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

Abstract

This invention relates to antibodies and antibody-drug conjugates that selectively bind tissue factors and their isotypes and homologs, as well as compositions comprising said antibodies. The invention also provides methods of using said antibodies and antibody-drug conjugates, such as therapeutic and diagnostic methods.

Description

[0001] Cross-reference to related applications This application claims and enjoys priority to U.S. Provisional Application No. 63 / 590,343, filed October 13, 2023, and U.S. Provisional Application No. 63 / 684,699, filed August 19, 2024. All provisional applications are incorporated herein by reference in their entirety for all purposes.

[0002] Electronic sequence list reference This application includes a sequence list submitted electronically in .XML format, which is incorporated herein by reference in its entirety. A copy of the .XML file was created on October 7, 2024, and is named “108843.00506.xml”, with a size of 1,460,613 bytes. The sequence list contained in the .XML file is an integral part of this specification and is incorporated herein by reference in its entirety. Invention Field

[0003] This invention generally relates to antibodies and antibody-drug conjugates that have binding specificity to tissue factor, and compositions comprising said antibodies or antibody-drug conjugates, including pharmaceutical compositions, diagnostic compositions, and kits. The invention also provides methods for preparing anti-tissue factor antibodies and antibody-drug conjugates, and methods for using said anti-tissue factor antibodies and antibody-drug conjugates, for example, for therapeutic, diagnostic, and research purposes. Background of the Invention Tissue factor (TF), also known as CD142, is a cell membrane glycoprotein. Tissue factor is sometimes called coagulation factor III because it is a major initiator of blood clotting. The complexation of factor VIIa with tissue factor (TF:FVIIa complex) activates the thrombin cascade. (Mackman) et al. , 2004, Atherosclerosis, Thrombosis and Vascular Biology 24:1015-1022. Tissue factor (TF) is expressed in the subendothelial layer. When the endothelium is damaged, tissue factor binds to circulating factor VII to activate factor X. Activated factor X initiates the coagulation cascade, leading to thrombus formation.

[0005] Aberrant expression of TF plays a role in thrombosis in various diseases, including sepsis, atherosclerosis, and cancer. TF is also associated with inflammation, angiogenesis, metastasis, and cell migration. (Mackman) et al. , 2004, Atherosclerosis, Thrombosis, and Vascular Biology 24:1015-1022. TF is widely expressed in a variety of solid tumor indications.

[0006] Therefore, there is a need to improve methods for regulating tissue factor (TF) activity and downstream coagulation signaling pathways activated by TF. Furthermore, given the role of TF in thrombosis, there is a need to improve therapeutic agents and methods that can specifically target cells and tissues expressing TF. Antibody-conjugates targeting TF can be used to partially deliver therapeutic or diagnostic payload groups to TF-expressing target cells for the treatment or diagnosis of such diseases. Invention Abstract

[0007] This invention provides antibodies that selectively bind to tissue factor (TF). In some embodiments, the antibody binds to human TF. In some embodiments, the antibody also binds to a homolog of human TF. In some embodiments, the homolog includes a cynomolgus monkey homolog.

[0008] This invention also provides antibody-drug conjugates that selectively bind to TF. The antibody-drug conjugate comprises an antibody capable of binding to TF, the antibody being linked to one or more payload group portions. The antibody can be directly linked to the payload via a covalent bond or indirectly linked to the payload via a linker. This invention describes in detail TF antibodies, available payload group portions, and available linkers.

[0009] In some embodiments, the antibody or antibody-drug conjugate comprises the exemplary CDR, V provided by the present invention. H V L HC or LC sequences, or variants thereof. In some states, the variant is a variant having one or more conserved amino acid substitutions. In some states, the variant has sequence identity with one or more exemplary sequences.

[0010] On the other hand, the present invention provides compositions comprising the said antibody or antibody-drug conjugate. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the pharmaceutical composition is for parenteral administration. Any suitable pharmaceutical composition can be used. In some embodiments, the pharmaceutical composition is a composition for parenteral administration. In a further aspect, the present invention provides kits comprising the said antibody or antibody-drug conjugate or pharmaceutical composition.

[0011] This invention also provides methods for using the anti-TF antibody or antibody-drug conjugate provided by this invention. In some embodiments, these methods are methods for delivering one or more payload group portions to target cells or target tissues expressing TF. In some embodiments, the methods are methods for treatment. In some embodiments, the methods are diagnostic methods. In some embodiments, the methods are analytical methods. In some embodiments, the methods are methods for purifying and / or quantifying TF.

[0012] In some embodiments, the antibody, antibody-drug conjugate, or pharmaceutical composition thereof is used to treat a disease or condition. In some embodiments, the disease or condition is a malignant tumor expressing TF. In some embodiments, the disease or condition is selected from cancer, autoimmune diseases, and infections.

[0013] In some embodiments, the antibody or antibody-drug conjugate binds to human TF. In some embodiments, the antibody or antibody-drug conjugate also binds to homologs of human TF. In some embodiments, the antibody or antibody-drug conjugate also binds to homologs of cynomolgus monkey and / or mouse TF.

[0014] The present invention and its many features are described in more detail below with reference to the text and accompanying drawings.

[0015] Brief description of the attached figures Figure 1A A comparison of the Kabat and Chothia numbering systems for CDR-H1 is provided. Adapted from Martin ACR (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In R. Kontermann & S. Dübel (Eds.), Antibody Engineering vol. 2 (pp. 33-51). Springer-Verlag, Berlin Heidelberg.

[0016] Figure 1B A general schematic design of a representative antibody conjugate of the present invention is provided, wherein 1 is TF, 2 is a non-natural amino acid (pAMF), 3 is a β-glucuronidase linker, and 4 is an exatecan payload.

[0017] Figure 2 Thrombin generation data for conjugate 1 and conjugate 26 are provided.

[0018] Figure 3A Provided coupling 7 in 4 o C, 25 o C and 37 o HPLC-SEC results comparing the formulation buffer under C conditions.

[0019] Figure 3B Provided coupling element 2 in 4 o C, 25 o C and 37 o HPLC-SEC results under C conditions.

[0020] Figure 4 HPLC-SEC results are provided for conjugate 2 in one formulation buffer and conjugate 7 in three different formulation buffers after five freeze-thaw cycles.

[0021] Figure 5 The viability of CD66b+ cells in neutrophil precursor cells treated with conjugates 2, 3, and 6 is provided (expressed as a percentage relative to the PBS control group).

[0022] Figure 6A The results of the drug-antibody ratio (DAR) assay for conjugates 2, 6 and 7 over 21 days are provided.

[0023] Figure 6B Deconvolution mass spectra of anti-TF ADC samples for coupling compounds 2, 6, and 7 in the study of in vivo linker payload stability are provided.

[0024] Figures 7A-7C Growth curves of HCC1954 tumors after a single intravenous injection of TF-targeted ADC were provided, with the doses being ( Figure 7A 0.5 mg / kg or ( Figure 7B 5 mg / kg. Figure 7C A scatter plot of tumor volume at day 35 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of drug administration. Statistical analysis of tumor volume at day 35 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM.

[0025] Figures 8A-8B Growth curves of H1975 tumors after a single intravenous injection of TF-targeted ADC at doses of 1 mg / kg or 2 mg / kg are provided. Figure 8A ). Figure 8B A scatter plot of tumor volume on day 17 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 17 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM.

[0026] Figures 9A-9B Growth curves for H1975 tumors after a single intravenous injection of TF-targeted ADC at doses ranging from 0.5 mg / kg to 2 mg / kg are provided. Figure 9A ). Figure 9B A scatter plot of tumor volume on day 18 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 18 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM.

[0027] Figures 10A-10D Growth curves of MDA-MB-231 tumors after treatment with TF-targeted ADC at doses ranging from 0.5 mg / kg to 2 mg / kg via twice-weekly intravenous injection (qwx2) are provided. Figure 10A ). Figure 10B A scatter plot of tumor volume at day 42 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume at day 42 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM. Figure 10C Growth curves of MDA-MB-231 tumors after treatment with TF-targeted ADC at doses ranging from 0.25 mg / kg to 1 mg / kg via twice-weekly intravenous injection (qwx2). Figure 10D A scatter plot of tumor volume on day 41 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 41 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM.

[0028] Figures 11A-11D Growth curves for H1975 tumors after a single intravenous injection of TF-targeted ADC therapy at doses ranging from 0.25 mg / kg to 2 mg / kg are provided. Figure 11A ). Figure 11BA scatter plot of tumor volume on day 24 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 24 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. *** = p<0.001; **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM. Figure 11C Growth curves of H1975 tumors after single intravenous injection of TF-targeted ADCs ranging from 0.125 mg / kg to 1 mg / kg are provided. Figure 11D Scatter plots of tumor volumes on day 25 post-treatment (when tumors in the control group reached the study endpoint) are provided. Statistical analysis of tumor volumes on day 25 was performed using one-way ANOVA and Dunnett's multiple comparison test, and comparisons were made with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. ** = p<0.01; **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM.

[0029] Figures 12A-12D Growth curves of Detroit 562 tumors after treatment with conjugate 7 at a single intravenous dose of 1 mg / kg or 2 mg / kg are provided. Figure 12A ). Figure 12B A scatter plot of tumor volume on day 21 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 21 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM. Figure 12C Growth curves of Detroit562 tumors after single intravenous injection of TF-targeted ADCs ranging from 0.25 mg / kg to 2 mg / kg are provided. Figure 12DScatter plots of tumor volumes on day 21 post-treatment (when tumors in the control group reached the study endpoint) are provided. Statistical analysis of tumor volumes on day 21 was performed using one-way ANOVA and Dunnett's multiple comparison test, and comparisons were made with the vehicle group. A probability less than 5% (p < 0.05) was considered statistically significant. **** = p < 0.0001. All figures are presented as single values ​​or mean ± SEM.

[0030] Figures 13A-13B Growth curves for HCT-116 tumors after single intravenous injection of TF-targeted ADCs ranging from 2.5 mg / kg to 15 mg / kg are provided. Figure 13A ). Figure 13B Scatter plots of tumor volumes on day 21 post-treatment (when tumors in the control group reached the study endpoint) are provided. Statistical analysis of tumor volumes on day 21 was performed using one-way ANOVA and Dunnett's multiple comparison test, and comparisons were made with the vehicle group. A probability less than 5% (p < 0.05) was considered statistically significant. **** = p < 0.0001. All figures are presented as single values ​​or mean ± SEM.

[0031] Figures 14A-14D Growth curves for MC38-hTF tumors after a single intravenous injection of conjugate 7, multiple intraperitoneal injections of anti-PD-1, or combination therapy are provided. Figure 14A ). Figure 14B A scatter plot of tumor volume on day 6 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 6 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. ** = p<0.01; **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM. Figure 14C Growth curves for MC38-hTF tumors after a single intravenous injection of conjugate 35, multiple intraperitoneal injections of anti-PD-1 at 10 mg / kg, or combination therapy are provided. The number of complete responses (CRs) is indicated on the right side of the tumor growth curve. Figure 14DA scatter plot of tumor volume on day 8 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 8 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.0001. All figures are presented as single values ​​or mean ± SEM.

[0032] Figures 15A-15B Tumor growth curves of NSCLC PDX models after single intravenous injection of conjugate 7 at doses ranging from 0.3 mg / kg to 10 mg / kg are provided. Figure 15A ). Figure 15B A scatter plot of tumor volume on day 37 post-treatment (when tumors in the control group reached the study endpoint) is provided. Arrows indicate the number of days of treatment. Statistical analysis of tumor volume on day 37 was performed using one-way ANOVA and Dunnett's multiple comparison test, and compared with the vehicle group. A probability less than 5% (p<0.05) was considered statistically significant. **** = p<0.01; **** = p<0.001. All figures are presented as single values ​​or mean ± SEM. Detailed Implementation

[0033] 1. Definition Unless otherwise defined, all technical terms, symbols, and other scientific terms used in this invention are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In many cases, terms having a commonly understood meaning are defined in this invention for clear and / or easy reference, and their inclusion in this invention should not be construed as indicating a difference from that commonly understood in the art. The techniques and procedures described or referred to in this invention are generally well understood by one of ordinary skill in the art and are frequently employed using conventional methods, such as, for example, the widely used Sambrook et al. Molecular Cloning: A Laboratory Manual Molecular cloning methods described in 2nd ed. (1989) ColdSpring Harbor Laboratory Press, Cold Spring Harbor, NY. Methods involving the use of kits and reagents obtained commercially are generally performed according to manufacturer-defined protocols and conditions, where appropriate, unless otherwise stated.

[0034] The singular forms “a / a / item” and “the” used in this invention include plural references unless the context clearly indicates otherwise.

[0035] The term "about / approximately" indicates and covers the value shown and the range above and below this value. In some embodiments, the term "about / approximately" indicates ±10%, ±5%, or ±1% of the specified value. In some embodiments, the term "about / approximately" indicates ± one standard deviation of the specified value.

[0036] The term “the combination thereof” includes all possible combinations of the elements referred to by the term. For example, a sentence expressed as “A, B, C, and the combination thereof” includes the following combinations: (1) A, (2) A and B, (3) A, B and C, (4) A and C, (5) B, (6) B and C, and (7) C.

[0037] The terms "tissue factor," "TF," and "TF antigen" are used interchangeably in this invention. Unless otherwise stated, these terms include any variant, isotype, and species homolog of human tissue factor that is naturally expressed by cells or by cells transfected with the tissue factor gene. Tissue factor proteins include, for example, human tissue factor (SEQ ID NO: 1). In some embodiments, tissue factor proteins include cynomolgus monkey tissue factor (SEQ ID NO: 2). In some embodiments, tissue factor proteins include mouse tissue factor (SEQ ID NO: 3160). In some embodiments, tissue factor proteins include human tissue factor isotype 2 precursor (SEQ ID NO: 3161). In some embodiments, tissue factor proteins include mouse tissue factor precursor (SEQ ID NO: 3162).

[0038] The term "immunoglobulin" refers to a class of structurally related proteins that typically consist of two pairs of polypeptide chains: a pair of light (L) chains and a pair of heavy (H) chains. In a "complete immunoglobulin," all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been characterized in detail. See, for example, Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. In short, each heavy chain generally contains a heavy chain variable region (V... H ) and heavy chain constant region (C H The heavy chain constant region generally contains three structural domains, abbreviated as C. H1 C H2 and C H3 Each light chain generally contains a light chain variable region (V). L ( ) and the light chain constant region. The light chain constant region generally contains a structural domain, abbreviated as C. L .

[0039] The term "antibody" describes an immunoglobulin molecule and is used in its broadest sense throughout this invention. Antibodies specifically include intact antibodies (e.g., intact immunoglobulins) and antibody fragments. An antibody contains at least one antigen-binding domain. An example of an antigen-binding domain is a V... H -V L The antigen-binding domain formed by the dimer. The terms "tissue factor antibody," "anti-tissue factor antibody," "tissue factor Ab," "tissue factor specific antibody," or "anti-tissue factor Ab," or their equivalents, as used in this invention, all refer to the antibodies described in this invention capable of specifically binding to the antigen tissue factor. In some embodiments, the antibody binds to the extracellular domain of tissue factor.

[0040] V H District and V L The region can be further subdivided into high-variance regions ("HVR", also known as "complementary determinant regions (CDR)") scattered with more conservative regions. These more conservative regions are called frame regions (FR). Each V H and V L It typically contains three CDRs and four FRs (from N-terminus to C-terminus) arranged in the following order: FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. All CDRs participate in antigen binding and influence antigen specificity and antibody binding affinity. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, the entire contents of which are incorporated herein by reference.

[0041] Light chains of any vertebrate species can be classified into one of two types, called κ and λ, based on the sequence of constant structural domains.

[0042] The heavy chains of any vertebrate species can be classified into one of five distinct types (or allotypes): IgA, IgD, IgE, IgG, and IgM. These types are also named α, δ, ε, γ, and µ, respectively. IgG and IgA types are further subdivided based on sequence differences and function. Humans express the following subtypes: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0043] The amino acid sequence boundaries of a CDR can be determined by any of the known numbering schemes used by someone with ordinary knowledge in the relevant technical field, including Kabat et al., ibid. (“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 Honeggeand Plückthun, J. Mol. Biol. Those referenced in , 2001, 309:657-70 (“AHo” numbering scheme) are determined, and each reference is incorporated herein by reference in its entirety.

[0044] Table 1 provides the locations of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 identified using the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0045] Table 1. Residues in CDRs according to the Kabat and Chothia numbering schemes CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H1 (Kabbar ID) H31-H35B H26-H32 or H34* H1 (Coxie ID) H31-H35 H26-H32 H2 H50-H65 H52-H56 H3 H95-H102 H95-H102 * When using the Kaspersky numbering convention, the C-terminal of CDR-H1 will vary between H32 and H34 depending on the length of the CDR, such as... Figure 1A As shown.

[0046] Unless otherwise stated, the numbering scheme used to identify a specific CDR in this invention is the Kabat / Chothia numbering scheme. When the residues covered by these two numbering schemes branch (CDR-H1 and / or CDR-H2), the numbering scheme will be designated as Kabat or Chothia. For convenience, CDR-H3 is sometimes referred to as Kabat or Chothia in this invention. However, this is not intended to imply the absence of sequence differences, and those skilled in the art can easily determine whether the sequences are identical or different by examining the sequences.

[0047] CDRs can be assigned, for example, using antibody numbering software such as Abnum, which is available from http: / / www.bioinf.org.uk / abs / abnum / and is documented in Abhinandan and Martin. Immunology The entire contents of each of the references in this paper are incorporated herein by reference in 2008, 45:3832-3839.

[0048] When referring to residues in the constant region of the antibody heavy chain, the “EU numbering scheme” is typically used (e.g., Kabat et al., as reported above). Unless otherwise stated, the EU numbering scheme is used to refer to residues in the constant region of the antibody heavy chain as described in this invention.

[0049] An "antibody fragment" contains a portion of a complete antibody, such as the antigen-binding region or variable region of the complete antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0050] The “Fv” fragment is a non-covalently linked dimer of a heavy chain variable domain and a light chain variable domain.

[0051] In addition to the variable structural domains of the heavy and light chains, the “Fab” segment contains the constant structural domain of the light chain and the first constant structural domain (C) of the heavy chain. H1 Fab fragments can be generated, for example, by digesting full-length antibodies with papain or through recombinant methods.

[0052] The “F(ab’)2” fragment contains two Fab’ fragments linked by disulfide bonds near the hinge region. The F(ab’)2 fragment can be generated, for example, by digesting an intact antibody with pepsin or by recombinant methods. The F(ab’) fragment can be dissociated, for example, by treatment with β-mercaptoethanol.

[0053] A "single-chain Fv" or "sFv" or "scFv" antibody fragment is a V-shaped fragment contained within a single polypeptide chain. H Domain and V L Domain. V H and V L Typically, the linker is connected using a peptide linker. See Plückthun A. (1994). In some embodiments, the linker is SEQ ID NO: 3071. Antibodies from Escherichia coli . In Rosenberg M.&Moore GP (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, the entire text of which is incorporated herein by reference.

[0054] The “scFv-Fc” segment contains an scFv that is attached to the Fc structure field. For example, the Fc structure field can be attached to the C end of the scFv. The Fc structure field can be located at V. H or V L Then, depending on the directionality of the variable structural domain in scFv (i.e., V) H -VL or V L -V H Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises the IgG1 Fc domain. In some embodiments, the IgG1 Fc domain comprises SEQ ID NO: 3062 or a portion thereof, or SEQ ID NO: 3068. SEQ ID NO: 3062 provides the C0 of the human IgG1 constant region. H1 C H2 and C H3 The sequence of the constant region. In some embodiments, the constant region may contain a sequence selected from SEQ ID NO: 3062, SEQ ID NO: 3063, SEQ ID NO: 3064, and SEQ ID NO: 3065. SEQ ID NO: 3068 provides the sequence of the constant region used in the exemplary scFv-Fc antibody provided by the present invention. In some embodiments, the sequence of the constant region may be linked to scFv via a linker (e.g., but not limited to, the linker shown in SEQ ID NO: 3071). In some embodiments, the linker may be located at the N-terminus of the sequence shown in SEQ ID NO: 3068. In some embodiments, the constant region may further contain a FlagHis tag (e.g., the tag shown in SEQ ID NO: 3069), which may be located, for example, but not limited to, the C-terminus of the Fc sequence.

[0055] The term "monoclonal antibody" refers to an antibody derived from a family of substantially homogeneous antibodies. A family of substantially homogeneous antibodies comprises antibodies that are substantially similar and bind to the same epitope, excluding variants that normally occur during the production of monoclonal antibodies. Such variants are typically present only in small amounts. Monoclonal antibodies are generally obtained through a process involving the selection of a single antibody from a plurality of antibodies. For example, the selection process may involve choosing a unique clone from a set of multiple clones such as hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody may be further modified, for example, to improve affinity for the target ("affinity maturation"), humanize the antibody, improve its production in cell cultures, and / or reduce its immunogenicity in subjects.

[0056] The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or light chain is derived from a specific source or species, while the remainder of the heavy chain and / or light chain is derived from a different source or species.

[0057] A “humanized” form of a nonhuman antibody refers to a chimeric antibody containing a minimum sequence derived from a nonhuman antibody. Humanized antibodies are typically human immunoglobulins (recipient antibodies), in which one or more CDR residues are replaced by one or more CDR residues of a nonhuman antibody (donor antibody). The donor antibody can be any suitable nonhuman antibody, such as mouse, rat, rabbit, chicken, or nonhuman primate antibodies with the desired specificity, affinity, or biological effect. In some embodiments, selected frame region residues of the recipient antibody are replaced by residues of the corresponding frame region of the donor antibody. Humanized antibodies may also contain residues not present in either the recipient or donor antibody. Such modifications can be made to further improve antibody function. See Jones et al. for further details. Nature , 1986, 321:522-525; Riechmann et al., Nature , 1988, 332: 323-329; and Presta, Curr. Op. Struct. Biol. References, 1992, 2:593-596, are incorporated herein by reference in their entirety.

[0058] "Human antibody" refers to an antibody having an amino acid sequence corresponding to that of an antibody produced by a human or human cell, or an antibody derived from a non-human source using a human antibody repository or a human antibody coding sequence (e.g., obtained from a human source or redesigned). Human antibodies specifically exclude humanized antibodies.

[0059] "Isolated antibody" refers to an antibody that has been separated from and / or recovered from its components in its natural environment. Components in the natural environment may include enzymes, hormones, and other proteinaceous or non-proteinaceous substances. In some embodiments, the isolated antibody is purified to a degree sufficient, for example, by using a rotor sequencer, to obtain at least 15 N-terminal or internal amino acid sequence residues. In some embodiments, the isolated antibody is purified to a degree of homogeneity as detected by gel electrophoresis (e.g., SDS-PAGE) under reducing or non-reducing conditions by Coomassie blue or silver staining. Isolated antibodies include in situ antibodies within recombinant cells, since at least one component of the antibody's natural environment is absent. In some cases, the isolated antibody is prepared by at least one purification step.

[0060] 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 containing at least 85%, 90%, 95%, 98%, 99%, to 100% (by volume) antibody. In some embodiments, the isolated antibody is provided as a solution containing at least 85%, 90%, 95%, 98%, 99%, to 100% (by volume) antibody.

[0061] The term "non-natural amino acid" refers to an amino acid that is not a protein-originating amino acid or a post-translational modified variant thereof. Specifically, the term refers to an amino acid that is not one of the 20 common amino acids, or pyrrolidone, selenocysteine, or a post-translational modified variant thereof.

[0062] "Affinity" refers to the sum strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise stated, "binding affinity" as used in this invention refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y can be expressed by a dissociation constant (K). D Affinity can be determined by methods commonly known in the art, including those described in this invention. Affinity can be determined using, for example, surface plasmon resonance (SPR) techniques such as Biacore. ® The instrument is used for measurement. In some implementation schemes, affinity is measured at 25°C.

[0063] Regarding antibody binding to target molecules, the terms "specific binding," "specifically binding to," "specific to," "selectively binding," and "selectively to" refer to binding to a specific antigen (e.g., a peptide target) or an epitope of a specific antigen that is assayably different from nonspecific or nonselective interactions. Specific binding can be measured, for example, by measuring the binding of a molecule against that of a control molecule. Specific binding can also be measured by competition with a control molecule that simulates the antibody binding site against the target. In this case, if the binding of the antibody to the target is competitively inhibited by the control molecule, it indicates specific binding.

[0064] The term "k" used in this invention d (sec) -1 (k) refers to the dissociation rate constant of a specific antibody-antigen interaction. This value is also known as k. 解离 value.

[0065] The term "k" used in this invention a(M) -1 ×sec -1 This refers to the association rate constant of a specific antibody-antigen interaction. This value is also known as k. 缔合 value.

[0066] The term "K" used in this invention D (M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction. D = k d / k a .

[0067] The term "K" used in this invention A (M) -1 K refers to the association equilibrium constant of a specific antibody-antigen interaction. A =k a / k d .

[0068] "Affinity-matured" antibodies refer to antibodies with one or more alterations in one or more CDRs or FRs, said alterations resulting in increased affinity of the antibody for its antigen compared to a parent antibody without the alterations. In one embodiment, the affinity-matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity-matured antibodies can be generated using a variety of methods known in the art. For example, Marks et al. ( Bio / Technology (1992, 10:779-783, the entire text of which is incorporated herein by reference) describes the invention by V H and V L Affinity maturation resulting from domain substitution. The random mutagenicity of CDRs and / or framework residues is described, for example, in Barbas et al. ( Proc. Nat. Acad. Sci. USA , 1994, 91:3809-3813); Schier et al., Gene , 1995, 169:147-155; Yelton et al., J. Immunol. , 1995, 155:1994-2004; Jackson et al., J. Immunol. , 1995, 154:3310-33199; and Hawkins et al, J. Mol. Biol. In , 1992, 226:889-896, the full text of each document is incorporated herein by reference.

[0069] In this invention, when used in the context of two or more antibodies, the term "competes with" or "cross-competes with" means that two or more antibodies compete to bind to an antigen (e.g., TF). In one exemplary assay, TF is coated onto a plate and bound to a first antibody, followed by the addition of a labeled second antibody. If the presence of the first antibody reduces the binding of the second antibody, the antibodies compete with each other. In another exemplary assay, a first antibody is coated onto a plate and bound to an antigen, followed by the addition of a second antibody. The term "competes with" 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 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%.

[0070] The term "epitope" refers to a portion of an antigen that can specifically bind to an antibody. Epitopes often consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural features and specific charge characteristics. The difference between conformational and non-conformational epitopes is that binding to the former disappears in the presence of denaturing solvents, while binding to the latter does not. Epitopes may contain amino acid residues directly involved in binding and other amino acid residues not directly involved in binding. Epitopes bound by antibodies can be determined using known epitope assay techniques, such as, for example, testing the binding of antibodies to TF variants with different point mutations or to chimeric TF variants, as further described in the embodiments provided in this invention.

[0071] The percentage of "identity" between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in a polypeptide sequence that are identical to those in the reference sequence after alignment, and if necessary, the introduction of vacancies to achieve the maximum percentage of sequence identity. Alignment for determining the percentage of amino acid sequence identity can be achieved in various ways within the art, such as using publicly available computer software like BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE. Those skilled in the art can determine appropriate parameters for the alignment sequence, including any algorithm required to achieve maximum alignment of the full length of the comparison sequence.

[0072] "Conservative substitution" or "conservative amino acid substitution" refers to the substitution of an amino acid with a chemically or functionally similar amino acid. The table of conserved substitutions provides similar amino acids well-known in the art. Peptide sequences having such substitutions are known as "conservatively modified variants." Such conservedly modified variants are complementary to polymorphic variants, interspecies homologs, and alleles, and do not exclude polymorphic variants, interspecies homologs, and alleles. For example, the amino acid groups provided in Tables 2 through 4 are considered to be conserved substitutions of each other in some embodiments.

[0073] Table 2. Selected amino acid groups considered as conservative substitutions for each other in some implementations. D and E K, R, and H S, T, N, and Q G, A, V, L and I C, M, and P F, Y and W S and T I, L, V, and M F, H, W, and Y A, C, F, G, H, I, L, M, R, T, V, W and Y D and E C, D, E, H, K, N, Q, R, S, and T H, K and R A, C, D, G, N, P, S, T and V A, G, and S A, C, D, E, G, H, K, N, Q, R, S, P and T Q, T, K, S, G, P, D, E, and R Table 3. Other selected amino acid groups considered as conservative substitutions for each other in some implementation schemes. A, S, and T D and E N and Q R and K I, L and M F, Y and W Table 4. Further selected groups of amino acids considered as conservative substitutions for each other in some embodiments. A and G D and E N and Q R, K and H I, L, M, V F, Y and W S and T C and M Other conservative substitutions can be found, for example, in Creighton. Proteins: Structures and Molecular Properties According to 2nd ed. (1993) WH Freeman & Co., New York, NY, antibodies produced by making one or more conserved substitutions of amino acid residues in parental antibodies are called "conservatively modified variants".

[0074] The term "payload" refers to a molecular group portion that can be conjugated to an antibody. In a particular embodiment, the payload is selected from the group consisting of a therapeutic group portion and a labeling group portion.

[0075] Triple-negative breast cancer (TNBC) is breast cancer characterized by estrogen receptor negativity, progesterone receptor negativity, and human epidermal growth factor receptor 2 negativity (HER2 negativity). TNBC can be BRCA1 / 2 wild-type or BRCA1 / 2 mutant. Those skilled in the art can readily determine the negative status of estrogen, progesterone, and Her2 / neu expression according to currently accepted guidelines. For example, guidelines developed by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) are widely accepted. ASCO / CAP recommends using immunohistochemistry (IHC) or in situ hybridization (ISH) techniques for detection. Furthermore, the cancer is Her2 negative if a single test (or all tests) on a tumor specimen meets any of the following criteria: (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 should understand that the triple-negative cancers described in this invention do not include any cancers with significantly inconsistent histopathological features observed by a pathologist. Wolff, AC et al. J Clin Oncol. 2013 Nov. 1:31(31):3997-4013. If there is evidence that the sample expresses ER or PR and the rate of immune response in the tumor cell nucleus is <1% (see positive endogenous control), then the cancer is ER negative or PR negative.

[0076] The term "growth inhibition" as used in this invention (e.g., referring to cells such as tumor cells) is intended to include any measurable reduction in cell growth (e.g., tumor cell growth) upon contact with the TF antibody or antibody-drug conjugate described in this invention, compared to the growth of the same cells not in contact with the TF antibody. In some embodiments, growth may be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. The reduction in cell growth can occur through a variety of mechanisms, including but not limited to antibody internalization, apoptosis, cell necrosis, and / or effector function-mediated activity.

[0077] In some of the chemical structures shown in this invention, certain substituents, chemical groups, and atoms are represented by curves / wavy lines (e.g., The curve / wavy line is depicted as intersecting one or more bonds to represent atoms that connect the substituents, chemical groups, and atoms. For example, in some structures, such as, but not limited to... The curve / wavy line represents the connection point where the illustrated chemical entity is linked to atoms in the main chain of the coupling agent or linker-payload structure. In some structures, for example, but not limited to... The curves / wavy lines represent the connection points where the chemical entity is connected to the atoms in the antibody or antibody fragment, and the connection points where the chemical entity is connected to the atoms in the main chain of the conjugate or linker-payload structure.

[0078] Spirocyclic compounds depicted using overlapping rings demonstrate that these rings can bond at any vertex. For example, in spirocyclic groups... In this context, the two rings can bond at any of the three available vertex atoms of either ring.

[0079] When referring to the compounds provided by this invention, unless otherwise stated, the following terms have the following meanings. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. If there are multiple definitions for terms used in this invention, unless otherwise stated, the definitions in this section shall prevail.

[0080] "Alkoxy" and "alkoxy group" both refer to the –OR′′ group, where R′′ is an alkyl or cycloalkyl group. In some embodiments, the alkoxy group includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, etc.

[0081] As used in this invention, the term "alkoxyamine" refers to the group -alkylene-O-NH2, wherein the alkylene group is as defined herein. In some embodiments, the alkoxyamine group may react with an aldehyde to form an oxime residue. Examples of alkoxyamine groups include -CH2CH2-O-NH2, -CH2-O-NH2, and -O-NH2.

[0082] The term "alkyl" as used in this invention, unless otherwise specified, refers to a saturated straight-chain or branched hydrocarbon. In some embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In some embodiments, the alkyl group comprises 1-10 carbon atoms (i.e., C1-C1). 10 Alkyl group). In some embodiments, the alkyl group is a lower alkyl group, such as C10. 1-6Alkyl groups, etc. In some 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 some embodiments, "substituted alkyl" means that the alkyl group is substituted by, for example, one, two, or three groups independently selected from halogens (e.g., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I)), alkyl, -CN, -NO2, amide, -C(O)-, -C(S)-, ester, carbamate, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, dialkylamino, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, the alkyl group is unsubstituted.

[0083] As used in this invention, the term "alkylene" refers to a divalent alkyl group, as defined herein, unless otherwise specified. "Substituted alkylene" refers to an alkylene group that has been substituted with respect to an alkyl group according to this invention. In some embodiments, the alkylene group is unsubstituted.

[0084] "Alkenyl" refers to an olefinic unsaturated hydrocarbon group that, in some embodiments, has up to about 11 carbon atoms or 2 to 6 carbon atoms (e.g., "lower alkenyl"), which may be straight-chain or branched, and has at least one or 1-2 olefinic unsaturation sites. "Substituted alkenyl" refers to an alkenyl group that has been substituted with respect to an alkyl group according to the present invention.

[0085] "Alkenyl" refers to a divalent alkenyl group as defined in this invention. Lower alkenyl groups are, for example, C2-C6-alkenyl groups.

[0086] "Alynyl" refers to an alkyne-unsaturated hydrocarbon group that, in some embodiments, has up to about 11 carbon atoms or 2-6 carbon atoms (e.g., "lower alynyl"), can be straight-chain or branched, and has at least one or 1-2 alynyl unsaturated sites. Non-limiting examples of alynyl groups include ethynyl (-C≡CH), propynyl (-CH₂C≡CH), etc. "Substituted alynyl" refers to an alynyl group substituted with respect to an alkyl group according to the present invention.

[0087] "Imyynyl" refers to a divalent ynyl group as defined in this invention. Lower imynyl groups are, for example, C2-C6-imynyl groups.

