Antibody-drug conjugates targeting uPARAP containing exatecan derivatives

Abstract

The present invention relates to antibody-drug conjugates (ADCs) that target the receptor uPARAP, and in particular to antibody-drug conjugates (ADCs) comprising humanized antibodies directed against uPARAP, and their use in delivering active agents to cells and tissues expressing exatecan derivatives and uPARAP. The present invention further relates to the use of the ADCs in the treatment of diseases involving uPARAP-expressing cells, such as certain cancers.

Description

[Technical Field]

[0001] The present invention relates to antibody-drug conjugates (ADCs) that target the receptor uPARAP, and in particular to antibody-drug conjugates (ADCs) comprising humanized antibodies directed against uPARAP, and to exatecan derivatives and their use in delivering active agents to cells and tissues that express uPARAP. The present invention further relates to the use of the ADCs in the treatment of diseases involving uPARAP-expressing cells, such as certain cancers. [Background technology]

[0002] Urokinase-type plasminogen activator receptor-associated protein (uPARAP) (also known as CD280, Endo180, and mannose receptor type C2) is a member of the macrophage mannose receptor family of endocytic transmembrane glycoproteins. uPARAP is a membrane protein involved in matrix metabolism, particularly collagen uptake and intracellular degradation, during tissue remodeling. The uPARAP receptor consists of an N-terminal cysteine-rich domain (CysR), a fibronectin type II (FN-II) domain, and eight C-type lectin-like domains (CTLD1-8).

[0003] The receptor uPARAP is upregulated in tumor cells of certain cancers, including sarcoma and late-stage glioblastoma. Furthermore, the receptor is most commonly upregulated in stromal cells surrounding solid tumors, and some literature suggests high expression of uPARAP in bone metastases from prostate cancer (Caley et al., 2012, J. Patol 5:775-783). In healthy adult individuals, the receptor exhibits a restricted expression pattern (Melander et al., 2015, Int J Oncol 47:1177-1188).

[0004] Antibody-drug conjugates (ADCs) are a class of highly potent biopharmaceuticals designed specifically as targeted therapies for the treatment of cancer. ADCs are conjugated molecules composed of an antibody (whole mAb or antibody fragment) linked to an active agent, e.g., a biologically active drug or cytotoxic compound, via a stable chemical linker that may have a labile bond. By combining the unique targeting capabilities of antibodies with the cell-killing capabilities of cytotoxic agents, antibody-drug conjugates can sensitively distinguish between healthy and diseased tissue based on antibody-antigen expression. This means that, in contrast to traditional chemotherapeutic agents, antibody-drug conjugates actively target and attack cancer cells, leaving healthy cells with little or no antigen expression less severely affected. Currently, more than 10 ADCs have been approved on the market, and several more are currently in clinical trials.

[0005] WO2010 / 111198 discloses a conjugate comprising an anti-uPARAP antibody and suggests the use of such a conjugate in delivering a therapeutic agent to cells expressing uPARAP.

[0006] WO2017 / 133745 discloses ADCs directed against uPARAP.

[0007] WO2022 / 068878 discloses exatecan derivatives and ADCs containing them.

[0008] Currently, treatments exist for most types of cancer. However, in many cases, they are inefficient or involve adverse effects due to high doses of therapeutic agents. Therefore, more effective treatments with increased efficacy are needed. Summary of the Invention

[0009] Provided herein are antibody-drug conjugates and exatecan derivatives comprising a humanized form of the murine 9b7 antibody that targets the uPARAP receptor. The murine 9b7 antibody was first described in WO2017 / 133745. The antibody-drug conjugates described herein can specifically target cells and tissues that express uPARAP. ADCs comprising the humanized 9b7 antibody described herein exhibit improved potency compared to ADCs comprising the murine 9b7 antibody, as well as improved potency compared to ADCs comprising other humanized versions of the murine 9b7 antibody.

[0010] In particular, the present disclosure provides: a. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and / or b. An antibody-drug conjugate comprising an antibody that binds to uPARAP, the antibody comprising an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:6, the antibody-drug conjugate comprises an active agent having a structure according to one selected from the group consisting of formula (IA), formula (II-A), and formula (III-A), as described herein below; and The antibody-drug conjugate optionally includes a linker that connects the antibody to the active agent.

[0011] The present disclosure further provides a method for producing the antibody-drug conjugates described herein, the method comprising the use of a compound according to one selected from the group consisting of Formula (IA), Formula (II-Fx), Formula (II-Fy), and Formula (III-F) described herein.

[0012] The present disclosure further relates to a method of treating a disease characterized by cells expressing uPARAP, the method comprising administering to a subject an antibody-drug conjugate as defined herein or a pharmaceutical composition comprising an antibody-drug conjugate as defined herein.

[0013] Yet another aspect of the present disclosure is a kit comprising an antibody drug conjugate as defined herein, or a pharmaceutical composition comprising an antibody drug conjugate as defined herein, optionally further comprising a means for administering the antibody drug conjugate to a subject and / or instructions for use. [Brief explanation of the drawings]

