O)-; Z is selected from -NR 2 - and -O-; AA is an amino acid residue or a peptide residue; L 4 is wherein Su is the hexose form of a monosaccharide; d is an integer independently selected from 1, 2 and 3; D is a drug moiety; COMP is a residue of an anti-ROR1 antibody; and Denotes attachment to the remainder of the compound.

36. The conjugate according to any one of claims 1-15, which has formula (V): or a pharmaceutically acceptable salt and / or regioisomer thereof; wherein L 5 is a linker containing a non-natural amino acid; Y a is *-C(O)-(CR a R b ) c -NH- or *-C(O)-(CR a R b ) c -, where * indicates that Y a is combined with RL; c is an integer selected from 1, 2, 3, 4, 5 or 6; RL is a reactive group residue; L 2 is absent or is a linker that includes hydrophilic polymer residues; L 3 is absent, -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)-Z-L 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)O-L 4 -Z-C(O)-(CR a R b ) a -Z-C(O)-, -AA-Z-; and –(CR a R b ) a -Z-AA-C(O)-; R a and R b are independently selected from 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 an integer independently selected from 0, 1, 2, 3, 4, 5 and 6; Z is selected from -NR 2 - and -O-; AA is an amino acid residue or a peptide residue; L 4 is wherein Su is the hexose form of a monosaccharide; d is an integer independently selected from 1, 2 and 3; D is a drug moiety; COMP is a residue of an anti-ROR1 antibody; and Indicates attachment to the remainder of the compound.

37. The conjugate according to claim 35, wherein ring B is selected from 38. The conjugate according to claim 35, wherein ring B is selected from wherein X 1a 、X 2a 、X 3 and X 4 are independently selected from -C(R 4 ) 2 -, -NH-, -O- and -S-, provided that when X 1a 、X 2a and X 3 are present, at least one of X 1a -X 3 is -C(R 4 ) 2 - and when X 1a 、X 2a 、X 3 and X 4 are present, at least two of X 1a -X 4 are -C(R 4 ) 2 ; and R 4 independently selected from 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 4 groups together on the same carbon form an oxo group.

39. The conjugate according to claim 35, wherein ring B is selected from 40. The conjugate according to claim 35, wherein ring A is selected from wherein X 1a , X 2a , X 3 and X 4 are independently selected from -C(R 4 ) 2 -, -NH-, -O- and -S-, provided that when X 1a , X 2a and X 3 are present, at least one of X 1a -X 3 is -C(R 4 ) 2 - and when X 1a , X 2a , X 3 and X 4 are present, at least two of X 1a -X 4 are -C(R 4 ) 2 ; X 5 is N or CR 4 ; and R 4 independently selected from 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 4 groups on the same carbon together form an oxo group.

41. The conjugate according to any one of claims 35 and 37 - 40, wherein L 1a is 42. The conjugate according to any one of claims 35-41, wherein L 2 is -(CR a R b ) a -POLY 1 -, wherein POLY 1 - is a divalent residue of polyethylene glycol (PEG), poly(propylene glycol) (PPG), or a copolymer of ethylene glycol and propylene glycol; wherein denotes attachment to the remainder of the compound.

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

44. The conjugate according to any one of claims 35 - 43, wherein Su is 45. The conjugate according to any one of claims 35-44, wherein the 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 hamitrine residue, a camptothecin residue, a camptothecin derivative, an anthracycline residue, PNU-159682 and PNU-159682 derivatives, PBD, bleomycin analogs.

46. The antibody conjugate according to any one of the preceding claims, wherein the antibody conjugate has a structure selected from the group consisting of: wherein n2 is an integer from 1 to 10.

47. The antibody conjugate according to claim 1, wherein the antibody conjugate has a structure selected from the group consisting of: wherein n2 is an integer from 1 to 10.

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

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

50. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L Three heavy chain CDRs or their variants and three light chain CDRs or their variants: SEQ ID NO: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, 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, 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 / 1021, 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, 936 / 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, 950 / 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, 979 / 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 / 1021, 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.

51. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L The three heavy-chain CDRs or variants thereof and the three light-chain CDRs or variants thereof: SEQ ID NO: 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, 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 / 1022, 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 / 1022, 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, 936 / 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, 950 / 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, 979 / 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 / 1022, 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.

52. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L Three heavy-chain CDRs of the antibody or their variants, and three light-chain CDRs of the antibody or their variants: SEQ ID NO: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, 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 / 1023, 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 / 1023, 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, 936 / 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, 950 / 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, 979 / 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 / 1023, 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.

53. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of H / V L Three heavy-chain CDRs or their variants and three light-chain CDRs or their variants: SEQ ID NO: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, 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 / 1024, 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 / 1024, 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, 936 / 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, 950 / 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, 979 / 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 / 1024, 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.

54. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of H / V L Three heavy-chain CDRs or their variants and three light-chain CDRs or their variants: SEQ ID NO: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, 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 / 1025, 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 / 1025, 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, 936 / 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, 950 / 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, 979 / 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 / 1025, 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.

55. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L Three heavy-chain CDRs or variants thereof and three light-chain CDRs or variants thereof: SEQ ID NO: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, 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 / 1026, 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 / 1026, 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, 936 / 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, 950 / 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, 979 / 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 / 1026, 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.

56. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from SEQ ID NO: 854-1020 H .

57. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from SEQ ID NO: 1021-1026 L .

58. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L pair, or its variants: SEQ ID NO: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, 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, 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 / 1021, 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, 936 / 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, 950 / 1021, 951 / 1021, 952 / 1021, 953 / 1021, 954 / 1021, 955 / 1021, 956 / 1021, 957 / 1021, 958 / 1021, 959 / 1021, 960 / 1021, 961 / 1021, 962 / 1021963 / 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, 979 / 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 / 1021, 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.

59. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L Pairs, or variants thereof: SEQ ID NO: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, 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 / 1022, 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 / 1022, 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, 936 / 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, 950 / 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, 979 / 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 / 1022, 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.

60. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of H / V L pair, or its variants: SEQ ID NO: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, 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 / 1023, 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 / 1023, 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, 936 / 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, 950 / 1023, 951 / 1023, 952 / 1023, 953 / 1023, 954 / 1023, 955 / 1023, 956 / 1023, 957 / 1023, 958 / 1023, 959 / 1023, 960 / 1023, 961 / 1023, 962 / 1023963 / 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, 979 / 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 / 1023, 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.

61. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L Pairs, or variants thereof: SEQ ID NO: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, 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 / 1024, 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 / 1024, 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, 936 / 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, 950 / 1024, 951 / 1024, 952 / 1024, 953 / 1024, 954 / 1024, 955 / 1024, 956 / 1024, 957 / 1024, 958 / 1024, 959 / 1024, 960 / 1024, 961 / 1024, 962 / 1024963 / 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, 979 / 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 / 1024, 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.

62. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L pair, or its variants: SEQ ID NO: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, 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 / 1025, 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 / 1025, 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, 936 / 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, 950 / 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, 979 / 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 / 1025, 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.

63. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises a V selected from the group consisting of the following H / V L pair, or its variants: SEQ ID NO: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, 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 / 1026, 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 / 1026, 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, 936 / 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, 950 / 1026, 951 / 1026, 952 / 1026, 953 / 1026, 954 / 1026, 955 / 1026, 956 / 1026, 957 / 1026, 958 / 1026, 959 / 1026, 960 / 1026, 961 / 1026, 962 / 1026963 / 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, 979 / 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 / 1026, 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.

64. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises three Chothia HC CDRs according to one of the following HC CDR sets: SEQ ID NO: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 / 693; 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 / 393 / 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 / 749; 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; 133 / 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; 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.; 65. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises six CDRs according to one of the following CDR sets: SEQ ID NO: 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 / 682 / 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 / 844 / 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 / 839 / 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 / 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 conjugate according to any one of the preceding claims, wherein the antibody comprises three Kabat HC CDRs according to one of the following HC CDR sets: SEQ ID NO: 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 / 524 / 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 / 701; 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 / 565 / 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 / 742; 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; 335 / 669 / 836; 336 / 670 / 837; and 337 / 671 / 838.

67. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises six CDRs according to one of the following CDR sets: SEQ ID NO: 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 / 844 / 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 / 697 / 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 / 839 / 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； 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 conjugate according to any one of the preceding claims, wherein the antibody comprises: (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 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.

69. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises three heavy chain CDRs of the V H region SEQ ID NO: 854 and three light chain CDRs of the V L region SEQ ID NO: 1021.

70. The antibody conjugate according to any one of the preceding claims, wherein the antibody comprises: (a)V H , which comprises: a CDR-H1 comprising at least one of SEQ ID NO:4 and 171; a CDR-H2 comprising at least one of SEQ ID NO:338 and 505; and a CDR-H3 comprising SEQ ID NO:672; and V L , which comprises: a CDR-L1 comprising SEQ ID NO:839; a CDR-L2 comprising SEQ ID NO:844; and a CDR-L3 comprising SEQ ID NO:849; (b)V H , comprising: a CDR-H1 comprising at least one of SEQ ID NO:9 and 176; a CDR-H2 comprising at least one of SEQ ID NO:343 and 510; and a CDR-H3 comprising SEQ ID NO:677; and V L , comprising: a CDR-L1 comprising SEQ ID NO:839; a CDR-L2 comprising SEQ ID NO:844; and a CDR-L3 comprising SEQ ID NO:849; or (c)V H , comprising: a CDR-H1 comprising at least one of SEQ ID NO: 45 and 212; a CDR-H2 comprising at least one of SEQ ID NO: 379 and 546; and a CDR-H3 comprising SEQ ID NO: 713; and V L , comprising: a CDR-L1 comprising SEQ ID NO: 839; a CDR-L2 comprising SEQ ID NO: 844; and a CDR-L3 comprising SEQ ID NO:

849.

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

72. The antibody conjugate according to claim 71, wherein the amino acid substitution is a conservative amino acid substitution.

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

74. The antibody conjugate according to any one of the preceding claims, wherein the antibody conjugate comprises: (a) An antibody, which comprises V H , said V H comprising: CDR-H1 comprising at least one of SEQ ID NO: 45 and 212; CDR-H2 comprising at least one of SEQ ID NO: 379 and 546; and CDR-H3 comprising SEQ ID NO: 713; and V L , which comprises: CDR-L1 comprising SEQ ID NO: 839; CDR-L2 comprising SEQ ID NO: 844; and CDR-L3 comprising SEQ ID NO: 849; (b) a para - azidomethylphenylalanine residue at the antibody site HC404; and (c) the following linker - payload structure, wherein n2 is 2, and each linker - payload is bonded to one of the side chains of the para - azidomethylphenylalanine residue:

75. The antibody conjugate according to any one of the preceding claims, wherein the antibody conjugate comprises: (a) An antibody, which comprises V H wherein the V H comprises: CDR-H1 comprising at least one of SEQ ID NO: 45 and 212; CDR-H2 comprising at least one of SEQ ID NO: 379 and 546; and CDR-H3 comprising SEQ ID NO: 713; and V L which comprises: CDR-L1 comprising SEQ ID NO: 839; CDR-L2 comprising SEQ ID NO: 844; and CDR-L3 comprising SEQ ID NO: 849; (b) para - azidomethylphenylalanine residues at antibody sites HC180 and HC404; and (c) the following linker - payload structures, where n2 is 4, and each linker - payload is bonded to one of the side chains of the para - azidomethylphenylalanine residue:

76. The antibody conjugate according to any one of the preceding claims, wherein the antibody conjugate comprises: (a) An antibody, which comprises V H wherein the V H comprises: CDR-H1 comprising at least one of SEQ ID NO: 45 and 212; CDR-H2 comprising at least one of SEQ ID NO: 379 and 546; and CDR-H3 comprising SEQ ID NO: 713; and V L which comprises: CDR-L1 comprising SEQ ID NO: 839; CDR-L2 comprising SEQ ID NO: 844; and CDR-L3 comprising SEQ ID NO: 849; (b) para - azidomethylphenylalanine residues at antibody sites HC180, HC241, HC404, and LC42; and (c) the following linker - payload structures, where n2 is 8, and each linker - payload is bonded to one of the side chains of the para - azidomethylphenylalanine residue:

77. The antibody conjugate according to any one of the preceding claims, wherein the antibody conjugate comprises: (a) An antibody comprising V H wherein said V H comprises: CDR-H1 comprising at least one of SEQ ID NO: 45 and 212; CDR-H2 comprising at least one of SEQ ID NO: 379 and 546; and CDR-H3 comprising SEQ ID NO: 713; and V L which comprises: CDR-L1 comprising SEQ ID NO: 839; CDR-L2 comprising SEQ ID NO: 844; and CDR-L3 comprising SEQ ID NO: 849; (b) para - azidomethylphenylalanine residues at antibody sites HC180, HC241, HC404, and LC42; and (c) the following linker - payload structures, where n2 is 8, and each linker - payload is bonded to one of the side chains of the para - azidomethylphenylalanine residue:

78. The antibody conjugate according to any one of the preceding claims, wherein the antibody conjugate comprises: (a) An antibody comprising a V H wherein the V H comprises: CDR-H1 comprising at least one of SEQ ID NO:45 and 212; CDR-H2 comprising at least one of SEQ ID NO:379 and 546; and CDR-H3 comprising SEQ ID NO:713; and a V L which comprises: CDR-L1 comprising SEQ ID NO:839; CDR-L2 comprising SEQ ID NO:844; and CDR-L3 comprising SEQ ID NO:849; (b) para - azidomethylphenylalanine residues at antibody sites HC180, HC241, HC404, and LC42; and (c) the following linker - payload structures, where n2 is 8, and each linker - payload is bonded to one of the side chains of the para - azidomethylphenylalanine residue:

79. The antibody conjugate according to any one of the preceding claims, wherein the antibody conjugate comprises: (a) An antibody, which comprises V H , said V H comprising: CDR-H1 comprising at least one of SEQ ID NO: 45 and 212; CDR-H2 comprising at least one of SEQ ID NO: 379 and 546; and CDR-H3 comprising SEQ ID NO: 713; and V L , which comprises: CDR-L1 comprising SEQ ID NO: 839; CDR-L2 comprising SEQ ID NO: 844; and CDR-L3 comprising SEQ ID NO: 849; (b) para - azidomethylphenylalanine residues at antibody sites HC180, HC241, and HC404; and (c) the following linker - payload structures, where n2 is 8, and each linker - payload is bonded to one of the side chains of the para - azidomethylphenylalanine residue:

80. The antibody conjugate according to any one of claims 74-79, wherein the antibody comprises V H / V L to SEQ ID NO: 895 / 1021.

81. The antibody conjugate according to any one of the preceding claims, wherein the antibody binds to the same epitope as a second antibody having a V H region selected from SEQ ID NO: 854-1020 and a V L region selected from SEQ ID NO: 1021-1026.

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

83. The antibody conjugate according to any one of the preceding claims, wherein the antibody has a k of about 9.17 x 10 4 M -1 × sec -1 to about 5.94 x 10 6 M -1 × sec -1 when associating with human ROR1 at 25 °C a .

84. The antibody conjugate according to any one of the preceding claims, wherein the antibody has a k of about 1.01×10 -4 sec -1 to about 0.05 sec -1 when dissociating from human ROR1 at a temperature of 25°C. d .

85. The antibody conjugate according to any one of the preceding claims, wherein the antibody has a K of about 1.39x10 -10 M to about 1.01x10 -7 M when binding to human ROR1 at a temperature of 25°C D .

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

87. The antibody conjugate according to claim 86, wherein the constant region comprises a sequence selected from SEQ ID NO: 1027 - 1029.

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

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

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

91. The antibody conjugate according to any one of the preceding claims, wherein the antibody is glycosylated.

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

93. The antibody conjugate according to claim 92, wherein the antibody fragment is selected from Fv fragments, Fab fragments, F(ab’) 2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

94. The antibody conjugate according to claim 92, wherein the antibody is a scFv fragment.

95. An isolated antibody that specifically binds to ROR1, wherein the antibody comprises three heavy chain CDRs from a V H sequence selected from SEQ ID NO: 854 - 1020 or variants thereof, and three light chain CDRs from a V L sequence selected from SEQ ID NO: 1021 - 1026 or variants thereof.

96. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Three heavy-chain CDRs or their variants and three light-chain CDRs or their variants: SEQ ID NO: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, 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, 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 / 1021, 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, 936 / 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, 950 / 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, 979 / 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 / 1021, 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.

97. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of H / V L Three heavy-chain CDRs or variants thereof and three light-chain CDRs or variants thereof: SEQ ID NO: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, 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 / 1022, 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 / 1022, 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, 936 / 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, 950 / 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, 979 / 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 / 1022, 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.

98. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L The three heavy chain CDRs or their variants and the three light chain CDRs or their variants: SEQ ID NO: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, 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 / 1023, 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 / 1023, 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, 936 / 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, 950 / 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, 979 / 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 / 1023, 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.

99. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Three heavy-chain CDRs or variants thereof and three light-chain CDRs or variants thereof: SEQ ID NO: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, 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 / 1024, 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 / 1024, 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, 936 / 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, 950 / 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, 979 / 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 / 1024, 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.

100. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Three heavy chain CDRs or their variants and three light chain CDRs or their variants: SEQ ID NO: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, 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 / 1025, 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 / 1025, 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, 936 / 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, 950 / 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, 979 / 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 / 1025, 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.

101. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Three heavy-chain CDRs or variants thereof and three light-chain CDRs or variants thereof: SEQ ID NO: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, 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 / 1026, 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 / 1026, 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, 936 / 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, 950 / 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, 979 / 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 / 1026, 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.

102. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from SEQ ID NO: 854-1020 H .

103. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from SEQ ID NO: 1021-1026 L .

104. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Pairs, or variants thereof: SEQ ID NO: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, 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, 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 / 1021, 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, 936 / 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, 950 / 1021, 951 / 1021, 952 / 1021, 953 / 1021, 954 / 1021, 955 / 1021, 956 / 1021, 957 / 1021, 958 / 1021, 959 / 1021, 960 / 1021, 961 / 1021, 962 / 1021963 / 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, 979 / 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 / 1021, 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.

105. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L pair, or its variants: SEQ ID NO: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, 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 / 1022, 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 / 1022, 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, 936 / 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, 950 / 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, 979 / 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 / 1022, 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.

106. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Pairs, or variants thereof: SEQ ID NO: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, 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 / 1023, 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 / 1023, 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, 936 / 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, 950 / 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, 979 / 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 / 1023, 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.

107. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Pairs, or variants thereof: SEQ ID NO: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, 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 / 1024, 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 / 1024, 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, 936 / 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, 950 / 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, 979 / 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 / 1024, 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.

108. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Pairs, or variants thereof: SEQ ID NO: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, 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 / 1025, 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 / 1025, 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, 936 / 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, 950 / 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, 979 / 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 / 1025, 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.

109. The isolated antibody according to claim 95, wherein the antibody comprises a V selected from the group consisting of the following H / V L Pairs, or variants thereof: SEQ ID NO: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, 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 / 1026, 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 / 1026, 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, 936 / 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, 950 / 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, 979 / 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 / 1026, 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.

110. The isolated antibody according to claim 95, wherein the antibody comprises three Chothia HC CDRs according to one of the following HC CDR sets: SEQ ID NO: 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 / 693; 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 / 393 / 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 / 749; 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; 133 / 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; 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 isolated antibody according to claim 95, wherein the antibody comprises six CDRs according to one of the following CDR sets: SEQ ID NO: 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 / 682 / 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 / 844 / 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 / 839 / 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 / 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 isolated antibody according to claim 95, wherein the antibody comprises three Kabat HC CDRs according to one of the following HC CDR sets: SEQ ID NO: 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 / 524 / 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 / 701; 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 / 565 / 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 / 742; 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; 335 / 669 / 836; 336 / 670 / 837; and 337 / 671 / 838.

113. The isolated antibody according to claim 95, wherein the antibody comprises six CDRs according to one of the following CDR sets: SEQ ID NO: 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 / 844 / 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 / 697 / 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 / 839 / 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； 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 isolated antibody according to any one of claims 95-109, wherein the antibody comprises: (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 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.