[0088] "Amino" refers to -NH2.

[0089] The term "alkylamino" as used in this invention, unless otherwise stated, refers to the group –NHR′′, where R′′ is, for example, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12Carbon rings, heterocycles consisting of 3 to 12 atoms, C 1-10 Halogenated alkyl groups, as defined in this invention. In some embodiments, the alkylamino group is C10. 1-6 Alkylamino.

[0090] The term "dialkylamino" as used in this invention, unless otherwise stated, refers to the group –NR′′R′′, wherein each R′′ is independently C. 1-10 Alkyl group, as defined in this invention. In some embodiments, the dialkylamino group is, for example, a di-C... 1-6 Alkylamino, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, C 1-10 Halogenated alkyl groups, etc.

[0091] The term "aryl" as used in this invention, unless otherwise specified, refers to phenyl, biphenyl, or naphthyl. The term includes both substituted and unsubstituted group portions. An aryl group may be substituted by any of the described group portions, including but not limited to one or more group portions selected from the group consisting of (e.g., in some embodiments, 1, 2, or 3 group portions): halogens (fluorine (F), chlorine (Cl), bromine (Br), or iodine (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, wherein each group portion is independently unprotected or, if necessary, protected as known to those skilled in the art (see, for example, Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991); and wherein the aryl group in the arylamino group and the aryloxy substituent is not further substituted.

[0092] The term "arylamino" as used in this invention, unless otherwise stated, refers to the -NR′R′′ group, wherein R′ is H or C1-C6-alkyl; and R′′ is aryl, as defined in this invention.

[0093] The term "aryl" as used in this invention, unless otherwise stated, refers to a divalent aryl group, wherein the aryl group is as defined in this invention.

[0094] The term "aryloxy group" as used in this invention, unless otherwise stated, refers to an -OR group, where R is an aryl group as defined in this invention.

[0095] "Alkylene group" refers to an arylene group as defined in this invention, wherein the aryl ring is substituted by one or two alkyl groups. "Substituted alkylene group" refers to an alkylene group as defined in this invention, wherein the arylene group is further substituted as defined in this invention for aryl groups.

[0096] "Arylenealkyl" refers to a -CH2-arylene-, -arylene-CH2-, or -CH2-arylene-CH2- group, wherein the arylene group is as defined in this invention. "Substituted arylenealkyl" refers to an arylenealkyl group as defined in this invention, wherein the arylenealkyl group is substituted as defined in this invention for aryl groups.

[0097] "Carboxyl group" or "carboxyl group" refers to -C(O)OH or -COOH.

[0098] The term "cycloalkyl" as used in this invention, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In some embodiments, the "cycloalkyl" group may be a saturated, and / or bridged, and / or unbridged, and / or fused bicyclic group, and / or a spirocyclic bicyclic group. In some embodiments, the "cycloalkyl" group comprises 3-10 carbon atoms (i.e., C3-C4). 10 (Cycloalkyl). In some embodiments, the "cycloalkyl" has 3-15 carbon atoms (C60-C15). 3-15 ), 3-10 carbon atoms (C 3-10 ), 3-7 carbon atoms (C 3-7), or 3-6 carbon atoms (C3-C6) (i.e., "lower cycloalkyl"). In some 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 monocyclic rings of 3 to 10 atoms, bicyclic rings of 6 to 12 atoms, and bridged rings of 6 to 12 atoms. Each ring of a bicyclic cycloalkyl or carbocyclic ring may be selected from saturated rings, unsaturated rings, and aromatic rings. Bicyclic cycloalkyl or bicyclic carbocyclic rings include any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings, provided the valence allows. Bicyclic cycloalkyl or bicyclic carbocyclic groups include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Non-limiting examples of bridging bicyclic cycloalkyl or bridging bicyclic carbocyclic groups include, but are not limited to, bicyclic [1.1.1]pentyl, bicyclic [2.1.1]hexyl, bicyclic [2.1.1]hexyl, bicyclic [3.1.1]heptyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [2.2.2]octyl, bicyclic [3.3.1]nonyl, bicyclic [3.3.2]decyl, and 2-oxabicyclic [2.2.2]octyl. Non-limiting examples of spirocyclic cycloalkyl or spirocyclic 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.

[0099] The term "bicyclic ring system" refers to a structure consisting of 6-12 (e.g., 8-12 or 9, 10 or 11) atoms forming two rings, wherein the two rings have at least one common atom (e.g., two common atoms). The bicyclic rings can be fused, bridged, or spirocyclic. Bicyclic ring systems include bicyclic aliphatic compounds (e.g., bicyclic alkyl or bicyclic alkenyl), bicyclic heteroaliphatic compounds, bicyclic aryl compounds, and bicyclic heteroaryl compounds.

[0100] The term "bridging bicyclic ring system" refers to a bicyclic heterocyclic alicyclic ring system or a bicyclic alicyclic ring system in which rings are bridged together. Examples of bridging bicyclic ring systems include, but are not limited to, adamantyl, norbornel, bicyclic [1.1.1]pentyl, bicyclic [2.1.1]hexyl, bicyclic [2.1.1]hexyl, bicyclic [3.1.1]heptyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [2.2.2]octyl, bicyclic [3.3.1]nonyl, bicyclic [3.3.2]decyl, and 2-oxabicyclic [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, 2-oxabicyclo[3.1.1]heptyl, and 2,6-dioxatricyclo[3.3.1.0] 3,7 Nonyl. The bridging bicyclic ring system may optionally be substituted with one or more substituents, such as alkyl (including carboxylalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, arylyl, heteroarylyl, arylylacyl, heteroarylacyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyl Oxygen, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocyclic alkyl)carbonylamino, (heterocyclic alkyl)carbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, cyano, halogen, hydroxyl, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, aminosulfonyl, sulfonamide, oxo, or carbamoyl.

[0101] The term "spirobicyclic ring system" refers to a bicyclic heterocyclic alicyclic ring system or a bicyclic alicyclic ring system in which two or three rings are linked together by a common atom. Spiro compounds described using overlapping rings indicate that these rings can be linked at any vertex. For example, in the spiro group... In this context, the two rings can be connected at any of the three available vertex atoms in either ring.

[0102] As used in this invention, the term "cycloalkylene" refers to a divalent cycloalkyl group, as defined herein. In some embodiments, the cycloalkylene group is a cycloalkylene group. , cyclobutylene Cyclopentylene , cyclohexylene , heptyl cycloheptahydrate etc. A lower subcycloalkyl group refers to a C3-C6-subcycloalkyl group. <00033,00>The term "cycloalkylalkyl" used in the present invention, unless otherwise specified, refers to an alkyl group as defined in the present invention substituted with 1 or 2 cycloalkyl groups as defined in the present invention.

[0104] The term "ester" used in the present invention refers to -C(O)OR or -COOR, where R is an alkyl group as defined in the present invention.

[0105] The term "fluorene" used in the present invention refers to where any one or more C atoms bearing one or more H atoms may be substituted with a chemical functional group as described in the present invention.

[0106] The term "haloalkyl" refers to an alkyl group as defined in the present invention substituted with one or more independently selected halogen atoms (e.g., 1, 2, 3, 4 or 5 in some embodiments).

[0107] The term "heteroalkyl" refers to an alkyl group as defined in the present invention, where one or more carbon atoms are replaced by heteroatoms. The "heteroalkenyl" used in the present invention refers to an alkenyl group as defined in the present invention, where one or more carbon atoms are replaced by heteroatoms. The "heteroalkynyl" used in the present invention refers to an alkynyl group as defined in the present invention, where 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 may each be optionally substituted. Examples of heteroalkyl group moieties include, but are not limited to, aminoalkyl, sulfonylalkyl and sulfinylalkyl. Examples of heteroalkyl group moieties also include, but are not limited to, methylamino, methylsulfonyl and methylsulfinyl. "Substituted heteroalkyl" refers to a heteroalkyl substituted with 1, 2 or 3 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, a heteroalkyl group may contain 1, 2, 3 or 4 heteroatoms. Those skilled in the art will recognize that a heteroalkyl composed of 4 atoms generally may contain 1 or 2 heteroatoms, a heteroalkyl composed of 5 or 6 atoms generally may contain 1, 2 or 3 heteroatoms, and a heteroalkyl composed of 7 to 10 atoms generally may contain 1, 2, 3 or 4 heteroatoms.

[0108] The term "subheteroalkyl" used in the present invention refers to a divalent heteroalkyl as defined in the present invention. "Substituted subheteroalkyl" refers to a divalent heteroalkyl as defined in the present invention substituted as described for heteroalkyl in the present invention.

[0109] The term "heterocyclic alkyl" refers to a monovalent, monocyclic, or polycyclic nonaromatic ring system in which one or more ring atoms are heteroatoms independently selected from oxygen (O), sulfur (S), and nitrogen (N) (e.g., the N or S atom may optionally be oxidized, and the N atom may optionally be quaternized), and the remaining ring atoms of the nonaromatic ring are carbon atoms. In some embodiments, a "heterocyclic alkyl" is a fully saturated monovalent monocyclic or polycyclic ring system. In some embodiments, the "heterocyclic alkyl" group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, 4 to 11, or 5 to 6 ring atoms. The "heterocyclic alkyl" may be attached to a parent core structure at any of its heteroatoms or carbon atoms to form a stable compound. In some embodiments, the "heterocyclic alkyl" is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, and / or bridged bicyclic groups, and / or spirocyclic bicyclic groups, and wherein the N or S atom may optionally be oxidized, and / or the N atom may optionally be quaternized. In some embodiments, the "heterocyclic alkyl" group includes, but is not limited to, 2,5-diazabicyclo[2.2.2]octyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrroleyl, dioxanepentyl, 1,4-dithiohexacyclohexyl, furanoneyl, imidazoalkyl, imidazolinyl, indoline. The heterocyclic alkyl group can be substituted with alkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinone, oxazolyl, ethylene oxide, piperazine, piperidinyl, 4-piperidinone, pyrazolyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiamorpholinyl, thiazolyl, tetrahydroquinolinyl, and 1,3,5-trithiohexacyclohexyl. In some embodiments, the heterocyclic alkyl group may also be optionally substituted as described herein. In some embodiments, the heterocyclic alkyl group is substituted with 1, 2, or 3 groups independently selected from halogens (e.g., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy groups. In some embodiments, the heterocyclic alkyl group may contain 1, 2, 3, or 4 heteroatoms. Those skilled in the art should understand that a heterocyclic alkyl group consisting of 4 atoms typically contains 1 or 2 heteroatoms, a heterocyclic alkyl group consisting of 5-6 atoms typically contains 1, 2 or 3 heteroatoms, and a heterocyclic alkyl group consisting of 7-10 atoms typically contains 1, 2, 3 or 4 heteroatoms.In some embodiments, "heterocyclic" or "heterocyclic" groups include, but are not limited to, 2,5-diazabicyclo[2.2.2]octyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrroleyl, dioxanepentyl, 1,4-dithionecyclohexyl, furanoneyl, imidazoalkyl, imidazolinyl, and others. Indololinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinone, oxazolyl, ethylene oxide, piperazine, piperidinyl, 4-piperidinone, pyrazolyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiamorpholinyl, thiazolyl, tetrahydroquinolinyl, and 1,3,5-trithiacyclohexyl. Non-limiting examples of bridging heterocyclic alkyl groups or bridging 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, 2-oxabicyclo[3.1.1]heptyl, and 2,6-dioxa-tricyclo[3.3.1.0]. 3,7 Nonyl. Non-limiting examples of spirocyclic heterocyclic alkyl groups or spirocyclic 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.

[0110] "Heterocyclic alkylene" refers to a divalent heterocyclic alkylene, as defined in this invention.

[0111] 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 O, S, and N. Each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and / or 1-4 N atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least one carbon atom. In some embodiments, the heteroaryl group has 5-20, 5-15, or 5-10 ring atoms. The heteroaryl group may be attached to the remainder of the molecule via a nitrogen or carbon atom. In some embodiments, the monocyclic heteroaryl group includes, but is not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroleyl, triazolyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzopyridyl, benzothiazolyl, benzothiophene, benzotriazolyl, benzooxazolyl, furanopyridyl, imidazopyridyl, imidazothiazolyl, indoleazinyl, indoleyl, indazole, isobenzofuranyl, isobenzothiaphene, isoindoleyl, isoquinolinyl, naphridyl, oxazolopyridyl, phthalazinyl, pteridine, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazopyrimidinyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinel, benzoindolyl, carbazolel, dibenzofuranyl, perimidinyl, phenanthrololinyl, phenanthidyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthonyl. In some embodiments, the heteroaryl group may optionally be substituted as described in this invention. "Substituted heteroaryl" refers to a heteroaryl group substituted as defined herein with respect to aryl groups.

[0112] The term "heteroaryl" refers to a divalent heteroaryl group, as defined in this invention. "Substituted heteroaryl" is a heteroaryl group that has been substituted as defined in this invention for aryl groups.

[0113] 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 of the (protected) oxygen, nitrogen, or phosphorus, or for other purposes. A wide variety of oxygen-protecting 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).

[0114] "Pharmaceutically acceptable salt" means any salt of the compounds provided in this invention that retains its biological properties and is non-toxic or otherwise undesirable for medicinal use. Such salts can be derived from a variety of organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) salts reacting with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aminosulfonic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, 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, glucoheponic acid, 3-Phenylacetic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthyl carboxylic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, mucoconic acid and similar acids form an acid addition salt; or (2) when an acidic proton is present in the parent compound, then (a) a salt formed by substitution with a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide and barium hydroxide, or ammonia, or (b) a salt formed 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 -Benzylphenylethylamine, N α-Methylglucosamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc., coordinate to form basic addition salts.

[0115] By way of example only and not limitation, pharmaceutically acceptable salts further include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts; when the compound contains a basic functional group, it is a salt of a non-toxic organic or inorganic acid, such as hydrohalides like hydrochlorides and hydrobroms, sulfates, phosphates, aminosulfonates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbic acid salts, malates, maleates, fumarates, tartrates, citrates, benzoates, and 3-(4-hydroxybenzoyl) Benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (methanesulfonate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphor sulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, gluconate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthylcarboxylate, salicylate, stearate, cyclohexylaminosulfonate, quinic acid salt, mucoconate, etc.

[0116] With respect to the composition, the terms "substantially free" or "substantially absent" mean that the composition contains at least 85% or 90% by weight, in some embodiments, 95%, 98%, 99% or 100% by weight, or in some embodiments, 95%, 98%, 99%, or 100% of a specified enantiomer or diastereomer of the compound. In some embodiments, in the methods and compounds provided by the present invention, the compound is substantially free of one of the two enantiomers. In some embodiments, in the methods and compounds provided by the present invention, the compound is substantially free of one of the two diastereomers. In some embodiments, in the methods and compounds provided by the present invention, the compound is substantially free of enantiomers (i.e., the compound is not a racemic compound or a mixture of 50:50 compounds).

[0117] Similarly, with respect to a composition, the term "isolated" means that the composition comprises at least 85% to 100% by weight of the compound, with the remainder comprising other chemical substances, enantiomers, or diastereomers.

[0118] "Solvate" refers to a compound or salt thereof provided by the present invention that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0119] "Isotopic composition" refers to the amount of each isotope present for a given atom, while "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom. Atoms containing their natural isotopic composition may also be referred to as "non-enriched" atoms in this invention. Unless otherwise specified, the atoms of the compounds described in this invention are intended to represent any stable isotope of the atom. For example, unless otherwise stated, when a position is specifically designated as "hydrogen" (H), that position is understood to be hydrogen having its natural isotopic composition.

[0120] "Isotope enrichment" refers to the percentage of a specific isotope incorporated at a given atom in a molecule, replacing the natural isotopic abundance of that atom. For example, 1% deuterium (D) enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that specified position. Since the natural distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotopic enrichment of the compounds provided by this invention can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0121] "Isotope-enriched" means having atoms with an isotopic composition other than the natural isotopic composition of the atoms. "Isotope-enriched" can also mean a compound containing at least one atom with an isotopic composition other than the natural isotopic composition of the atoms.

[0122] The "alkyl", "alkylene", "alkylamino", "dialkylamino", "cycloalkyl", "aryl", "aryene", "alkoxy", "amino", "carboxyl", "heterocycloalkyl", "heteroaryl", "heteroaryl", "carboxyl", and "amino acid" groups used in this invention optionally contain deuterium (D) at one or more positions where a hydrogen atom (H) is present, and the deuterium composition of said one or more atoms is not a natural isotopic composition.

[0123] Similarly, the "alkyl", "alkylene", "alkylamino", "dialkylamino", "cycloalkyl", "aryl", "aryene", "alkoxy", "amino", "carboxyl", "heterocyclic", "heteroaryl", "heteroaryl", "carboxyl", and "amino acid" groups used in this invention optionally contain C-13 in amounts other than those of the natural isotopic composition. 13 C).

[0124] The term "macromolecule" or "macromolecule group portion" refers to proteins, peptides, antibodies, nucleic acids, carbohydrates, or other macromolecules composed of polymeric monomers. It includes peptides comprising two or more residues or ten or more residues. In some embodiments, the macromolecule has a mass of at least 1000 Da. In some embodiments, the macromolecule has at least 1000 atoms. In some embodiments, the macromolecule may be modified. For example, proteins, peptides, or antibodies may be modified with one or more carbohydrates and / or small molecule therapeutic compounds.

[0125] The term "amino acid" refers to 20 common, naturally occurring amino acids. These 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 (V), as well as the less common pyrrolidone and selenocysteine. Citrulline is also a natural amino acid. Naturally encoded amino acids include 22 naturally occurring post-translational variants, such as pentadienylated amino acids, isopreneated amino acids, myristoylated amino acids, palmitoylated amino acids, etc. N -Links to glycosylated amino acids, O- Connects glycosylated amino acids, phosphorylated amino acids, and acylated amino acids. The term "amino acid" also includes non-natural (or unnatural) or synthetic α-, β-, γ-, or δ-amino acids, and includes, but is not limited to, 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 some embodiments, the amino acid is in the L-configuration. In some embodiments, the amino acid is in the D-configuration. Alternatively, the amino acid may be a derivative of alanyl, valine, leucyl, isoleucyl, proline, phenylalanyl, tryptophanyl, methionine, glycyl, serine, threonyl, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamate, lysine, arginine, histidine, β-alanyl, β-valine, β-leucyl, β-isoleucyl, β-proline, β-phenylalanyl, β-tryptophanyl, β-methionine, β-glycyl, β-serine, β-threonyl, β-cysteine, β-tyrosine, β-asparagine, β-glutamine, β-aspartic acid, β-glutamate, β-lysine, β-arginine, or β-histidine. Non-natural amino acids are not proteogenic amino acids, nor are they post-translational modified variants. Specifically, the term non-natural amino acid refers to an amino acid that is not one of the 20 common amino acids, or pyrrolidone, or selenocysteine, nor is it a post-translational modified variant.

[0126] The term "conjugate" or "antibody conjugate" refers to a compound or pharmaceutical group portion of the present invention that is linked to one or more macromolecular group portions. The macromolecular group portion is as defined in the present invention, or any macromolecule that a person skilled in the art would consider suitable. The compound or pharmaceutical group portion can be any compound or pharmaceutical group portion described in the present invention. The compound or pharmaceutical group portion can be directly linked to the macromolecular group portion via covalent bonds, or the compound or pharmaceutical group portion can be indirectly linked to the macromolecular group portion via a linker. Typically, the linker is covalently linked to both the macromolecular group portion and the compound or pharmaceutical group portion.

[0127] “pAMF”, “pAMF residue” or “pAMF mutation” refers to a variant phenylalanine residue (i.e., p-azidomethyl-L-phenylalanine) added to or substituted into a polypeptide.

[0128] The term "linker" refers to a molecular group portion capable of forming at least two covalent bonds. Typically, a linker is capable of forming at least one covalent bond with a macromolecular group portion and at least another covalent bond with a compound or drug group portion. In some embodiments, the linker may form more than one covalent bond with a macromolecular group portion. In some embodiments, the linker may form more than one covalent bond with a compound or drug group portion, or may form multiple covalent bonds with more than one compound or drug group portion. After the linker forms bonds with a macromolecular group portion, or a compound or drug group portion, or both, the remaining structure (i.e., the residues of the linker after the formation of one or more covalent bonds ("linker residues")) may still be referred to as "linker" in this invention. The term "linker precursor" refers to a linker having one or more reactive groups capable of forming covalent bonds with a macromolecular, or a compound or drug group portion, or both. Those skilled in the art, upon understanding the context of the term "linker," will understand whether "linker" refers to a linker precursor having one active group, a linker precursor having more than one active group, a linker residue covalently linked to a macromolecule, a linker residue partially covalently linked to a compound or drug group, and / or a linker residue covalently linked to both a macromolecule and a compound or drug group. In some embodiments, the linker is a cleavable linker. For example, a cleavable linker may be a linker released through bioinstability or enzymatic function, which may or may not be engineered. In some embodiments, the linker is an incleavable linker. For example, an incleavable linker may be a linker released after partial degradation of a macromolecular group.

[0129] The term "EC" used in this invention 50 "" refers to the dose, concentration, or amount of a specific test compound that elicits a dose-dependent response at 50% of the maximum expression of a specific response induced, triggered, or enhanced by the specific test compound.

[0130] Unless otherwise stated, the term "IC" as used in this invention is used in general. 50 "" refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum response in a test that measures this response.

[0131] The terms "subject" and "patient" used in this invention are used interchangeably. The term "subject" refers to an animal, such as a mammal including non-primates (e.g., cattle, 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 some embodiments, a human. In some embodiments, the subject is a farm animal (e.g., a horse, cattle, pig, etc.) or a pet (e.g., a dog or cat). In some embodiments, the subject is a human. In some embodiments, the subject suffers from a disease that can be treated or diagnosed using antibodies or antibody-drug conjugates provided by this invention. 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 epithelial-derived cancer.

[0132] As used in this invention, the terms "therapeutic agent" and "therapeutic medicine / pharmaceutical" refer to any medicine / pharmaceutical that can be used to treat or prevent a disease / condition or one or more symptoms thereof. In some embodiments, the term "therapeutic agent" includes antibodies or antibody-drug conjugates provided by this invention. In some embodiments, a therapeutic agent is a medicine / pharmaceutical that is known to be used, has been used, or is currently used to treat or prevent a disease / condition or one or more symptoms thereof.

[0133] In some embodiments, “treatment” or “management” of any disease or condition means improving the disease or condition present in the subject. In another embodiment, “treatment” or “management” includes improving at least one physical parameter that may not be perceived by the subject. In yet another embodiment, “treatment” or “management” includes modulating the disease or condition, whether physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physiological parameters) or both. In another embodiment, “treatment” or “management” includes delaying or preventing the onset of the disease or condition, or delaying or preventing the recurrence of the disease or condition. In yet another embodiment, “treatment” or “management” includes reducing or eliminating the disease or condition, or delaying the progression of the disease or condition or one or more symptoms of the disease or condition, or reducing the severity of the disease or condition or one or more symptoms of the disease or condition.

[0134] The terms "preventive agent" and "preventive medicine / pharmaceutical" as used in this invention refer to any medicine / pharmaceutical that can be used to prevent a disease / symptom or one or more symptoms thereof. In some embodiments, the term "preventive agent" includes compounds, pharmaceutical group portions, or conjugates provided by this invention. In some other embodiments, the term "preventive agent" does not refer to compounds, pharmaceutical group portions, or conjugates provided by this invention. For example, a preventive agent is a medicine / pharmaceutical known to be used, or has been used, or is being used to prevent or stop the onset, development, progression, and / or severity of a disease / symptom.

[0135] The phrase "preventive effective amount" as used in this invention refers to an amount of treatment / therapy (e.g., a preventive agent) sufficient to prevent or reduce the development, recurrence, or onset of one or more symptoms associated with the disease / condition, or an amount that enhances or improves the preventive effect of another treatment / therapy (e.g., another preventive agent).

[0136] In some of the chemical structures shown in this invention, certain substituents, chemical groups, and atoms are represented by curves / wavy lines / bent lines (e.g., or The curve / wavy line / bent line is depicted as intersecting one or more bonds to represent atoms that connect the substituents, chemical groups, and atoms. For example, in certain structures, such as, but not limited to... ,or The curve / wavy line / bent line represents the connection point where the shown chemical entity is linked to atoms in the main chain of the coupling agent, compound, or drug group. In some structures, for example, but not limited to... The curves / wavy lines / bent lines represent the connection points between the shown chemical entity and the atoms in the macromolecule, as well as the connection points between the shown chemical entity and the atoms in the main chain of the coupling agent, compound, or drug group.

[0137] As used in this invention, the examples of substituents connected to cyclic groups (e.g., aromatic rings, heteroaromatic rings, fused rings, and saturated or unsaturated cycloalkyl or heterocycloalkyl groups) via interatomic bonds are intended to illustrate that, unless otherwise stated, according to the technology described in this invention or known in the art to which this invention pertains, the cyclic group can be substituted at any ring position of the cyclic group or on any ring of the fused ring group. For example, groups or The subscript q is an integer from 0 to 4, and the substituent R is... 1 The positions are general descriptions, meaning they are not directly connected to any vertex of the bond line structure, i.e., not directly connected to a specific ring carbon atom, including the following substituents R. 1 Non-limiting examples of groups attached to a specific ring carbon atom: .

[0138] The term "carbocyclic ring" as used in this invention, unless otherwise specified, refers to a saturated, unsaturated, or aromatic ring in which all atoms are carbon atoms. In some embodiments, the carbocyclic group may be a saturated, and / or bridged, and / or unbridged, and / or fused bicyclic group, and / or a spirocyclic bicyclic group. In some embodiments, the carbocyclic group comprises 3-10 carbon atoms (i.e., C3-C4). 10 (Carbon ring). In some embodiments, the carbon ring has 3-15 carbon atoms (C). 3-15 ), 3-10 carbon atoms (C 3-10 ), 3-7 carbon atoms (C 3-7 ), or 3-6 carbon atoms (C3-C6). In some embodiments, the carbocyclic group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, or adamantyl.

[0139] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms, wherein the N or S atom may optionally be oxidized, the N atom may optionally be quaternized, and the remaining ring atoms of the non-aromatic ring are carbon atoms. Heterocycles include monocyclic rings of 3 to 10 atoms, bicyclic rings of 6 to 12 atoms, and bridged rings of 6 to 12 atoms. In some embodiments, the heterocycle is a fully saturated monocyclic or polycyclic ring system. In some embodiments, the heterocyclic alkyl or "heterocyclic" group may be unsaturated, and / or bridged, and / or unbridged, and / or fused bicyclic groups, and / or spirocyclic bicyclic groups.

[0140] The term "site-specific" refers to a modification of a polypeptide at a predetermined sequence position within the polypeptide. The modification is on a single, predictable residue of the polypeptide, with little or no change. In a particular embodiment, a modified amino acid is introduced at the sequence position, for example, through recombination or synthesis. Similarly, a group moiety may be "site-specifically" attached to residues at a specific sequence position in the polypeptide. In some embodiments, the polypeptide may contain more than one site-specific modification.

[0141] As used in this invention, the term "therapeutic effective amount" or "effective amount" refers to the amount of an antibody, antibody-drug conjugate, or composition that, when administered to a subject, is effective in treating the disease or condition. In some embodiments, the therapeutic effective amount or effective amount refers to the amount of an antibody, antibody-drug conjugate, or composition that, when administered to a subject, is effective in preventing or alleviating the disease or disease progression, thereby alleviating symptoms. The "therapeutic effective amount" can vary depending on, in particular, the compound, the disease or condition and its severity, and the age, weight, etc., of the subject to be treated.

[0142] As used in this invention, the term "subject" refers to a mammalian subject. Exemplary subjects include, but are not limited to, humans, monkeys, dogs, cats, mice, rats, cattle, horses, camels, birds, goats, and sheep. In some embodiments, the subject is a human. In some embodiments, the subject suffers from a disease that can be treated or diagnosed using the antibodies provided by this invention. In some embodiments, the disease is gastric cancer, colorectal cancer, renal cell carcinoma, cervical cancer, non-small cell lung cancer, ovarian cancer, prostate cancer, and / or epithelial cancer.

[0143] 2. Antibodies and antibody specificity This invention provides antibodies that selectively bind to TF. Specifically, this invention provides antibodies that selectively bind to human TF. In some embodiments, the antibody selectively binds to the extracellular domain of human TF.

[0144] The present invention also provides conjugates comprising antibodies that selectively bind to human TF. In some embodiments, the antibody in the conjugate selectively binds to the extracellular domain of human TF.

[0145] In some embodiments, the antibody binds to a homolog of human TF. In some embodiments, the antibody binds to a homolog of human TF selected from species such as monkeys, mice, dogs, cats, rats, cattle, horses, goats, and sheep. In some embodiments, the homolog is a cynomolgus monkey homolog.

[0146] 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, or 13 residues.

[0147] In some samples, the Kabat / Chothia CDR-L1 of the antibody has a length of 10, 11, 12, 13, 14, 15, or 16 residues. In some samples, the Kabat / Chothia CDR-L2 of the antibody has a length of 6, 7, or 8 residues. In some samples, the Kabat / Chothia CDR-L3 of the antibody has a length of 8, 9, or 10 residues.

[0148] In some embodiments, the antibody comprises a light chain. In some states, the light chain is a κ light chain. In some states, the light chain is a λ light chain.

[0149] In some embodiments, the antibody comprises a heavy chain. In some samples, the heavy chain is IgA. In some samples, the heavy chain is IgD. In some samples, the heavy chain is IgE. In some samples, the heavy chain is IgG. In some samples, the heavy chain is IgM. In some samples, the heavy chain is IgG1. In some samples, the heavy chain is IgG2. In some samples, the heavy chain is IgG3. In some samples, the heavy chain is IgG4. In some samples, the heavy chain is IgA1. In some samples, the heavy chain is IgA2.

[0150] In some embodiments, the antibody is an antibody fragment. In some samples, the antibody fragment is an Fv fragment. In some samples, the antibody fragment is a Fab fragment. In some samples, the antibody fragment is an F(ab')2 fragment. In some samples, the antibody fragment is a Fab' fragment. In some samples, the antibody fragment is an scFv (sFv) fragment. In some samples, the antibody fragment is an scFv-Fc fragment.

[0151] In some embodiments, the scFv-Fc fragment includes a constant region, wherein the constant region comprises SEQ ID NO: 3068. The constant region in SEQ ID NO: 3068 differs from the human IgG1 constant region of SEQ ID NO: 3062 in several respects. First, the sequence shown in SEQ ID NO: 3068 includes the linker AAGSDQEPKSS (SEQ ID NO: 3071). SEQ ID NO: 3068 also does not include the CH1 domain of the IgG1 constant region. SEQ ID NO: 3068 further includes a C220S (EU numbering system) mutation that removes an unpaired cysteine ​​residue, which is not desired when the light chain constant region is absent (e.g., in the scFv-Fc form). SEQ ID NO: 3068 further includes two optional P to S mutations (P230S and P238S, respectively, according to the EU numbering system). One or both of these two serine residues can be reduced to naturally occurring proline residues. Finally, SEQ ID NO: 3068 contains an aspartic acid (D) residue at EU position 356 and a leucine (L) residue at EU position 358. In contrast, SEQ ID NO: 3062 contains glutamic acid (E) at EU position 356 and methionine (M) at EU position 358. In some embodiments, the antibody provided by this invention contains a constant region comprising D356 / L358, E356 / M358, D356 / M358, or E356 / L358 (EU number). However, those skilled in the art will understand that the antibody provided by this invention may contain any suitable constant region, and the constant region sequences provided by this invention are for illustrative purposes only.

[0152] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.

[0153] 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.

[0154] In some embodiments, the antibody is an affinity-matured antibody. In some embodiments, the antibody is an affinity-matured antibody derived from the exemplary sequences provided in this invention.

[0155] The antibodies provided by this invention can be used to treat a variety of diseases and conditions, including cancer. In some embodiments, the antibodies provided by this invention can be used to treat solid tumor cancers. For example, the antibodies provided by this invention can be used to treat colorectal cancer.

[0156] 2.2 V containing exemplary CDRs H sequence In some embodiments, the antibody comprises V H Sequence, the V H The sequence comprises one or more CDR-H sequences, which comprise, consist of, or substantially consist of the following: one or more exemplary CDR-H sequences provided by the present invention, and variations thereof. In some embodiments, the CDR-H sequence comprises, consists of, or substantially consists of the following: in V selected from SEQ ID NO: 2625 to SEQ ID NO: 2949 H One or more CDR-H sequences provided in the sequence.

[0157] 2.2.1. V containing an exemplary Kabat CDR H sequence In some embodiments, the antibody comprises V H Sequence, the V H The sequence comprises one or more Kabat CDR-H sequences, which comprise, consist of, or substantially consist of the following: one or more exemplary Kabat CDR-H sequences provided by the present invention, and variants thereof.

[0158] 2.2.1.1. Kabat CDR-H1 + Kabat CDR-H2 + Kabat CDR-H3 In some embodiments, the antibody comprises V H Sequence, the V HThe sequences include Kaspersky CDR-H1, Kaspersky CDR-H2, and Kaspersky CDR-H3 sequences. The Kaspersky CDR-H1 sequence comprises, consists of, or substantially comprises the following sequences selected from SEQ ID NO: 430, SEQ ID NO: 439, SEQ ID NO: 442, SEQ ID NO: 454 to SEQ ID NO: 541, SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 562, and SEQ ID NO: 563. The Kaspersky CDR-H2 sequence comprises, consists of, or substantially comprises the following sequences selected from SEQ ID NO: 1080, SEQ ID NO: 1089, SEQ ID NO: 1092, SEQ ID NO: 1104 to SEQ ID NO: 1191, SEQ ID NO: 1193, SEQ ID NO: 1199, SEQ ID NO: 1204, ...199, SEQ ID NO: 1204, SEQ ID NO: 1199, SEQ ID NO: 1199, SEQ ID NO: 1204, SEQ ID NO: 1199, SEQ ID NO: 1199, SEQ ID NO: 1199, SEQ ID NO: 1204, SEQ ID NO: 1199, SEQ ID NO: 1199, SEQ ID NO: 1199, SEQ ID NO: 11 The Kaspersky CDR-H3 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 1730, SEQ ID NO: 1739, SEQ ID NO: 1742, SEQ ID NO: 1754 to SEQ ID NO: 1841, SEQ ID NO: 1843, SEQ ID NO: 1849, SEQ ID NO: 1854, SEQ ID NO: 1860, SEQ ID NO: 1862, and SEQ ID NO: 1863. In some embodiments, the Kaspersky CDR-H1, Kaspersky CDR-H2, and Kaspersky CDR-H3 sequences are all derived from a single exemplary V provided by the present invention. H Sequence. For example, in some versions, all of Kaspersky CDR-H1, Kaspersky CDR-H2, and Kaspersky CDR-H3 are derived from a single exemplary V selected from SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, SEQ ID NO: 2859, and SEQ ID NO: 2860. H sequence.