[0014] [Figure 1] In vitro cell viability assay of the U937 cancer cell line exposed to MMAE-based ADCs containing either the LC0HC0 antibody (containing the variable domains of the original murine 9b7 antibody fused to a human IgG constant region) or the humanized LC4HC3 antibody. Other than the antibody, the two ADCs are identical and produced by the same method. Cells were incubated for 96 hours and then analyzed by a colorimetric viability assay. Assays on the U937 cell line show that the LC4HC3-based ADC has a significantly greater reduction in overall cell viability compared to the LC0HC0 ADC. [Figure 2] Internalization of humanized antibodies LC4HC3 and LC3HC3 in SAOS-2 osteosarcoma cells. A detailed protocol is provided in Example 2. The data show that LC4HC3 is not only internalized more rapidly than LC3HC3, but also more extensively in SAOS-2 osteosarcoma cells. [Figure 3a] In vivo efficacy of vedotin-type ADCs based on LC4HC3 (LC4HC3-vc-MMAE, 3a) and LC3HC3 (LC3HC3-vc-MMAE, 3b). CB17 mice were inoculated with U937 cells to induce tumor growth. Tumor size was closely monitored, and treatment was initiated when tumors reached approximately 80–150 mm3. Except for the antibody, the two ADCs were identical and produced by the same method. Each line represents tumor size in mice treated with the reference ADC at a dose of 4 mg / kg twice daily for 7 days. This data demonstrates that ADCs based on the humanized 9b7 antibody LC4HC3 are superior antitumor agents compared to ADCs based on the different humanized 9b7 antibody LC3HC3. [Figure 3b]In vivo efficacy of vedotin-type ADCs based on LC4HC3 (LC4HC3-vc-MMAE, 3a) and LC3HC3 (LC3HC3-vc-MMAE, 3b). CB17 mice were inoculated with U937 cells to induce tumor growth. Tumor size was closely monitored, and treatment was initiated once tumors reached approximately 80–150 mm3. However, in the case of antibodies, the two ADCs were identical and produced by the same method. Each line represents tumor size in mice treated with the reference ADC at a dose of 4 mg / kg twice daily for 7 days. Each line represents tumor size in mice treated with the reference ADC at a dose of 4 mg / kg twice daily for 7 days. [Figure 4a] Tumor size calculated from caliper measurements using the formula: tumor size = {(length * width 2) / 2}. 4a: Dosage 3 mg / kg. 4b: Dosage 10 mg / kg. Data shown are mean ± standard deviation (SD) for mice surviving at least 50% (n=7). Mice were treated intravenously into the tail vein three times weekly, as indicated by triangles on the x-axis. The cell line used was SK-LMS-1, and the ADCs used were ADCE-D01 (squares) and control ADCE-D51 (circles). Both ADCs are also compared to vehicle treatment with PBS (triangles). [Figure 4b] Tumor size calculated from caliper measurements using the formula: tumor size = {(length * width 2) / 2}. 4a: Dosage 3 mg / kg. 4b: Dosage 10 mg / kg. Data shown are mean ± standard deviation (SD) for mice surviving at least 50% (n=7). Mice were treated intravenously into the tail vein three times weekly, as indicated by triangles on the x-axis. The cell line used was SK-LMS-1, and the ADCs used were ADCE-D01 (squares) and control ADCE-D51 (circles). Both ADCs are also compared to vehicle treatment with PBS (triangles). [Figure 5a]Tumor size calculated from caliper measurements using the formula: tumor size = {(length * width 2) / 2}. 5a: Dosage 3 mg / kg. 5b: Dosage 6 mg / kg. Data shown are mean ± SD when 50% or more of the mice survive. Mice were treated IV into the tail vein three times weekly, as indicated by the triangles on the x-axis. The cell line used was RD, and the ADCs used were ADCE-D01 (squares) and control ADCE-D51 (circles). Both ADCs are also compared to vehicle treatment with PBS (triangles). [Figure 5b] Tumor size calculated from caliper measurements using the formula: tumor size = {(length * width 2) / 2}. 5a: Dosage 3 mg / kg. 5b: Dosage 6 mg / kg. Data shown are mean ± SD when 50% or more of the mice survive. Mice were treated IV into the tail vein three times weekly, as indicated by the triangles on the x-axis. The cell line used was RD, and the ADCs used were ADCE-D01 (squares) and control ADCE-D51 (circles). Both ADCs are also compared to vehicle treatment with PBS (triangles). DETAILED DESCRIPTION OF THE INVENTION

[0015] The ADCs of the present disclosure are internalized upon binding to the cell surface uPARAP receptor, thus allowing the intracellular action of the active agent of the antibody drug conjugate.

[0016] Humanized anti-uPARAP antibody Methods for producing antibodies are well known in the art. For example, antibodies can be produced via any one of several methods, including inducing in vivo production of antibody molecules, screening immunoglobulin libraries, or utilizing the production of monoclonal antibody molecules by cell lines in culture. These techniques include, but are not limited to, hybridoma technology, human B-cell hybridoma technology, and Epstein-Barr virus (EBV)-hybridoma technology.

[0017] Humanized antibodies are generally preferred in pharmaceuticals intended for humans, and methods for humanizing antibodies are well known in the art. Although humanization techniques are known, it can be difficult to achieve a humanized antibody that retains the binding characteristics of the original antibody, and even more difficult to achieve a humanized antibody with improved properties, such as improved ligand affinity and efficacy, compared to the original antibody.

[0018] The inventors herein provide ADCs comprising improved anti-uPARAP antibodies that are humanized versions of the 9b7 murine antibody and that exhibit improved ligand affinity and potency compared to the 9b7 murine antibody, as well as improved internalization and in vivo efficacy compared to other humanized versions of the 9b7 antibody.

[0019] ADCs comprising the anti-uPARAP antibodies described herein may be of any immunoglobulin type, including IgG, IgM, IgD, IgE, IgA, and subclasses thereof. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. In one embodiment, the antibody is an IgG monoclonal antibody. In one embodiment, the antibody is an IgG1κ.

[0020] The anti-uPARAP antibody of the present disclosure is a humanized 9b7 antibody that binds to the uPARAP receptor, and more specifically, the humanized 9b7 antibody disclosed herein binds to at least the fibronectin type II (FN-II) domain of the uPARAP receptor.

[0021] The humanized 9b7 antibody, also referred to herein as 980.2 LC4HC3, comprises a light chain variable region of amino acids comprising SEQ ID NO: 3, the variable region of LC4, and a heavy chain variable region of amino acids comprising SEQ ID NO: 6, the variable region of HC3.

[0022] The humanized 9b7 antibody, also referred to herein as 980.2 LC4HC3, can comprise a light chain of amino acids comprising or consisting of SEQ ID NO:1, which is LC4, and a heavy chain of amino acids comprising or consisting of SEQ ID NO:4, which is HC3.

[0023] In one embodiment of the present disclosure, the anti-uPARAP antibody defined herein is a. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:3, and b. Comprises an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:6.

[0024] In one embodiment of the present disclosure, an antibody that binds to uPARAP as defined herein is a. an immunoglobulin light chain (LC4) comprising the amino acid sequence of SEQ ID NO: 1, and b. Contains an immunoglobulin heavy chain (HC3) comprising the amino acid sequence of SEQ ID NO:4.

[0025] Antibody-drug conjugates (ADCs) containing humanized anti-uPARAP antibodies Our data surprisingly show that ADCs comprising the humanized LC4HC3 antibody result in a significant reduction in total cell viability compared to LC0HC0-based ADCs (which have the variable domains of the 9b7 murine antibody fused to a human IgG constant region). LC4HC3-based ADCs also show improved internalization and in vivo efficacy compared to LC3HC3-based ADCs (another humanized 9b7 antibody).

[0026] The antibody-drug conjugates described herein comprise a specific humanized version of the murine 9b7 antibody, which targets the uPARAP receptor, more specifically LC4HC3, and an exatecan derivative. In some embodiments, the ADCs described herein also comprise a linker connecting the exatecan derivative to LC4HC3. The exatecan derivatives disclosed herein, their preparation, and methods of conjugation to antibodies, are described in WO2022 / 068878, the entire teachings of which are incorporated by reference.