115. The isolated antibody according to claim 114, wherein the antibody comprises three heavy chain CDRs of the V H region SEQ ID NO: 854 and three light chain CDRs of the V L region SEQ ID NO: 1021.

116. The isolated antibody according to any one of claims 95-115, wherein the antibody comprises: (a)V H , which comprises: a CDR-H1 comprising at least one of SEQ ID NO: 4 and 171; a CDR-H2 comprising at least one of SEQ ID NO: 338 and 505; and a CDR-H3 comprising SEQ ID NO: 672; and V L , which comprises: a CDR-L1 comprising SEQ ID NO: 839; a CDR-L2 comprising SEQ ID NO: 844; and a CDR-L3 comprising SEQ ID NO: 849; (b)V H , which comprises: a CDR-H1 comprising at least one of SEQ ID NO:9 and 176; a CDR-H2 comprising at least one of SEQ ID NO:343 and 510; and a CDR-H3 comprising SEQ ID NO:677; and V L , which comprises: a CDR-L1 comprising SEQ ID NO:839; a CDR-L2 comprising SEQ ID NO:844; and a CDR-L3 comprising SEQ ID NO:849; or (c)V H , which comprises: a CDR-H1 comprising at least one of SEQ ID NO: 45 and 212; a CDR-H2 comprising at least one of SEQ ID NO: 379 and 546; and a CDR-H3 comprising SEQ ID NO: 713; and V L , which comprises: a CDR-L1 comprising SEQ ID NO: 839; a CDR-L2 comprising SEQ ID NO: 844; and a CDR-L3 comprising SEQ ID NO:

849.

117. The isolated antibody according to any one of claims 95-116, wherein the antibody comprises the following: V H , which comprises: CDR-H1 comprising at least one of SEQ ID NO: 4 and 171; CDR-H2 comprising at least one of SEQ ID NO: 338 and 505; and CDR-H3 comprising SEQ ID NO: 672; and V L , which comprises: CDR-L1 comprising SEQ ID NO: 839; CDR-L2 comprising SEQ ID NO: 844; and CDR-L3 comprising SEQ ID NO:

849.

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

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

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

121. An isolated antibody that specifically binds to ROR1, wherein the antibody binds to the same epitope as a second antibody having a V H region selected from SEQ ID NO: 854 - 1020 and a V L region selected from SEQ ID NO: 1021 - 1026.

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

123. The isolated antibody according to any one of claims 95-122, wherein the antibody has a k of about 9.17x10 4 M -1 ×sec -1 to about 5.94×10 6 M -1 ×sec -1 when associating with human ROR1 at a temperature of 25°C a .

124. The isolated antibody according to any one of claims 95-123, wherein the antibody has a k of about 1.01×10 -4 sec -1 to about 0.05 sec -1 when dissociating from human ROR1 at a temperature of 25°C. d .

125. The isolated antibody according to any one of claims 95-124, wherein the antibody has a K of about 1.39x10 -10 M to about 1.01x10 -7 M when binding to human ROR1 at a temperature of 25°C D .

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

127. The isolated antibody according to claim 126, wherein the constant region comprises a sequence selected from SEQ ID NO: 1027-1029.

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

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

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

131. The isolated antibody according to any one of claims 95-130, wherein the antibody is non-glycosylated.

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

133. The isolated antibody according to claim 132, wherein the antibody fragment is selected from Fv fragment, Fab fragment, F(ab’) 2 fragment, Fab’ fragment, scFv (sFv) fragment, and scFv-Fc fragment.

134. The isolated antibody according to claim 133, wherein the antibody is a scFv fragment.

135. A kit comprising the antibody conjugate according to any one of claims 1-94 or the isolated antibody according to any one of claims 95-134, and an instruction manual.

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

137. The kit according to claim 136, which further comprises a liquid for reconstituting the lyophilized antibody conjugate or the isolated antibody.

138. A polynucleotide encoding an antibody as claimed in any one of claims 95 - 134.

139. A vector comprising the polynucleotide as claimed in claim 138.

140. A recombinant host cell comprising the vector as claimed in claim 139.

141. The host cell as claimed in claim 140, wherein the host cell is selected from bacterial cells, fungal cells and mammalian cells.