[0159] 2.2.1.2. V containing an exemplary Kabat CDR H Sequence variants In some implementations, the V provided by the present invention H The sequences include variants of the exemplary Kabat CDR-H3, CDR-H2, and / or CDR-H1 sequences provided by this invention.

[0160] In some samples, the Kaba CDR-H3 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary Kaba CDR-H3 sequence provided by the present invention. In some samples, the Kaba CDR-H3 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Kaba CDR-H3 sequence provided by the present invention. In some samples, the Kaba CDR-H3 sequence comprises, consists of, or substantially consists of the following: any exemplary Kaba CDR-H3 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0161] In some samples, the Kaba CDR-H2 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary Kaba CDR-H2 sequence provided by the present invention. In some samples, the Kaba CDR-H2 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Kaba CDR-H2 sequence provided by the present invention. In some samples, the Kaba CDR-H2 sequence comprises, consists of, or substantially consists of the following: any exemplary Kaba CDR-H2 sequence provided by the present invention, having 1, 2, or 3 amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0162] In some samples, the Kaba CDR-H1 sequence comprises, consists of, or substantially consists of variants of the exemplary Kaba CDR-H1 sequence provided by this invention. In some samples, the Kaba CDR-H1 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Kaba CDR-H1 sequence provided by this invention. In some samples, the Kaba CDR-H1 sequence comprises, consists of, or substantially consists of any exemplary Kaba CDR-H1 sequence provided by this invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0163] 2.2.2. V containing the exemplary Chothia CDR H sequence In some embodiments, the antibody comprises V H Sequence, the V H The sequence comprises one or more Chothia CDR-H sequences, which comprise, consist of, or substantially consist of the following: one or more exemplary Chothia CDR-H sequences provided by the present invention, and variants thereof.

[0164] 2.2.2.1. Chothia CDR-H1 + Chothia CDR-H2 + Chothia CDR-H3 In some embodiments, the antibody comprises V H Sequence, the V HThe sequences comprise Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 sequences. The Chothia CDR-H1 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 105, SEQ ID NO: 114, SEQ ID NO: 117, SEQ ID NO: 129 to SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 224, SEQ ID NO: 229, SEQ ID NO: 235, SEQ ID NO: 237, and SEQ ID NO: 238. The Chothia CDR-H2 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 755, SEQ ID NO: 764, SEQ ID NO: 767, SEQ ID NO: 779 to SEQ ID NO: 866, SEQ ID NO: 868, and SEQ ID NO: 238. The Chothia CDR-H3 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 1405, SEQ ID NO: 1414, SEQ ID NO: 1417, SEQ ID NO: 1429 to SEQ ID NO: 1516, SEQ ID NO: 1518, SEQ ID NO: 1524, SEQ ID NO: 1529, SEQ ID NO: 1535, SEQ ID NO: 1537, and SEQ ID NO: 1538. In some embodiments, the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 sequences are all derived from a single exemplary V provided by the present invention. HSequence. For example, in some states, all of Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are derived from a single exemplary V selected from SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, SEQ ID NO: 2859, and SEQ ID NO: 2860. H sequence.

[0165] 2.2.2.2. V containing the exemplary Chothia CDR H Sequence variants In some implementations, the V provided by the present invention H The sequences include variants of the exemplary Chothia CDR-H3, CDR-H2, and / or CDR-H1 sequences provided by this invention.

[0166] In some samples, the Chothia CDR-H3 sequence comprises, consists of, or substantially consists of variants of the exemplary Chothia CDR-H3 sequence provided by the present invention. In some samples, the Chothia CDR-H3 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Chothia CDR-H3 sequence provided by the present invention. In some samples, the Chothia CDR-H3 sequence comprises, consists of, or substantially consists of any exemplary Chothia CDR-H3 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0167] In some samples, the Chothia CDR-H2 sequence comprises, consists of, or substantially consists of variants of the exemplary Chothia CDR-H2 sequence provided by the present invention. In some samples, the Chothia CDR-H2 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Chothia CDR-H2 sequence provided by the present invention. In some samples, the Chothia CDR-H2 sequence comprises, consists of, or substantially consists of any exemplary Chothia CDR-H2 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0168] In some samples, the Chothia CDR-H1 sequence comprises, consists of, or substantially consists of variants of the exemplary Chothia CDR-H1 sequence provided by this invention. In some samples, the Chothia CDR-H1 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Chothia CDR-H1 sequence provided by this invention. In some samples, the Chothia CDR-H1 sequence comprises, consists of, or substantially consists of any exemplary Chothia CDR-H1 sequence provided by this invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0169] 2.3.V H sequence In some embodiments, the antibody comprises, consists of, or substantially consists of the following: V of the scFv sequence provided in SEQ ID NO: 3073 and SEQ ID NO: 3079 HSequence. In some embodiments, the antibody comprises, is composed of, or is substantially composed of: the V provided in SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, SEQ ID NO: 2859, and SEQ ID NO: 2860. H sequence.

[0170] In some embodiments, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or is substantially composed of the following: sequences selected from SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, SEQ ID NO: 2859, and SEQ ID NO: 2860.

[0171] In some embodiments, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2727. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2736. In some samples, the antibody comprises V H Sequence, the V H The sequence contains, consists of, or is substantially composed of the following: SEQ ID NO: 2739.

[0172] In some samples, the antibody contains V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2751. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2752. In some samples, the antibody comprises V. H Sequence, the VH The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2753. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2754. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2755. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2756. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2757. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2758. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2759. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2760. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2761. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2762. In some samples, the antibody comprises V. H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2763. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2764. In some samples, the antibody comprises V HSequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2765. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2766. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2767. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2768. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2769. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2770. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2771. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2772. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2773. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2774. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2775. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2776. In some samples, the antibody comprises VH Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2777. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2778. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2779. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2780. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2781. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2782. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2783. In some samples, the antibody comprises V. H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2784. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2785. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2786. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2787. In some samples, the antibody comprises V H Sequence, the V HThe sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2788. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2789. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2790. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2791. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2792. In some samples, the antibody comprises V. H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2793. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2794. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2795. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2796. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2797. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2798. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2799. In some samples, the antibody comprises V H Sequence, the VH The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2800. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2801. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2802. In some samples, the antibody comprises V. H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2803. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2804. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2805. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2806. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2807. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2808. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2809. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2810. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2811. In some samples, the antibody comprises V HSequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2812. In some samples, the antibody comprises V. H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2813. In some samples, the antibody comprises V. H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2814. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2815. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2816. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2817. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2818. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2819. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2820. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2821. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2822. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2823. In some samples, the antibody comprises VH Sequence, the V H The sequence contains, consists of, or is substantially composed of the following: SEQ ID NO: 2824.

[0173] In some samples, the antibody contains V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2825. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2826. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2827. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2828. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2829. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2830. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2831. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2832. In some samples, the antibody comprises V. H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2833. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2834. In some samples, the antibody comprises V H Sequence, the V HThe sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2835. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2836. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2837. In some samples, the antibody comprises V H Sequence, the V H The sequence contains, consists of, or is substantially composed of the following: SEQ ID NO: 2838.

[0174] In some samples, the antibody contains V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2840. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2846. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2851. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2857. In some samples, the antibody comprises V H Sequence, the V H The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2859. In some samples, the antibody comprises V H Sequence, the V H The sequence contains, consists of, or is substantially composed of the following: SEQ ID NO: 2860.

[0175] 2.3.1.V H Sequence variants In some implementations, the V provided by the present invention H The sequence comprises, consists of, or substantially consists of the following: Exemplary V provided by the present invention H Variations of the sequence.

[0176] In some states, the V H The sequence comprises, consists of, or substantially consists of the following: Exemplary V provided by the present invention H Variations of the sequence. In some states, the V... H The sequence comprises, consists of, or substantially consists of the following: any exemplary V provided by this invention H A sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity.

[0177] In some implementations, the V H The sequence comprises, consists of, or substantially consists of any of the following exemplary V provided by the present invention having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. H Sequence. In some states, the amino acid substitutions are all conserved amino acid substitutions.

[0178] 2.4. V containing an exemplary CDR L sequence In some embodiments, the antibody comprises V L Sequence, the V L The sequence comprises one or more CDR-L sequences, which comprise, consist of, or substantially consist of the following: one or more exemplary CDR-L sequences provided by the present invention, and variations thereof.

[0179] 2.4.1. V containing an exemplary Kabat CDR L sequence In some embodiments, the antibody comprises V L Sequence, the V L The sequence comprises one or more Kabat CDR-L sequences, which comprise, consist of, or substantially consist of the following: one or more exemplary Kabat CDR-L sequences provided by the present invention, and variants thereof.

[0180] 2.4.1.1. Kabat CDR-L1 + Kabat CDR-L2 + Kabat CDR-L3 In some embodiments, the antibody comprises V L Sequence, the V LThe sequences include Kaspersky CDR-L1, Kaspersky CDR-L2, and Kaspersky CDR-L3 sequences. The Kaspersky CDR-L1 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 2066, SEQ ID NO: 2072, SEQ ID NO: 2077, SEQ ID NO: 2083, SEQ ID NO: 2085, SEQ ID NO: 2086, and SEQ ID NO: 2176. The Kaspersky CDR-L2 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 2290, SEQ ID NO: 2296, SEQ ID NO: 2301, SEQ ID NO: 2307, SEQ ID NO: 2309, SEQ ID NO: 2310, and SEQ ID NO: 2400. The Kaspersky CDR-L3 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 2514, SEQ ID NO: 2066, SEQ ID NO: 2072, SEQ ID NO: 2077, SEQ ID NO: 2083, SEQ ID NO: 2085, SEQ ID NO: 2086, and SEQ ID NO: 2176. The sequences IDNO: 2520, SEQ ID NO: 2525, SEQ ID NO: 2531, SEQ ID NO: 2533, SEQ ID NO: 2534, and SEQ ID NO: 2624. In some samples, the Kaspersky CDR-L1, Kaspersky CDR-L2, and Kaspersky CDR-L3 sequences are all derived from a single exemplary V provided by this invention. L Sequences. For example, in some samples, the Kaspersky CDR-L1 sequence, Kaspersky CDR-L2 sequence, and Kaspersky CDR-L3 are all derived from a single exemplary V selected from SEQ ID NO: 2951, SEQ ID NO: 2957, SEQ ID NO: 2962, SEQ ID NO: 2968, SEQ ID NO: 2970, SEQ ID NO: 2971, and SEQ ID NO: 3061. L sequence.

[0181] 2.4.1.2. V containing an exemplary Kabat CDR L Sequence variants In some implementations, the V provided by the present invention L The sequences include variants of the exemplary Kaspersky CDR-L3, CDR-L2, and / or CDR-L1 sequences provided by this invention.

[0182] In some samples, the Kaba CDR-L3 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary Kaba CDR-L3 sequence provided by this invention. In some samples, the Kaba CDR-L3 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Kaba CDR-L3 sequence provided by this invention. In some samples, the Kaba CDR-L3 sequence comprises, consists of, or substantially consists of the following: any exemplary Kaba CDR-L3 sequence provided by this invention, having 1, 2, or 3 amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0183] In some samples, the Kaba CDR-L2 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary Kaba CDR-L2 sequence provided by the present invention. In some samples, the Kaba CDR-L2 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Kaba CDR-L2 sequence provided by the present invention. In some samples, the Kaba CDR-L2 sequence comprises, consists of, or substantially consists of the following: any exemplary Kaba CDR-L2 sequence provided by the present invention, having 1, 2, or 3 amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0184] In some samples, the Kaba CDR-L1 sequence comprises, consists of, or substantially consists of variants of the exemplary Kaba CDR-L1 sequence provided by the present invention. In some samples, the Kaba CDR-L1 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Kaba CDR-L1 sequence provided by the present invention. In some samples, the Kaba CDR-L1 sequence comprises, consists of, or substantially consists of any exemplary Kaba CDR-L1 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0185] 2.4.2. V containing the exemplary Chothia CDR L sequence In some embodiments, the antibody comprises V L Sequence, the VL The sequence comprises one or more Chothia CDR-L sequences, which comprise, consist of, or substantially consist of the following: one or more exemplary Chothia CDR-L sequences provided by the present invention, and variants thereof.

[0186] 2.4.2.1. Chothia CDR-L1 + Chothia CDR-L2 + Chothia CDR-L3 In some embodiments, the antibody comprises V L Sequence, the V L The sequences comprise the Cosia CDR-L1 sequence, the Cosia CDR-L2 sequence, and the Cosia CDR-L3 sequence. The Cosia CDR-L1 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 1954, SEQ ID NO: 1960, SEQ ID NO: 1965, SEQ ID NO: 1971, SEQ ID NO: 1973, SEQ ID NO: 1974, and SEQ ID NO: 2064. The Cosia CDR-L2 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 2178, SEQ ID NO: 2184, SEQ ID NO: 2189, SEQ ID NO: 2195, SEQ ID NO: 2197, SEQ ID NO: 2198, and SEQ ID NO: 2288. The Cosia CDR-L3 sequence comprises, consists of, or substantially consists of sequences selected from SEQ ID NO: 2402, SEQ ID NO: 2064, SEQ ID NO: 2064, SEQ ID NO: 2065, SEQ ID NO: 2178, SEQ ID NO: 2184, SEQ ID NO: 2189, SEQ ID NO: 2195, SEQ ID NO: 2197, SEQ ID NO: 2198, and SEQ ID NO: 2288. The sequences NO: 2408, SEQ ID NO: 2413, SEQ ID NO: 2419, SEQ ID NO: 2421, SEQ ID NO: 2422, and SEQ ID NO: 2512. In some samples, the Kosia CDR-L1, Kosia CDR-L2, and Kosia CDR-L3 sequences are all derived from a single exemplary V provided by the present invention. L Sequences. For example, in some samples, the Kosia CDR-L1 sequence, Kosia CDR-L2 sequence, and Kosia CDR-L3 are all derived from a single exemplary V selected from SEQ ID NO: 2951, SEQ ID NO: 2957, SEQ ID NO: 2962, SEQ ID NO: 2968, SEQ ID NO: 2970, SEQ ID NO: 2971, and SEQ ID NO: 3061. L sequence.

[0187] 2.4.2.2. V containing the exemplary Chothia CDR L Sequence variants In some implementations, the V provided by the present invention L The sequences include variants of the exemplary Kosia CDR-L3, CDR-L2, and / or CDR-L1 sequences provided by this invention.

[0188] In some samples, the Cosia CDR-L3 sequence comprises, consists of, or substantially consists of variants of the exemplary Cosia CDR-L3 sequence provided by the present invention. In some samples, the Cosia CDR-L3 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Cosia CDR-L3 sequence provided by the present invention. In some samples, the Cosia CDR-L3 sequence comprises, consists of, or substantially consists of any exemplary Cosia CDR-L3 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0189] In some samples, the Cosia CDR-L2 sequence comprises, consists of, or substantially consists of variants of the exemplary Cosia CDR-L2 sequence provided by the present invention. In some samples, the Cosia CDR-L2 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Cosia CDR-L2 sequence provided by the present invention. In some samples, the Cosia CDR-L2 sequence comprises, consists of, or substantially consists of any exemplary Cosia CDR-L2 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0190] In some samples, the Cosia CDR-L1 sequence comprises, consists of, or substantially consists of variants of the exemplary Cosia CDR-L1 sequence provided by the present invention. In some samples, the Cosia CDR-L1 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Cosia CDR-L1 sequence provided by the present invention. In some samples, the Cosia CDR-L1 sequence comprises, consists of, or substantially consists of any exemplary Cosia CDR-L1 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0191] 2.5.V L sequence In some embodiments, the antibody comprises, consists of, or substantially consists of the following: V of the scFv sequence provided in SEQ ID NO: 3073 and SEQ ID NO: 3079 L Sequence. In some embodiments, the antibody comprises, consists of, or substantially consists of the following: V provided in SEQ ID NO: 2951, SEQ ID NO: 2957, SEQ ID NO: 2962, SEQ ID NO: 2968, SEQ ID NO: 2970, SEQ ID NO: 2971, and SEQ ID NO: 3061. L sequence.

[0192] In some embodiments, the antibody comprises V L Sequence, the V L The sequence comprises, consists of, or is substantially composed of the following sequences selected from SEQ ID NO: 2951, SEQ ID NO: 2957, SEQ ID NO: 2962, SEQ ID NO: 2968, SEQ ID NO: 2970, SEQ ID NO: 2971, and SEQ ID NO: 3061.

[0193] In some samples, the antibody contains V L Sequence, the V L The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2951. In some samples, the antibody comprises V L Sequence, the V LThe sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2957. In some samples, the antibody comprises V L Sequence, the V L The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2962. In some samples, the antibody comprises V. L Sequence, the V L The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2968. In some samples, the antibody comprises V L Sequence, the V L The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2970. In some samples, the antibody comprises V L Sequence, the V L The sequence comprises, consists of, or substantially consists of the following: SEQ ID NO: 2971. In some samples, the antibody comprises V L Sequence, the V L The sequence contains, consists of, or is substantially composed of the following: SEQ ID NO: 3061. 2.5.1.V L Sequence variants In some implementations, the V provided by the present invention L The sequence comprises, consists of, or substantially consists of the following: Exemplary V provided by the present invention L Variations of the sequence.

[0194] In some states, the V L The sequence comprises, consists of, or substantially consists of the following: Exemplary V provided by the present invention L Variations of the sequence. In some states, the V... L The sequence comprises, consists of, or substantially consists of the following: any exemplary V provided by this invention L A sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity.

[0195] In some implementations, the V LThe sequence comprises, consists of, or substantially consists of any of the following exemplary V provided by the present invention having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. L Sequence. In some states, the amino acid substitutions are all conserved amino acid substitutions.

[0196] 2.6. Pairing 2.6.1.V H –V L pair In some embodiments, the antibody comprises V H Sequence and V L sequence.

[0197] In some states, the V H A sequence is a V that contains, consists of, or is substantially composed of the following. H Sequences: SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, SEQ ID NO: 2859, and SEQ ID NO: 2860, and the V L A sequence is a V that contains, consists of, or is substantially composed of the following. L Sequences: SEQ ID NO:2951, SEQ ID NO:2957, SEQ ID NO:2962, SEQ ID NO:2968, SEQ ID NO:2970, SEQ ID NO:2971, and SEQ ID NO:3061.

[0198] In some embodiments, the antibody comprises V H / V L Pairing, the V H / V LThe paired sequences together comprise, consist of, or substantially consist of any pair of sequences selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO:2779 / SEQ ID NO:3061;SEQ ID NO:2780 / SEQ ID NO:3061;SEQ IDNO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ ID NO:2783 / SEQ IDNO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ ID NO:3061;SEQ IDNO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ ID NO:2788 / SEQ IDNO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ ID NO:3061;SEQ IDNO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ ID NO:2793 / SEQ IDNO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ ID NO:3061;SEQ IDNO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ ID NO:2798 / SEQ IDNO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ ID NO:3061;SEQ IDNO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ ID NO:2803 / SEQ IDNO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ ID NO:3061;SEQ IDNO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ ID NO:2808 / SEQ IDNO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ ID NO:3061;SEQ IDNO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ ID NO: 2813 / SEQ ID NO: 3061; SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.;

[0199] In some aspects, the antibody comprises V H / V L Pairing, the V H / V L The pairs together contain, consist of, or are substantially composed of any of the following: any pair of sequences shown in Table 5 below: Table 5. V H / V L pair SRP2799-A05 2727 3061 SRP2799-B03 2736 3061 SRP2799-B06 2739 3061 SRP2900-A01 2751 3061 SRP2900-A02 2752 3061 SRP2900-A03 2753 3061 SRP2900-A04 2754 3061 SRP2900-A05 2755 3061 SRP2900-A06 2756 3061 SRP2900-A07 2757 3061 SRP2900-A08 2758 3061 SRP2900-A09 2759 3061 SRP2900-A10 2760 3061 SRP2900-A11 2761 3061 SRP2900-B01 2762 3061 SRP2900-B02 2763 3061 SRP2900-B03 2764 3061 SRP2900-B04 2765 3061 SRP2900-B05 2766 3061 SRP2900-B06 2767 3061 SRP2900-B07 2768 3061 SRP2900-B08 2769 3061 SRP2900-B09 2770 3061 SRP2900-B10 2771 3061 SRP2900-B11 2772 3061 SRP2900-C01 2773 3061 SRP2900-C02 2774 3061 SRP2900-C03 2775 3061 SRP2900-C04 2776 3061 SRP2900-C05 2777 3061 SRP2900-C06 2778 3061 SRP2900-C07 2779 3061 SRP2900-C08 2780 3061 SRP2900-C09 2781 3061 SRP2900-C10 2782 3061 SRP2900-C11 2783 3061 SRP2900-D01 2784 3061 SRP2900-D02 2785 3061 SRP2900-D03 2786 3061 SRP2900-D04 2787 3061 SRP2900-D05 2788 3061 SRP2900-D06 2789 3061 SRP2900-D07 2790 3061 SRP2900-D08 2791 3061 SRP2900-D09 2792 3061 SRP2900-D10 2793 3061 SRP2900-D11 2794 3061 SRP2900-E01 2795 3061 SRP2900-E02 2796 3061 SRP2900-E03 2797 3061 SRP2900-E04 2798 3061 SRP2900-E05 2799 3061 SRP2900-E06 2800 3061 SRP2900-E07 2801 3061 SRP2900-E08 2802 3061 SRP2900-E09 2803 3061 SRP2900-E10 2804 3061 SRP2900-E11 2805 3061 SRP2900-F01 2806 3061 SRP2900-F02 2807 3061 SRP2900-F03 2808 3061 SRP2900-F04 2809 3061 SRP2900-F05 2810 3061 SRP2900-F06 2811 3061 SRP2900-F07 2812 3061 SRP2900-F08 2813 3061 SRP2900-F09 2814 3061 SRP2900-F10 2815 3061 SRP2900-F11 2816 3061 SRP2900-G01 2817 3061 SRP2900-G02 2818 3061 SRP2900-G03 2819 3061 SRP2900-G04 2820 3061 SRP2900-G05 2821 3061 SRP2900-G06 2822 3061 SRP2900-G07 2823 3061 SRP2900-G08 2824 3061 SRP2900-G09 2825 3061 SRP2900-G10 2826 3061 SRP2900-G11 2827 3061 SRP2900-H01 2828 3061 SRP2900-H02 2829 3061 SRP2900-H03 2830 3061 SRP2900-H04 2831 3061 SRP2900-H05 2832 3061 SRP2900-H06 2833 3061 SRP2900-H07 2834 3061 SRP2900-H08 2835 3061 SRP2900-H09 2836 3061 SRP2900-H10 2837 3061 SRP2900-H11 2838 3061 SRP2842-B01 2840 2951 SRP2842-G04 2846 2957 SRP2901-B05 2851 2962 SRP2901-D03 2857 2968 SRP2901-E03 2859 2970 SRP2901-F01 2860 2971 2.6.1.1.V H –V L Pairing variants In some implementations, the V provided by the present invention H - V L The pairing includes the exemplary V provided by the present invention. H and / or V L Variations of the sequence.

[0200] In some states, the V H The sequence comprises, consists of, or substantially consists of the following: Exemplary V provided by the present invention H Variations of the sequence. In some states, the V... H The sequence comprises, consists of, or substantially consists of the following: any exemplary V provided by this invention H A sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity.

[0201] In some implementations, the V H The sequence comprises, consists of, or substantially consists of any of the following exemplary V provided by the present invention having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. H Sequence. In some states, the amino acid substitutions are all conserved amino acid substitutions.

[0202] In some states, the V L The sequence comprises, consists of, or substantially consists of the following: Exemplary V provided by the present invention L Variations of the sequence. In some states, the V... L The sequence comprises, consists of, or substantially consists of the following: any exemplary V provided by this invention LA sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity.

[0203] In some implementations, the V L The sequence comprises, consists of, or substantially consists of any of the following exemplary V provided by the present invention having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. L Sequence. In some states, the amino acid substitutions are all conserved amino acid substitutions.

[0204] 2.7. Antibodies containing all six CDRs In some embodiments, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 sequences. In some samples, the CDR sequence is V. H (For CDR-H) or V L (For CDR-L) Part of it.

[0205] In some cases, the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 105, SEQ ID NO: 114, SEQ ID NO: 117, SEQ ID NO: 129 to SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 224, SEQ ID NO: 229, SEQ ID NO: 235, SEQ ID NO: 237, and SEQ ID NO: 238; the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 755, SEQ ID NO: 764, SEQ ID NO: 767, SEQ ID NO: 779 to SEQ ID NO: 866, SEQ ID NO: 868, SEQ ID NO: 874, SEQ ID NO: 879, SEQ ID NO: 885, ... SEQ ID NO: 887 and SEQ ID NO: 888; the CDR-H3 sequence is a Chothia CDR-H3 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 1405, SEQ ID NO: 1414, SEQ ID NO: 1417, SEQ ID NO: 1429 to SEQ ID NO: 1516, SEQ ID NO: 1518, SEQ ID NO: 1524, SEQ ID NO: 1529, SEQ ID NO: 1535, SEQ ID NO: 1537, and SEQ ID NO: 1538; the CDR-L1 sequence is a Chothia CDR-L1 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 1954, SEQ ID NO: 1960, SEQ ID NO: 1965, SEQ ID NO: 1971, SEQ ID NO: 1973, SEQ ID NO: 1974, and SEQ ID NO: 888. NO: 2064; The CDR-L2 sequence is a Chothia CDR-L2 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 2178, SEQ ID NO: 2184, SEQ ID NO: 2189, SEQ ID NO: 2195, SEQ ID NO: 2197, SEQ ID NO: 2198, and SEQ ID NO: 2288;The CDR-L3 sequence is a Chothia CDR-L3 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 2402, SEQ ID NO: 2408, SEQ ID NO: 2413, SEQ ID NO: 2419, SEQ ID NO: 2421, SEQ ID NO: 2422, and SEQ ID NO: 2512.

[0206] In some cases, the CDR-H1 sequence is a Kabat CDR-H1 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 430, SEQ ID NO: 439, SEQ ID NO: 442, SEQ ID NO: 454 to SEQ ID NO: 541, SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 562, and SEQ ID NO: 563; the CDR-H2 sequence is a Kabat CDR-H2 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 1080, SEQ ID NO: 1089, SEQ ID NO: 1092, SEQ ID NO: 1104 to SEQ ID NO: 1191, SEQ ID NO: 1193, SEQ ID NO: 1199, SEQ ID NO: 1204, SEQ ID NO: 120 ... SEQ ID NO: 1212 and SEQ ID NO: 1213; the CDR-H3 sequence is a Kabat CDR-H3 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 1730, SEQ ID NO: 1739, SEQ ID NO: 1742, SEQ ID NO: 1754 to SEQ ID NO: 1841, SEQ ID NO: 1843, SEQ ID NO: 1849, SEQ ID NO: 1854, SEQ ID NO: 1860, SEQ ID NO: 1862, and SEQ ID NO: 1863; the CDR-L1 sequence is a Kabat CDR-L1 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 2066, SEQ ID NO: 2072, SEQ ID NO: 2077, SEQ ID NO: 2083, SEQ ID NO: 2085, SEQ ID NO: 2086, and SEQ ID NO: 1212. NO: 2176; The CDR-L2 sequence is a Kabat CDR-L2 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 2290, SEQ ID NO: 2296, SEQ ID NO: 2301, SEQ ID NO: 2307, SEQ ID NO: 2309, SEQ ID NO: 2310, and SEQ ID NO: 2400;The CDR-L3 sequence is a Kabat CDR-L3 sequence comprising, consisting of, or substantially consisting of the following: SEQ ID NO: 2514, SEQ ID NO: 2520, SEQ ID NO: 2525, SEQ ID NO: 2531, SEQ ID NO: 2533, SEQ ID NO: 2534, and SEQ ID NO: 2624.

[0207] In some samples, the antibody contains antibodies derived from V H The three heavy chain CDRs of the sequence and from V L The sequence consists of three light chain CDRs, wherein the V H The sequence is selected from SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, SEQ ID NO: 2859, and SEQ ID NO: 2860, or variations thereof; and the V L The sequence is selected from SEQ ID NO: 2951, SEQ ID NO: 2957, SEQ ID NO: 2962, SEQ ID NO: 2968, SEQ ID NO: 2970, SEQ ID NO: 2971, and SEQ ID NO: 3061, or variations thereof. The CDR may employ any CDR scheme known to those skilled in the art. In some embodiments, the CDR is a (Kabat) CDR. In some embodiments, the CDR is a (Chothia) CDR.

[0208] In some embodiments, the antibody comprises V H / V L The V consists of three paired heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof. H / V LThe pairs are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO: 2779 / SEQ ID NO: 3061;SEQ ID NO:2780 / SEQ ID NO:3061;SEQ ID NO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ ID NO:2783 / SEQ ID NO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ ID NO:3061;SEQ ID NO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ ID NO:2788 / SEQ ID NO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ ID NO:3061;SEQ ID NO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ ID NO:2793 / SEQ ID NO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ ID NO:3061;SEQ ID NO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ ID NO:2798 / SEQ ID NO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ ID NO:3061;SEQ ID NO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ ID NO:2803 / SEQ ID NO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ ID NO:3061;SEQ ID NO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ ID NO:2808 / SEQ ID NO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ ID NO:3061;SEQ ID NO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ ID NO: 2813 / SEQ ID NO: 3061; SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.;

[0209] In some embodiments, the antibody comprises V H / V L The V consists of three paired heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof. H / V L The pairings are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; and SEQ ID NO: 2739 / SEQ ID NO: 3061. In some embodiments, the antibody comprises V from the antibody shown in SEQ ID NO: 2752 / SEQ ID NO: 3061. H / V L Paired three heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof.

[0210] The CDR can be based on any CDR scheme known to those skilled in the art. In some embodiments, the CDR is a Kabat CDR. In some embodiments, the CDR is a Chothia CDR. In some embodiments, the antibody further comprises the V H / V L Paired frame areas.

[0211] 2.7.1. Antibody variants containing all six CDRs In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 provided by the present invention comprise variations of the exemplary CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3 sequences provided by the present invention.

[0212] In some samples, the CDR-H1 sequence comprises, consists of, or substantially consists of variants of the exemplary Chothia or Kabat CDR-H1 sequences provided by this invention. In some samples, the CDR-H1 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Chothia or Kabat CDR-H1 sequence provided by this invention. In some samples, the CDR-H1 sequence comprises, consists of, or substantially consists of any exemplary Chothia or Kabat CDR-H1 sequence provided by this invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0213] In some samples, the CDR-H2 sequence comprises, consists of, or substantially consists of variants of the exemplary Chothia or Kabat CDR-H2 sequences provided by the present invention. In some samples, the CDR-H2 sequence comprises, consists of, or substantially consists of sequences having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary Chothia or Kabat CDR-H2 sequence provided by the present invention. In some samples, the CDR-H2 sequence comprises, consists of, or substantially consists of any exemplary Chothia or Kabat CDR-H2 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0214] In some samples, the CDR-H3 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary CDR-H3 sequence provided by the present invention. In some samples, the CDR-H3 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary CDR-H3 sequence provided by the present invention. In some samples, the CDR-H3 sequence comprises, consists of, or substantially consists of the following: any exemplary CDR-H3 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0215] In some samples, the CDR-L1 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary CDR-L1 sequence provided by the present invention. In some samples, the CDR-L1 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary CDR-L1 sequence provided by the present invention. In some samples, the CDR-L1 sequence comprises, consists of, or substantially consists of the following: any exemplary CDR-L1 sequence provided by the present invention, having 1, 2, or 3 amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0216] In some samples, the CDR-L2 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary CDR-L2 sequence provided by the present invention. In some samples, the CDR-L2 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary CDR-L2 sequence provided by the present invention. In some samples, the CDR-L2 sequence comprises, consists of, or substantially consists of the following: any exemplary CDR-L2 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0217] In some samples, the CDR-L3 sequence comprises, consists of, or substantially consists of the following: variants of the exemplary CDR-L3 sequence provided by the present invention. In some samples, the CDR-L3 sequence comprises, consists of, or substantially consists of the following: a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any exemplary CDR-L3 sequence provided by the present invention. In some samples, the CDR-L3 sequence comprises, consists of, or substantially consists of the following: any exemplary CDR-L3 sequence provided by the present invention, having one, two, or three amino acid substitutions. In some samples, all amino acid substitutions are conserved amino acid substitutions.

[0218] 3. Couplings This invention provides conjugates of anti-TF antibodies. The conjugates comprise anti-TF antibodies covalently linked to a payload, either directly or indirectly via a linker. In some embodiments, the conjugates comprise antibodies that specifically bind to TF, the antibody site being specifically linked to at least one payload group portion, and the antibody comprising one or more non-natural amino acids. In some embodiments, the antibody is linked to one payload. In further embodiments, the antibody is linked to more than one payload. In some embodiments, the antibody is linked to 2, 3, 4, 5, 6, 7, 8, 9, 10, or more payloads.

[0219] The payload can be any payload that a person skilled in the art would consider useful. In some embodiments, the payload is a therapeutic group portion. In some embodiments, the payload is a diagnostic group portion, such as a label. Useful payloads will be described in the following sections and examples.

[0220] 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.

[0221] In the conjugates provided by this invention, the antibody can be any antibody with binding specificity to TF. TF can be from any species. In some embodiments, TF is vertebrate TF. In some embodiments, TF is mammalian TF. In some embodiments, TF is human TF. In some embodiments, TF is mouse TF. In some embodiments, TF is cynomolgus monkey TF.

[0222] In some embodiments, the anti-TF antibody competes for binding with the antibody of the present invention. In some embodiments, the anti-TF antibody binds to the same epitope as the antibody of the present invention.