[0027] One embodiment of the present disclosure is an antibody drug conjugate (ADC) comprising: i. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:3, and ii. an antibody that binds to uPARAP, comprising an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; Antibody-drug conjugates: a. Formula (IA), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )-, -P(R 2 )-, and -S-; L 2 is -(C(R 3a )(R 3b )) m -R, L 2 and 0 or 1 or more methylene units are independently -Cy-, -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, L 1 is -(C(R 5a )(R 5b )) n - and In the formula, L 1and 0 or 1 or more methylene units are independently -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, -Cy- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cy- is unsubstituted or independently represents one or more substituents R 7 is replaced by In the formula, each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 , or R 4 and R 6are each independently optionally joined together with the atoms therebetween to form ring B, wherein ring B is selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and ring B is unsubstituted or independently contains one or more substituents R 8 is replaced by In the formula, each R 2 , each R 7 , and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m and n are each independently selected from the group consisting of integers ≧1; R 1 binds the structure of formula (IA) to the antibody either directly or, optionally, via a linker); b. Formula (II-A), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, X 1is selected from the group consisting of N, P, and saturated or unsaturated C; X 1 If C is saturated, then X 1 But R n is replaced by Ring A attaches the structure according to formula II-A to the antibody, either directly or optionally through a linker; X 1 is a saturated C, then ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R 1a is replaced by or X 1 is an unsaturated C, then ring A is selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclyl, and 3-10 membered partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R 1b is replaced by or X 1 is N or P, then ring A is selected from the group consisting of 5-8 membered heteroaryl and 3-10 membered saturated or partially unsaturated heterocyclyl, wherein ring A contains zero or more substituents R 1c is replaced by When ring A is selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, ring A is preferably selected from the group consisting of pL 2 wherein L 2 is R n Instead, Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl, ring A is pL 2 or ring A is substituted with q ring-forming heteroatom X 2 Contains X 2 is used to attach formula (II-A) to an antibody, either directly or optionally via a linker, X 2 is selected from the group consisting of N and P; L 2 -R2 -L 3 - and R 2 is used to attach formula (II-A) to an antibody, either directly or optionally via a linker, L 3 Ha-(C(R 3a )(R 3b )) m - in which L 3 If contains a methylene unit, L 3 and 0 or 1 or more methylene units of -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, R 2 is -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-, L 1 is -(C(R 5a )(R 5b )) n - in which L 1 If contains a methylene unit, L 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6)-, -N=N-, -C=N-, -N=C- or -C(=N2)-, In the formula, each R 1a , each R 1b , each R 1c , each R 2a , each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , each R 6 and each R n are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m and n are each independently selected from the group consisting of integers >= 0, and p and q are each independently selected from the group consisting of integers >= 1; c. Formula (III-A), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, R 1 is -O-, -(R 2)N-, -P(=O)(R 2 )-, and -S-; R 1 is attached to the antibody directly or optionally via a linker a structure according to formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 - and -L 3 -L 2 - selected from the group consisting of L 1 is -(C(R 3a )(R 3b )) m - in which L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, L 0 is -C(R 2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 2 is -C(R 5a )(R 5b )-, wherein L 2 0 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, L3 is -(C(R 7a )(R 7b )) n - and L 3 one or more methylene units independently represent -N(R 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- can also be substituted, In the formula, each R 1a , each R 1b , each R 2 , each R 2a , each R 2b , each R 3a , each R 3b , each R 4a , each R 4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R bare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -HN- and X is -L 1 -L 0 - and L 0 If is -CH2-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -O- and X is -L 3 -C(O)- and L 3 One methylene unit is -NR 8 If replaced by R 8 is not -CH2-CH2-NH2, R 1 is -NH- and X is -L 3 -C(O)-, L 3 One or more methylene units of -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-), and The antibody-drug conjugate optionally includes a linker that connects the antibody to the active agent.

[0028] IA implementation In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to Formula (IA), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-, L 2 is -(C(R 3a )(R 3b )) m -R, wherein m is selected from the group consisting of integers ≧1; L 2 and 0 or 1 or more methylene units are independently -Cy-, -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; L 1 is -(C(R 5a )(R 5b )) n-, and n may be selected from the group consisting of integers > 1; L 1 and 0 or 1 or more methylene units are independently -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; -Cy- can be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cy- is unsubstituted or independently represents one or more substituents R 7 may be replaced by In the formula, each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R 2 , each R 7 , and each R 8are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0029] In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to Formula (IA), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-, L 2 is -(C(R 3a )(R 3b )) m -R, wherein m is selected from the group consisting of integers ≧1; L 2 and 0 or 1 or more methylene units are independently -Cy-, -N(R 4 )C(O)-, -C(O)N(R 4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers > 1; L 1 and 0 or 1 or more methylene units are independently -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; -Cy- can be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cy- is unsubstituted or independently represents one or more substituents R 7 may be replaced by In the formula, each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R 2 , each R 7 , and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0030] In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to Formula (IA), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] For example, in the formula, R 3a and R 5a , R4 and R 5a , R 3a and R 6 , or R 4 and R 6 may each independently optionally be joined together with the atoms therebetween to form ring B, which may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and ring B may be unsubstituted or may contain one or more substituents R 8 and each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 , or R 4 and R 6 may each independently optionally join together with the atoms therebetween to form ring B, wherein ring B may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and ring B may be unsubstituted or may contain one or more substituents R 8 may be replaced by For example, R 3a and R 5amay be taken together with the atoms therebetween to form ring B, ring B may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially saturated heterocyclylene, ring B may be unsubstituted or may contain one or more substituents R 8 and each R 3b , each R 4 , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 or R 4 and R 6 may each independently optionally be joined together with the atoms therebetween to form ring B, which may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially saturated heterocyclylene, and ring B may be unsubstituted or may contain one or more substituents R 8 may be replaced by For example, R 4 and R 5a may be taken together with the atoms therebetween to form ring B, ring B may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially saturated heterocyclylene, ring B may be unsubstituted or may contain one or more substituents R 8 and each R 3a , each R 3b , each R 5b and each R 6are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 or R 4 and R 6 may each independently optionally form ring B with the atoms therebetween, and ring B may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially saturated heterocyclylene, and ring B may be unsubstituted or may contain one or more substituents R 8 may be replaced by For example, in the formula, R 3a and R 6 may be taken together with the atoms therebetween to form ring B, wherein ring B may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and ring B may be unsubstituted or may independently contain one or more substituents R 8 and each R 3b , each R 4 , each R 5a and each R 5b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 , or R 4 and R 6 may each independently optionally join together with the atoms therebetween to form ring B, wherein ring B may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and ring B may be unsubstituted or may independently contain one or more substituents R 8 may be replaced by For example, R 4 and R 6 may be taken together with the atoms therebetween to form ring B, ring B may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially saturated heterocyclylene, ring B may be unsubstituted or may contain one or more substituents R 8 and each R 3a , each R 3b , each R 5a , and each R 5b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 or R 4 and R 6may each independently optionally be joined together with the atoms therebetween to form ring B, which may be selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially saturated heterocyclylene, and ring B may be unsubstituted or may contain one or more substituents R 8 may be substituted with