142. The host cell as claimed in claim 141, wherein the host cell is selected from Escherichia coli cells, Saccharomyces cerevisiae cells and CHO cells.

143. A cell-free expression reaction comprising the vector as claimed in claim 139.

144. A pharmaceutical composition comprising an antibody conjugate as claimed in any one of claims 1 - 94 or an isolated antibody as claimed in any one of claims 95 - 134 and a pharmaceutically acceptable carrier.

145. A pharmaceutical composition comprising (a) an antibody conjugate as claimed in any one of claims 1 - 94 or an isolated antibody as claimed in any one of claims 95 - 134, (b) one or more additional active agents; and (c) a pharmaceutically acceptable carrier.

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

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

148. The pharmaceutical composition as claimed in claim 147, wherein the one or more checkpoint inhibitors are PD-1 inhibitors or PD-L1 inhibitors.

149. The pharmaceutical composition as claimed in 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 as claimed in 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 pharmaceutical composition according to any one of claims 147 to 150, wherein 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, cemiplimab, TSR-042, tislelizumab / BGB-A317, CK-301, BMS-936559, camrelizumab, sintilimab, toripalimab, golimumab, 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. The pharmaceutical composition according to claim 145, wherein the one or more additional active agents are one or more PARP inhibitors.

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

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

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

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

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

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

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

160. The method according to claim 158, wherein the effective amount of the antibody conjugate as described in any one of claims 1 to 94, or the isolated antibody as described in any one of claims 95 - 134, or the pharmaceutical composition as described in any one of claims 144 to 154, and the one or more additional active agents are administered in parallel.

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

162. The method according to claim 161, wherein the one or more checkpoint inhibitors are PD - 1 inhibitors, PD - Ll inhibitors, PD - L2 inhibitors, CTLA - 4 inhibitors, LAG - 3 inhibitors or TIM - 3 inhibitors.

163. The method according to claim 162, wherein the one or more checkpoint inhibitors are PD - 1 inhibitors or PD - Ll inhibitors.

164. The method according to 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. The method according to 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 method according to claim 163, wherein 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, cemiplimab, TSR-042, tislelizumab / BGB-A317, CK-301, BMS-936559, camrelizumab, sintilimab, toripalimab, golimumab, 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. The method according to any one of claims 158-160, wherein the one or more additional active agents are one or more PARP inhibitors.

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

169. The method according to claim 168, wherein the one or more PARP inhibitors are olaparib.

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

171. The method according to any one of claims 155-169, wherein the disease or disorder is hematological cancer.

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

173. The method according to any one of claims 155-169, wherein the disease or disorder is colorectal cancer.

174. The method according to any one of claims 155-169, wherein the disease or disorder is breast cancer.

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

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

177. The method according to claim 175 or 176, wherein the triple-negative breast cancer is BRCA 1 / 2 wild-type triple-negative breast cancer.

178. The method according to claim 175 or 176, wherein the triple-negative breast cancer is a BRCA1 / 2-mutated triple-negative breast cancer.

179. The method according to any one of claims 155-169, wherein the disease or disorder is ovarian cancer.

180. The method according to any one of claims 155-169, wherein the disease or disorder is cervical cancer.

181. The method according to any one of claims 155-169, wherein the disease or disorder is lung cancer.

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

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

184. The method according to any one of claims 155-169, wherein the disease or disorder is endometrial cancer.

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

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

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

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

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

190. A method of diagnosing cancer in a subject in need thereof, the method comprising: a) administering to the subject an effective amount of an antibody conjugate according to any one of claims 1 to 94, or an isolated antibody according to any one of claims 95-134, or a pharmaceutical composition according to any one of claims 144 to 154, wherein the antibody-drug conjugate contained in the antibody-drug conjugate according to any one of claims 1-94, the isolated antibody according to any one of claims 95-134, or the pharmaceutical composition according to any one 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.

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

192. A method for diagnosing cancer in a subject in need thereof, the method comprises: a) detecting the expression of ROR1 in a cell or tissue of the subject; and b) administering to the subject an effective amount of an antibody conjugate as described in any one of claims 1 to 94 or an isolated antibody as described in any one of claims 95 - 134, or a pharmaceutical composition as described in any one of claims 144 to 154.

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