[0223] Antibodies are typically proteins comprising multiple polypeptide chains. In some embodiments, antibodies are heterotetramers comprising two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain via a covalent disulfide bond. Each heavy chain is linked to another heavy chain via one or more covalent disulfide bonds. Each heavy chain and each light chain may also have one or more intrachain disulfide bonds. As known to those skilled in the art, each heavy chain typically contains a variable domain (V... H Then there are multiple constant structural domains. Each light chain typically contains a variable structural domain (V0) at one end. L ), and contains constant structural domains. As is known to those skilled in the art, antibodies typically have selective affinity for their target molecules, namely antigens.

[0224] The antibodies provided by this invention can be in 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.

[0225] In some embodiments, the antibody of the conjugate comprises 1, 2, 3, 4, 5, or 6 CDR sequences as described in this invention. In some embodiments, the antibody of the conjugate comprises the heavy chain variable domain (V) as described in this invention. H In some embodiments, the antibody of the conjugate comprises the light chain variable domain (V) described in this invention. L In some embodiments, the antibody of the conjugate comprises the heavy chain variable domain (V) described in this invention. H ) and the light chain variable structural domain (V) described in this invention LIn some embodiments, the antibody of the conjugate comprises the paired heavy chain variable domain and light chain variable domain (V) as described in this invention. H - V L (Pairing). In some embodiments, the antibody of the conjugate comprises the heavy chain (HC) described in this invention. In some embodiments, the antibody of the conjugate comprises the light chain (LC) described in this invention. In some embodiments, the antibody of the conjugate comprises both the heavy chain (HC) and the light chain (LC) described in this invention. In some embodiments, the antibody of the conjugate comprises paired heavy and light chains as described in this invention (HC-LC pairing). In some embodiments, the antibody of the conjugate comprises the heavy chain (HC) described in this invention. In some embodiments, the antibody of the conjugate comprises the light chain (LC) described in this invention. In some embodiments, the antibody of the conjugate comprises both the heavy chain (HC) and the light chain (LC) described in this invention. In some embodiments, the antibody of the conjugate comprises paired heavy and light chains as described in this invention (HC-LC pairing).

[0226] In some embodiments, the antibody of the conjugate comprises any amino acid sequence of the antibody of the present invention. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 10 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 9 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 8 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 7 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 6 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 5 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 4 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 3 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 2 amino acid substitutions. In some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 1 conserved amino acid substitution. In some embodiments, all amino acid substitutions are conserved amino acid substitutions. For example, in some embodiments, the antibody comprises any of the above-described amino acid sequences having up to 10 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 9 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 8 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 7 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 6 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 5 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 4 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 3 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 2 conserved amino acid substitutions. In some embodiments, the antibody comprises any of the above-mentioned amino acid sequences having up to 1 conserved amino acid substitution.

[0227] In some embodiments, the antibody conjugate may be formed from an antibody comprising one or more reactive groups. In some embodiments, the antibody conjugate may 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 active groups capable of being conjugated to a payload or a linker. These active groups include cysteine ​​side chains, lysine side chains, and amino-terminal groups. In these embodiments, the antibody conjugate may comprise a payload or linker linked to residues of an antibody active group. In these embodiments, the payload precursor or linker precursor comprises an active group capable of forming a bond with the antibody active group. Typical active groups include maleimide groups, activated carbonates (including but not limited to p-nitrobenzene esters), and activated esters (including but not limited to...). N -Hydroxysuccinimide, p-nitrobenzene ester, and aldehydes). Particularly useful active groups include maleimide and succinimide, for example... N -Hydroxysuccinimide is used to form bonds with cysteine ​​and lysine side chains. Other active groups include alkynes (e.g., strained alkynes) and azides, used to form bonds with non-natural amino acids incorporated into the antibody polypeptide chain. Further active groups are described in the following sections and examples.

[0228] In some embodiments, the antibody comprises one or more modified amino acids having an active group, as described in this invention. Typically, the modified amino acid is not a naturally encoded amino acid. These modified amino acids may contain an active group for forming a covalent bond with a linker precursor or a payload precursor. Those skilled in the art can use the active group to link peptides to any molecular entity capable of forming a covalent bond with the modified amino acid. Therefore, this invention provides conjugates comprising antibodies containing modified amino acid residues, which are directly or indirectly linked to a payload via a linker. Exemplary modified amino acids are described in the following sections. Typically, the modified amino acid has an active group capable of forming a bond with a linker or payload having a complementary active group.

[0229] Non-natural amino acids are located at selected positions in the antibody's polypeptide chain. These positions are identified as optimal sites for providing non-natural amino acid substitutions. Each site is capable of carrying a non-natural amino acid with optimal structure, function, and / or method of antibody generation.

[0230] In some embodiments, the site-specific location used for substitution provides a stable antibody. Stability can be determined by any technique readily apparent to those skilled in the art.

[0231] In some embodiments, the site-specific position used for substitution provides an antibody with optimal functional properties. For example, the antibody exhibits little or no loss of binding affinity to its target antigen compared to antibodies lacking site-specific non-natural amino acids. In some embodiments, the antibody may show enhanced binding compared to antibodies lacking site-specific non-natural amino acids.

[0232] In some embodiments, the site-specific position for substitution provides an antibody that can be advantageously produced. For example, in some embodiments, the antibody exhibits advantageous properties in its synthesis method, as described below. In some embodiments, the antibody shows little or no loss in production yield compared to antibodies without site-specific non-natural amino acids. In some embodiments, the antibody may show increased production yield compared to antibodies without site-specific non-natural amino acids. In some embodiments, the antibody may show little or no loss of tRNA inhibition compared to antibodies without site-specific non-natural amino acids. In some embodiments, the antibody may show enhanced tRNA inhibition during production compared to antibodies without site-specific non-natural amino acids.

[0233] In some embodiments, the site-specific position for substitution provides an antibody with favorable solubility. In some embodiments, the antibody exhibits little or no loss of solubility compared to antibodies without site-specific non-natural amino acids. In some embodiments, the antibody may show enhanced solubility compared to antibodies without site-specific non-natural amino acids.

[0234] In some embodiments, the site-specific position used for substitution provides an antibody with favorable expression. In some embodiments, the antibody may show little or no loss of expression compared to antibodies without site-specific non-natural amino acids. In some embodiments, the antibody may show enhanced expression compared to antibodies without site-specific non-natural amino acids.

[0235] In some embodiments, the site-specific position for substitution provides an antibody with favorable folding properties. In some embodiments, the antibody may exhibit little or no loss in proper folding compared to antibodies without site-specific non-natural amino acids. In some embodiments, the antibody may exhibit enhanced folding properties compared to antibodies without site-specific non-natural amino acids.

[0236] In some embodiments, the site-specific position for substitution provides an antibody capable of favorable conjugation. As described below, several non-natural amino acids have side chains or functional groups that can facilitate antibody conjugation to a second drug directly or via a linker. In some embodiments, the antibody may exhibit enhanced conjugation efficiency compared to antibodies that do not have the same or other non-natural amino acids at other positions. In some embodiments, the antibody may exhibit enhanced conjugation yield compared to antibodies that do not have the same or other non-natural amino acids at other positions. In some embodiments, the antibody may exhibit enhanced conjugation specificity compared to antibodies that do not have the same or other non-natural amino acids at other positions.

[0237] One or more non-natural 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, without limitation, including light or heavy chains. The site-specific positions can be located in any domain of the antibody, including any variable domain and any constant domain.

[0238] In some embodiments, the antibody provided by the present invention contains one non-natural amino acid at a site-specific position. In some embodiments, the antibody provided by the present invention contains two non-natural amino acids at a site-specific position. In some embodiments, the antibody provided by the present invention contains three non-natural amino acids at a site-specific position. In some embodiments, the antibody provided by the present invention contains more than three non-natural amino acids at a site-specific position. In some embodiments, the antibody provided by the present invention contains four non-natural amino acids at a site-specific position.

[0239] In some embodiments, the antibody provided by the present invention comprises one or more non-natural amino acids, each located at a position selected from the group consisting of the following heavy chain residues or light chain residues: HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, HC-Y391, 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, or their translated modified variants, according to the Kabat, Chothia, or EU numbering schemes. In some embodiments, the antibody provided by the present invention comprises one or more non-natural amino acids, each located at a position selected from the group consisting of the following heavy chain residues or light chain residues: HC-F404, HC-Y180, HC-F241, HC-Y391, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering schemes, or their translated modified variants. In some embodiments, the antibody provided by the present invention comprises one or more non-natural amino acids, each located at a position selected from the group consisting of the following heavy chain residues or light chain residues: HC-F404, HC-Y180, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering schemes, or their translated modified variants. In some embodiments, the antibody provided by the present invention comprises one or more non-natural amino acids, each located at a position selected from the group consisting of heavy or light chain residues: HC-F404, HC-Y180, HC-Y391, HC-F241, and LC-K42 according to the Kabat, Chothia, or EU numbering schemes, or their translated variants. In some embodiments, the antibody provided by the present invention comprises a non-natural amino acid at position HC-F404 according to the Kabat, Chothia, or EU numbering schemes, or its translated variant. In some embodiments, the antibody provided by the present invention comprises a non-natural amino acid at position HC-Y180 according to the Kabat, Chothia, or EU numbering schemes, or its translated variant. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-F404 and HC-Y180 according to the Kabat, Chothia, or EU numbering scheme, or their post-translational modified variants.In some embodiments, the antibody provided by the present invention comprises a non-natural amino acid at position HC-F241 according to the Kabat, Chothia, or EU numbering scheme, or a post-translational modified variant thereof. In some embodiments, the antibody provided by the present invention comprises a non-natural amino acid at position LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or a post-translational modified variant thereof. In some embodiments, the antibody provided by the present invention comprises a non-natural amino acid at position LC-E161 according to the Kabat, Chothia, or EU numbering scheme, or a post-translational modified variant thereof. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-F404, HC-Y180, and LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or post-translational modified variants thereof. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-F404, HC-Y180, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering scheme, or their translated variants. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-F404, HC-Y180, and HC-F241 according to the Kabat, Chothia, or EU numbering scheme, or their translated variants. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or their translated variants. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42 according to the Kabat, Chothia, or EU numbering scheme, or their translated variants. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-F241 and HC-F404 according to the Kabat, Chothia, or EU numbering scheme, or their translated variants. In some embodiments, the antibody provided by the present invention comprises non-natural amino acids at positions HC-Y180, HC-F404, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering scheme, or their translated variants.In some embodiments, the antibodies provided by this invention comprise non-natural amino acids, or post-translational modified variants thereof, at positions HC-Y180, HC-F241, HC-F404, and HC-Y391 according to the Kabat, Chothia, or EU numbering schemes. In these designations, HC represents heavy chain residues, and LC represents light chain residues.

[0240] In some cases, the present invention provides antibody conjugates with the following formula: Or, or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or tautomer thereof, wherein: COMP stands for residues of anti-tissue factor antibodies; i. PAY is the effective payload group portion; ii.LINK is a connector; and iii. n2 is an integer from 1 to 10. iv. COMP contains one or more non-natural amino acids.

[0241] In some embodiments, the present invention provides the coupling shown in formula (C1) or (C2): Or its pharmaceutically acceptable salts, solvates, stereoisomers, regioisomers, or tautomers, wherein: COMP stands for residues of anti-tissue factor antibodies; PAY is the payload group portion; W 1 W 2 W 3 W 4 and W 5 Each is an independent single bond, or each is independent of the others, or each is an independent divalent linker; EG is absent, or EG is an eliminator group. Each RT is a release trigger group, which is located in the main chain of formula (C1) or (C2) or connected to EG, wherein each RT is optional; HP is a single bond, or it may not exist, or it may be a divalent hydrophilic group; Each SG is a single bond, or none of them, or each is a divalent spacer group; R is H, a terminal coupling group, or a divalent residue of a terminal coupling group; and n2 is an integer from 1 to 10.

[0242] In some embodiments, the coupling shown in formula (C1) or (C2) comprises n2 linked PAY group portions, 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.

[0243] 1. Linking group Linking groups facilitate the introduction of eliminating groups, release triggering groups, hydrophobic groups, spacer groups, and / or coupling groups into compounds. Useful linking groups are known and apparent to those skilled in the art. This invention provides examples of useful linking groups. In some embodiments, the linking group is specified as W. 1 W 2 W 3 W 4 、 or W 5 In some embodiments, the linking group may comprise a divalent ketone, divalent ester, divalent ether, divalent amide, divalent amine, alkylene, arylene, sulfide, disulfide, carbonylene, or a combination thereof. In some embodiments, the linking group may comprise –C(O)–, –O–, –C(O)NH–, –C(O)NH-alkyl–, –OC(O)NH–, –SC(O)NH–, –NH–, –NH-alkyl–, –N(CH3)CH2CH2N(CH3)–, –S–, –SS–, –OCH2CH2O–, or their opposites (e.g., –NHC(O)–), or a combination thereof.

[0244] 2. Elimination of radicals Elimination groups facilitate the separation of the bioactive group portion of the compound or conjugate of the present invention from the remainder of the compound or conjugate in vivo and / or in vitro. Elimination groups can also be used in combination with release-initiating groups to promote the separation of the bioactive group portion of the compound or conjugate of the present invention. For example, elimination groups and release-initiating groups can undergo a release reaction to release the bioactive group portion of the compound or conjugate of the present invention from the compound or conjugate in vivo and / or in vitro. After a release reaction is initiated by a release-initiating group, the elimination group cleaves the bioactive group portion or its prodrug form to form a stable, non-toxic entity that does not further affect the activity of the bioactive group portion.

[0245] In some embodiments, the eliminating group is specified as EG in this invention. Useful eliminating groups include those described in this invention. In some embodiments, the eliminating group is: Among them, R EG The benzene ring is selected from the group consisting of: H, alkyl, biphenyl, -CF3, -NO2, -CN, F, Br, Cl, alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)-. In each structure, the benzene ring may be with 1, 2, 3, or in some cases with 4 R groups. EG Group linkage. In the second and third structures, those skilled in the art will understand that EG is linked to RT, which is not within the main chain of formula (C1), as described in the above description of formula (C1). In some embodiments, R EG The group consisting of H, alkyl, biphenyl, -CF3, alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)- is selected. In a further embodiment, R EG The group selected is from the group consisting of: H, -NO2, -CN, F, Br, and Cl. In some embodiments, the eliminating group is... In some embodiments, the elimination group is In some embodiments, the elimination group is .

[0246] In some embodiments, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein EG comprises a phenylene group, a carboxylidene group, an amine group, or a combination thereof. In some embodiments, the eliminating group is: Where Z can be CH or N, R EG The benzene ring is selected from the group consisting of: H, alkyl, biphenyl, -CF3, -NO2, -CN, F, Br, Cl, alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)-. In each structure, the benzene ring may be with 1, 2, 3, or in some cases with 4 R groups. EG Group linkage. In both the first and second structures, those skilled in the art will understand that EG is linked to RT, which is not within the main chain of formula (C1), as described in the above description of formula (C1). In some embodiments, R EG The group consisting of H, alkyl, biphenyl, -CF3, alkoxy, alkylamino, dialkylamino, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)- is selected. In a further embodiment, R EGThe following groups are selected: H, -NO2, -CN, F, Br, and Cl. In some embodiments, each R in the EG... EG They are H, respectively. In some embodiments, the elimination group is... In some embodiments, the elimination group is In some embodiments, the elimination group is .

[0247] 3. Release trigger groups Release triggering groups facilitate the separation of the bioactive group portion of the compound or conjugate of the present invention from the remainder of the compound or conjugate in vivo and / or in vitro. Release triggering groups can also be used in conjunction with elimination groups to promote the separation of the bioactive group portion of the compound or conjugate of the present invention. For example, elimination groups and release triggering groups can react in a release reaction to release the bioactive group portion of the compound or conjugate of the present invention from the compound or conjugate in vivo and / or in vitro. In some embodiments, release triggering groups may function through biodriven reactions with high tumor:non-tumor specificity (e.g., proteolytic activity of enzymes overexpressed in the tumor microenvironment).

[0248] In some embodiments, the release triggering group is designated as RT in this invention. In some embodiments, RT is divalent and linked within the main chain of formula (C1). In other embodiments, RT is monovalent and linked to EG as shown above. Useful release triggering groups include those described in this invention. In some embodiments, the release triggering group comprises residues of natural or non-natural amino acids or residues of sugar rings. In some embodiments, the release triggering group is: .

[0249] Those skilled in the art should understand that the first structure is bivalent and can be connected within the main chain of formula (C1) or as shown in formula (C2); and the second structure is monovalent and can be connected to EG as shown in formula (C1) above.

[0250] In some embodiments, the release trigger group is In some embodiments, the release trigger group is .

[0251] In some embodiments, the release trigger group is a protease-cleavable R1-Val-X peptide having the following structure: Where R1 is H or R2 is CH3, CH2CH2CO2H, or (CH2)3NHCONH2; the release triggering group is an Ala-Ala-Asn or Ala-Ala-Asp peptide that can be cleaved by legumain, having the following structure: Wherein Z is OH or NH2; or the release triggering group is a β-glucuronide that can be cleaved by β-glucuronidase, having the following structure: Alternatively, the release triggering group may be a Val-Lys-Gly peptide having the following structure: .

[0252] Those skilled in the art will recognize that, and These are bivalent structures, and can be connected within the main chain of formula (C1), or connected as shown in formula (C2); the structures It is monovalent and can be connected to EG as shown in equation (C1) above.

[0253] In some embodiments, the release trigger group 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 some embodiments, the release trigger group further comprises a non-natural amino acid. In some embodiments, the non-natural amino acid has the structure shown in the following formula: Wherein POLY is a polymer, such as a hydrophilic polymer. In some embodiments, the non-natural amino acid has the structure shown in the following formula: , where m1 is an integer from 1 to 25, such as 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25.

[0254] 4. Hydrophilic groups Hydrophilic groups contribute to improving the hydrophilicity of the compounds described in this invention. It is believed that increased hydrophilicity enhances the solubility of the compounds in aqueous solutions (e.g., aqueous solutions in biological systems). Hydrophilic groups can also function as spacer groups, which will be described in further detail in this invention.

[0255] In some embodiments, the hydrophilic group is designated as HP in this invention. Available hydrophilic groups include those described in this invention. In some embodiments, the hydrophilic group is divalent polyethylene glycol. In some embodiments, the hydrophilic group is divalent polyethylene glycol having the structure shown below: ; Where 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 some implementations, m1 is 4. In some implementations, m1 is 12. In some implementations, m1 is 13.

[0256] In some embodiments, the hydrophilic group is divalent polyethylene glycol, which has the structure shown in the following formula: .

[0257] In some other embodiments, the hydrophilic group is divalent polyethylene glycol, which has the structure shown in the following formula: .

[0258] In other embodiments, the hydrophilic group is divalent polyethylene glycol, which has the structure shown in the following formula: .

[0259] In other embodiments, the hydrophilic group is divalent polyethylene glycol, which has the structure shown in the following formula: .

[0260] In some embodiments, the hydrophilic group is a sulfonic acid. In some embodiments, the hydrophilic group is a cysteine ​​side chain. In some embodiments, the hydrophilic group may contain a chain sulfonic acid having the structure shown below: (a) In some embodiments, the hydrophilic group is a side chain of a non-natural amino acid having the structure shown below: , where m1 is an integer from 1 to 25, such as 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25.

[0261] 5. Spacer group The spacer group helps to separate the coupling group from other groups of the compound described in this invention. This spacer allows for more efficient coupling of the compound to the antibody and more efficient cleavage of the active catabolic metabolite. The spacer group also stabilizes the coupling group, thereby improving the overall properties of the antibody-drug conjugate.

[0262] In some embodiments, the spacer group is designated as SP in this invention. Useful spacer groups include those described in this invention. In some embodiments, the spacer group is: In some embodiments, the spacer group W 4 Together with the hydrophilic groups, they form divalent polyethylene glycol, which has the structure shown in the following formula: ; Where m1 is an integer from 1 to 13, optionally from 1 to 4, optionally from 2 to 4, or optionally from 4 to 8.

[0263] In some implementations, the SP is .

[0264] In some embodiments, the divalent polyethylene glycol has the structure shown in the following formula: .

[0265] In some other embodiments, the divalent polyethylene glycol has the structure shown in the following formula: .

[0266] In other embodiments, the divalent polyethylene glycol has the structure shown in the following formula: .

[0267] In other embodiments, the divalent polyethylene glycol has the structure shown in the following formula: .

[0268] In some embodiments, the spacer group may contain a chain sulfonic acid having the structure shown below: In some embodiments, the spacer group is a diamine. In some embodiments, the spacer group has the structure shown in the following formula: .

[0269] In some embodiments, the spacer group comprises a fused ring or a spirocyclic ring. In some embodiments, the spacer group has the structure shown in the following formula: , where each n a m a o a and p a Each of the numbers is an integer independently selected from 1, 2, 3, 4, and 5. In some embodiments, the spacer group has the structure shown in the following formula: , where each n a ma o a and p a Each of the numbers is an integer independently selected from 1, 2, 3, 4, and 5. In some embodiments, the spacer group is selected from the group consisting of: .

[0270] 6. Coupling groups and their residues The coupling group facilitates the coupling of the payload described in this invention to a second compound, such as the antibody described in this invention. In some embodiments, the coupling group is designated as R in this invention. The coupling group can react via any suitable reaction mechanism known to those skilled in the art. In some embodiments, the coupling group reacts via a [3+2] alkyne-azide cycloaddition reaction, a reverse electron-demanding Diels-Alder linkage reaction, a thiol-electrophile reaction, or a carbonyl-oxyamine reaction, the specific reaction mechanism of which will be described in detail in this invention. In some embodiments, the coupling group comprises an alkyne, a strained alkyne, a tetrazine, a thiol, a p-acetylphenylalanine residue, an oxyamine, a maleimide, or an azide. In some embodiments, the coupling group is: Or –SH; where R 201 It is a lower alkyl group. In one embodiment, R 201 It is methyl, ethyl, or propyl. In one embodiment, R 201 It is methyl. Other coupling groups are described, for example, in U.S. Patent Application Publication No. US2014 / 0356385, U.S. Patent Application Publication No. US2013 / 0189287, U.S. Patent Application Publication No. US2013 / 0251783, U.S. Patent No. US8,703,936, U.S. Patent No. US9,145,361, U.S. Patent No. US9,222,940 and U.S. Patent No. US8,431,558.

[0271] After coupling, a divalent residue of the coupling group is formed and linked to residues of the antibody. The structure of the divalent residue is determined by the type of coupling reaction used to form the conjugate.

[0272] In some embodiments, when the coupling compound is formed via a [3+2]-yne-azide cycloaddition reaction, the divalent residue of the coupling group comprises a triazole ring or a fused cyclic group containing a triazole ring. In some embodiments, when the coupling compound is formed via a strain-promoted [3+2]-yne-azide cycloaddition (SPAAC) reaction, the divalent residue of the coupling group is: .

[0273] In some embodiments, when the coupling compound is formed via a tetrazine anti-electron-demanding Diels-Alder linkage reaction, the divalent residue of the coupling group comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In some embodiments, when the coupling compound is formed via a tetrazine anti-electron-demanding Diels-Alder linkage reaction, the divalent residue of the coupling group is: .

[0274] In some embodiments, when the coupling compound is formed via a thiol-maleimide reaction, the divalent residue of the coupling group comprises a succinimide group and a sulfur bond. In some embodiments, when the coupling compound is formed via a thiol-maleimide reaction, the divalent residue of the coupling group is: .

[0275] In some embodiments, the coupling compound is obtained by using thiols with the following groups: N -Hydroxysuccinimide reaction forms: .

[0276] The reaction involving the formation of the coupling compound includes the following steps: , The divalent residues of the resulting coupling group are: .

[0277] In some embodiments, when the coupling compound is formed via a carbonyl-oxoamine reaction, the divalent residue of the coupling group comprises a divalent residue of a non-natural amino acid. In some embodiments, when the coupling compound is formed via a carbonyl-oxoamine reaction, the divalent residue of the coupling group is: .

[0278] In some embodiments, when the coupling compound is formed via a carbonyl-oxoamine reaction, the divalent residue of the coupling group comprises an oxime bond. In some embodiments, when the coupling compound is formed via a carbonyl-oxoamine reaction, the divalent residue of the coupling group is: .

[0279] In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R comprises a triazole ring. In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is a triazole ring or a fused cyclic group containing a triazole ring. In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is: .

[0280] In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is: .

[0281] In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R comprises a sulfur bond. In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is: .

[0282] In one embodiment, the present invention provides a conjugate of 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 one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is: .

[0283] In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R comprises an amide bond. In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is: .

[0284] In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R comprises an oxime bond. In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is: .

[0285] In one embodiment, the present invention provides a conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein R is: .

[0286] In one embodiment, the present invention provides a compound of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein COMP is a residue of any compound known to be conjugated with the payload and optional linker of the present invention. In one embodiment, the present invention provides a compound of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof; wherein COMP is a residue of an antibody chain.

[0287] On one hand, the present invention provides antibody conjugates comprising the payload described herein and an optional linker described herein, the linker being linked to an anti-tissue factor antibody, wherein COMP is a residue of the antibody. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer 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 one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0288] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R comprises a fused bicyclic ring, wherein the fused bicyclic ring has at least two adjacent nitrogen atoms in the ring. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0289] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R comprises a sulfur bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R is: .

[0290] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R comprises a divalent residue of a non-natural amino acid. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R is: .

[0291] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R comprises an amide bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R is: .

[0292] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R comprises an oxime bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the polypeptide; and R is: .

[0293] On one hand, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein the antibody conjugate comprises the payload described in the present invention and an optional linker described in the present invention, the linker being linked to an antibody, wherein COMP is a residue of the antibody. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer 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 one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0294] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R comprises a fused bicyclic ring, wherein the fused bicyclic ring has at least two adjacent nitrogen atoms in the ring. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0295] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R comprises a sulfur bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0296] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R comprises a divalent residue of a non-natural amino acid. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0297] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R comprises an amide bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0298] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R comprises an oxime bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody; and R is: .

[0299] On one hand, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein the antibody conjugate comprises the payload described herein and an optional linker described herein, the linker being connected to an antibody chain, wherein COMP is a residue of the antibody chain. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer 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 one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R is: .

[0300] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R comprises a fused bicyclic ring, wherein the fused bicyclic ring has at least two adjacent nitrogen atoms in the ring. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R is: .

[0301] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R comprises a sulfur bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R is: .

[0302] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R comprises a divalent residue of a non-natural amino acid. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R is: .

[0303] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R comprises an amide bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R is: .

[0304] In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R comprises an oxime bond. In one embodiment, the present invention provides an antibody conjugate of formula (C1) or (C2), or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: COMP is a residue of the antibody chain; and R is: .

[0305] (b) Couplings In one embodiment, the present invention provides a conjugate of any of the following formulas, wherein COMP represents residues of an anti-tissue factor antibody, and PAY represents the payload group portion: In one embodiment, the present invention provides a conjugate of any of the following formulas, wherein COMP represents residues of an anti-tissue factor antibody, and PAY represents the payload group portion: In one embodiment, the present invention provides a conjugate of any of the following formulas, wherein COMP represents residues of an anti-tissue factor antibody, and PAY represents the payload group portion: .

[0306] In one embodiment, the present invention provides conjugates of any of formulas 101a-104b, wherein COMP represents residues of an anti-tissue factor antibody, and PAY represents the payload group portion: .

[0307] In any of the foregoing embodiments, the coupling comprises n2 PAY group portions, 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.

[0308] In some embodiments, the present invention provides antitissue factor conjugates comprising modified hemiasterlin and a linker, for example, as described in PCT Publication No. WO 2016 / 123582. For instance, the conjugate may have a structure comprising any of the formulas 1000-1000b, 1001-1001b, 1002-1002b, I-XIXb-2, 101-111b, or 1-8b as described in PCT Publication No. WO 2016 / 123582. Examples of conjugates comprising modified hemiasterlin and a linker are provided below.

[0309] In some embodiments, the present invention provides the coupling shown in formula (I): Or its pharmaceutically acceptable salt, wherein, COMP is a residue of the anti-tissue factor (TF) antibody provided in this invention; L 1 It 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 imidene-[X] 1 -C 2-6 [Alkenyl] n -[X 1 ] p – or –X 1 -C 2-6 Ethyne-[X] 1 -C 2-6 [Iso-ynyl] n -[X 1 ] p – wherein at least one alkylene, alkenylene, or ynylene group in Y is selected from one or more groups chosen from R. 50Substituents; and The alkylene, alkenylene, or alkyne group in Y is optionally selected from one or more groups selected from R. 51 Substituents of the substituents; R 50 Yes –C 1-6 Alkylene-X 2 -[C 1-6 [alkylene] m -POLY、–C 2-6 imide-X 2 -[C 2-6 [Alkenyl] m -POLY, or –C 2-6 Ethyne-X 2 -[C 2-6 [Iso-ynyl] m -POLY, where R 50 Each alkylene, alkenylene, or ynylene group may optionally be substituted by one or more substituents selected from the following: halogen, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; R 51 Independently selected from halogens, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; X 1 and X 2 Each is independently selected from –C(O)– and –N(R)–. 10 )C(O)–; R 10 Each time it appears, it is independently selected from H and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; 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 the monosaccharide; D is the drug group moiety; and RL stands for reactive group residue.

[0310] In some embodiments, the present invention provides the coupling shown in formula (II): Or its pharmaceutically acceptable salt, wherein, COMP is a residue of the anti-tissue factor antibody provided in this invention; L 1 It 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 imidene-[X] 1 -C 2-6 [Alkenyl] n -X 1 – or –X 1 -C 2-6 Ethyne-[X] 1 -C 2-6 [Iso-ynyl] n -X 1 – wherein at least one alkylene, alkenylene, or ynylene group in Y is selected from one or more groups chosen from R. 50 Substituents of the substituents; R 50 Yes –C 1-6 Alkylene-X 2 -[C 1-6 [alkylene] m -POLY、–C 2-6 imide-X 2 -[C 2-6 [Alkenyl] m -POLY, or –C 2-6 Ethyne-X 2 -[C 2-6[Iso-ynyl] m -POLY, where R 50 Each alkylene, alkenylene, or ynylene group may optionally be substituted by one or more substituents selected from the following: halogen, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; X 1 and X 2 Each is independently selected from –C(O)– and –N(R)–. 10 )C(O)–; R 10 Each time it appears, it is independently selected from H and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; 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 the monosaccharide; D is the drug group moiety; and RL stands for active group residue.

[0311] In some embodiments, the present invention provides the coupling shown in formula (IIA): Or its pharmaceutically acceptable salt.

[0312] In some embodiments, the compound represented by formula (II) has the structure represented by formula (IIB): Or its pharmaceutically acceptable salt.

[0313] In some implementations of formulas (I), (II), (IIA), or (IIB), L 1 It is -C 1-3 Alkylene-. In some embodiments, L 1It is -CH2-. In some embodiments of formula (I), (II), (IIA), or (IIB), L 1 It is -CH2CH2-. In some implementations, L 1 It is -CH2CH2CH2-.

[0314] In some embodiments of equation (I), including any of the aforementioned embodiments, p is 0. In some embodiments of equation (I), including any of the aforementioned embodiments, p is 1.

[0315] In some embodiments of equations (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X 1 -C 1-6 Alkylene-[X] 1 -C 1-6 [alkylene] n -X 1 – where at least one alkylene group in Y is selected from one or more of R 50 Substituents are substituted. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X. 1 -C 1-6 Alkylene-[X] 1 -C 1-6 [alkylene] n – where at least one alkylene group in Y is selected from one or more of R 50 Substituents are substituted. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X. 1 -C 2-6 imidene-[X] 1 -C 2-6 [Alkenyl] n -X 1 – where at least one alkenyl group in Y is selected from one or more groups of R 50 Substituents are substituted. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X. 1 -C 2-6 imidene-[X] 1 -C 2-6 [Alkenyl] n – where at least one alkenyl group in Y is selected from one or more groups of R 50 Substituents are substituted. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X. 1 -C 2-6 Ethyne-[X] 1-C 2-6 [Iso-ynyl] n -X 1 – where at least one alkyne group in Y is selected from one or more groups from R 50 Substituents are substituted. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X. 1 -C 2-6 Ethyne-[X] 1 -C 2-6 [Iso-ynyl] n – where at least one alkyne group in Y is selected from one or more groups from R 50 Substituents are substituted. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n is 0. In some embodiments of formula (I), (II), (IIA), or (IIB), n is 1. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n is 2. In some embodiments, including any of the foregoing embodiments, n is 3.

[0316] In some embodiments of equations (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X 1 -C 1-4 Alkylene-[X] 1 -C 1-4 [alkylene] n -X 1 – where at least one alkylene group in Y is selected from one or more of R 50 Substituents are substituted. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n is 0. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n is 1. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n is 2. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n is 3.

[0317] In some embodiments of equations (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 -C 1-4Alkylene-X 1 – where at least one alkylene group in Y is selected from one or more of R 50 Substituent substitution. In certain embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X. 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 – where at least one alkylene group in Y is selected from one or more of R 50 Substituent substitution. In certain embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, Y is –X. 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 – where at least one alkylene group in Y is selected from one or more of R 50 Substituents are substituted.

[0318] In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, R 50 Yes –C 1-6 Alkylene-X 2 -[C 1-6 [alkylene] m -POLY, where R 50 Each alkylene group is optionally bonded by one or more elements selected from halogens, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Substituents of the haloalkyl group. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, R 50 Yes –C 1-4 Alkylene-X 2 -[C 1-4 [alkylene] m -POLY, where R 50Each alkylene group is optionally bonded by one or more elements selected from halogens, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Substituents of the haloalkyl group. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, R 50 Each alkylene group is optionally bonded by one or more elements selected from halogen, -OH, -N(R) 10 )2、-C(O)N(R 10 )2、-C(O)-、C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Substituents of haloalkyl groups. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, m is 0. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, m is 1.

[0319] In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, R 50 Yes –C 2-6 imide-X 2 -[C 2-6 [Alkenyl] m -POLY, where R 50 Each of the alkenyl groups is optionally surrounded by one or more elements selected from halogen, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10Substituents of haloalkyl groups. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, m is 0. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, m is 1.

[0320] In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, R 50 Yes –C 2-6 Ethyne-X 2 -[C 2-6 [Iso-ynyl] m -POLY, where R 50 Each of the alkyne groups is optionally surrounded by one or more groups selected from halogen, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Substituents of haloalkyl groups. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, m is 0. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, m is 1.