[0031] In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to Formula (IA), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, L 2 is -(C(R 3a )(R 3b )) m -R, where m may be selected from the group consisting of integers 1 to 3; L 2 0 methylene units may be replaced, L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers 2 to 4; L 1 0, 1, or 2 methylene units of -N(R 6 )C(O)-, -C(O)-, -OC(O)-, -NR 6 may be replaced by -, -O-, or -C(=S)-; In the formula, each R 3a , each R 3b , each R 5a , each R 5b , and each R 6 each independently represents hydrogen, halogen, or C, which may be optionally substituted with R 1-6 may be an aliphatic group, or R 3a and R 5amay be taken together with the atoms therebetween to form ring B, wherein ring B may be selected from 5-membered saturated heterocyclylene, ring B is unsubstituted, R can be hydrogen or halogen.

[0032] In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to Formula (IA), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, L 2 is -(C(R 3a )(R 3b )) m -R, where m may be selected from the group consisting of integers 1 and 2; L 2 0 methylene units may be replaced, L 1 is -(C(R 5a )(R 5b )) n -, where n may be selected from the group consisting of the integers 2 and 3; In the formula, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; In the formula, each R 3a , each R 3b , each R 5a , and each R 5b may each independently be hydrogen, or R 3a and R 5a may be taken together with the atoms therebetween to form ring B, wherein ring B may be selected from 5-membered saturated heterocyclylenes having one nitrogen heteroatom, ring B is unsubstituted, R can be hydrogen.

[0033] In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to Formula (IA), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, L 2 is -(C(R 3a )(R 3b )) m -R, where m may be selected from the group consisting of integers 1 and 2; L 2 0 methylene units may be replaced, L 1 is -(C(R 5a )(R 5b ))2-, L 1 one methylene unit may be replaced by -C(O)-, In the formula, each R 3a , each R 3b , each R 5a , and each R 5b may each independently be hydrogen, or R 3a and R 5a may be taken together with the atoms therebetween to form ring B, wherein ring B may be selected from 5-membered saturated heterocyclylenes having one nitrogen heteroatom, ring B is unsubstituted, R can be hydrogen.

[0034] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to any one of formulas (IA-1) to (IA-17), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1may be selected from the group consisting of -O-, -HN-, -P(=O)H-, and -S-, wherein R 1 The structure represented by any one of formulas (IA-1) to (IA-17) is bound to the antibody described herein directly or via a linker.

[0035] Embodiment II-A In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be selected from the group consisting of n, P, and saturated or unsaturated C; X 1 If can be saturated C, X 1 is R n and Ring A optionally connects the structure shown as formula (II-A) to another molecular moiety, X 1 may be a saturated C, then ring A may be selected from the group consisting of 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R 1a may be replaced by or X 1 where R may be an unsaturated C, ring A may be selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclyl, and 3-10 membered partially unsaturated carbocyclyl, and ring A may contain zero or more substituents R 1b may be replaced by or X 1 where R can be N or P, ring A can be selected from the group consisting of 5-8 membered heteroaryl and 3-10 membered saturated or partially unsaturated heterocyclyl, wherein ring A contains zero or more substituents R 1c may be replaced by When ring A can be selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, ring A can be selected from the group consisting of pL 2 wherein L 2 is R n This is not possible, Alternatively, when ring A can be a 3- to 10-membered saturated or partially unsaturated heterocyclyl, ring A can be pL 2 or ring A may be substituted with q ring-forming heteroatoms X 2 may include X 2 is used to attach the structure shown in formula (II-A) to other molecular moieties, X 2 may be selected from the group consisting of N and P; L 2 Ha-R 2 -L 3 - may be R 2 is used to attach the structure shown as formula (II-A) to other molecular moieties, L 3 Ha-(C(R 3a )(R 3b )) m -, wherein L 3 If L may contain methylene units, 3 and 0 or 1 or more methylene units of -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(RR 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; R 2 is -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-, L1 is -(C(R 5a )(R 5b )) n -, wherein L 1 If L may contain methylene units, 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; In the formula, each R 1a , each R 1b , each R 1c , each R 2a , each R 3a , each R 3b , each R 4 , each R 5a , each R 5b and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R bare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 may be an aliphatic group, m and n may each independently be selected from the group consisting of integers > 0, and p and q may each independently be selected from the group consisting of integers > 1.

[0036] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ax), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be saturated C, and X 1 is R n may be replaced by Ring A may be selected from the group consisting of 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R 1a may be replaced by Ring A is pL 2 wherein p may be selected from the group consisting of integers ≧1; 2 is R n This is not possible, L 2 Ha-R 2 -L 3 -can be, L 3 is -(C(R 3a )(R 3b )) m and m may be selected from the group consisting of integers >= 0; L 3 If L may contain methylene units, 3 0 or 1 methylene unit of N(R4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; R 2 is -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-, L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers > 0; In the formula, L 1 If L may contain methylene units, 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; In the formula, each R 1a , each R 2a , each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , each R 6 , and each R nare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0037] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ay), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be saturated C, and X 1 is R n may be replaced by Ring A can be a 3- to 10-membered saturated or partially unsaturated heterocyclyl, and Ring A can be unsubstituted or contain one or more substituents R 1a may be replaced by Ring A is a ring-forming heteroatom X 2 may include X 2 is used to bind to the antibody, optionally via a linker, q may be selected from the group consisting of integers ≧1, X 2may be selected from the group consisting of N and P; L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers > 0; L 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; In the formula, each R 1a , each R 5a , each R 5b , each R 6 and each R n are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C1-6 It may be an aliphatic group.

[0038] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ax), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be unsaturated C, Ring A may be selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 10-membered partially unsaturated heterocyclyl, and 3- to 10-membered partially unsaturated carbocyclyl, and Ring A may be unsubstituted or may contain one or more substituents R 1b may be replaced by Ring A is pL 2 wherein p is selected from the group consisting of integers >= 1; L 2 Ha-R 2 -L 3 - may be R 2 is used to bind to the antibody, optionally via a linker, L 3 is -(C(R 3a )(R 3b )) m and m may be selected from the group consisting of integers >= 0; L 3 and 0 or 1 or more methylene units of -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; R 2 is -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-, L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers > 0; L 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; In the formula, each R 1b , each R 2a , each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R bare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0039] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ay), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be unsaturated C, Ring A can be a 3- to 10-membered saturated or partially unsaturated heterocyclyl, and Ring A can be unsubstituted or contain one or more substituents R 1b may be replaced by Ring A is a ring-forming heteroatom X 2 and X 2 is used to bind to the antibody directly or via a linker, q can be selected from the group consisting of integers ≧1, and X 2 may be selected from the group consisting of N and P; L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers > 0; L 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6)-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; In the formula, each R 1b , each R 5a , each R 5b and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0040] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ax), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 can be N or P, Ring A may be selected from the group consisting of 5-8 membered heteroaryl and 3-10 membered saturated or partially unsaturated heterocyclyl, and Ring A may be unsubstituted or may contain one or more substituents R 1cmay be replaced by Ring A is pL 2 wherein p is selected from the group consisting of integers >= 1; L 2 Ha-R 2 -L 3 - may be R 2 is used to bind to the antibody, either directly or via a linker, L 3 is -(C(R 3a )(R 3b )) m and m may be selected from the group consisting of integers >= 0; L 3 and 0 or 1 or more methylene units of -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; R 2 is -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-, L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers > 0; L 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6)-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; In the formula, each R 1c , each R 2a , each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0041] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ay), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1can be N or P, Ring A can be a 3- to 10-membered saturated or partially unsaturated heterocyclyl, and Ring A can be unsubstituted or contain one or more substituents R 1c may be replaced by Ring A is a ring-forming heteroatom X 2 and X 2 is used to bind to the antibody directly or via a linker, q can be selected from the group consisting of integers ≧1, and X 2 may be selected from the group consisting of N and P; L 1 is -(C(R 5a )(R 5b )) n -, and n may be selected from the group consisting of integers > 0; L 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-; In the formula, each R 1c , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R or C optionally substituted with R1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0042] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ax), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be saturated C, and X 1 is R n may be replaced by Ring A may be selected from the group consisting of 3- to 6-membered saturated heterocyclyl and 3- to 6-membered saturated or partially unsaturated carbocyclyl; p can be 1, and L 2 is R n This is not possible, L 2 Ha-R 2 -L 3 -can be, L 3 is -(C(R 3a )(R 3b )) m -, and m may be selected from the group consisting of integers from 0 to 2, wherein L 3 If L may contain methylene units, 3 wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—, R 2 may be selected from -O-; L 1 is -(C(R 5a)(R 5b )) n -, where n may be selected from the group consisting of 0 and 1; In the formula, L 1 If L may contain methylene units, 1 wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—; In the formula, each R 3a , each R 3b , each R 5a , each R 5b , and each R n are each independently hydrogen, halogen, or C which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can independently be hydrogen or halogen.

[0043] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ax), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 can be saturated C, X 1 is R n is bonded to R n can be H, Ring A may be selected from the group consisting of 5-membered saturated heterocyclyl having one nitrogen heteroatom and 4-6-membered saturated carbocyclyl; P can be 1, L 2 Ha-R 2 -L 3 - may be L 3 is directly bonded to ring A, L 3 is -(C(R 3a )(R 3b )) m -, m may be 0 or 2; R 2 can be -O-, L 1can be —C(O)—, In the formula, each R 3a and each R 3b may each independently be hydrogen.

[0044] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ay), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be saturated C, and X 1 is R n may be replaced by Ring A can be a 3- to 6-membered saturated heterocyclyl; Ring A may contain one ring-forming heteroatom N, which is used to attach to an antibody, either directly or via a linker; L 1 is -(C(R 5a )(R 5b )) n -, where n may be selected from the group consisting of 0 and 1; L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—; In the formula, each R 5a , each R 5b , and each R n are each independently hydrogen, halogen, or C which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can independently be hydrogen or halogen.

[0045] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ay), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be saturated C, and X 1 may be replaced by H, Ring A can be a 5-membered saturated heterocyclyl having one heteroatom N; Ring A may contain one ring-forming heteroatom N, which is used to attach to an antibody, either directly or via a linker; L 1 can be —C(O)—.

[0046] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ax), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be unsaturated C, Ring A can be selected from the group consisting of 6-membered aryl, 5-8-membered heteroaryl, 3-10-membered partially unsaturated heterocyclyl, and 3-10-membered partially unsaturated carbocyclyl, and Ring A can be unsubstituted or can contain one substituent R 1b may be replaced by P can be 1, L 2 Ha-R 2 -L 3 - may be R 2 is used to bind to the antibody, either directly or via a linker, L 3 is -C(R 3a )(R 3b )-, R 2 is -O-, -(R 2a ) may be selected from the group consisting of -N- and -S-; L 1 is -C(R 5a )(R 5b )-, L 1wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—; In the formula, each R 1b , each R 2a , each R 3a , each R 3b , and each R 5a and each R 5b each independently represents hydrogen, halogen, or C, which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can independently be hydrogen or halogen.

[0047] For example, the compound may include the structure shown as formula (II-Ax): In the formula, X 1 may be unsaturated C, Ring A may be selected from the group consisting of 6-membered aryl and 5-8-membered heteroaryl; P can be 1, L 2 Ha-R 2 -L 3 may be used to bind to antibodies, either directly or via a linker, L 3 is -C(R 3a )(R 3b )-, R 2 is -O-, -(R 2a ) may be selected from the group consisting of -N- and -S-; L 1 is -C(R 5a )(R 5b )-, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—; In the formula, each R 2a , each R 3a , each R 3b , each R 5a , and each R 5b each independently represents hydrogen, halogen, or C, which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can independently be hydrogen or halogen.

[0048] For example, the compound may include the structure shown as formula (II-Ax): In the formula, X 1 may be unsaturated C, Ring A can be a 6-membered aryl; P can be 1, L 2 Ha-R 2 -L 3 - may be R 2 is used to bind to the antibody, either directly or via a linker, L 3 is -C(R 3a )(R 3b )-, R 2 can be -O-, L 1 can be —C(O)—, In the formula, each R 3a , each R 3b , each R 5a , and each R 5b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0049] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ay), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 may be unsaturated C, Ring A can be a 5-membered partially unsaturated heterocyclyl; Ring A may contain one ring-forming heteroatom N, which is used to attach to an antibody, either directly or via a linker; L 1 is -C(R 5a )(R 5b )-, L 1wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—; In the formula, each R 5a and each R 5b are each independently hydrogen, halogen, or C which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can independently be hydrogen or halogen.