[0321] In certain embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is polyethylene glycol (PEG), methoxy polyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(enol), poly(vinylpyrrolidone), poly(hydroxyalkyl methylacrylamide), poly(hydroxyalkyl methacrylate), poly(sugars), poly(α-hydroxy acids), poly(vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly( N-Acryloylmorpholine), polysarcosine, or combinations thereof. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is polyethylene glycol (PEG). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is methoxylated polyethylene glycol (mPEG). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, 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 embodiments, POLY is poly(oxyethylated polyol). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is poly(enol). In some embodiments, POLY is poly(vinylpyrrolidone). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is poly(hydroxyalkyl methacrylamide). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is poly(hydroxyalkyl methacrylate). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is poly(saccharide). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is poly(α-hydroxy acid). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is poly(vinyl alcohol). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is polyphosphazene. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is polyoxazoline (POZ). In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is a poly( N-Acryloylmorpholine). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is polysarcosine. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is a non-peptide water-soluble polymer. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY comprises polyethylene glycol (PEG) or methoxy polyethylene glycol (mPEG). In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, POLY is ,in This represents a connection point connecting to the remainder of the compound, where n1 is an integer from 1 to 20. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n1 is an integer from 5 to 15. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n1 is 1. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n1 is 2. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n1 is 3. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n1 is 4. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n1 is 5. In some embodiments of formula (I), (II), (IIA), or (IIB), including any of the foregoing embodiments, n1 is 6. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 7. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 8. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 9. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 10. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 11. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 12. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 13. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 14. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 15. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 16. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 17. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 18. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 19.In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 20. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 21. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 22. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 23. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 24. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 25. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 26. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 27. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 28. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 29. In some embodiments of formulas (I), (II), (IIA), or (IIB), including any of the aforementioned embodiments, n1 is 30.

[0322] In some embodiments, RL includes an alkyne, a cyclooctyne, a strained olefin, a tetrazine, an amine, a methylcyclopropene, a thiol, a p-acetylphenylalanine residue, an oxyamine, a maleimide, or an azide. In some embodiments, RL includes an alkyne. In some embodiments, RL includes a cyclooctyne. In some embodiments, RL includes a strained olefin. In some embodiments, RL includes a tetrazine. In some embodiments, RL includes an amine. In some embodiments, RL includes a methylcyclopropene. In some embodiments, RL includes a thiol. In some embodiments, RL includes a p-acetylphenylalanine residue. In some embodiments, RL includes an oxyamine. In some embodiments, RL includes a maleimide. In some embodiments, RL includes an azide. In some embodiments, RL is selected from the group consisting of: (c) and This indicates the connection point to the rest of the compound. In some embodiments, RL is... or ,and This indicates the connection point to the rest of the compound. In some embodiments, RL is... or ,and This indicates the connection point to the rest of the compound. In some embodiments, RL is... ,and This indicates the connection point to the rest of the compound. In some embodiments, RL is... ,and This indicates the connection point to the rest of the compound. In some embodiments, RL is... ,and This indicates the connection point to the rest of the compound. In some embodiments, RL is... ,in This indicates the connection point to the rest of the compound. In some embodiments, RL is... ,and This indicates the connection point to the rest of the compound. In some embodiments, RL is... ,and This indicates the connection point to the rest of the compound. In some embodiments, RL is... ,and This indicates a connection point to the remainder of the compound. In some embodiments, Su is a sugar group moiety. In some embodiments, Su is a hexose form of a monosaccharide. Su can be a glucuronic acid residue or a mannose residue. In some embodiments, Su is... ,in This indicates a connection point that connects to the rest of the compound. In some embodiments, Su is... ,in This indicates the connection point that connects to the rest of the compound.

[0323] On the one hand, the present invention provides the coupling shown in formula (III): Or its pharmaceutically acceptable salts and / or regioisomers; in L 1a Selected from and ; Ring A is an optionally substituted bridging, fused, or spirobicyclic carbocyclic ring, or an optionally substituted bridging, fused, or spirobicyclic heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring of ring A is optionally substituted by one or more substituents selected from: alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2R 3 )2、-C(O)-、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; Ring B is optional. N - A bridging, fused, or spirocyclic bicyclic heterocycle, wherein ring B is optionally substituted by one or more substituents selected from: alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -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, aralkyl, heteroaryl, and heteroarylalkyl; R a and R b Each is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; a is an integer independently selected from 0, 1, 2, 3, 4, 5, and 6; R 1 It is H or an alkyl group, wherein the alkyl group is optionally substituted by one or more substituents selected from: cycloalkyl, halogen, alkoxy, -CN, -NO2, -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 Each is independently selected from H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; Y a It is *-C(O)-(CR) a R b ) c -NH-, or *-C(O)-(CR) a R b ) c -, where * represents Ya The location connected to RL; c is an integer selected from 1, 2, 3, 4, 5, or 6; RL stands for active group residue; L 2 Does not exist, or L 2 It is a linker containing hydrophilic polymer residues; L 3 Does not exist, or L 3 It 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)-ZL 4 -OC(O)-, -Z-AA-, -AA-, -C(O)-, -C(O)-AA-Z-(CR a R b ) a -、-AA-C(O)-、-C(O)-(CR a R b ) a -Z-(CR a R b )-Z-AA-C(O)-、-C(O)OL 4 -ZC(O)-(CR a R b ) a -ZC(O)-, -AA-Z-, or -(CR) a R b ) a -Z-AA-C(O)-; Z is selected from -NR 2 -、and -O-; AA stands for amino acid residue or peptide residue; L 4 yes , where Su is the hexose form of the monosaccharide; d is an integer independently selected from 1, 2, and 3; D is the drug group part; COMP stands for the residues of tissue factor antibody; and This indicates the connection point that connects to the rest of the compound.

[0324] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIIA): (IIIA); Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers c, RL, and R are... a R b Ring B, L 2 L 3 D and COMP all have the definitions described in this invention.

[0325] In some embodiments, the compound represented by formula (IIIA) is selected from the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0326] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIIB): (IIIB); Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers c, RL, and R are... a R b Ring B, L 2 L 3 D and COMP all have the definitions described in this invention.

[0327] In some embodiments, the compound represented by formula (IIIB) is selected from the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0328] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIIC): (IIIC); Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers a, c, RL, and R are... a R b Ring A, L 2 L 3 D and COMP all have the definitions described in this invention.

[0329] In some embodiments, the compound represented by formula (IIIC) is selected from the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0330] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIID): (IIID); Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers a, c, RL, and R are... a R b Ring A, L 2 L 3 D and COMP all have the definitions described in this invention.

[0331] In some embodiments, the compound represented by formula (IIID) is selected from the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0332] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIIE): (IIIE); Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers a, c, RL, and R are... a R b Ring B, L 3 POLY 2 D and COMP all have the definitions described in this invention.

[0333] In some embodiments, the compound represented by formula (IIIE) is selected from the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0334] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIIF): (IIIF) Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers a, c, RL, and R are... a R b Ring B, L 3 POLY 2 D and COMP all have the definitions described in this invention.

[0335] In some embodiments, the compound represented by formula (IIIF) is selected from the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0336] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIIG): (IIIG) Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers a, c, RL, and R are... a R b Ring A, L 3 POLY 2 D and COMP all have the definitions described in this invention.

[0337] In some embodiments, the compound represented by formula (IIIG) is selected from the following formulas: Or its pharmaceutically acceptable salts and / or regioisomers.

[0338] In some embodiments, the compound represented by formula (III) is the compound represented by formula (IIIH): (IIIH); Or its pharmaceutically acceptable salts and / or regioisomers; Where the integers a, c, RL, and R are... a R b Ring A, L 3 POLY 2 D and COMP all have the definitions described in this invention.

[0339] In some embodiments, the compound represented by formula (IIIH) is selected from the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0340] On the one hand, the present invention provides the coupling shown in formula (V): Or its pharmaceutically acceptable salts and / or regioisomers; in L 5 It is a linker containing non-natural amino acids; and RL, COMP, Y a L 2 L 3 Both D and D have the definition described in this invention.

[0341] In some embodiments, the compound represented by formula (V) is the compound represented by formula (VA): (VA); Or its pharmaceutically acceptable salts and / or regioisomers; Among them, RL, COMP, Y a L 2 L 3 Both D and D have the definition described in this invention.

[0342] In some embodiments, the compound represented by formula (V) is the compound represented by formula (VB): (VB); Or its pharmaceutically acceptable salts and / or regioisomers; Where integers a, c, RL, COMP, and R are... a R b POLY 1 AA and D all have the definitions described in this invention.

[0343] In some embodiments, the compound represented by formula (VB) is a compound represented by the following formula: Or its pharmaceutically acceptable salts and / or regioisomers.

[0344] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a yes or In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes or In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes or In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes or In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes or In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes .

[0345] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a yes In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a yes .

[0346] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a The ring B consists of 5 to 12 atoms that are optionally substituted. N - Connected bridging, fusion, or spirocyclic bicyclic heterocycles, consisting of 5 to 12 atoms N- The bridging, fused, or spirocyclic bicyclic heterocycles comprise one, two, or three independent heteroatoms selected from N, O, and S (including the N atom connected to the ring), wherein ring B is optionally substituted by one or more substituents selected from: alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -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, aralkyl, heteroaryl, and heteroarylalkyl. In certain embodiments of formulas (III)-(VB), including any of the foregoing embodiments, L 1a The ring B consists of 5 to 12 atoms that are optionally substituted. N - A connected spirocyclic bicyclic heterocycle, consisting of 5 to 12 atoms N - The connected spirocyclic bicyclic heterocycle contains one, two, or three independent heteroatoms selected from N, O, and S (including the N atom connected to the ring).

[0347] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is selected from ; Where m a It is an integer selected from 1, 2, 3, 4, and 5; and n a and o a Each is an integer independently selected from 1, 2, and 3.

[0348] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is In some implementations of equations (III)-(VB), Selected from In some implementations of equations (III)-(VB), Selected from In some implementations of equations (III)-(VB), L 1a Ring B is In some implementations, ring B is... .

[0349] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is In some implementations of equations (III)-(VB), Selected from In some implementations of equations (III)-(VB), Selected from and In some implementations of equations (III)-(VB), L 1a Ring B is In some implementations of equations (III)-(VB), L 1a Ring B is .

[0350] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is In some implementations of equations (III)-(VB), , where m a It is 1, 2, or 3. In some implementations of equation (III)-(VB), , where m a It is 1, 2, or 3. In some implementations of equation (III)-(VB), , where m a It is 1, 2, or 3. In some implementations of equation (III)-(VB), , where m a It is 1, 2, or 3.

[0351] In some implementations of equation (III)-(VB), In some implementations of equations (III)-(VB) plan, In some implementations of equations (III)-(VB), In some implementations of equations (III)-(VB), yes In some implementations of equations (III)-(VB), .

[0352] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is In some implementations of equations (III)-(VB), , where m a It is 1, 2, or 3. In some implementations of equation (III)-(VB), , where m a It is 1, 2, or 3. In some implementations of equation (III)-(VB), , where m a It is 1, 2, or 3. In some implementations of equation (III)-(VB), , where m a It is 1, 2, or 3.

[0353] In some implementations of equation (III)-(VB), In some implementations of equations (III)-(VB), In some implementations of equations (III)-(VB), In some implementation schemes, yes In some implementations of equations (III)-(VB), .

[0354] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is , or .

[0355] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is selected from .

[0356] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is selected from .

[0357] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Selected from , ; Where m a It is an integer selected from 1, 2, 3, 4, and 5; and n a and o a Each is an integer independently selected from 1, 2, and 3.

[0358] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Selected from , .

[0359] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is selected from Among them, X 1a X 2a X 3 and X 4 Each is independently selected from -C(R) 4 )2-, -NH-, -O-, and -S-; where X 1a X 2a and X 3 If both exist, then X 1a -X 3 At least one of them is -C(R) 4 )2-, and when X 1a X 2a X 3 and X 4 If both exist, then X 1a -X 4 At least two of them are -C(R) 4 )2-; and R 4 Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; or, two R on the same carbon atom 4 The groups together form an oxo group.

[0360] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring B is selected from Among them, X 1a X 2a X 3 and X 4 Each is independently selected from -C(R) 4 )2-, -NH-, -O-, and -S-; where X 1a X 2a and X 3 If both exist, then X 1a -X 3 At least one of them is -C(R) 4)2-, and when X 1a X 2a X 3 and X 4 If both exist, then X 1a -X 4 At least two of them are -C(R) 4 )2-; and R 4 Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; or, two R on the same carbon atom 4 The groups together form an oxo group.

[0361] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring A is an optionally substituted bridging, fused, or spirocyclic bicyclic carbocyclic ring, wherein the carbocyclic ring or the heterocyclic ring of ring A is optionally substituted by one or more substituents selected from: alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -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, aralkyl, heteroaryl, and heteroarylalkyl. In some embodiments, including any of the foregoing embodiments, L 1a Ring A is an optional substitution of C 4-12 Bridging, fusion, or spirocyclic bicyclic carbon rings. In certain embodiments of formulas (III)-(VB), including any of the foregoing embodiments, L 1a Ring A is an optional substitution of C 4-12 Bridging bicyclic carbon rings. In certain embodiments of formulas (III)-(VB), including any of the foregoing embodiments, L 1a Ring A is an optional substitution of C 4-8 Bridging double-ring carbon rings.

[0362] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1aRing A is selected from , Among them, X 1a X 2a X 3 and X 4 Each is independently selected from -C(R) 4 )2-, -NH-, -O-, and -S-; where X 1a X 2a and X 3 If both exist, then X 1a -X 3 At least one of them is -C(R) 4 )2-, and when X 1a X 2a X 3 and X 4 If both exist, then X 1a -X 4 At least two of them are -C(R) 4 )2-; X 5 It is CR 4 Or N; and R 4 Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; or, two R on the same carbon atom 4 The groups together form an oxo group.

[0363] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring A is selected from .

[0364] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring A is selected from .

[0365] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring A is selected from , .

[0366] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring A is selected from .

[0367] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a Ring A is In certain embodiments of equations (III)-(VB), including any of the foregoing embodiments, L 1a Ring A is .

[0368] In certain implementations of equations (III)-(VB), including any of the foregoing implementations, X 1a X 2a X 3 and / or X 4 They are -C(R) 4 )2-. In some embodiments of equation (III)-(VB), including any of the foregoing embodiments, X 1a and X 2a They are -C(R) 4 )2-. In some embodiments of equation (III)-(VB), including any of the foregoing embodiments, X 1a X 2a and X 3 They are -C(R) 4 )2-. In some embodiments of equation (III)-(VB), including any of the foregoing embodiments, X 1a X 2a X 3 and X 4 They are -C(R) 4 )2-. In some embodiments of equation (III)-(VB), including any of the foregoing embodiments, X 1a It is -NH-. In some embodiments of formula (III)-(VB), including any of the foregoing embodiments, X 2a It is NH-. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, X 3 It is -NH-. In some embodiments of formula (III)-(VB), including any of the foregoing embodiments, X 4 It is -NH-. In some implementations, including any of the foregoing implementations, X 1aYes -O-. In some embodiments of equation (III)-(VB), including any of the foregoing embodiments, X 2a Yes -O-. In some embodiments of equation (III)-(VB), including any of the foregoing embodiments, X 3 Yes -O-. In some embodiments of equation (III)-(VB), including any of the foregoing embodiments, X 4 Yes -O-.

[0369] In some implementations of equations (III)-(VB), including any of the foregoing implementations, L 1a yes (d) In some implementations, L 1a yes .

[0370] In some implementations, including any of the foregoing implementations, a is 0. In some implementations, including any of the foregoing implementations, a is 1. In some implementations, including any of the foregoing implementations, a is 2. In some implementations, including any of the foregoing implementations, a is 3. In some implementations, including any of the foregoing implementations, a is 4. In some implementations, including any of the foregoing implementations, a is 5. In some implementations, including any of the foregoing implementations, a is 6.

[0371] In some implementations of equations (III)-(VB), b is 0. In some implementations, b is 1.

[0372] In some implementations of equation (III)-(VB), b is 0 and a is 0. In some implementations of equation (III)-(VB), b is 0 and a is 1. In some implementations of equation (III)-(VB), b is 0 and a is 2. In some implementations of equation (III)-(VB), b is 0 and a is 3. In some implementations of equation (III)-(VB), b is 0 and a is 4. In some implementations of equation (III)-(VB), b is 0 and a is 5. In some implementations of equation (III)-(VB), b is 0 and a is 6. In some implementations of equation (III)-(VB), b is 1 and a is 1. In some implementations of equation (III)-(VB), b is 1 and a is 2. In some implementations of equation (III)-(VB), b is 1 and a is 3. In some implementations of equation (III)-(VB), b is 1 and a is 4. In some implementations of equation (III)-(VB), b is 1 and a is 5. In some implementations of equation (III)-(VB), b is 1 and a is 6.

[0373] In certain implementations of equations (III)-(VB), including any of the foregoing implementations, R 1 It is H. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R 1 It is an unsubstituted alkyl group. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R 1 It is methyl. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R 1 It is an alkyl group, which is optionally substituted by one or more substituents selected from cycloalkyl, halogen, alkoxy, -CN, -NO2, and -OH.

[0374] In some implementations of formulas (III)-(IVB), L 5 It is a linker containing at least one amino acid selected from sulfoalanine, hydroxyproline (Hyp), β-alanine, citrulline (Cit), ornithine (Orn), ortholeucine (Nle), 3-nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr), naphthylalanine (Nal), 2,4-diaminobutyric acid (DAB), methionine sulfoxide, and methionine sulfone. In some embodiments of formulas (III)-(IVB), L 5 It is a connector, the connector comprising In some embodiments of formulas (III)-(IVB), L 5 It is a connector, the connector comprising In some embodiments of formulas (III)-(IVB), L 5 yes In some embodiments of formulas (III)-(IVB), L 5 yes .

[0375] In some implementations, including any of the foregoing implementations, R a It's H, and R b Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl. In some embodiments, including any of the foregoing embodiments, R a It's H, and R bSelected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, -C(O)OH, aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl. In some embodiments, including any of the foregoing embodiments, R a It's H, and R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH. In some embodiments, including any of the foregoing embodiments, R a and R b They are H respectively.

[0376] In certain implementations of equations (III)-(VB), including any of the foregoing implementations, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; R 1 H is 1; a is 1; and b is 1. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; R 1 It is H; a is 2; and b is 1. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; R 1 H is 3; a is 3; and b is 1.

[0377] In certain implementations of equations (III)-(VB), including any of the foregoing implementations, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; a is 1; and b is 0. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; a is 2; and b is 0. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a It is H; Rb Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; a is 3; and b is 0.

[0378] In certain implementations of equations (III)-(VB), including any of the foregoing implementations, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; R 1 It is methyl; a is 1; and b is 1. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; R 1 It is methyl; a is 2; and b is 1. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; R 1 It is a methyl group; a is 3; and b is 1.

[0379] In some implementations, including any of the foregoing implementations of formulas (III)-(VB), R a and R b H and R respectively 1 H is 1; a is 1, and b is 1. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 It is H; a is 2, and b is 1. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 H is H; a is 3, and b is 1. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 It is H; a is 4, and b is 1. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1It is H; a is 5, and b is 1. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 It is H; a is 6, and b is 1.

[0380] In certain implementations of equations (III)-(VB), including any of the foregoing implementations, R a and R b H is H; a is 1; and b is 0. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H is H; a is 2; and b is 0. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H is H; a is 3; and b is 0. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H is H; a is 4; and b is 0. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b H is H; a is 5; and b is 0. In some embodiments of equations (III)-(VB), including any of the foregoing embodiments, R a and R b The values ​​are H, a is 6, and b is 0.

[0381] In certain implementations of equations (III)-(VB), including any of the foregoing implementations, R a and R b H and R respectively 1 It is methyl; a is 1; and b is 0. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 It is methyl; a is 2; and b is 0. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 It is methyl; a is 3; and b is 0. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 It is methyl; a is 4; and b is 0. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, Ra and R b H and R respectively 1 It is methyl; a is 5; and b is 0. In certain embodiments of formula (III)-(VB), including any of the foregoing embodiments, R a and R b H and R respectively 1 It is a methyl group; a is 6; and b is 0.

[0382] In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; a is 1; and c is 1. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; a is 2; and c is 1. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, R a It is H; R b Selected from H, alkyl, halogen, alkoxy, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)OH; a is 3; and c is 1.

[0383] In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b ) c -NH-, where * represents Y a The location connected to RL. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2) c -NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)-NH-. In some embodiments, including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)2-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)3-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y aIt is *-C(O)-(CH2)4-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)5-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)6-NH-.

[0384] In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )2-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )3-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )4-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )5-NH-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )6-NH-.

[0385] In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b ) c -NH-, where R a It's H, and R b Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Y a It 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 It's H, and R b Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl.

[0386] In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b ) c -, where * represents Y a The location connected to RL. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2) c - In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)2-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)3-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)4-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments of formula (III)-(IVB), Y a It is *-C(O)-(CH2)5-. In some embodiments, including any of the foregoing embodiments, Y aIt is *-C(O)-(CH2)6-.

[0387] In some implementations, including any of the foregoing implementations of formulas (III)-(IVB), Y a It is *-C(O)-(CR) a R b In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )2-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )3-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )4-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )5-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )6-.

[0388] In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b ) c -, where R a It's H, and R b Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CR) a R b )2-、*-C(O)-(CR aR b )3-, or *-C(O)-(CR a R b )4-, where R a It's H, and R b Selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl.

[0389] In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, Y a It is *-C(O)-(CH2)2-NH- or *-C(O)-(CH2)4-.

[0390] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It does not exist. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 It is a linker containing hydrophilic polymer residues.

[0391] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is CH2-POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)3-POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)4-POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)5-POLY 1-. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)6-POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes -CR a R b -POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b )2-POLY 1 - In some implementations, including any of the foregoing implementations, L 2 Yes - (CR) a R b 3-POLY 1 -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b )4-POLY 1 -

[0392] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - POLY 1 -

[0393] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -(CR a R b ) a -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (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 equations (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1-(CH2) a - where a is independently selected from 0, 1, 2, 3, 4, 5, or 6. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1 -(CR a R b ) a - where a is independently selected from 1, 2, 3, 4, 5, or 6. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -(CH2) a - where a is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0394] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of a non-peptide hydrophilic polymer. In some embodiments of formula (III)-(IVB), POLY 1 It includes polyethylene glycol (PEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyols), poly(enols), poly(vinylpyrrolidone), poly(hydroxyalkyl methylacrylamide), poly(hydroxyalkyl methacrylates), poly(sugars), poly(α-hydroxy acids), poly(vinyl alcohol), polyphosphazenes, polyoxazoline derivatives (POZ), and poly( N -Acryloylmorpholine), polysarcosine, or divalent residues of combinations thereof. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of polyethylene glycol (PEG), poly(propylene glycol) (PPG), or a copolymer of ethylene glycol and propylene glycol.

[0395] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of polyethylene glycol (PEG). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(propylene glycol) (PPG). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of a copolymer of ethylene glycol and propylene glycol. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY1 It is a divalent residue of poly(oxyethylated polyol). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(enol). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(vinylpyrrolidone). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(hydroxyalkylmethylacrylamide). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(hydroxyalkyl methacrylate). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(saccharides). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(α-hydroxy acid). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of poly(vinyl alcohol). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of polyphosphazene. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of polyoxazoline (POZ). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a gathering ( N -Acryloylmorpholine) divalent residue. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 1 It is a divalent residue of polysarcosine.

[0396] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 1 yes , where R 5 It is H or methyl, x is an integer from 1 to 100, inclusive of 1 and 100, and This indicates a connection point connected to the remainder of the compound or conjugate. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is an integer between 1 and 25. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is an integer between 5 and 15. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 1. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 2. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 3. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 4. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 5. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 6. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 7. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 8. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 9. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 10. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 11. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 12. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 13. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 14. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 15. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 16. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 17. In some embodiments, including any of the aforementioned embodiments, x is 18. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 19. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is 20. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 25 and 50. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 35 and 45. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 50 and 75.In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 55 and 65. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 75 and 100. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 85 and 95. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer in the range of 1 to 25, 20 to 45, 40 to 65, 60 to 85, 70 to 95, or 75 to 100.

[0397] In some implementations of equations (III)-(IVB), including any of the foregoing implementations, R 5 It is H. In some implementations, including any of the foregoing implementations, R 5 It is a methyl group.

[0398] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1 -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, among which POLY 1yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -, among which POLY 1 yes .

[0399] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In some implementations, including any of the foregoing implementations, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -(CR a R b ) a -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a Rb ) a -POLY 1 -(CR a R b ) a -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -(CR a R b ) a -, among which POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -(CR a R b ) a -, among which POLY 1 yes .

[0400] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Selected from , In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes .

[0401] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes .

[0402] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of non-peptide hydrophilic polymers. In some embodiments of formula (III)-(IVB), POLY 2 It includes polyethylene glycol (PEG), methoxy polyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyols), poly(enols), poly(vinylpyrrolidone), poly(hydroxyalkyl methylacrylamide), poly(hydroxyalkyl methacrylates), poly(sugars), poly(α-hydroxy acids), poly(vinyl alcohol), polyphosphazenes, polyoxazoline compounds (POZ), and poly( N -Acryloylmorpholine), polysarcosine, or residues of combinations thereof. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 It is a residue of polyethylene glycol (PEG), methoxy polyethylene glycol (mPEG), poly(propylene glycol) (PPG), or a copolymer of ethylene glycol and propylene glycol. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 It is a residue of methoxy polyethylene glycol (mPEG).

[0403] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of polyethylene glycol (PEG). In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of poly(propylene glycol) (PPG). In some embodiments, including any of the foregoing embodiments, POLY 2 These are residues of copolymers of ethylene glycol and propylene glycol. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of poly(oxyethylated polyol). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of poly(enol). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 It is a residue of poly(vinylpyrrolidone). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2It is a residue of poly(hydroxyalkylmethylacrylamide). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 It is a residue of poly(hydroxyalkyl methacrylate). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are polysaccharide residues. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 It is a residue of poly(α-hydroxy acid). In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of poly(vinyl alcohol). In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of polyphosphazene. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 These are residues of polyoxazoline (POZ). In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 It is a gathering ( N -Acryloylmorpholine residues. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, POLY 2 It is a residue of polysarcosine.

[0404] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, POLY 2 yes , where R 5 It is H or methyl, x is an integer from 1 to 100, inclusive of 1 and 100, and This indicates a connection point connected to the remainder of the compound or conjugate. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is an integer between 1 and 25. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is an integer between 5 and 15. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 1. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 2. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 3. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 4. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 5. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 6. In some embodiments, including any of the foregoing embodiments, x is 7. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, x is 8. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 9. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 10. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 11. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 12. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 13. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 14. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 15. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 16. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments of equations (III)-(IVB), x is 17. In some embodiments, including any of the aforementioned embodiments of equations (III)-(IVB), x is 18. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 19. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is 20. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is an integer between 25 and 50. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is an integer between 35 and 45. In some embodiments of equations (III)-(IVB), including any of the aforementioned embodiments, x is an integer between 50 and 75.In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 55 and 65. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 75 and 100. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer between 85 and 95. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, x is an integer in the range of 1 to 25, 20 to 45, 40 to 65, 60 to 85, 70 to 95, or 75 to 100.

[0405] In some implementations of equations (III)-(IVB), including any of the foregoing implementations, R 5 It is H. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, R 5 It is a methyl group.

[0406] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Choose from the following groups: .

[0407] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Choose from the following groups: .

[0408] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes .

[0409] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes .

[0410] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3It is -C(O)-AA-.

[0411] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-AA-Z-(CR) a R b ) a -Z-(CR a R b ) a -C(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-AA-NR 2 -(CR a R b ) a -NR 2 -(CR a R b ) a -C(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-AA-NH-(CR) a R b ) a -NH-(CR a R b ) a -C(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-AA-NH-(CH2) a -NH-(CH2) a -C(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-AA-NH-(CH2) a -NH-(CH2) a -C(O)-, where a is selected from 1, 2, and 3. In some embodiments, including any of the foregoing embodiments, L 3 It is -C(O)-AA-NH-CH2-NH-CH2-C(O)-.

[0412] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-AA-Z-(CR) a R b ) a In some implementations, including any of the foregoing implementations, L 3 It is -C(O)-AA-NR2 -(CH2) a In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-AA-NH-(CH2)2.

[0413] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 Yes -AA-. In some implementations, including any of the foregoing implementations, L 3 yes .

[0414] In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, -AA- is an amino acid residue. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, -AA- is a peptide residue. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, -AA- is a dipeptide residue, tripeptide residue, tetrapeptide residue, or pentapeptide residue. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, -AA- contains at least one amino acid residue selected from alanine, glycine, valine, and asparagine. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, -AA- contains at least one amino acid residue selected from alanine and glycine. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, -AA- is selected from the group consisting of: .

[0415] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, -AA- is selected from the group consisting of: .

[0416] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-.

[0417] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-Z-(CR) a R b )a -C(O)-ZL 4 -OC(O)-, where L 4 yes , and Su are the hexose forms of the monosaccharide, and d are integers independently selected from 1, 2, and 3. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-NR 2 -(CR a R b ) a -C(O)-NR 2 -L 4 -OC(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-NR 2 -(CH2)2-C(O)-NR 2 -L 4 -OC(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-NH-(CR) a R b ) a -C(O)-NH-L 4 -OC(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-NH-(CH2)2-C(O)-NH-L 4 -OC(O)-.

[0418] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 4 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 4 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 4 yes .

[0419] In some embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Su is a sugar group moiety. In some embodiments, Su is a hexose form of a monosaccharide. Su can be a glucuronic acid residue or a mannose residue. In some embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Su is ,in This indicates a connection point that connects to the remainder of the compound. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, Su is... ,in This indicates the connection point that connects to the rest of the compound.

[0420] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 4 yes .

[0421] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-NH-(CH2)2-C(O)-NH-L 4 -OC(O)-, where L 4 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 3 It is -C(O)-NH-(CH2)2-C(O)-NH-L 4 -OC(O)-, where L 4 yes .

[0422] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, and L 3 It is -C(O)-AA-. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -;L 3 It is -C(O)-AA-; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1 -;L 3 is-C(O)-AA-; POLY 1 yes ; and x are integers between 10 and 15. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2It is -(CH2)2-POLY 1 -;L 3 It is -C(O)-AA-; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 is-C(O)-AA-; POLY 1 yes ; and AA are dipeptide residues, tripeptide residues, tetrapeptide residues, or pentapeptide residues.

[0423] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, and L 3 It is -C(O)-AA-Z-(CR) a R b ) a -Z-(CR a R b ) a -C(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -;L 3 It is -C(O)-AA-Z-(CR) a R b ) a -Z-(CR a R b ) a -C(O)-;POLY 1 yes And Z is -NH-. In some embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1 -;L 3 It is -C(O)-AA-NH-(CH2) a -NH-(CH2) a -C(O)-;POLY 1 yes ; and x are integers between 10 and 15. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 It is -C(O)-AA-NH-CH2-NH-CH2-C(O)-; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 It is -C(O)-AA-NH-CH2-NH-CH2-C(O)-; POLY 1 yes ; and AA are dipeptide residues, tripeptide residues, tetrapeptide residues, or pentapeptide residues.

[0424] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, and L 3 It is -C(O)-. In certain embodiments of formula (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -;L 3 It is -C(O)-; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1 -;L 3 It is -C(O)-; POLY 1 yes ; and x are integers between 10 and 15. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 It is -C(O)-; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2It is -(CH2)2-POLY 1 -;L 3 It is -C(O)-; POLY 1 yes ; and AA are dipeptide residues, tripeptide residues, tetrapeptide residues, or pentapeptide residues.

[0425] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, and L 3 It does not exist. In certain embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -;L 3 Does not exist; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1 -;L 3 Does not exist; POLY 1 yes ; and x are integers between 10 and 15. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 Does not exist; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 Does not exist; POLY 1 yes ; and AA are dipeptide residues, tripeptide residues, tetrapeptide residues, or pentapeptide residues.

[0426] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -, and L3 It is -C(O)-AA-Z-(CR) a R b ) a -. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Yes - (CR) a R b ) a -POLY 1 -;L 3 It is -C(O)-AA-Z-(CR) a R b ) a -; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2) a -POLY 1 -;L 3 It is -C(O)-AA-NR 2 -(CR a R b ) a -;POLY 1 yes ; and x are integers between 10 and 15. In some embodiments of equations (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 It is -C(O)-AA-NH-(CR) a R b ) a -; and POLY 1 yes In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 It is -(CH2)2-POLY 1 -;L 3 It is -C(O)-AA-NH-(CR) a R b ) a -;POLY 1 yes ; and AA are dipeptide residues, tripeptide residues, tetrapeptide residues, or pentapeptide residues.

[0427] -L 2 -L 3 - Non-restrictive examples include: .

[0428] -L 2 -L 3 - Non-restrictive examples include: .

[0429] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes , and L 3 yes -C(O)-Z-(CR a R b ) a -C(O)-ZL 4 -OC(O)-, where L 4 yes , and Su are the hexose forms of the monosaccharide, and d are integers independently selected from 1, 2, and 3. In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes , and L 3 It is -C(O)-Z-(CR) a R b ) a -C(O)-ZL 4 -OC(O)-.

[0430] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 yes , and L 3 It is -C(O)-. In some implementations, including any of the foregoing implementations, L 2 yes , and L 3 It does not exist.

[0431] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Choose from the following groups: , and L 3 It is -C(O)-NH-(CR) a R b ) a -C(O)-NH-L 4 -OC(O)-.

[0432] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Choose from the following groups: , and L 3 It is -C(O)-NH-(CR) a R b ) a -C(O)-NH-L 4 -OC(O)-.

[0433] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Choose from the following groups: and , and L 3 It is -C(O)-NH-(CH2)2-C(O)-NH-L 4 -OC(O)-, where L 4 yes .

[0434] In certain embodiments of formulas (III)-(IVB), including any of the foregoing embodiments, L 2 Choose from the following groups: ,and , and L 3 It is -C(O)-.

[0435] In some embodiments, including any of the foregoing embodiments, D is a cytotoxic payload selected from microtubule inhibitors, DNA topoisomerase I inhibitors, and DNA topoisomerase II inhibitors. In some embodiments, including any of the f...

Claims

1. An antibody conjugate comprising an antibody that specifically binds to tissue factor (TF), wherein the antibody site is specifically linked to at least one payload group moiety, wherein the antibody comprises one or more non-natural amino acids.