[0050] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ax), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 can be N, Ring A can be a 6-membered saturated heterocyclyl; P can be 1, L 2 Ha-R 2 -L 3 - may be R 2 is used to bind to the antibody, either directly or via a linker, L 3 is -(C(R 3a )(R 3b )) m -, and m may be 1 or 2; L 3 wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—; R 2 is -O-, -(R 2a ) may be selected from the group consisting of -N- and -S-; L 1 is -C(R 5a )(R 5b )-, L 1 wherein one methylene unit may be replaced by —C(O)— or —C(═S)—; In the formula, each R 2a , each R3a , each R 3b , each R 5a , and each R 5b each independently represents hydrogen, halogen, or C, which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can independently be hydrogen or halogen.

[0051] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ay), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 can be N, Ring A can be a 5-membered partially unsaturated heterocyclyl; Ring A may contain one ring-forming heteroatom N, which is used to attach to an antibody, either directly or via a linker; L 1 is -C(R 5a )(R 5b )-, L 1 one or more methylene units may be replaced by -C(O)- or -C(=S)-; In the formula, each R 5a and each R 5b are each independently hydrogen, halogen, or C which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can independently be hydrogen or halogen.

[0052] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to any one of Formulas (II-A-1) through (II-A-12), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 2 may be selected from the group consisting of -O-, -HN-, -P(=O)H-, and -S-; X 2 may be selected from the group consisting of N and P, and R 2 or X 2 binds any one of the structures represented by formulae (II-A-1) to (II-A-12) directly or via a linker to an antibody described herein.

[0053] Embodiment III-A In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-, X is -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 - and -L 3 -L 2 - may be selected from the group consisting of L 1 is -(C(R 3a )(R 3b )) m -, wherein L 1 If L may contain methylene units, 1 wherein zero or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, L 0 is -C(R2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 2 is -C(R 5a )(R 5b )-, L 2 0 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; L 3 is -(C(R 7a )(R 7b )) n - may be L 3 one or more methylene units independently represent -N(R 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, L 3 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)-, In the formula, each R 1a , each R 1b , each R 2 , each R 2a , each R 2b , each R3a , each R 3b , each R 4a , each R 4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 may be an aliphatic group, m may be selected from the group consisting of integers > 0, and n may be selected from the group consisting of integers > 1; R 1 can be -O- or -HN-, and X is -L 1 -CH2-C(O)-, and L 1 If L may contain methylene units, 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, or L 1 Each -C(R 3a )(R 3b )-, R 3a and R 3b cannot both be hydrogen, R 1 can be -HN- and X is -L 1 -L 0 - and L 0 When L can be -CH2-, 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b cannot both be hydrogen, R 1 can be -O- and X is -L 3 -C(O)-, and L 3 One methylene unit is -NR 8 If it can be replaced by R 8 cannot be -CH2-CH2-NH2, R 1 can be -NH- and X is -L 3 -C(O)-, L 3 One or more methylene units of -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-.

[0054] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O-, -(R 2 ) may be selected from the group consisting of -N-, and -S-; X is -L 1 -C(R 1a )(R1b )-C(S)-, L 1 is -(C(R 3a )(R 3b )) m and m may be selected from the group consisting of integers >= 0; L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, R 2 is halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O))R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R 1a , each R 1b , each R 3a , each R 3b and each R 4b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R bare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0055] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -S- or -(R 2 )N-, X is -L 1 -C(R 1a )(R 1b )—C(O)—, L 1 is -(C(R 3a )(R 3b )) m and m may be selected from the group consisting of integers >= 0; L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, R 2 is halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O))R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R 1a , each R 1b , each R 3a , each R 3b and each R 4b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0056] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O- or -HN-; X is -L 1 may be —CH—C(O)—; L 1 is -(C(R 3a )(R 3b )) m and m may be selected from the group consisting of integers >= 1; L1 one or more methylene units independently represent -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, In the formula, each R 3a , each R 3b , and each R 4b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0057] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O- or -HN-; X is -L 1 may be —CH—C(O)—; L 1 is -(C(R 3a )(R 3b)) m and m may be selected from the group consisting of integers >= 0; R 3a and R 3b is each -C(R 3a )(R 3b )-, both cannot be hydrogen, or L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, In the formula, each R 3a , each R 3b , and each R 4b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0058] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O-, -S- or -(R 2 )N-, X is -L 1 -L 0 -can be, L 0 is -C(R 2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 1 is -(C(R 3a )(R 3b )) m and m may be selected from the group consisting of integers >= 0; L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, R 2 is halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O))R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R 2a , each R 2b , each R 3a , each R 3b and each R 4a , and each R 4b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0059] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -HN-, X is -L 1 -L 0 -can be, L 0 is -C(R 2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 1 is -(C(R 3a )(R 3b )) m -, m may be selected from the group consisting of integers ≧0, and each R 3a and each R 3b cannot both be hydrogen, L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR4b )- or -C(=N2)-, In the formula, each R 2a , each R 2b , each R 3a , each R 3b and each R 4a , and each R 4b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0060] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X is -L 3 -L 2 -can be, L 2 is -C(R 5a )(R 5b )-, L 20 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; R 1 is -S- or -(R 2 )N-, or R 1 can be -O-, L 2 cannot be -C(O)-, or R 1 can be -NH-, and L 2 cannot be -C(O)-, L 3 is -(C(R 7a )(R 7b )) n -, and n may be selected from the group consisting of integers > 1; L 3 one or more methylene units of 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N- or -N=C-, L 3 wherein zero or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)-, R 2 is halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b), -C(O)R, -CO2R, -C(O)C(O))R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R, or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0061] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 is -(C(R 7a )(R 7b )) n -, and n may be selected from the group consisting of integers > 0; L 3 one or more methylene units of 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N- or -N=C-, L 3 wherein zero or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)-, In the formula, each R 7a , each R 7b , and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R bare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 may be an aliphatic group, L 3 One methylene unit is -NR 8 If it can be replaced by R 8 may be substituted with -NH 1-6 It cannot be an aliphatic group.

[0062] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -HN-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 is -(C(R 7a )(R 7b )) n -, and n may be selected from the group consisting of integers > 1; L 3 one or more methylene units of 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N- or -N=C-, L 3 and 0 or 1 or more methylene units are independently -C(O)N(R8 )-, -NR 8 - or -O-, L 3 wherein zero or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)-, In the formula, each R 7a , each R 7b , and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R or C optionally substituted with R 1-6 may be an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0063] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O-, -S- or -(R 2 )N-, X is -L 1-C(R 1a )(R 1b )-C(S)-, L 1 is -(C(R 3a )(R 3b )) m -, and m may be 0, 1 or 2; In the formula, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; In the formula, each R 1a , each R 1b , each R 2 , each R 3a , and each R 3b are each independently hydrogen, halogen, or C which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can be hydrogen.