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

4. The antibody conjugate according to any one of the preceding claims, wherein, The antibody contains one or more non-natural amino acids located at sites selected from the group consisting of: HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, HC-Y391, 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 schemes.

5. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites selected from the group consisting of: HC-F404, HC-Y180, HC-F241, HC-Y391, LC-K42, and LC-E161 according to the Kabat, Chothia, or EU numbering schemes.

6. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites selected from the group consisting of: HC-F404, HC-Y180, HC-Y391, LC-K42, and LC-E161 according to the Kabat EU numbering scheme.

7. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites selected from the group consisting of: HC-F404, HC-Y180, HC-Y391, HC-F241, and LC-K42 according to the Kabat EU numbering scheme.

8. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites HC-Y180 and HC-F404.

9. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites HC-F241 and HC-F404.

10. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites HC-Y180, HC-F404, and LC-K42.

11. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites HC-Y180, HC-F241, and HC-F404.

12. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites HC-Y180, HC-F404, LC-K42, and LC-E161.

13. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites HC-Y180, HC-F241, HC-F404, and LC-K42.

14. The antibody conjugate according to claim 4, wherein, The antibody contains one or more non-natural amino acids located at sites HC-Y180, HC-F241, HC-F404, and HC-Y391.

15. The antibody conjugate according to any one of the preceding claims, wherein, The residues of one or more non-natural amino acids are attached to the payload group portion via a hydrolyzed stabilizer.

16. The antibody conjugate according to any one of the preceding claims, wherein, The residues of one or more non-natural amino acids are connected to the payload group portion via a cleavable linker.

17. The antibody conjugate according to any one of the preceding claims, wherein, The one or more non-natural amino acids are selected from the group consisting of: p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, L-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-azidomethyl-L-phenylalanine, compound 56, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-iodophenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and p-propynoxy-phenylalanine.

18. The antibody conjugate according to any one of the preceding claims, wherein, The residues of the one or more non-natural amino acids are residues of compound (30) or compound (56).

19. The antibody conjugate according to any one of the preceding claims, wherein, The one or more non-natural amino acids are azidomethylphenylalanine.

20. The antibody conjugate according to any one of the preceding claims, wherein, The one or more non-natural amino acids are azidomethyl-L-phenylalanine.

21. The antibody conjugate according to any one of the preceding claims, wherein, The effective payload group is selected from the group consisting of: maytansines, hemiasterlins, amanitins, camptothecins, exatecans, anthracyclines, pyrrolobenzodiazepines, and auristatins.

22. The antibody conjugate according to any one of the preceding claims, wherein, The effective payload group is selected from the group consisting of: DM1, hemiasterlin, amanitin, camptothecin, exatecan, deruxtecan (DXd), SN-38, PNU-159862, PNU-EDA, pyrrolobenzodiazepine, MMAF, and MMAE.

23. The antibody conjugate according to any one of the preceding claims, having the structure shown in Formula I: Or its pharmaceutically acceptable salt, wherein, COMP is a residue of the anti-TF 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 imide-[X] 1 -C 2-6 [Alkenyl] n -[X 1 ] p – or –X 1 -C 2-6 Ethyne-[X] 1 -C 2-6 [Iso-ynyl] n -[X 1 ] p – wherein at least one alkylene, alkenylene, or ynylene group in Y is selected from one or more groups chosen from R. 50 Substituents; and The alkylene, alkenylene, or alkyne group in Y is optionally selected from one or more groups selected from R. 51 Substituents of the substituents; R 50 Yes –C 1-6 Alkylene-X 2 -[C 1-6 [alkylene] m -POLY、–C 2-6 imide-X 2 -[C 2-6 [Alkenyl] m -POLY, or –C 2-6 Ethyne-X 2 -[C 2-6 [Iso-ynyl] m -POLY, where R 50 Each alkylene, alkenylene, or ynylene group may optionally be substituted by one or more substituents selected from the following: halogen, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; R 51 Independently selected from halogens, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; X 1 and X 2 Each is independently selected from –C(O)– and –N(R)–. 10 )C(O)–; R 10 Each time it appears, it is independently selected from H and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; 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 the monosaccharide; D is the drug group moiety; and RL stands for reactive group residue.

24. The antibody conjugate according to any one of the preceding claims, having the structure shown in Formula II: Or its pharmaceutically acceptable salt, wherein, COMP represents the residues of the TF antibody; L 1 It 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 imide-[X] 1 -C 2-6 [Alkenyl] n -X 1 – or –X 1 -C 2-6 Ethyne-[X] 1 -C 2-6 [Iso-ynyl] n -X 1 – wherein at least one alkylene, alkenylene, or ynylene group in Y is selected from one or more groups chosen from R. 50 Substituents of the substituents; R 50 Yes –C 1-6 Alkylene-X 2 -[C 1-6 [alkylene] m -POLY、–C 2-6 imide-X 2 -[C 2-6 [Alkenyl] m -POLY, or –C 2-6 Ethyne-X 2 -[C 2-6 [Iso-ynyl] m -POLY, where R 50 Each alkylene, alkenylene, or ynylene group may optionally be substituted by one or more substituents selected from the following: halogen, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; X 1 and X 2 Each is independently selected from –C(O)– and –N(R)–. 10 )C(O)–; R 10 Each time it appears, it is independently selected from H and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups; 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 the monosaccharide; D is the drug group moiety; and RL stands for active group residue.

25. The antibody conjugate according to claim 24, wherein, The compound represented by formula (II) has the structure represented by formula (IIA): 。 26. The antibody conjugate according to any one of claims 22-24, wherein, Su is ,in This indicates the connection point that connects to the rest of the compound.

27. The antibody conjugate according to any one of claims 23-26, wherein, Su is ,in This indicates the connection point that connects to the rest of the compound.

28. The antibody conjugate according to any one of claims 23-27, wherein, D is the cytotoxic payload.

29. The antibody conjugate according to claim 28, wherein, The cytotoxic payload is a microtubule inhibitor, a DNA topoisomerase I inhibitor, or a DNA topoisomerase II inhibitor.

30. The antibody conjugate according to any one of claims 23-29, wherein, Choose group D, which consists of the following: hemiasterlins, camptothecins, anthracyclines, PNU-159682, and EDA PNU-159682 derivatives.

31. The antibody conjugate according to any one of claims 23-29, wherein, D is a derivative of hemiasterlin, exatecan, PNU-159682, or EDA PNU-159682.

32. The antibody conjugate according to any one of claims 23-31, wherein, L 1 It is -C 1-3 Alkylene-.

33. The antibody conjugate according to any one of claims 23-32, wherein, Y is –X 1 -C 1-6 Alkylene-[X] 1 -C 1-6 [alkylene] n -X 1 – wherein at least one alkylene group in Y is selected from one or more of R 50 Substituents are substituted.

34. The antibody conjugate according to any one of claims 23-33, 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 group in Y is selected from one or more of R 50 Substituents are substituted.

35. The antibody conjugate according to any one of claims 23-33, wherein, Y is –X 1 -C 1-4 Alkylene-X 1 -C 1-4 Alkylene-X 1 – wherein at least one alkylene group in Y is selected from one or more of R 50 Substituents are substituted.

36. The antibody conjugate according to any one of claims 23-35, wherein, R 50 Yes –C 1-6 Alkylene-X 2 -[C 1-6 [alkylene] m -POLY, where R 50 Each alkylene group may optionally be substituted by one or more substituents selected from the following: halogen, -CN, -NO2, -OH, -N(R) 10 )2、-C(O)N(R 10 )2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 Carbon rings, heterocycles consisting of 3 to 12 atoms, and C 1-10 Halogenated alkyl groups.

37. The antibody conjugate according to any one of claims 23-36, wherein, m is 1.

38. The antibody conjugate according to any one of claims 23-37, wherein, POLY is a compound containing polyethylene glycol (PEG), methoxylated polyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyols), poly(enols), poly(vinylpyrrolidone), poly(hydroxyalkyl methylacrylamide), poly(hydroxyalkyl methacrylates), poly(sugars), poly(α-hydroxy acids), poly(vinyl alcohol), polyphosphazenes, polyoxazoline compounds (POZ), and poly( N α-Acryloylmorpholine), polysarcosine, or combinations thereof.

39. The antibody conjugate according to any one of claims 23-38, wherein, POLY contains polyethylene glycol (PEG) or methoxy polyethylene glycol (mPEG).

40. The antibody conjugate according to any one of claims 23-39, wherein, RL includes alkynes, cyclooctynes, strained alkenes, tetrazines, thiols, acetylphenylalanine residues, oxyamines, amines, maleimides, or azides.

41. The antibody conjugate according to any one of claims 23-40, wherein, RL selects groups from the following: 。 42. The antibody conjugate according to any one of claims 1-22, having the structure shown in Formula III: Or its pharmaceutically acceptable salt; in L 1a Selected from and ; Ring A is an optionally substituted bridging, fused, or spirobicyclic carbocyclic ring, or an optionally substituted bridging, fused, or spirobicyclic heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring of ring A is optionally substituted by one or more substituents selected from: alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -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, aralkyl, heteroaryl, and heteroarylalkyl; Ring B is optional. N - A bridging, fused, or spirocyclic bicyclic heterocycle, wherein ring B is optionally substituted by one or more substituents selected from: alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -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, aralkyl, heteroaryl, and heteroarylalkyl; R a and R b Each is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, 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 It is H or an alkyl group, wherein the alkyl group is optionally substituted by one or more substituents selected from: cycloalkyl, halogen, alkoxy, -CN, -NO2, -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 Each is independently selected from H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; Y a It is *-C(O)-(CR) a R b ) c -NH-, or *-C(O)-(CR) a R b ) c -, where * represents Y a The location connected to RL; c is an integer selected from 1, 2, 3, 4, 5, or 6; RL stands for active group residue; L 2 Does not exist, or L 2 It is a linker containing hydrophilic polymer residues; L 3 is absent, or L 3 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 stands for amino acid residue or peptide residue; L 4 yes , where Su is the hexose form of the monosaccharide; d is an integer independently selected from 1, 2, and 3; D is the drug group part; COMP represents the residues of the TF antibody; and This indicates the connection point that connects to the rest of the compound.

43. The antibody conjugate according to any one of claims 1-22, having the structure shown in formula (V): Or its pharmaceutically acceptable salts and / or regioisomers; in L 5 It is a linker containing non-natural amino acids; Y a It is *-C(O)-(CR) a R b ) c -NH-, or *-C(O)-(CR) a R b ) c -, where * represents Y a The location connected to RL; c is an integer selected from 1, 2, 3, 4, 5, or 6; RL stands for active group residue; L 2 Does not exist, or L 2 It is a linker containing hydrophilic polymer residues; L 3 Absent, or L 3 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-, and -(CR a [[ID=五十]]R[[ID=五十一]] b [[ID=五十二]])[[ID=五十三]] a [[ID=五十四]]-Z-AA-C(O)-; R a and R b Each is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, 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 stands for amino acid residue or peptide residue; L 4 yes , where Su is the hexose form of the monosaccharide; d is an integer independently selected from 1, 2, and 3; D is the drug group part; COMP represents the residues of the TF antibody; and This indicates the connection point that connects to the rest of the compound.

44. The antibody conjugate according to claim 42, wherein, Ring B is selected from .

45. The antibody conjugate according to claim 42, wherein, Ring B is selected from Among them, X 1a X 2a X 3 and X 4 Each is independently selected from -C(R) 4 )2-, -NH-, -O-, and -S-; where X 1a X 2a and X 3 If both exist, then X 1a -X 3 At least one of them is -C(R) 4 )2-, and when X 1a X 2a X 3 and X 4 If both exist, then X 1a -X 4 At least two of them are -C(R) 4 )2-; and R 4 Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; or, two R on the same carbon atom 4 The groups together form an oxo group.

46. ​​The antibody conjugate according to claim 42, wherein, Ring B is selected from .

47. The antibody conjugate according to claim 42, wherein, Ring A is selected from Among them, X 1a X 2a X 3 and X 4 Each is independently selected from -C(R) 4 )2-, -NH-, -O-, and -S-; where X 1a X 2a and X 3 If both exist, then X 1a -X 3 At least one of them is -C(R) 4 )2-, and when X 1a X 2a X 3 and X 4 If both exist, then X 1a -X 4 At least two of them are -C(R) 4 )2-; X 5 Is it N or CR? 4 ;and R 4 Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, halogen, alkoxy, -CN, -NO2, -OH, -N(R) 2 R 3 )2、-C(O)N(R 2 R 3 )2、-C(O)OR 2 Aminoalkyl, hydroxyalkyl, haloalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl; or, two R on the same carbon atom 4 The groups together form an oxo group.

48. The antibody conjugate according to any one of claims 42 and 44-47, wherein, L 1a yes 。 49. The antibody conjugate according to any one of claims 42-48, wherein, L 2 Yes - (CR) a R b ) a -POLY 1 -、 ,or ; Among them, POLY 1 - is a divalent form of polyethylene glycol (PEG), poly(propylene glycol) (PPG), or a copolymer of ethylene glycol and propylene glycol. residues; among which This indicates the connection point that connects to the rest of the compound.

50. The antibody conjugate according to any one of claims 42-49, 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-.

51. The antibody conjugate according to any one of claims 42-50, wherein, Su is or .

52. The antibody conjugate according to any one of claims 42-51, wherein, D is selected from the following drug group moiety: tubulin inhibitors, DNA damage drugs, DNA topoisomerase I inhibitors, DNA topoisomerase II inhibitors, RNA polymerase II inhibitors, hemiasterlin residues, camptothecin residues, camptothecin derivatives, anthracycline residues, PNU-159682 and PNU-159682 derivatives, PBD class, and duocarmycins.

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

54. The antibody conjugate according to claim 53, wherein, The antibody conjugate has a structure selected from the group consisting of: Where n2 is an integer from 1 to 10.

55. The antibody conjugate according to claim 53 or 54, wherein, n2 is an integer from 2 to 8, from 2 to 6, from 2 to 4, or from 6 to 10.

56. The antibody conjugate according to claim 53 or 54, wherein, n² is 2, 4, 6, 8, or 10.

57. The antibody conjugate according to any one of the preceding claims, wherein, The antibody contains V H The three heavy chain CDRs of the sequence and from V L The sequence consists of three light chain CDRs; wherein the V H The sequence is selected from SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, SEQ ID NO: 2859, and SEQ ID NO: 2860, or variations thereof, and the V L The sequences are selected from SEQ ID NO: 2951, SEQ ID NO: 2957, SEQ ID NO: 2962, SEQ ID NO: 2968, SEQ ID NO: 2970, SEQ ID NO: 2971, and SEQ ID NO: 3061, or variations thereof.

58. The antibody conjugate according to any one of the preceding claims, wherein, The antibody contains V H / V L The V consists of three paired heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof. H / V L The pairs are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO: 2779 / SEQ ID NO: 3061;SEQ ID NO:2780 / SEQ ID NO:3061;SEQ ID NO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ ID NO:2783 / SEQ ID NO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ ID NO:3061;SEQ ID NO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ ID NO:2788 / SEQ ID NO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ ID NO:3061;SEQ ID NO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ ID NO:2793 / SEQ ID NO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ ID NO:3061;SEQ ID NO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ ID NO:2798 / SEQ ID NO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ ID NO:3061;SEQ ID NO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ ID NO:2803 / SEQ ID NO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ ID NO:3061;SEQ ID NO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ ID NO:2808 / SEQ ID NO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ ID NO:3061;SEQ ID NO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ ID NO: 2813 / SEQ ID NO: 3061; SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.; 59. The antibody conjugate according to any one of the preceding claims, wherein, The antibody contains V H The V H Selected from SEQ ID NO:2727, SEQ ID NO:2736, SEQ ID NO:2739, SEQ ID NO:2751 to SEQ ID NO:2838, SEQ ID NO:2840, SEQ ID NO:2846, SEQ ID NO:2851, SEQ ID NO:2857, SEQ ID NO:2859, and SEQ ID NO:2860.

60. The antibody conjugate according to any one of the preceding claims, wherein, The antibody contains V L The V L Selected from SEQ ID NO:2951, SEQ ID NO:2957, SEQ ID NO:2962, SEQ ID NO:2968, SEQ ID NO:2970, SEQ ID NO:2971, and SEQ ID NO:3061.

61. The antibody conjugate according to any one of the preceding claims, wherein, The antibody contains V H / V L Pairing or its variants, the V H / V L The pairs are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO: 2779 / SEQ ID NO: 3061;SEQ ID NO:2780 / SEQ ID NO:3061;SEQ ID NO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ ID NO:2783 / SEQ ID NO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ ID NO:3061;SEQ ID NO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ ID NO:2788 / SEQ ID NO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ ID NO:3061;SEQ ID NO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ ID NO:2793 / SEQ ID NO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ ID NO:3061;SEQ ID NO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ ID NO:2798 / SEQ ID NO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ ID NO:3061;SEQ ID NO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ ID NO:2803 / SEQ ID NO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ ID NO:3061;SEQ ID NO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ ID NO:2808 / SEQ ID NO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ ID NO:3061;SEQ ID NO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ ID NO: 2813 / SEQ ID NO: 3061; SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.; 62. The antibody conjugate according to any one of the preceding claims, wherein, The antibody comprises: (1) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 105 and SEQ ID NO: 430; CDR-H2 containing one or more of SEQ ID NO: 755 and SEQ ID NO: 1080; and CDR-H3 containing one or more of SEQ ID NO: 1405 and SEQ ID NO: 1730; (2) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 114 and SEQ ID NO: 439; CDR-H2 containing one or more of SEQ ID NO: 764 and SEQ ID NO: 1089; and CDR-H3 containing one or more of SEQ ID NO: 1414 and SEQ ID NO: 1739; (3) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 117 and SEQ ID NO: 442; CDR-H2 containing one or more of SEQ ID NO: 767 and SEQ ID NO: 1092; and CDR-H3 containing one or more of SEQ ID NO: 1417 and SEQ ID NO: 1742; (4) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 129 and SEQ ID NO: 454; CDR-H2 containing one or more of SEQ ID NO: 779 and SEQ ID NO: 1104; and CDR-H3 containing one or more of SEQ ID NO: 1429 and SEQ ID NO: 1754; (5) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing one or more of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing one or more of SEQ ID NO: 1430 and SEQ ID NO: 1755; (6) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 131 and SEQ ID NO: 456; CDR-H2 containing one or more of SEQ ID NO: 781 and SEQ ID NO: 1106; and CDR-H3 containing one or more of SEQ ID NO: 1431 and SEQ ID NO: 1756; (7) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 132 and SEQ ID NO: 457; CDR-H2 containing one or more of SEQ ID NO: 782 and SEQ ID NO: 1107; and CDR-H3 containing one or more of SEQ ID NO: 1432 and SEQ ID NO: 1757; (8) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 133 and SEQ ID NO: 458; CDR-H2 containing one or more of SEQ ID NO: 783 and SEQ ID NO: 1108; and CDR-H3 containing one or more of SEQ ID NO: 1433 and SEQ ID NO: 1758; (9) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 134 and SEQ ID NO: 459; CDR-H2 containing one or more of SEQ ID NO: 784 and SEQ ID NO: 1109; and CDR-H3 containing one or more of SEQ ID NO: 1434 and SEQ ID NO: 1759; (10) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 135 and SEQ ID NO: 460; CDR-H2 containing one or more of SEQ ID NO: 785 and SEQ ID NO: 1110; and CDR-H3 containing one or more of SEQ ID NO: 1435 and SEQ ID NO: 1760; (11) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 136 and SEQ ID NO: 461; CDR-H2 containing one or more of SEQ ID NO: 786 and SEQ ID NO: 1111; and CDR-H3 containing one or more of SEQ ID NO: 1436 and SEQ ID NO: 1761; (12) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 137 and SEQ ID NO: 462; CDR-H2 containing one or more of SEQ ID NO: 787 and SEQ ID NO: 1112; and CDR-H3 containing one or more of SEQ ID NO: 1437 and SEQ ID NO: 1762; (13) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 138 and SEQ ID NO: 463; CDR-H2 containing one or more of SEQ ID NO: 788 and SEQ ID NO: 1113; and CDR-H3 containing one or more of SEQ ID NO: 1438 and SEQ ID NO: 1763; (14) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 139 and SEQ ID NO: 464; CDR-H2 containing one or more of SEQ ID NO: 789 and SEQ ID NO: 1114; and CDR-H3 containing one or more of SEQ ID NO: 1439 and SEQ ID NO: 1764; (15) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 140 and SEQ ID NO: 465; CDR-H2 containing one or more of SEQ ID NO: 790 and SEQ ID NO: 1115; and CDR-H3 containing one or more of SEQ ID NO: 1440 and SEQ ID NO: 1765; (16) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 141 and SEQ ID NO: 466; CDR-H2 containing one or more of SEQ ID NO: 791 and SEQ ID NO: 1116; and CDR-H3 containing one or more of SEQ ID NO: 1441 and SEQ ID NO: 1766; (17) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 142 and SEQ ID NO: 467; CDR-H2 containing one or more of SEQ ID NO: 792 and SEQ ID NO: 1117; and CDR-H3 containing one or more of SEQ ID NO: 1442 and SEQ ID NO: 1767; (18) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 143 and SEQ ID NO: 468; CDR-H2 containing one or more of SEQ ID NO: 793 and SEQ ID NO: 1118; and CDR-H3 containing one or more of SEQ ID NO: 1443 and SEQ ID NO: 1768; (19) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 144 and SEQ ID NO: 469; CDR-H2 containing one or more of SEQ ID NO: 794 and SEQ ID NO: 1119; and CDR-H3 containing one or more of SEQ ID NO: 1444 and SEQ ID NO: 1769; (20) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 145 and SEQ ID NO: 470; CDR-H2 containing one or more of SEQ ID NO: 795 and SEQ ID NO: 1120; and CDR-H3 containing one or more of SEQ ID NO: 1445 and SEQ ID NO: 1770; (21) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 146 and SEQ ID NO: 471; CDR-H2 containing one or more of SEQ ID NO: 796 and SEQ ID NO: 1121; and CDR-H3 containing one or more of SEQ ID NO: 1446 and SEQ ID NO: 1771; (22) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 147 and SEQ ID NO: 472; CDR-H2 containing one or more of SEQ ID NO: 797 and SEQ ID NO: 1122; and CDR-H3 containing one or more of SEQ ID NO: 1447 and SEQ ID NO: 1772; (23) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 148 and SEQ ID NO: 473; CDR-H2 containing one or more of SEQ ID NO: 798 and SEQ ID NO: 1123; and CDR-H3 containing one or more of SEQ ID NO: 1448 and SEQ ID NO: 1773; (24) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 149 and SEQ ID NO: 474; CDR-H2 containing one or more of SEQ ID NO: 799 and SEQ ID NO: 1124; and CDR-H3 containing one or more of SEQ ID NO: 1449 and SEQ ID NO: 1774; (25) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 150 and SEQ ID NO: 475; CDR-H2 containing one or more of SEQ ID NO: 800 and SEQ ID NO: 1125; and CDR-H3 containing one or more of SEQ ID NO: 1450 and SEQ ID NO: 1775; (26) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 151 and SEQ ID NO: 476; CDR-H2 containing one or more of SEQ ID NO: 801 and SEQ ID NO: 1126; and CDR-H3 containing one or more of SEQ ID NO: 1451 and SEQ ID NO: 1776; (27) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 152 and SEQ ID NO: 477; CDR-H2 containing one or more of SEQ ID NO: 802 and SEQ ID NO: 1127; and CDR-H3 containing one or more of SEQ ID NO: 1452 and SEQ ID NO: 1777; (28) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 153 and SEQ ID NO: 478; CDR-H2 containing one or more of SEQ ID NO: 803 and SEQ ID NO: 1128; and CDR-H3 containing one or more of SEQ ID NO: 1453 and SEQ ID NO: 1778; (29) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 154 and SEQ ID NO: 479; CDR-H2 containing one or more of SEQ ID NO: 804 and SEQ ID NO: 1129; and CDR-H3 containing one or more of SEQ ID NO: 1454 and SEQ ID NO: 1779; (30) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 155 and SEQ ID NO: 480; CDR-H2 containing one or more of SEQ ID NO: 805 and SEQ ID NO: 1130; and CDR-H3 containing one or more of SEQ ID NO: 1455 and SEQ ID NO: 1780; (31) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 156 and SEQ ID NO: 481; CDR-H2 containing one or more of SEQ ID NO: 806 and SEQ ID NO: 1131; and CDR-H3 containing one or more of SEQ ID NO: 1456 and SEQ ID NO: 1781; (32) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 157 and SEQ ID NO: 482; CDR-H2 containing one or more of SEQ ID NO: 807 and SEQ ID NO: 1132; and CDR-H3 containing one or more of SEQ ID NO: 1457 and SEQ ID NO: 1782; (33) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 158 and SEQ ID NO: 483; CDR-H2 containing one or more of SEQ ID NO: 808 and SEQ ID NO: 1133; and CDR-H3 containing one or more of SEQ ID NO: 1458 and SEQ ID NO: 1783; (34) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 159 and SEQ ID NO: 484; CDR-H2 containing one or more of SEQ ID NO: 809 and SEQ ID NO: 1134; and CDR-H3 containing one or more of SEQ ID NO: 1459 and SEQ ID NO: 1784; (35) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 160 and SEQ ID NO: 485; CDR-H2 containing one or more of SEQ ID NO: 810 and SEQ ID NO: 1135; and CDR-H3 containing one or more of SEQ ID NO: 1460 and SEQ ID NO: 1785; (36) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 161 and SEQ ID NO: 486; CDR-H2 containing one or more of SEQ ID NO: 811 and SEQ ID NO: 1136; and CDR-H3 containing one or more of SEQ ID NO: 1461 and SEQ ID NO: 1786; (37) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 162 and SEQ ID NO: 487; CDR-H2 containing one or more of SEQ ID NO: 812 and SEQ ID NO: 1137; and CDR-H3 containing one or more of SEQ ID NO: 1462 and SEQ ID NO: 1787; (38) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 163 and SEQ ID NO: 488; CDR-H2 containing one or more of SEQ ID NO: 813 and SEQ ID NO: 1138; and CDR-H3 containing one or more of SEQ ID NO: 1463 and SEQ ID NO: 1788; (39) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 164 and SEQ ID NO: 489; CDR-H2 containing one or more of SEQ ID NO: 814 and SEQ ID NO: 1139; and CDR-H3 containing one or more of SEQ ID NO: 1464 and SEQ ID NO: 1789; (40) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 165 and SEQ ID NO: 490; CDR-H2 containing one or more of SEQ ID NO: 815 and SEQ ID NO: 1140; and CDR-H3 containing one or more of SEQ ID NO: 1465 and SEQ ID NO: 1790; (41) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 166 and SEQ ID NO: 491; CDR-H2 containing one or more of SEQ ID NO: 816 and SEQ ID NO: 1141; and CDR-H3 containing one or more of SEQ ID NO: 1466 and SEQ ID NO: 1791; (42) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 167 and SEQ ID NO: 492; CDR-H2 containing one or more of SEQ ID NO: 817 and SEQ ID NO: 1142; and CDR-H3 containing one or more of SEQ ID NO: 1467 and SEQ ID NO: 1792; (43) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 168 and SEQ ID NO: 493; CDR-H2 containing one or more of SEQ ID NO: 818 and SEQ ID NO: 1143; and CDR-H3 containing one or more of SEQ ID NO: 1468 and SEQ ID NO: 1793; (44) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 169 and SEQ ID NO: 494; CDR-H2 containing one or more of SEQ ID NO: 819 and SEQ ID NO: 1144; and CDR-H3 containing one or more of SEQ ID NO: 1469 and SEQ ID NO: 1794; (45) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 170 and SEQ ID NO: 495; CDR-H2 containing one or more of SEQ ID NO: 820 and SEQ ID NO: 1145; and CDR-H3 containing one or more of SEQ ID NO: 1470 and SEQ ID NO: 1795; (46) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 171 and SEQ ID NO: 496; CDR-H2 containing one or more of SEQ ID NO: 821 and SEQ ID NO: 1146; and CDR-H3 containing one or more of SEQ ID NO: 1471 and SEQ ID NO: 1796; (47) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 172 and SEQ ID NO: 497; CDR-H2 containing one or more of SEQ ID NO: 822 and SEQ ID NO: 1147; and CDR-H3 containing one or more of SEQ ID NO: 1472 and SEQ ID NO: 1797; (48) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 173 and SEQ ID NO: 498; CDR-H2 containing one or more of SEQ ID NO: 823 and SEQ ID NO: 1148; and CDR-H3 containing one or more of SEQ ID NO: 1473 and SEQ ID NO: 1798; (49) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 174 and SEQ ID NO: 499; CDR-H2 containing one or more of SEQ ID NO: 824 and SEQ ID NO: 1149; and CDR-H3 containing one or more of SEQ ID NO: 1474 and SEQ ID NO: 1799; (50) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 175 and SEQ ID NO: 500; CDR-H2 containing one or more of SEQ ID NO: 825 and SEQ ID NO: 1150; and CDR-H3 containing one or more of SEQ ID NO: 1475 and SEQ ID NO: 1800; (51) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 176 and SEQ ID NO: 501; CDR-H2 containing one or more of SEQ ID NO: 826 and SEQ ID NO: 1151; and CDR-H3 containing one or more of SEQ ID NO: 1476 and SEQ ID NO: 1801; (52) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 177 and SEQ ID NO: 502; CDR-H2 containing one or more of SEQ ID NO: 827 and SEQ ID NO: 1152; and CDR-H3 containing one or more of SEQ ID NO: 1477 and SEQ ID NO: 1802; (53) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 178 and SEQ ID NO: 503; CDR-H2 containing one or more of SEQ ID NO: 828 and SEQ ID NO: 1153; and CDR-H3 containing one or more of SEQ ID NO: 1478 and SEQ ID NO: 1803; (54) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 179 and SEQ ID NO: 504; CDR-H2 containing one or more of SEQ ID NO: 829 and SEQ ID NO: 1154; and CDR-H3 containing one or more of SEQ ID NO: 1479 and SEQ ID NO: 1804; (55) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 180 and SEQ ID NO: 505; CDR-H2 containing one or more of SEQ ID NO: 830 and SEQ ID NO: 1155; and CDR-H3 containing one or more of SEQ ID NO: 1480 and SEQ ID NO: 1805; (56) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 181 and SEQ ID NO: 506; CDR-H2 containing one or more of SEQ ID NO: 831 and SEQ ID NO: 1156; and CDR-H3 containing one or more of SEQ ID NO: 1481 and SEQ ID NO: 1806; (57) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 182 and SEQ ID NO: 507; CDR-H2 containing one or more of SEQ ID NO: 832 and SEQ ID NO: 1157; and CDR-H3 containing one or more of SEQ ID NO: 1482 and SEQ ID NO: 1807; (58) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 183 and SEQ ID NO: 508; CDR-H2 containing one or more of SEQ ID NO: 833 and SEQ ID NO: 1158; and CDR-H3 containing one or more of SEQ ID NO: 1483 and SEQ ID NO: 1808; (59) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 184 and SEQ ID NO: 509; CDR-H2 containing one or more of SEQ ID NO: 834 and SEQ ID NO: 1159; and CDR-H3 containing one or more of SEQ ID NO: 1484 and SEQ ID NO: 1809; (60) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 185 and SEQ ID NO: 510; CDR-H2 containing one or more of SEQ ID NO: 835 and SEQ ID NO: 1160; and CDR-H3 containing one or more of SEQ ID NO: 1485 and SEQ ID NO: 1810; (61) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 186 and SEQ ID NO: 511; CDR-H2 containing one or more of SEQ ID NO: 836 and SEQ ID NO: 1161; and CDR-H3 containing one or more of SEQ ID NO: 1486 and SEQ ID NO: 1811; (62) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 187 and SEQ ID NO: 512; CDR-H2 containing one or more of SEQ ID NO: 837 and SEQ ID NO: 1162; and CDR-H3 containing one or more of SEQ ID NO: 1487 and SEQ ID NO: 1812; (63) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 188 and SEQ ID NO: 513; CDR-H2 containing one or more of SEQ ID NO: 838 and SEQ ID NO: 1163; and CDR-H3 containing one or more of SEQ ID NO: 1488 and SEQ ID NO: 1813; (64) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 189 and SEQ ID NO: 514; CDR-H2 containing one or more of SEQ ID NO: 839 and SEQ ID NO: 1164; and CDR-H3 containing one or more of SEQ ID NO: 1489 and SEQ ID NO: 1814; (65) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 190 and SEQ ID NO: 515; CDR-H2 containing one or more of SEQ ID NO: 840 and SEQ ID NO: 1165; and CDR-H3 containing one or more of SEQ ID NO: 1490 and SEQ ID NO: 1815; (66) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 191 and SEQ ID NO: 516; CDR-H2 containing one or more of SEQ ID NO: 841 and SEQ ID NO: 1166; and CDR-H3 containing one or more of SEQ ID NO: 1491 and SEQ ID NO: 1816; (67) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 192 and SEQ ID NO: 517; CDR-H2 containing one or more of SEQ ID NO: 842 and SEQ ID NO: 1167; and CDR-H3 containing one or more of SEQ ID NO: 1492 and SEQ ID NO: 1817; (68) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 193 and SEQ ID NO: 518; CDR-H2 containing one or more of SEQ ID NO: 843 and SEQ ID NO: 1168; and CDR-H3 containing one or more of SEQ ID NO: 1493 and SEQ ID NO: 1818; (69) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 194 and SEQ ID NO: 519; CDR-H2 containing one or more of SEQ ID NO: 844 and SEQ ID NO: 1169; and CDR-H3 containing one or more of SEQ ID NO: 1494 and SEQ ID NO: 1819; (70) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 195 and SEQ ID NO: 520; CDR-H2 containing one or more of SEQ ID NO: 845 and SEQ ID NO: 1170; and CDR-H3 containing one or more of SEQ ID NO: 1495 and SEQ ID NO: 1820; (71) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 196 and SEQ ID NO: 521; CDR-H2 containing one or more of SEQ ID NO: 846 and SEQ ID NO: 1171; and CDR-H3 containing one or more of SEQ ID NO: 1496 and SEQ ID NO: 1821; (72) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 197 and SEQ ID NO: 522; CDR-H2 containing one or more of SEQ ID NO: 847 and SEQ ID NO: 1172; and CDR-H3 containing one or more of SEQ ID NO: 1497 and SEQ ID NO: 1822; (73) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 198 and SEQ ID NO: 523; CDR-H2 containing one or more of SEQ ID NO: 848 and SEQ ID NO: 1173; and CDR-H3 containing one or more of SEQ ID NO: 1498 and SEQ ID NO: 1823; (74) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 199 and SEQ ID NO: 524; CDR-H2 containing one or more of SEQ ID NO: 849 and SEQ ID NO: 1174; and CDR-H3 containing one or more of SEQ ID NO: 1499 and SEQ ID NO: 1824; (75) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 200 and SEQ ID NO: 525; CDR-H2 containing one or more of SEQ ID NO: 850 and SEQ ID NO: 1175; and CDR-H3 containing one or more of SEQ ID NO: 1500 and SEQ ID NO: 1825; (76) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 201 and SEQ ID NO: 526; CDR-H2 containing one or more of SEQ ID NO: 851 and SEQ ID NO: 1176; and CDR-H3 containing one or more of SEQ ID NO: 1501 and SEQ ID NO: 1826; (77) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 202 and SEQ ID NO: 527; CDR-H2 containing one or more of SEQ ID NO: 852 and SEQ ID NO: 1177; and CDR-H3 containing one or more of SEQ ID NO: 1502 and SEQ ID NO: 1827; (78) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 203 and SEQ ID NO: 528; CDR-H2 containing one or more of SEQ ID NO: 853 and SEQ ID NO: 1178; and CDR-H3 containing one or more of SEQ ID NO: 1503 and SEQ ID NO: 1828; (79) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 204 and SEQ ID NO: 529; CDR-H2 containing one or more of SEQ ID NO: 854 and SEQ ID NO: 1179; and CDR-H3 containing one or more of SEQ ID NO: 1504 and SEQ ID NO: 1829; (80) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 205 and SEQ ID NO: 530; CDR-H2 containing one or more of SEQ ID NO: 855 and SEQ ID NO: 1180; and CDR-H3 containing one or more of SEQ ID NO: 1505 and SEQ ID NO: 1830; (81) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 206 and SEQ ID NO: 531; CDR-H2 containing one or more of SEQ ID NO: 856 and SEQ ID NO: 1181; and CDR-H3 containing one or more of SEQ ID NO: 1506 and SEQ ID NO: 1831; (82) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 207 and SEQ ID NO: 532; CDR-H2 containing one or more of SEQ ID NO: 857 and SEQ ID NO: 1182; and CDR-H3 containing one or more of SEQ ID NO: 1507 and SEQ ID NO: 1832; (83) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 208 and SEQ ID NO: 533; CDR-H2 containing one or more of SEQ ID NO: 858 and SEQ ID NO: 1183; and CDR-H3 containing one or more of SEQ ID NO: 1508 and SEQ ID NO: 1833; (84) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 209 and SEQ ID NO: 534; CDR-H2 containing one or more of SEQ ID NO: 859 and SEQ ID NO: 1184; and CDR-H3 containing one or more of SEQ ID NO: 1509 and SEQ ID NO: 1834; (85) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 210 and SEQ ID NO: 535; CDR-H2 containing one or more of SEQ ID NO: 860 and SEQ ID NO: 1185; and CDR-H3 containing one or more of SEQ ID NO: 1510 and SEQ ID NO: 1835; (86) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 211 and SEQ ID NO: 536; CDR-H2 containing one or more of SEQ ID NO: 861 and SEQ ID NO: 1186; and CDR-H3 containing one or more of SEQ ID NO: 1511 and SEQ ID NO: 1836; (87) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 212 and SEQ ID NO: 537; CDR-H2 containing one or more of SEQ ID NO: 862 and SEQ ID NO: 1187; and CDR-H3 containing one or more of SEQ ID NO: 1512 and SEQ ID NO: 1837; (88) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 213 and SEQ ID NO: 538; CDR-H2 containing one or more of SEQ ID NO: 863 and SEQ ID NO: 1188; and CDR-H3 containing one or more of SEQ ID NO: 1513 and SEQ ID NO: 1838; (89) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 214 and SEQ ID NO: 539; CDR-H2 containing one or more of SEQ ID NO: 864 and SEQ ID NO: 1189; and CDR-H3 containing one or more of SEQ ID NO: 1514 and SEQ ID NO: 1839; (90) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 215 and SEQ ID NO: 540; CDR-H2 containing one or more of SEQ ID NO: 865 and SEQ ID NO: 1190; and CDR-H3 containing one or more of SEQ ID NO: 1515 and SEQ ID NO: 1840; (91) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 216 and SEQ ID NO: 541; CDR-H2 containing one or more of SEQ ID NO: 866 and SEQ ID NO: 1191; and CDR-H3 containing one or more of SEQ ID NO: 1516 and SEQ ID NO: 1841; (92) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 218 and SEQ ID NO: 543; CDR-H2 containing one or more of SEQ ID NO: 868 and SEQ ID NO: 1193; and CDR-H3 containing one or more of SEQ ID NO: 1518 and SEQ ID NO: 1843; (93) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 224 and SEQ ID NO: 549; CDR-H2 containing one or more of SEQ ID NO: 874 and SEQ ID NO: 1199; and CDR-H3 containing one or more of SEQ ID NO: 1524 and SEQ ID NO: 1849; (94) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 229 and SEQ ID NO: 554; CDR-H2 containing one or more of SEQ ID NO: 879 and SEQ ID NO: 1204; and CDR-H3 containing one or more of SEQ ID NO: 1529 and SEQ ID NO: 1854; (95) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 235 and SEQ ID NO: 560; CDR-H2 containing one or more of SEQ ID NO: 885 and SEQ ID NO: 1210; and CDR-H3 containing one or more of SEQ ID NO: 1535 and SEQ ID NO: 1860; (96) V H It comprises: CDR-H1 containing one or more of SEQ ID NO: 237 and SEQ ID NO: 562; CDR-H2 containing one or more of SEQ ID NO: 887 and SEQ ID NO: 1212; and CDR-H3 containing one or more of SEQ ID NO: 1537 and SEQ ID NO: 1862; or (97) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 238 and SEQ ID NO: 563; CDR-H2 containing one or more of SEQ ID NO: 888 and SEQ ID NO: 1213; and CDR-H3 containing one or more of SEQ ID NO: 1538 and SEQ ID NO: 1863.