[0064] For example, the compound may include the structure shown in formula (III-A): In the formula, R 1 can be -O-, X is -L 1 -C(R 1a )(R 1b )-C(S)-, L 1 is -(CH2) m -, m may be 1 or 2; In the formula, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; In the formula, each R 1a and each R 1b are each independently hydrogen, halogen, or C which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can be hydrogen.

[0065] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -S- or -(R 2 )N-, X is -L 1 -C(R 1a )(R 1b )—C(O)—, L 1 is -(C(R 3a )(R 3b )) m -, and m may be 0, 1 or 2; In the formula, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; R 2 is C 1-6 may be an aliphatic group, In the formula, each R 1a , each R 1b , each R 3a , and each R 3b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0066] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -S- or -(R 2 )N-, X is -L 1 -C(R 1a )(R 1b )—C(O)—, L 1 is -(C(R 3a )(R 3b )) m -, and m may be 1 or 2; In the formula, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; R 2 is C 1-6 may be an aliphatic group, In the formula, each R 1a , each R 1b , each R 3a , and each R 3b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0067] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 However, -S- or -(R 2 )N-, X is -L 1 -C(R 1a )(R 1b )—C(O)—, L 1 But -(C(R 3a )(R 3b )) m -, and m can be 0, 1 or 2; L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; R 2 is C 1-6 may be an aliphatic group, In the formula, each R 1a , each R 1b , each R 3a , and each R 3b are each independently hydrogen or C 1-6 may be an aliphatic group, Or, R 1 can be -O-, X is -L 1 may be —CH—C(O)—, and L 1 But -(C(R 3a )(R 3b ))2- If it is possible, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; In the formula, each R 3a and each R 3b are each independently hydrogen or C 1-6 may be an aliphatic group, Each R 3a and each R 3b and L cannot both be hydrogen, or 1 wherein one methylene unit may be replaced by —C(O)—; In the formula, each R 3a and each R 3b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0068] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 1 may be —CH—C(O)—; L 1 is -(C(R 3a )(R 3b ))2-, In the formula, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; In the formula, each R 3a and each R 3b are each independently hydrogen or C 1-6 may be an aliphatic group, Each R 3a and each R 3b and L cannot both be hydrogen, or 1 wherein one methylene unit may be replaced by —C(O)—; In the formula, each R 3a and each R3b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0069] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 However, -S- or -(R 2 )N-, X is -L 1 -C(R 1a )(R 1b )—C(O)—, L 1 But -(C(R 3a )(R 3b )) m -, and m can be 0, 1 or 2; L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; R 2 is C 1-6 may be an aliphatic group, In the formula, each R 1a , each R 1b , each R 3a , and each R 3b are each independently hydrogen or C 1-6 may be an aliphatic group, Or, R 1 can be -O-, and X is -L 1 -CH2-C(O)-, L 1 is -C(R 3a )(R 3b )-, R 3a and R 3b Both are -C( R3a )( R3b )- cannot be hydrogen, In the formula, each R 3a and each R3b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0070] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 1 may be —CH—C(O)—; L 1 is -(C(R 3a )(R 3b ))2-, In the formula, L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)—; In the formula, each R 3a and each R 3b are each independently hydrogen or C 1-6 may be an aliphatic group, R 3a and R 3b Both of them are -C(R 3a )(R 3b ) or L 1 wherein one methylene unit may be replaced by —C(O)—; In the formula, each R 3a and each R 3b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0071] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 1 may be —CH—C(O)—; L 1 can be —(CH)—; L 1 One methylene unit of may be replaced by -C(O)-.

[0072] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 1 may be —CH—C(O)—; L 1 -C(R 3a )(R 3b )- m -, m may be selected from the group consisting of integers 1 to 5, and R 3a and R 3b is each -C(R 3a )(R 3b )-, both cannot be hydrogen, In the formula, each R 3a and each R 3b are each independently hydrogen, halogen, or C which may be optionally substituted with R 1-6 may be an aliphatic group, wherein each R can be hydrogen or halogen.

[0073] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 1 may be —CH—C(O)—; L 1 -C(R 3a )(R 3b )-, R 3a and R 3b cannot both be hydrogen, In the formula, each R 3a and each R 3b are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0074] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O- or -(R 2 )N-, X is -L 1 -L 0 -can be, L 0 can be -CH2-, or L 0 can be -C(=S)-, L 1 is -(CH2) m -, and m may be selected from the group consisting of integers from 0 to 2; L 1 wherein 0 or 1 methylene unit may be replaced by —C(O)— or —C(═S)—; R 2 is C 1-6 It may be an aliphatic group.

[0075] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -NH-, X is -L 1 -L 0 -can be, L 0 can be -CH2-, or L 0 can be -C(=S)-, L 1 is -(CH2) m -, and m may be selected from the group consisting of integers from 0 to 2; L 1 may be replaced by -C(O)- or -C(=S)-.

[0076] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -S- or -(R 2 )N-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 is -(CH2) n -, n may be 4 or 5; L 3 One methylene unit of -NR 8 may be replaced by -, -O-, -S-, or -SO-; R2 is C 1-6 It may be an aliphatic group.

[0077] For example, the compound may include the structure shown in formula (III-A): In the formula, R 1 is -S- or -(R 2 )N-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 is -(CH2) n -, n may be 4 or 5; L 3 one methylene unit may be replaced by -O-, R 2 is C 1-6 It may be an aliphatic group.

[0078] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 Ha-(C(R 7a )(R 7b )) n -, and n may be 4 or 5; L 3 One methylene unit is -NR 8 - or -O-, L 3 wherein zero or one methylene unit may be independently replaced by -C(O)- or -C(=S)-; In the formula, each R 7a , each R 7b and each R 8 are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0079] For example, the compound may include the structure shown in formula (III-A): In the formula, R 1 can be -O-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 is -(C(R 7a )(R 7b ))4-, In the formula, L 3 One methylene unit is -NR 8 - or -O-, In the formula, each R 7a , each R 7b and each R 8 are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0080] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 is -(C(R 7a )(R 7b ))4-, In the formula, L 3One methylene unit of -NR 8 - may be replaced by In the formula, each R 7a , each R 7b and each R 8 are each independently hydrogen or C 1-6 It may be an aliphatic group.

[0081] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -NH-, X is -L 3 -L 2 -can be, In the formula, L 2 can be —C(O)—, L 3 is -(CH2) n -, n may be 4 or 5; L 3 One methylene unit may be replaced by -S-.

[0082] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to any one of Formulas (II-A-1) through (II-A-17), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 2 is C, which can be arbitrarily replaced by R 1-6may be an aliphatic group, where R is hydrogen, protium, deuterium, tritium, halogen, —NO2, —CN, —OH, —SH, —NH2, —C(O)H, —CO2H, —C(O)C(O)H, —C(O)CH2C(O)H, —S(O)H, —S(O)2H, —C(O)NH2, —SON2NH2, —OC(O)H, —N(H)SO2H, or C 1-6 may be an aliphatic group, or 2 is halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1~6 may be an aliphatic group, and the wavy line indicates the attachment, directly or via a linker, of the structure shown in any one of formulas (III-A-1) to (III-A-17) to an antibody defined herein.