63. The antibody conjugate according to claim 60, wherein, The antibody comprises: (1) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1954 and SEQ ID NO: 2066; CDR-L2 containing one or more of SEQ ID NO: 2178 and SEQ ID NO: 2290; and CDR-L3 containing one or more of SEQ ID NO: 2402 and SEQ ID NO: 2514; (2) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1960 and SEQ ID NO: 2072; CDR-L2 containing one or more of SEQ ID NO: 2184 and SEQ ID NO: 2296; and CDR-L3 containing one or more of SEQ ID NO: 2408 and SEQ ID NO: 2520; (3) V L It includes: a CDR-L1 containing one or more of SEQ ID NO: 1965 and SEQ ID NO: 2077; a CDR-L2 containing one or more of SEQ ID NO: 2189 and SEQ ID NO: 2301; and a CDR-L3 containing one or more of SEQ ID NO: 2413 and SEQ ID NO: 2525; (4) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1971 and SEQ ID NO: 2083; CDR-L2 containing one or more of SEQ ID NO: 2195 and SEQ ID NO: 2307; and CDR-L3 containing one or more of SEQ ID NO: 2419 and SEQ ID NO: 2531; (5) V L It includes: a CDR-L1 containing one or more of SEQ ID NO: 1973 and SEQ ID NO: 2085; a CDR-L2 containing one or more of SEQ ID NO: 2197 and SEQ ID NO: 2309; and a CDR-L3 containing one or more of SEQ ID NO: 2421 and SEQ ID NO: 2533; (6) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1974 and SEQ ID NO: 2086; CDR-L2 containing one or more of SEQ ID NO: 2198 and SEQ ID NO: 2310; and CDR-L3 containing one or more of SEQ ID NO: 2422 and SEQ ID NO: 2534; or (7) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 2064 and SEQ ID NO: 2176; CDR-L2 containing one or more of SEQ ID NO: 2288 and SEQ ID NO: 2400; and CDR-L3 containing one or more of SEQ ID NO: 2512 and SEQ ID NO: 2624.

64. The antibody conjugate according to any one of claims 57-63, wherein, The variants have 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitution.

65. The antibody conjugate according to claim 64, wherein, All amino acid substitutions mentioned are conservative amino acid substitutions.

66. The antibody conjugate according to any one of claims 57-65, wherein, The variants have 90%, 95%, 96%, 97%, 98%, or 99% sequence identity.

67. The antibody conjugate according to any one of the preceding claims, wherein, The antibody conjugate comprises: (a) An antibody, which comprises: (i) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (ii) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 161 and SEQ ID NO: 486; CDR-H2 containing at least one of SEQ ID NO: 811 and SEQ ID NO: 1136; and CDR-H3 containing at least one of SEQ ID NO: 1461 and SEQ ID NO: 1786; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (iii) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 189 and SEQ ID NO: 514; CDR-H2 containing at least one of SEQ ID NO: 839 and SEQ ID NO: 1164; and CDR-H3 containing at least one of SEQ ID NO: 1489 and SEQ ID NO: 1814; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (iv) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 192 and SEQ ID NO: 517; CDR-H2 containing at least one of SEQ ID NO: 842 and SEQ ID NO: 1167; and CDR-H3 containing at least one of SEQ ID NO: 1492 and SEQ ID NO: 1817; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (v) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 211 and SEQ ID NO: 536; CDR-H2 containing at least one of SEQ ID NO: 861 and SEQ ID NO: 1186; and CDR-H3 containing at least one of SEQ ID NO: 1511 and SEQ ID NO: 1836; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (vi) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 214 and SEQ ID NO: 539; CDR-H2 containing at least one of SEQ ID NO: 864 and SEQ ID NO: 1189; and CDR-H3 containing at least one of SEQ ID NO: 1514 and SEQ ID NO: 1839; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (vii) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 218 and SEQ ID NO: 543; CDR-H2 containing at least one of SEQ ID NO: 868 and SEQ ID NO: 1210; and CDR-H3 containing at least one of SEQ ID NO: 1518 and SEQ ID NO: 1843; and the V L Contains: CDR-L1 containing at least one of SEQ ID NO: 1974 and SEQ ID NO: 2086; CDR-L2 containing at least one of SEQ ID NO: 2198 and SEQ ID NO: 2310; and CDR-L3 containing at least one of SEQ ID NO: 2422 and SEQ ID NO: 2534; (viii) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 105 and SEQ ID NO: 430; CDR-H2 containing at least one of SEQ ID NO: 755 and SEQ ID NO: 1080; and CDR-H3 containing at least one of SEQ ID NO: 1405 and SEQ ID NO: 1730; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (ix) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 114 and SEQ ID NO: 439; CDR-H2 containing at least one of SEQ ID NO: 764 and SEQ ID NO: 1089; and CDR-H3 containing at least one of SEQ ID NO: 1414 and SEQ ID NO: 1739; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (x) V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 117 and SEQ ID NO: 442; CDR-H2 containing at least one of SEQ ID NO: 767 and SEQ ID NO: 1092; and CDR-H3 containing at least one of SEQ ID NO: 1417 and SEQ ID NO: 1742; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) A p-azidomethylphenylalanine residue located at the antibody site, said antibody site being selected from the group consisting of: HC180, HC241, HC404, HC391, LC42, LC161, and combinations thereof; and (c) Connector – payload, selected from the group consisting of: Where n2 is 2, 4, 6, 8, or 10, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues.

68. The antibody conjugate according to any one of the preceding claims, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) A p-azidomethylphenylalanine residue located at the antibody site, said antibody site being selected from the group consisting of: HC180, HC241, HC404, HC391, LC42, LC161, and combinations thereof; and (c) Connector – payload, selected from the group consisting of: Where n2 is 2, 4, 6, 8, or 10, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues.

69. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC241 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 70. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC241, HC404, HC180 and HC391; (c) The following linker-loads, where n2 is 8, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 71. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 72. The antibody conjugate according to any one of claims 1-68, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC241 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 73. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180, HC404 and LC42; (c) The following linker-loads, where n2 is 6, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 74. The antibody conjugate according to any one of claims 1-68, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180, HC241 and HC404; (c) The following linker-loads, where n2 is 6, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 75. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180, HC404, LC42 and LC161; (c) The following linker-loads, where n2 is 8, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 76. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180, HC241, HC404 and LC42; (c) The following linker-loads, where n2 is 8, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 77. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180, HC241, HC404 and LC42; (c) The following linker-loads, where n2 is 8, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 78. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 79. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 80. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 81. The antibody conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing at least one of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing at least one of SEQ ID NO: 1430 and SEQ ID NO: 1755; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 82. The antibody-drug conjugate according to any one of the preceding claims, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2752 / SEQ ID NO: 3061.

83. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 161 and SEQ ID NO: 486; CDR-H2 containing at least one of SEQ ID NO: 811 and SEQ ID NO: 1136; and CDR-H3 containing at least one of SEQ ID NO: 1461 and SEQ ID NO: 1786; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 84. The antibody-drug conjugate according to claim 83, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2783 / SEQ ID NO: 3061.

85. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 189 and SEQ ID NO: 514; CDR-H2 containing at least one of SEQ ID NO: 839 and SEQ ID NO: 1164; and CDR-H3 containing at least one of SEQ ID NO: 1489 and SEQ ID NO: 1814; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 86. The antibody-drug conjugate according to claim 85, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2811 / SEQ ID NO: 3061.

87. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 192 and SEQ ID NO: 517; CDR-H2 containing at least one of SEQ ID NO: 842 and SEQ ID NO: 1167; and CDR-H3 containing at least one of SEQ ID NO: 1492 and SEQ ID NO: 1817; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 88. The antibody-drug conjugate according to claim 87, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2814 / SEQ ID NO: 3061.

89. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 211 and SEQ ID NO: 536; CDR-H2 containing at least one of SEQ ID NO: 861 and SEQ ID NO: 1186; and CDR-H3 containing at least one of SEQ ID NO: 1511 and SEQ ID NO: 1836; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 90. The antibody-drug conjugate according to claim 89, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2833 / SEQ ID NO: 3061.

91. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 214 and SEQ ID NO: 539; CDR-H2 containing at least one of SEQ ID NO: 864 and SEQ ID NO: 1189; and CDR-H3 containing at least one of SEQ ID NO: 1514 and SEQ ID NO: 1839; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 92. The antibody-drug conjugate according to claim 91, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2836 / SEQ ID NO: 3061.

93. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 218 and SEQ ID NO: 543; CDR-H2 containing at least one of SEQ ID NO: 868 and SEQ ID NO: 1210; and CDR-H3 containing at least one of SEQ ID NO: 1518 and SEQ ID NO: 1843; and the V L Contains: CDR-L1 containing at least one of SEQ ID NO: 1974 and SEQ ID NO: 2086; CDR-L2 containing at least one of SEQ ID NO: 2198 and SEQ ID NO: 2310; and CDR-L3 containing at least one of SEQ ID NO: 2422 and SEQ ID NO: 2534; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 94. The antibody-drug conjugate according to claim 93, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2855 / SEQ ID NO: 2971.

95. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 105 and SEQ ID NO: 430; CDR-H2 containing at least one of SEQ ID NO: 755 and SEQ ID NO: 1080; and CDR-H3 containing at least one of SEQ ID NO: 1405 and SEQ ID NO: 1730; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 96. The antibody-drug conjugate according to claim 95, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2727 / SEQ ID NO: 2961.

97. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Contains: CDR-H1 containing at least one of SEQ ID NO: 114 and SEQ ID NO: 439; CDR-H2 containing at least one of SEQ ID NO: 764 and SEQ ID NO: 1089; and CDR-H3 containing at least one of SEQ ID NO: 1414 and SEQ ID NO: 1739; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 98. The antibody-drug conjugate according to claim 97, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2736 / SEQ ID NO: 2961.

99. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 117 and SEQ ID NO: 442; CDR-H2 containing at least one of SEQ ID NO: 767 and SEQ ID NO: 1092; and CDR-H3 containing at least one of SEQ ID NO: 1417 and SEQ ID NO: 1742; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 100. The antibody-drug conjugate according to claim 99, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2739 / SEQ ID NO: 2961.

101. The antibody-drug conjugate according to any one of claims 1-67, wherein, The antibody conjugate comprises: (a) An antibody containing V H and V L Wherein V H Comprising: CDR-H1 containing at least one of SEQ ID NO: 128 and SEQ ID NO: 453; CDR-H2 containing at least one of SEQ ID NO: 778 and SEQ ID NO: 1103; and CDR-H3 containing at least one of SEQ ID NO: 1428 and SEQ ID NO: 1753; and the V L Includes: CDR-L1 containing SEQ ID NO: 2064; CDR-L2 containing SEQ ID NO: 2288; and CDR-L3 containing SEQ ID NO: 2512; (b) p-Azide-methylphenylalanine residues located at antibody sites HC180 and HC404; (c) The following linker-loads, where n2 is 4, and each linker-load is connected to one of the side chains of the p-azidomethylphenylalanine residues: 。 102. The antibody-drug conjugate according to claim 101, wherein, The antibody contains V H / V L Paired SEQ ID NO: 2750 / SEQ ID NO: 2961.

103. The antibody conjugate according to any one of the preceding claims, wherein, The antibody binds to the same epitope as the second antibody, the second antibody comprising V. H / V L Pairing or its variants, the V H / V L The pairs are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO: 2779 / SEQ ID NO: 3061; SEQ ID NO: 2780 / SEQ ID NO: 3061;SEQ ID NO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ IDNO:2783 / SEQ ID NO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ IDNO:3061;SEQ ID NO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ IDNO:2788 / SEQ ID NO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ IDNO:3061;SEQ ID NO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ IDNO:2793 / SEQ ID NO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ IDNO:3061;SEQ ID NO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ IDNO:2798 / SEQ ID NO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ IDNO:3061;SEQ ID NO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ IDNO:2803 / SEQ ID NO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ IDNO:3061;SEQ ID NO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ IDNO:2808 / SEQ ID NO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ IDNO:3061;SEQ ID NO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ IDNO:2813 / SEQ ID NO:3061;SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.; 104. The antibody conjugate according to claim 103, wherein, The antibody inhibits the binding of the second antibody to TF by at least 50%, or the second antibody inhibits the binding of the isolated antibody to TF by at least 50%.

105. The antibody conjugate according to any one of the preceding claims, wherein, When the antibody associates with human TF at a temperature of 25°C, the k of the antibody... a The value is approximately 5.4 × 10⁻⁶. 4 M -1 ×sec -1 Approximately 5.47 × 10 5 M -1 ×sec -1 .

106. The antibody conjugate according to any one of the preceding claims, wherein, When the antibody dissociates from human TF at 25°C, the antibody's k d The value is approximately 4.18 × 10 -4 sec -1 From approximately 5.94 × 10 -3 sec -1 .

107. The antibody conjugate according to any one of the preceding claims, wherein, When the antibody binds to human TF at a temperature of 25°C, the K of the antibody... D The value is approximately 3.59 × 10⁻⁶. -9 M to approximately 1.91 × 10 -8 M.

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

109. The antibody conjugate according to claim 108, wherein, The constant region comprises sequences selected from SEQ ID NO: 3062, SEQ ID NO: 3063, SEQ ID NO: 3064, SEQ ID NO: 3065, and SEQ ID NO: 3068.

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

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

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

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

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

115. The antibody conjugate according to claim 114, wherein, The antibody fragment is selected from Fv fragment, Fab fragment, F(ab')2 fragment, Fab' fragment, scFv (sFv) fragment, and scFv-Fc fragment.

116. The antibody conjugate according to claim 115, wherein, The antibody is an scFv fragment.

117. Isolated antibodies that specifically bind to tissue factor (TF), wherein, The antibody contains V H The three heavy chain CDRs of the sequence and from V L The sequence consists of three light chain CDRs, wherein the V H The sequence is selected from SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, and SEQ ID NO: 2859 to SEQ ID NO: 2860, or variations thereof; and the V L The sequences are selected from SEQ ID NO: 2951, SEQ ID NO: 2957, SEQ ID NO: 2962, SEQ ID NO: 2968, SEQ ID NO: 2970, SEQ ID NO: 2971, and SEQ ID NO: 3061, or variations thereof.

118. The isolated antibody according to claim 117, wherein, The antibody contains V H / V L The V consists of three paired heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof. H / V L The pairs are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO: 2779 / SEQ ID NO: 3061; SEQ ID NO: 2780 / SEQ ID NO: 3061;SEQ ID NO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ IDNO:2783 / SEQ ID NO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ IDNO:3061;SEQ ID NO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ IDNO:2788 / SEQ ID NO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ IDNO:3061;SEQ ID NO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ IDNO:2793 / SEQ ID NO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ IDNO:3061;SEQ ID NO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ IDNO:2798 / SEQ ID NO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ IDNO:3061;SEQ ID NO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ IDNO:2803 / SEQ ID NO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ IDNO:3061;SEQ ID NO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ IDNO:2808 / SEQ ID NO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ IDNO:3061;SEQ ID NO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ IDNO:2813 / SEQ ID NO:3061;SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.; 119. The isolated antibody according to claim 117, wherein, The antibody contains V H / V L The V consists of three paired heavy chain CDRs or variants thereof and three light chain CDRs or variants thereof. H / V L The pairings are selected from the following groups: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2783 / SEQ ID NO: 3061; SEQ ID NO: 2811 / SEQ ID NO: 3061; SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; and SEQ ID NO: 2857 / SEQ ID NO: 2968.

120. The isolated antibody according to any one of claims 117-119, wherein, The antibody contains V H The V H Selected from SEQ ID NO: 2727, SEQ ID NO: 2736, SEQ ID NO: 2739, SEQ ID NO: 2751 to SEQ ID NO: 2838, SEQ ID NO: 2840, SEQ ID NO: 2846, SEQ ID NO: 2851, SEQ ID NO: 2857, and SEQ ID NO: 2859 to SEQ ID NO: 2860.

121. The antibody according to claim 120, wherein, The antibody contains V L The V L Selected from SEQ ID NO:2951, SEQ ID NO:2957, SEQ ID NO:2962, SEQ ID NO:2968, SEQ ID NO:2970, SEQ ID NO:2971, and SEQ ID NO:3061.

122. The antibody according to any one of claims 117-121, wherein, The antibody contains V H / V L Pairing or its variants, the V H / V L The pairs are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO: 2779 / SEQ ID NO: 3061;SEQ ID NO:2780 / SEQ ID NO:3061;SEQ ID NO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ ID NO:2783 / SEQ ID NO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ ID NO:3061;SEQ ID NO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ ID NO:2788 / SEQ ID NO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ ID NO:3061;SEQ ID NO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ ID NO:2793 / SEQ ID NO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ ID NO:3061;SEQ ID NO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ ID NO:2798 / SEQ ID NO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ ID NO:3061;SEQ ID NO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ ID NO:2803 / SEQ ID NO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ ID NO:3061;SEQ ID NO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ ID NO:2808 / SEQ ID NO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ ID NO:3061;SEQ ID NO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ ID NO: 2813 / SEQ ID NO: 3061; SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.; 123. The antibody according to any one of claims 117-121, wherein, The antibody contains V H / V L Pairing or its variants, the V H / V L The pairings are selected from the following groups: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2783 / SEQ ID NO: 3061; SEQ ID NO: 2811 / SEQ ID NO: 3061; SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; and SEQ ID NO: 2857 / SEQ ID NO: 2968.

124. Isolated antibodies that specifically bind to tissue factor (TF), wherein, The antibody comprises: (1) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 105 and SEQ ID NO: 430; CDR-H2 containing one or more of SEQ ID NO: 755 and SEQ ID NO: 1080; and CDR-H3 containing one or more of SEQ ID NO: 1405 and SEQ ID NO: 1730; (2) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 114 and SEQ ID NO: 439; CDR-H2 containing one or more of SEQ ID NO: 764 and SEQ ID NO: 1089; and CDR-H3 containing one or more of SEQ ID NO: 1414 and SEQ ID NO: 1739; (3) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 117 and SEQ ID NO: 442; CDR-H2 containing one or more of SEQ ID NO: 767 and SEQ ID NO: 1092; and CDR-H3 containing one or more of SEQ ID NO: 1417 and SEQ ID NO: 1742; (4) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 129 and SEQ ID NO: 454; CDR-H2 containing one or more of SEQ ID NO: 779 and SEQ ID NO: 1104; and CDR-H3 containing one or more of SEQ ID NO: 1429 and SEQ ID NO: 1754; (5) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing one or more of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing one or more of SEQ ID NO: 1430 and SEQ ID NO: 1755; (6) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 131 and SEQ ID NO: 456; CDR-H2 containing one or more of SEQ ID NO: 781 and SEQ ID NO: 1106; and CDR-H3 containing one or more of SEQ ID NO: 1431 and SEQ ID NO: 1756; (7) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 132 and SEQ ID NO: 457; CDR-H2 containing one or more of SEQ ID NO: 782 and SEQ ID NO: 1107; and CDR-H3 containing one or more of SEQ ID NO: 1432 and SEQ ID NO: 1757; (8) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 133 and SEQ ID NO: 458; CDR-H2 containing one or more of SEQ ID NO: 783 and SEQ ID NO: 1108; and CDR-H3 containing one or more of SEQ ID NO: 1433 and SEQ ID NO: 1758; (9) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 134 and SEQ ID NO: 459; CDR-H2 containing one or more of SEQ ID NO: 784 and SEQ ID NO: 1109; and CDR-H3 containing one or more of SEQ ID NO: 1434 and SEQ ID NO: 1759; (10) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 135 and SEQ ID NO: 460; CDR-H2 containing one or more of SEQ ID NO: 785 and SEQ ID NO: 1110; and CDR-H3 containing one or more of SEQ ID NO: 1435 and SEQ ID NO: 1760; (11) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 136 and SEQ ID NO: 461; CDR-H2 containing one or more of SEQ ID NO: 786 and SEQ ID NO: 1111; and CDR-H3 containing one or more of SEQ ID NO: 1436 and SEQ ID NO: 1761; (12) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 137 and SEQ ID NO: 462; CDR-H2 containing one or more of SEQ ID NO: 787 and SEQ ID NO: 1112; and CDR-H3 containing one or more of SEQ ID NO: 1437 and SEQ ID NO: 1762; (13) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 138 and SEQ ID NO: 463; CDR-H2 containing one or more of SEQ ID NO: 788 and SEQ ID NO: 1113; and CDR-H3 containing one or more of SEQ ID NO: 1438 and SEQ ID NO: 1763; (14) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 139 and SEQ ID NO: 464; CDR-H2 containing one or more of SEQ ID NO: 789 and SEQ ID NO: 1114; and CDR-H3 containing one or more of SEQ ID NO: 1439 and SEQ ID NO: 1764; (15) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 140 and SEQ ID NO: 465; CDR-H2 containing one or more of SEQ ID NO: 790 and SEQ ID NO: 1115; and CDR-H3 containing one or more of SEQ ID NO: 1440 and SEQ ID NO: 1765; (16) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 141 and SEQ ID NO: 466; CDR-H2 containing one or more of SEQ ID NO: 791 and SEQ ID NO: 1116; and CDR-H3 containing one or more of SEQ ID NO: 1441 and SEQ ID NO: 1766; (17) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 142 and SEQ ID NO: 467; CDR-H2 containing one or more of SEQ ID NO: 792 and SEQ ID NO: 1117; and CDR-H3 containing one or more of SEQ ID NO: 1442 and SEQ ID NO: 1767; (18) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 143 and SEQ ID NO: 468; CDR-H2 containing one or more of SEQ ID NO: 793 and SEQ ID NO: 1118; and CDR-H3 containing one or more of SEQ ID NO: 1443 and SEQ ID NO: 1768; (19) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 144 and SEQ ID NO: 469; CDR-H2 containing one or more of SEQ ID NO: 794 and SEQ ID NO: 1119; and CDR-H3 containing one or more of SEQ ID NO: 1444 and SEQ ID NO: 1769; (20) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 145 and SEQ ID NO: 470; CDR-H2 containing one or more of SEQ ID NO: 795 and SEQ ID NO: 1120; and CDR-H3 containing one or more of SEQ ID NO: 1445 and SEQ ID NO: 1770; (21) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 146 and SEQ ID NO: 471; CDR-H2 containing one or more of SEQ ID NO: 796 and SEQ ID NO: 1121; and CDR-H3 containing one or more of SEQ ID NO: 1446 and SEQ ID NO: 1771; (22) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 147 and SEQ ID NO: 472; CDR-H2 containing one or more of SEQ ID NO: 797 and SEQ ID NO: 1122; and CDR-H3 containing one or more of SEQ ID NO: 1447 and SEQ ID NO: 1772; (23) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 148 and SEQ ID NO: 473; CDR-H2 containing one or more of SEQ ID NO: 798 and SEQ ID NO: 1123; and CDR-H3 containing one or more of SEQ ID NO: 1448 and SEQ ID NO: 1773; (24) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 149 and SEQ ID NO: 474; CDR-H2 containing one or more of SEQ ID NO: 799 and SEQ ID NO: 1124; and CDR-H3 containing one or more of SEQ ID NO: 1449 and SEQ ID NO: 1774; (25) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 150 and SEQ ID NO: 475; CDR-H2 containing one or more of SEQ ID NO: 800 and SEQ ID NO: 1125; and CDR-H3 containing one or more of SEQ ID NO: 1450 and SEQ ID NO: 1775; (26) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 151 and SEQ ID NO: 476; CDR-H2 containing one or more of SEQ ID NO: 801 and SEQ ID NO: 1126; and CDR-H3 containing one or more of SEQ ID NO: 1451 and SEQ ID NO: 1776; (27) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 152 and SEQ ID NO: 477; CDR-H2 containing one or more of SEQ ID NO: 802 and SEQ ID NO: 1127; and CDR-H3 containing one or more of SEQ ID NO: 1452 and SEQ ID NO: 1777; (28) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 153 and SEQ ID NO: 478; CDR-H2 containing one or more of SEQ ID NO: 803 and SEQ ID NO: 1128; and CDR-H3 containing one or more of SEQ ID NO: 1453 and SEQ ID NO: 1778; (29) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 154 and SEQ ID NO: 479; CDR-H2 containing one or more of SEQ ID NO: 804 and SEQ ID NO: 1129; and CDR-H3 containing one or more of SEQ ID NO: 1454 and SEQ ID NO: 1779; (30) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 155 and SEQ ID NO: 480; CDR-H2 containing one or more of SEQ ID NO: 805 and SEQ ID NO: 1130; and CDR-H3 containing one or more of SEQ ID NO: 1455 and SEQ ID NO: 1780; (31) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 156 and SEQ ID NO: 481; CDR-H2 containing one or more of SEQ ID NO: 806 and SEQ ID NO: 1131; and CDR-H3 containing one or more of SEQ ID NO: 1456 and SEQ ID NO: 1781; (32) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 157 and SEQ ID NO: 482; CDR-H2 containing one or more of SEQ ID NO: 807 and SEQ ID NO: 1132; and CDR-H3 containing one or more of SEQ ID NO: 1457 and SEQ ID NO: 1782; (33) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 158 and SEQ ID NO: 483; CDR-H2 containing one or more of SEQ ID NO: 808 and SEQ ID NO: 1133; and CDR-H3 containing one or more of SEQ ID NO: 1458 and SEQ ID NO: 1783; (34) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 159 and SEQ ID NO: 484; CDR-H2 containing one or more of SEQ ID NO: 809 and SEQ ID NO: 1134; and CDR-H3 containing one or more of SEQ ID NO: 1459 and SEQ ID NO: 1784; (35) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 160 and SEQ ID NO: 485; CDR-H2 containing one or more of SEQ ID NO: 810 and SEQ ID NO: 1135; and CDR-H3 containing one or more of SEQ ID NO: 1460 and SEQ ID NO: 1785; (36) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 161 and SEQ ID NO: 486; CDR-H2 containing one or more of SEQ ID NO: 811 and SEQ ID NO: 1136; and CDR-H3 containing one or more of SEQ ID NO: 1461 and SEQ ID NO: 1786; (37) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 162 and SEQ ID NO: 487; CDR-H2 containing one or more of SEQ ID NO: 812 and SEQ ID NO: 1137; and CDR-H3 containing one or more of SEQ ID NO: 1462 and SEQ ID NO: 1787; (38) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 163 and SEQ ID NO: 488; CDR-H2 containing one or more of SEQ ID NO: 813 and SEQ ID NO: 1138; and CDR-H3 containing one or more of SEQ ID NO: 1463 and SEQ ID NO: 1788; (39) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 164 and SEQ ID NO: 489; CDR-H2 containing one or more of SEQ ID NO: 814 and SEQ ID NO: 1139; and CDR-H3 containing one or more of SEQ ID NO: 1464 and SEQ ID NO: 1789; (40) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 165 and SEQ ID NO: 490; CDR-H2 containing one or more of SEQ ID NO: 815 and SEQ ID NO: 1140; and CDR-H3 containing one or more of SEQ ID NO: 1465 and SEQ ID NO: 1790; (41) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 166 and SEQ ID NO: 491; CDR-H2 containing one or more of SEQ ID NO: 816 and SEQ ID NO: 1141; and CDR-H3 containing one or more of SEQ ID NO: 1466 and SEQ ID NO: 1791; (42) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 167 and SEQ ID NO: 492; CDR-H2 containing one or more of SEQ ID NO: 817 and SEQ ID NO: 1142; and CDR-H3 containing one or more of SEQ ID NO: 1467 and SEQ ID NO: 1792; (43) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 168 and SEQ ID NO: 493; CDR-H2 containing one or more of SEQ ID NO: 818 and SEQ ID NO: 1143; and CDR-H3 containing one or more of SEQ ID NO: 1468 and SEQ ID NO: 1793; (44) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 169 and SEQ ID NO: 494; CDR-H2 containing one or more of SEQ ID NO: 819 and SEQ ID NO: 1144; and CDR-H3 containing one or more of SEQ ID NO: 1469 and SEQ ID NO: 1794; (45) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 170 and SEQ ID NO: 495; CDR-H2 containing one or more of SEQ ID NO: 820 and SEQ ID NO: 1145; and CDR-H3 containing one or more of SEQ ID NO: 1470 and SEQ ID NO: 1795; (46) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 171 and SEQ ID NO: 496; CDR-H2 containing one or more of SEQ ID NO: 821 and SEQ ID NO: 1146; and CDR-H3 containing one or more of SEQ ID NO: 1471 and SEQ ID NO: 1796; (47) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 172 and SEQ ID NO: 497; CDR-H2 containing one or more of SEQ ID NO: 822 and SEQ ID NO: 1147; and CDR-H3 containing one or more of SEQ ID NO: 1472 and SEQ ID NO: 1797; (48) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 173 and SEQ ID NO: 498; CDR-H2 containing one or more of SEQ ID NO: 823 and SEQ ID NO: 1148; and CDR-H3 containing one or more of SEQ ID NO: 1473 and SEQ ID NO: 1798; (49) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 174 and SEQ ID NO: 499; CDR-H2 containing one or more of SEQ ID NO: 824 and SEQ ID NO: 1149; and CDR-H3 containing one or more of SEQ ID NO: 1474 and SEQ ID NO: 1799; (50) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 175 and SEQ ID NO: 500; CDR-H2 containing one or more of SEQ ID NO: 825 and SEQ ID NO: 1150; and CDR-H3 containing one or more of SEQ ID NO: 1475 and SEQ ID NO: 1800; (51) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 176 and SEQ ID NO: 501; CDR-H2 containing one or more of SEQ ID NO: 826 and SEQ ID NO: 1151; and CDR-H3 containing one or more of SEQ ID NO: 1476 and SEQ ID NO: 1801; (52) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 177 and SEQ ID NO: 502; CDR-H2 containing one or more of SEQ ID NO: 827 and SEQ ID NO: 1152; and CDR-H3 containing one or more of SEQ ID NO: 1477 and SEQ ID NO: 1802; (53) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 178 and SEQ ID NO: 503; CDR-H2 containing one or more of SEQ ID NO: 828 and SEQ ID NO: 1153; and CDR-H3 containing one or more of SEQ ID NO: 1478 and SEQ ID NO: 1803; (54) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 179 and SEQ ID NO: 504; CDR-H2 containing one or more of SEQ ID NO: 829 and SEQ ID NO: 1154; and CDR-H3 containing one or more of SEQ ID NO: 1479 and SEQ ID NO: 1804; (55) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 180 and SEQ ID NO: 505; CDR-H2 containing one or more of SEQ ID NO: 830 and SEQ ID NO: 1155; and CDR-H3 containing one or more of SEQ ID NO: 1480 and SEQ ID NO: 1805; (56) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 181 and SEQ ID NO: 506; CDR-H2 containing one or more of SEQ ID NO: 831 and SEQ ID NO: 1156; and CDR-H3 containing one or more of SEQ ID NO: 1481 and SEQ ID NO: 1806; (57) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 182 and SEQ ID NO: 507; CDR-H2 containing one or more of SEQ ID NO: 832 and SEQ ID NO: 1157; and CDR-H3 containing one or more of SEQ ID NO: 1482 and SEQ ID NO: 1807; (58) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 183 and SEQ ID NO: 508; CDR-H2 containing one or more of SEQ ID NO: 833 and SEQ ID NO: 1158; and CDR-H3 containing one or more of SEQ ID NO: 1483 and SEQ ID NO: 1808; (59) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 184 and SEQ ID NO: 509; CDR-H2 containing one or more of SEQ ID NO: 834 and SEQ ID NO: 1159; and CDR-H3 containing one or more of SEQ ID NO: 1484 and SEQ ID NO: 1809; (60) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 185 and SEQ ID NO: 510; CDR-H2 containing one or more of SEQ ID NO: 835 and SEQ ID NO: 1160; and CDR-H3 containing one or more of SEQ ID NO: 1485 and SEQ ID NO: 1810; (61) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 186 and SEQ ID NO: 511; CDR-H2 containing one or more of SEQ ID NO: 836 and SEQ ID NO: 1161; and CDR-H3 containing one or more of SEQ ID NO: 1486 and SEQ ID NO: 1811; (62) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 187 and SEQ ID NO: 512; CDR-H2 containing one or more of SEQ ID NO: 837 and SEQ ID NO: 1162; and CDR-H3 containing one or more of SEQ ID NO: 1487 and SEQ ID NO: 1812; (63) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 188 and SEQ ID NO: 513; CDR-H2 containing one or more of SEQ ID NO: 838 and SEQ ID NO: 1163; and CDR-H3 containing one or more of SEQ ID NO: 1488 and SEQ ID NO: 1813; (64) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 189 and SEQ ID NO: 514; CDR-H2 containing one or more of SEQ ID NO: 839 and SEQ ID NO: 1164; and CDR-H3 containing one or more of SEQ ID NO: 1489 and SEQ ID NO: 1814; (65) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 190 and SEQ ID NO: 515; CDR-H2 containing one or more of SEQ ID NO: 840 and SEQ ID NO: 1165; and CDR-H3 containing one or more of SEQ ID NO: 1490 and SEQ ID NO: 1815; (66) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 191 and SEQ ID NO: 516; CDR-H2 containing one or more of SEQ ID NO: 841 and SEQ ID NO: 1166; and CDR-H3 containing one or more of SEQ ID NO: 1491 and SEQ ID NO: 1816; (67) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 192 and SEQ ID NO: 517; CDR-H2 containing one or more of SEQ ID NO: 842 and SEQ ID NO: 1167; and CDR-H3 containing one or more of SEQ ID NO: 1492 and SEQ ID NO: 1817; (68) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 193 and SEQ ID NO: 518; CDR-H2 containing one or more of SEQ ID NO: 843 and SEQ ID NO: 1168; and CDR-H3 containing one or more of SEQ ID NO: 1493 and SEQ ID NO: 1818; (69) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 194 and SEQ ID NO: 519; CDR-H2 containing one or more of SEQ ID NO: 844 and SEQ ID NO: 1169; and CDR-H3 containing one or more of SEQ ID NO: 1494 and SEQ ID NO: 1819; (70) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 195 and SEQ ID NO: 520; CDR-H2 containing one or more of SEQ ID NO: 845 and SEQ ID NO: 1170; and CDR-H3 containing one or more of SEQ ID NO: 1495 and SEQ ID NO: 1820; (71) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 196 and SEQ ID NO: 521; CDR-H2 containing one or more of SEQ ID NO: 846 and SEQ ID NO: 1171; and CDR-H3 containing one or more of SEQ ID NO: 1496 and SEQ ID NO: 1821; (72) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 197 and SEQ ID NO: 522; CDR-H2 containing one or more of SEQ ID NO: 847 and SEQ ID NO: 1172; and CDR-H3 containing one or more of SEQ ID NO: 1497 and SEQ ID NO: 1822; (73) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 198 and SEQ ID NO: 523; CDR-H2 containing one or more of SEQ ID NO: 848 and SEQ ID NO: 1173; and CDR-H3 containing one or more of SEQ ID NO: 1498 and SEQ ID NO: 1823; (74) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 199 and SEQ ID NO: 524; CDR-H2 containing one or more of SEQ ID NO: 849 and SEQ ID NO: 1174; and CDR-H3 containing one or more of SEQ ID NO: 1499 and SEQ ID NO: 1824; (75) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 200 and SEQ ID NO: 525; CDR-H2 containing one or more of SEQ ID NO: 850 and SEQ ID NO: 1175; and CDR-H3 containing one or more of SEQ ID NO: 1500 and SEQ ID NO: 1825; (76) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 201 and SEQ ID NO: 526; CDR-H2 containing one or more of SEQ ID NO: 851 and SEQ ID NO: 1176; and CDR-H3 containing one or more of SEQ ID NO: 1501 and SEQ ID NO: 1826; (77) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 202 and SEQ ID NO: 527; CDR-H2 containing one or more of SEQ ID NO: 852 and SEQ ID NO: 1177; and CDR-H3 containing one or more of SEQ ID NO: 1502 and SEQ ID NO: 1827; (78) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 203 and SEQ ID NO: 528; CDR-H2 containing one or more of SEQ ID NO: 853 and SEQ ID NO: 1178; and CDR-H3 containing one or more of SEQ ID NO: 1503 and SEQ ID NO: 1828; (79) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 204 and SEQ ID NO: 529; CDR-H2 containing one or more of SEQ ID NO: 854 and SEQ ID NO: 1179; and CDR-H3 containing one or more of SEQ ID NO: 1504 and SEQ ID NO: 1829; (80) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 205 and SEQ ID NO: 530; CDR-H2 containing one or more of SEQ ID NO: 855 and SEQ ID NO: 1180; and CDR-H3 containing one or more of SEQ ID NO: 1505 and SEQ ID NO: 1830; (81) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 206 and SEQ ID NO: 531; CDR-H2 containing one or more of SEQ ID NO: 856 and SEQ ID NO: 1181; and CDR-H3 containing one or more of SEQ ID NO: 1506 and SEQ ID NO: 1831; (82) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 207 and SEQ ID NO: 532; CDR-H2 containing one or more of SEQ ID NO: 857 and SEQ ID NO: 1182; and CDR-H3 containing one or more of SEQ ID NO: 1507 and SEQ ID NO: 1832; (83) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 208 and SEQ ID NO: 533; CDR-H2 containing one or more of SEQ ID NO: 858 and SEQ ID NO: 1183; and CDR-H3 containing one or more of SEQ ID NO: 1508 and SEQ ID NO: 1833; (84) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 209 and SEQ ID NO: 534; CDR-H2 containing one or more of SEQ ID NO: 859 and SEQ ID NO: 1184; and CDR-H3 containing one or more of SEQ ID NO: 1509 and SEQ ID NO: 1834; (85) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 210 and SEQ ID NO: 535; CDR-H2 containing one or more of SEQ ID NO: 860 and SEQ ID NO: 1185; and CDR-H3 containing one or more of SEQ ID NO: 1510 and SEQ ID NO: 1835; (86) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 211 and SEQ ID NO: 536; CDR-H2 containing one or more of SEQ ID NO: 861 and SEQ ID NO: 1186; and CDR-H3 containing one or more of SEQ ID NO: 1511 and SEQ ID NO: 1836; (87) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 212 and SEQ ID NO: 537; CDR-H2 containing one or more of SEQ ID NO: 862 and SEQ ID NO: 1187; and CDR-H3 containing one or more of SEQ ID NO: 1512 and SEQ ID NO: 1837; (88) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 213 and SEQ ID NO: 538; CDR-H2 containing one or more of SEQ ID NO: 863 and SEQ ID NO: 1188; and CDR-H3 containing one or more of SEQ ID NO: 1513 and SEQ ID NO: 1838; (89) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 214 and SEQ ID NO: 539; CDR-H2 containing one or more of SEQ ID NO: 864 and SEQ ID NO: 1189; and CDR-H3 containing one or more of SEQ ID NO: 1514 and SEQ ID NO: 1839; (90) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 215 and SEQ ID NO: 540; CDR-H2 containing one or more of SEQ ID NO: 865 and SEQ ID NO: 1190; and CDR-H3 containing one or more of SEQ ID NO: 1515 and SEQ ID NO: 1840; (91) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 216 and SEQ ID NO: 541; CDR-H2 containing one or more of SEQ ID NO: 866 and SEQ ID NO: 1191; and CDR-H3 containing one or more of SEQ ID NO: 1516 and SEQ ID NO: 1841; (92) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 218 and SEQ ID NO: 543; CDR-H2 containing one or more of SEQ ID NO: 868 and SEQ ID NO: 1193; and CDR-H3 containing one or more of SEQ ID NO: 1518 and SEQ ID NO: 1843; (93) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 224 and SEQ ID NO: 549; CDR-H2 containing one or more of SEQ ID NO: 874 and SEQ ID NO: 1199; and CDR-H3 containing one or more of SEQ ID NO: 1524 and SEQ ID NO: 1849; (94) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 229 and SEQ ID NO: 554; CDR-H2 containing one or more of SEQ ID NO: 879 and SEQ ID NO: 1204; and CDR-H3 containing one or more of SEQ ID NO: 1529 and SEQ ID NO: 1854; (95) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 235 and SEQ ID NO: 560; CDR-H2 containing one or more of SEQ ID NO: 885 and SEQ ID NO: 1210; and CDR-H3 containing one or more of SEQ ID NO: 1535 and SEQ ID NO: 1860; (96) V H It comprises: CDR-H1 containing one or more of SEQ ID NO: 237 and SEQ ID NO: 562; CDR-H2 containing one or more of SEQ ID NO: 887 and SEQ ID NO: 1212; and CDR-H3 containing one or more of SEQ ID NO: 1537 and SEQ ID NO: 1862; or (97) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 238 and SEQ ID NO: 563; CDR-H2 containing one or more of SEQ ID NO: 888 and SEQ ID NO: 1213; and CDR-H3 containing one or more of SEQ ID NO: 1538 and SEQ ID NO: 1863.

125. The isolated antibody according to claim 124, wherein, The antibody comprises: (1) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1954 and SEQ ID NO: 2066; CDR-L2 containing one or more of SEQ ID NO: 2178 and SEQ ID NO: 2290; and CDR-L3 containing one or more of SEQ ID NO: 2402 and SEQ ID NO: 2514; (2) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1960 and SEQ ID NO: 2072; CDR-L2 containing one or more of SEQ ID NO: 2184 and SEQ ID NO: 2296; and CDR-L3 containing one or more of SEQ ID NO: 2408 and SEQ ID NO: 2520; (3) V L It includes: a CDR-L1 containing one or more of SEQ ID NO: 1965 and SEQ ID NO: 2077; a CDR-L2 containing one or more of SEQ ID NO: 2189 and SEQ ID NO: 2301; and a CDR-L3 containing one or more of SEQ ID NO: 2413 and SEQ ID NO: 2525; (4) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1971 and SEQ ID NO: 2083; CDR-L2 containing one or more of SEQ ID NO: 2195 and SEQ ID NO: 2307; and CDR-L3 containing one or more of SEQ ID NO: 2419 and SEQ ID NO: 2531; (5) V L It includes: a CDR-L1 containing one or more of SEQ ID NO: 1973 and SEQ ID NO: 2085; a CDR-L2 containing one or more of SEQ ID NO: 2197 and SEQ ID NO: 2309; and a CDR-L3 containing one or more of SEQ ID NO: 2421 and SEQ ID NO: 2533; (6) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1974 and SEQ ID NO: 2086; CDR-L2 containing one or more of SEQ ID NO: 2198 and SEQ ID NO: 2310; and CDR-L3 containing one or more of SEQ ID NO: 2422 and SEQ ID NO: 2534; or (7) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 2064 and SEQ ID NO: 2176; CDR-L2 containing one or more of SEQ ID NO: 2288 and SEQ ID NO: 2400; and CDR-L3 containing one or more of SEQ ID NO: 2512 and SEQ ID NO: 2624.

126. Isolated antibodies that specifically bind to tissue factor (TF), wherein, The antibody comprises: (1) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 105 and SEQ ID NO: 430; CDR-H2 containing one or more of SEQ ID NO: 755 and SEQ ID NO: 1080; and CDR-H3 containing one or more of SEQ ID NO: 1405 and SEQ ID NO: 1730; (2) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 114 and SEQ ID NO: 439; CDR-H2 containing one or more of SEQ ID NO: 764 and SEQ ID NO: 1089; and CDR-H3 containing one or more of SEQ ID NO: 1414 and SEQ ID NO: 1739; (3) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 117 and SEQ ID NO: 442; CDR-H2 containing one or more of SEQ ID NO: 767 and SEQ ID NO: 1092; and CDR-H3 containing one or more of SEQ ID NO: 1417 and SEQ ID NO: 1742; (4) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 130 and SEQ ID NO: 455; CDR-H2 containing one or more of SEQ ID NO: 780 and SEQ ID NO: 1105; and CDR-H3 containing one or more of SEQ ID NO: 1430 and SEQ ID NO: 1755; (5) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 161 and SEQ ID NO: 486; CDR-H2 containing one or more of SEQ ID NO: 811 and SEQ ID NO: 1136; and CDR-H3 containing one or more of SEQ ID NO: 1461 and SEQ ID NO: 1786; (6) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 189 and SEQ ID NO: 514; CDR-H2 containing one or more of SEQ ID NO: 839 and SEQ ID NO: 1164; and CDR-H3 containing one or more of SEQ ID NO: 1489 and SEQ ID NO: 1814; (7) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 192 and SEQ ID NO: 517; CDR-H2 containing one or more of SEQ ID NO: 842 and SEQ ID NO: 1167; and CDR-H3 containing one or more of SEQ ID NO: 1492 and SEQ ID NO: 1817; (8) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 211 and SEQ ID NO: 536; CDR-H2 containing one or more of SEQ ID NO: 861 and SEQ ID NO: 1186; and CDR-H3 containing one or more of SEQ ID NO: 1511 and SEQ ID NO: 1836; (9) V H It comprises: CDR-H1 containing one or more of SEQ ID NO: 214 and SEQ ID NO: 539; CDR-H2 containing one or more of SEQ ID NO: 864 and SEQ ID NO: 1189; and CDR-H3 containing one or more of SEQ ID NO: 1514 and SEQ ID NO: 1839; or (10) V H It includes: CDR-H1 containing one or more of SEQ ID NO: 218 and SEQ ID NO: 543; CDR-H2 containing one or more of SEQ ID NO: 868 and SEQ ID NO: 1193; and CDR-H3 containing one or more of SEQ ID NO: 1518 and SEQ ID NO: 1843.

127. The isolated antibody according to claim 126, wherein, The antibody comprises: (1) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 1974 and SEQ ID NO: 2086; CDR-L2 containing one or more of SEQ ID NO: 2198 and SEQ ID NO: 2310; and CDR-L3 containing one or more of SEQ ID NO: 2422 and SEQ ID NO: 2534; or (2) V L It includes: CDR-L1 containing one or more of SEQ ID NO: 2064 and SEQ ID NO: 2176; CDR-L2 containing one or more of SEQ ID NO: 2288 and SEQ ID NO: 2400; and CDR-L3 containing one or more of SEQ ID NO: 2512 and SEQ ID NO: 2624.

128. Isolated antibodies that specifically bind to tissue factor, wherein, The antibody binds to the same epitope as the second antibody, the second antibody comprising V. H / V L Pairing or its variants, the V H / V L The pairs are selected from the group consisting of: SEQ ID NO: 2727 / SEQ ID NO: 3061; SEQ ID NO: 2736 / SEQ ID NO: 3061; SEQ ID NO: 2739 / SEQ ID NO: 3061; SEQ ID NO: 2751 / SEQ ID NO: 3061; SEQ ID NO: 2752 / SEQ ID NO: 3061; SEQ ID NO: 2753 / SEQ ID NO: 3061; SEQ ID NO: 2754 / SEQ ID NO: 3061; SEQ ID NO: 2755 / SEQ ID NO: 3061; SEQ ID NO: 2756 / SEQ ID NO: 3061; SEQ ID NO: 2757 / SEQ ID NO: 3061; SEQ ID NO: 2758 / SEQ ID NO: 3061; SEQ ID NO: 2759 / SEQ ID NO: 3061; SEQ ID NO: 2760 / SEQ ID NO: 3061; SEQ ID NO: 2761 / SEQ ID NO: 3061; SEQ ID NO: 2762 / SEQ ID NO: 3061; SEQ ID NO: 2763 / SEQ ID NO: 3061; SEQ ID NO: 2764 / SEQ ID NO: 3061; SEQ ID NO: 2765 / SEQ ID NO: 3061; SEQ ID NO: 2766 / SEQ ID NO: 3061; SEQ ID NO: 2767 / SEQ ID NO: 3061; SEQ ID NO: 2768 / SEQ ID NO: 3061; SEQ ID NO: 2769 / SEQ ID NO: 3061; SEQ ID NO: 2770 / SEQ ID NO: 3061; SEQ ID NO: 2771 / SEQ ID NO: 3061; SEQ ID NO: 2772 / SEQ ID NO: 3061; SEQ ID NO: 2773 / SEQ ID NO: 3061; SEQ ID NO: 2774 / SEQ ID NO: 3061; SEQ ID NO: 2775 / SEQ ID NO: 3061; SEQ ID NO: 2776 / SEQ ID NO: 3061; SEQ ID NO: 2777 / SEQ ID NO: 3061; SEQ ID NO: 2778 / SEQ ID NO: 3061; SEQ ID NO: 2779 / SEQ ID NO: 3061; SEQ ID NO: 2780 / SEQ ID NO: 3061;SEQ ID NO:2781 / SEQ ID NO:3061;SEQ ID NO:2782 / SEQ ID NO:3061;SEQ IDNO:2783 / SEQ ID NO:3061;SEQ ID NO:2784 / SEQ ID NO:3061;SEQ ID NO:2785 / SEQ IDNO:3061;SEQ ID NO:2786 / SEQ ID NO:3061;SEQ ID NO:2787 / SEQ ID NO:3061;SEQ IDNO:2788 / SEQ ID NO:3061;SEQ ID NO:2789 / SEQ ID NO:3061;SEQ ID NO:2790 / SEQ IDNO:3061;SEQ ID NO:2791 / SEQ ID NO:3061;SEQ ID NO:2792 / SEQ ID NO:3061;SEQ IDNO:2793 / SEQ ID NO:3061;SEQ ID NO:2794 / SEQ ID NO:3061;SEQ ID NO:2795 / SEQ IDNO:3061;SEQ ID NO:2796 / SEQ ID NO:3061;SEQ ID NO:2797 / SEQ ID NO:3061;SEQ IDNO:2798 / SEQ ID NO:3061;SEQ ID NO:2799 / SEQ ID NO:3061;SEQ ID NO:2800 / SEQ IDNO:3061;SEQ ID NO:2801 / SEQ ID NO:3061;SEQ ID NO:2802 / SEQ ID NO:3061;SEQ IDNO:2803 / SEQ ID NO:3061;SEQ ID NO:2804 / SEQ ID NO:3061;SEQ ID NO:2805 / SEQ IDNO:3061;SEQ ID NO:2806 / SEQ ID NO:3061;SEQ ID NO:2807 / SEQ ID NO:3061;SEQ IDNO:2808 / SEQ ID NO:3061;SEQ ID NO:2809 / SEQ ID NO:3061;SEQ ID NO:2810 / SEQ IDNO:3061;SEQ ID NO:2811 / SEQ ID NO:3061;SEQ ID NO:2812 / SEQ ID NO:3061;SEQ IDNO:2813 / SEQ ID NO:3061;SEQ ID NO: 2814 / SEQ ID NO: 3061; SEQ ID NO: 2815 / SEQ ID NO: 3061; SEQ ID NO: 2816 / SEQ ID NO: 3061; SEQ ID NO: 2817 / SEQ ID NO: 3061; SEQ ID NO: 2818 / SEQ ID NO: 3061; SEQ ID NO: 2819 / SEQ ID NO: 3061; SEQ ID NO: 2820 / SEQ ID NO: 3061; SEQ ID NO: 2821 / SEQ ID NO: 3061; SEQ ID NO: 2822 / SEQ ID NO: 3061; SEQ ID NO: 2823 / SEQ ID NO: 3061; SEQ ID NO: 2824 / SEQ ID NO: 3061; SEQ ID NO: 2825 / SEQ ID NO: 3061; SEQ ID NO: 2826 / SEQ ID NO: 3061; SEQ ID NO: 2827 / SEQ ID NO: 3061; SEQ ID NO: 2828 / SEQ ID NO: 3061; SEQ ID NO: 2829 / SEQ ID NO: 3061; SEQ ID NO: 2830 / SEQ ID NO: 3061; SEQ ID NO: 2831 / SEQ ID NO: 3061; SEQ ID NO: 2832 / SEQ ID NO: 3061; SEQ ID NO: 2833 / SEQ ID NO: 3061; SEQ ID NO: 2834 / SEQ ID NO: 3061; SEQ ID NO: 2835 / SEQ ID NO: 3061; SEQ ID NO: 2836 / SEQ ID NO: 3061; SEQ ID NO: 2837 / SEQ ID NO: 3061; SEQ ID NO: 2838 / SEQ ID NO: 3061; SEQ ID NO: 2840 / SEQ ID NO: 2951; SEQ ID NO: 2846 / SEQ ID NO: 2957; SEQ ID NO: 2851 / SEQ ID NO: 2962; SEQ ID NO: 2857 / SEQ ID NO: 2968; SEQ ID NO: 2859 / SEQ ID NO: 2970; and SEQ ID NO: 2860 / SEQ ID NO: 2971.; 129. The antibody according to claim 128, wherein, The isolated antibody inhibits the binding of the second antibody to the tissue factor by at least 50%, or the second antibody inhibits the binding of the isolated antibody to the tissue factor by at least 50%.

130. The antibody according to any one of claims 117-129, wherein, When the antibody associates with human tissue factor at a temperature of 25°C, the k of the antibody... a The value is approximately 5.4 × 10⁻⁶. 4 M -1 ×sec -1 Approximately 5.47 × 10 5 M -1 ×sec -1 .

131. The antibody according to any one of claims 117-130, wherein, When the antibody dissociates from human tissue factor at 25°C, the antibody's k d The value is approximately 2.75 × 10⁻⁶. -4 sec -1 From approximately 2.01 × 10 -2 sec -1 .

132. The antibody according to any one of claims 117-130, wherein, When the antibody binds to human tissue factor at a temperature of 25°C, the K of the antibody... D The value is approximately 3.59 × 10⁻⁶. -9 M to approximately 1.91 × 10 -8 M.

133. The antibody according to any one of claims 117-130, wherein, When the antibody associates with cynomolgus tissue factor at 25°C, the antibody's k... a The value is approximately 7.24 × 10⁻⁶. 4 M -1 ×sec -1 From approximately 1.21 × 10 6 M -1 ×sec -1 .

134. The antibody according to any one of claims 117-130, wherein, When the antibody dissociates from cynomolgus monkey tissue factor at 25°C, the antibody's k... d The value is approximately 3.09 × 10⁻⁶. -4 sec -1 Approximately 3.93 × 10 2 sec -1 .

135. The antibody according to any one of claims 117-130, wherein, When the antibody binds to cynomolgus monkey tissue factor at 25°C, the K of the antibody... D The value is approximately 2.55 × 10 -10 M to approximately 6.07 × 10 -8 M.

136. The antibody according to any one of claims 117-133, wherein, The antibody contains at least one constant region domain.

137. The antibody according to claim 136, wherein, The constant region comprises sequences selected from SEQ ID NO: 3062, SEQ ID NO: 3063, SEQ ID NO: 3064, SEQ ID NO: 3065, and SEQ ID NO: 3068.

138. The antibody according to any one of claims 117-137, wherein, The antibody is a monoclonal antibody.

139. The antibody according to any one of claims 117-138, wherein, The antibody is IgA, IgD, IgE, IgG, or IgM.

140. The antibody according to any one of claims 117-139, wherein, The antibody is humanized or human.

141. The antibody according to any one of claims 117-140, wherein, The antibody is glycosylated.

142. The antibody according to any one of claims 117-140, wherein, The antibody is aglycosylated.

143. The antibody according to any one of claims 117-142, wherein, The antibody is an antibody fragment.

144. The antibody according to claim 143, wherein, The antibody fragment is selected from Fv fragment, Fab fragment, F(ab')2 fragment, Fab' fragment, scFv (sFv) fragment, and scFv-Fc fragment.

145. The antibody according to claim 144, wherein, The antibody is an scFv fragment.

146. The antibody according to claim 145, wherein, The scFv fragment comprises an scFv sequence selected from SEQ ID NO: 3073 and SEQ ID NO: 3079, with or without the N-terminal M residue.

147. The antibody according to claim 144, wherein, The antibody is an scFv-Fc fragment.

148. The antibody according to claim 147, wherein, The scFv-Fc fragment comprises a sequence selected from SEQ ID NO: 3072 to SEQ ID NO: 3159, with or without the N-terminal M residue.

149. The antibody according to any one of claims 117-148, wherein, The antibody specifically binds to cynomolgus monkey tissue factor.

150. A kit comprising an antibody according to any one of claims 117-149, an antibody-drug conjugate according to any one of claims 1-116, or a pharmaceutical composition according to any one of claims 159-169, and instructions for use of the antibody, the antibody-drug conjugate, or the pharmaceutical composition.

151. The kit according to claim 150, wherein, The antibody, antibody-drug conjugate, or pharmaceutical composition is lyophilized.

152. The kit of claim 151, further comprising a liquid for reconstructing the lyophilized antibody, antibody-drug conjugate, or pharmaceutical composition.

153. A polynucleotide encoding an antibody as claimed in any one of claims 117-149.

154. A vector comprising the polynucleotide of claim 153.

155. A recombinant host cell comprising the vector of claim 154.

156. The host cell according to claim 155, wherein, The host cells are selected from the group consisting of bacterial cells, fungal cells, and mammalian cells.

157. The host cell according to claim 155, wherein, The host cells are selected from the group consisting of: Escherichia coli (E. coli) E. coli ) cells, brewer's yeast ( Saccharomyces cerevisiae ) cells, and CHO cells.

158. A cell-free expression response comprising the vector of claim 154.

159. A pharmaceutical composition comprising an isolated antibody as described in any one of claims 117-149 or an antibody-drug conjugate as described in any one of claims 1-116, and a pharmaceutically acceptable carrier.

160. A pharmaceutical composition comprising: (a) an isolated antibody according to any one of claims 117-149 or an antibody conjugate according to any one of claims 1-116; (b) one or more additional active pharmaceutical ingredients; and (c) a pharmaceutically acceptable carrier.

161. The pharmaceutical composition according to claim 159 or 160, wherein, The one or more additional active pharmaceutical ingredients are one or more checkpoint inhibitors.

162. The pharmaceutical composition according to claim 161, 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.

163. The pharmaceutical composition according to claim 162, wherein, The one or more checkpoint inhibitors are PD-1 inhibitors or PD-L1 inhibitors.

164. The pharmaceutical composition 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 pharmaceutical composition according to claim 163, wherein, The one or more PD-1 or PD-L1 inhibitors are antibodies that inhibit the activity of PD-1 or PD-L1.

166. The pharmaceutical composition according to any one of claims 162-165, 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, tizlelizumab / BGB-A317, CK 301, BMS-936559, Camrelizumab, Sintilimab, Toripalimab, Genolimzumab, 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 pharmaceutical composition according to claim 160, wherein, The one or more additional active pharmaceutical ingredients are one or more PARP inhibitors.

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

169. The pharmaceutical composition according to claim 167, wherein, The one or more PARP inhibitors mentioned are olaparib.

170. A method for reducing cell proliferation in a subject in need, comprising administering to the subject an effective amount of the isolated antibody of any one of claims 117-149, the antibody-drug conjugate of any one of claims 1-116, or the pharmaceutical composition of any one of claims 159-169.

171. A method for treating or preventing a disease or ailment of a subject in need, comprising administering to the subject an effective amount of an isolated antibody as described in any one of claims 117-149, an antibody-drug conjugate as described in any one of claims 1-116, or a pharmaceutical composition as described in any one of claims 159-169.

172. A method for diagnosing a disease or ailment of a subject in need, comprising administering to the subject an effective amount of the isolated antibody as described in any one of claims 117-149, the antibody-drug conjugate as described in any one of claims 1-116, or the pharmaceutical composition as described in any one of claims 159-169.

173. The method according to any one of claims 170-172, further comprising administering one or more additional active pharmaceutical ingredients to the subject.

174. The method according to claim 173, wherein, The one or more additional active drugs are checkpoint inhibitors.

175. The method according to claim 174, wherein, The checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, or a TIM-3 inhibitor.

176. The method according to claim 175, wherein, The checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor.

177. The method according to claim 176, wherein, The PD-1 inhibitor or PD-L1 inhibitor is a small molecule blocker of the PD-1 or PD-L1 pathway.

178. The method according to claim 176, wherein, The PD-1 inhibitor or PD-L1 inhibitor is an antibody that inhibits the activity of PD-1 or PD-L1.

179. The method according to any one of claims 170-178, wherein, The PD-1 inhibitors 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, tizlelizumab / BGB-A317, CK 301, BMS-936559, Camrelizumab, Sintilimab, Toripalimab, Genolimzumab, 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.

180. The method according to claim 173, wherein, The one or more additional active pharmaceutical ingredients are PARP inhibitors.

181. The method according to claim 180, wherein, The PARP inhibitors are selected from olaparib, rucaparib, niraparib, and talazoparib.

182. The method according to claim 181, wherein, The PARP inhibitor mentioned is olaparib.

183. The method according to any one of claims 173-182, wherein, The isolated antibody, the antibody-drug conjugate, or the pharmaceutical composition, and one or more additional drugs are administered sequentially.

184. The method according to any one of claims 173-182, wherein, The isolated antibody, the antibody-drug conjugate, or the pharmaceutical composition, along with one or more additional pharmaceutical agents, are administered simultaneously.

185. The method according to any one of claims 171-184, wherein, The disease or symptom mentioned is cancer.

186. The method according to any one of claims 171-184, wherein, The disease or condition mentioned is cancer that expresses TF.

187. The method according to any one of claims 171-184, wherein, The disease or condition described is a solid tumor or cancer.

188. The method according to any one of claims 171-184, wherein, The disease or condition is selected from the group consisting of: cervical cancer, squamous cell carcinoma of the head and neck, endometrial cancer, esophageal cancer, non-small cell lung cancer, and prostate cancer.

189. The method according to any one of claims 171-184, wherein, The disease or condition mentioned is colorectal cancer.

190. Use of the isolated antibody according to any one of claims 117-149, the antibody-drug conjugate according to any one of claims 1-116, or the pharmaceutical composition according to any one of claims 159-169 for reducing cell proliferation in a subject of need.

191. Use of the isolated antibody according to any one of claims 117-149, the antibody conjugate according to any one of claims 1-116, or the pharmaceutical composition according to any one of claims 159-169 in the preparation of a medicament for reducing cell proliferation in a subject in need.

192. Use of the isolated antibody according to any one of claims 117-149, the antibody conjugate according to any one of claims 1-116, or the pharmaceutical composition according to any one of claims 159-169 for the treatment or prevention of a disease or condition in a subject in need.

193. Use of the isolated antibody according to any one of claims 117-149, the antibody conjugate according to any one of claims 1-116, or the pharmaceutical composition according to any one of claims 159-169 in the preparation of a medicament for treating or preventing a disease or condition in a subject of need.

194. Methods for diagnosing and treating cancer in subjects in need, comprising: (a) Detecting TF expression in the subject's cells or tissues to diagnose the cancer; and (b) Administering an effective amount of the pharmaceutical composition according to any one of claims 159-169 to the subject.

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