[0083] For example, R 2 is hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 methyl, which may be optionally substituted with one or more aliphatic groups. For example, each R 2 is optionally hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It can be ethyl, which can be substituted with an aliphatic group. For example, R 2is hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 It can be propyl which can be optionally substituted with an aliphatic group.

[0084] In one embodiment, the antibody drug conjugate comprises an active agent having a structure selected from any one of the structures in Table 1, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [Table 1] JPEG2026502232000055.jpg217162JPEG2026502232000056.jpg212162JPEG2026502232000057.j pg212162JPEG2026502232000058.jpg206162JPEG2026502232000059.jpg217162JPEG20265022320 00060.jpg205162JPEG2026502232000061.jpg220162JPEG2026502232000062.jpg209162JPEG202 6502232000063.jpg201162JPEG2026502232000064.jpg187162JPEG2026502232000065.jpg188162 JPEG2026502232000066.jpg196162JPEG2026502232000067.jpg190162JPEG2026502232000068.j pg193162JPEG2026502232000069.jpg198162JPEG2026502232000070.jpg213162JPEG20265022320 00071.jpg212162JPEG2026502232000072.jpg211162JPEG2026502232000073.jpg210162JPEG202 6502232000074.jpg186162JPEG2026502232000075.jpg226162JPEG2026502232000076.jpg148162

[0085] There may be one or more units of drug per antibody molecule. The ratio between the number of drug molecules per antibody is expressed as the drug-to-antibody ratio (DAR). In one embodiment, the DAR is between 1 and 10, such as between 2 and 8, for example, between 2 and 6, such as 2 or 4.

[0086] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 is -O- or -(R 2 ) may be N- or -S-, and X is -L 1 may be -CH2-C(O)- or -AC(O)-; In the formula, X is -L 1 -CH2-C(O)-, L 1 Ha-(C(R 3a )(R 3b )) m wherein m may be selected from the group consisting of 0, 1, and 2; 1 wherein zero or one methylene unit may be independently replaced by -C(O)- or -C(S)-; wherein when X is -AC(O)-, A can be a ring moiety selected from the group consisting of phenyl, pyridyl, cyclohexyl, cyclopentyl, and cyclobutyl, and A can be unsubstituted or contain one or more substituents R 1c may be replaced by In the formula, R 2 , R 3a , R 3b and R 1c are each independently selected from hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b )), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R or methyl optionally substituted with R 1-6 may be an aliphatic group, wherein each R, each R a and each R bare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0087] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O- or -HN-, and X is -L 1 may be -CH2-C(O)- or -AC(O)-; In the formula, X is -L 1 -CH2-C(O)-, L 1 is -(C(R 3a )(R 3b )) m wherein m may be selected from the group consisting of 0, 1, and 2; 1 wherein zero or one methylene unit may be independently replaced by -C(O)-; wherein when X is -AC(O)-, A may be a ring moiety selected from the group consisting of phenyl, pyridyl, cyclohexyl, cyclopentyl, and cyclobutyl, and A may be unsubstituted or may contain one or more substituents R 1c may be replaced by In the formula, each R 3a , R 3b and R 1c are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R or C 1-6It may be an aliphatic group, such as methyl, which may be optionally substituted with R, where each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 It may be an aliphatic group.

[0088] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O- or -HN-, and X is -L 1 may be -CH2-C(O)- or -AC(O)-; In the formula, X is -L 1 -CH2-C(O)-, L 1 is -(C(R 3a )(R 3b )) m wherein m may be selected from the group consisting of 0, 1, and 2; 1 wherein zero or one methylene unit may be independently replaced by -C(O)-; wherein when X is -AC(O)-, A may be a ring moiety selected from the group consisting of phenyl, pyridyl, cyclohexyl, cyclopentyl, and cyclobutyl, and A may be unsubstituted or may contain one or more substituents R 1c may be replaced by R 3a , R 3b and R 1c Each of the groups is independently hydrogen or C, such as methyl, which may be optionally substituted with R. 1-6and R may be an aliphatic group, where R is hydrogen, halogen, —NO, —CN, —OH, —NH, or C. 1-6 It may be an aliphatic group.

[0089] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 can be -O- or -HN-, and X is -L 1 may be —CH—C(O)—; In the formula, L 1 is -(C(R 3a )(R 3b )) m wherein m may be selected from the group consisting of 0, 1 and 2, and wherein L 1 wherein zero or one methylene unit may be independently replaced by -C(O)-; In the formula, each R 3a and R 3b are each independently hydrogen or C such as methyl which may be optionally substituted with R 1-6 and R may be an aliphatic group, where R is hydrogen, halogen, —NO, —CN, —OH, —NH, or C. 1-6 It may be an aliphatic group.

[0090] In one embodiment of the above structure of formula (III-A), R 1 X L 1 is chemically bonded to the aforementioned X via the moiety.

[0091] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (IV-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In formula (IV-A), R 1 is -O- or -(R 2 ) may be N- or -S-, and X is -L 1 may be -CH2-C(O)- or -AC(O)-; In the formula, X is -L 1 -CH2-C(O)-, L 1 Ha-(C(R 3a )(R 3b )) m wherein m may be selected from the group consisting of 0, 1, and 2; 1 wherein zero or one methylene unit may be independently replaced by -C(O)- or -C(S)-; wherein when X is -AC(O)-, A can be a ring moiety selected from the group consisting of phenyl, pyridyl, cyclohexyl, cyclopentyl, and cyclobutyl, and A can be unsubstituted or contain one or more substituents R 1c may be replaced by In the formula, R 2 , R 3a , R 3b and R 1c are each independently selected from hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b )), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)S0R or methyl optionally substituted with R 1-6 may be an aliphatic group, wherein each R, each R a and each R bare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 may be an aliphatic group, or In formula (IV-A), R 1 can be -O- or -HN-, and X is -L 1 may be -CH2-C(O)- or -AC(O)-; In the formula, X is -L 1 -CH2-C(O)-, L 1 is -(C(R 3a )(R 3b )) m wherein m may be selected from the group consisting of 0, 1, and 2; 1 wherein zero or one methylene unit may be independently replaced by -C(O)-; wherein when X is -AC(O)-, A may be a ring moiety selected from the group consisting of phenyl, pyridyl, cyclohexyl, cyclopentyl, and cyclobutyl, and A may be unsubstituted or may contain one or more substituents R 1c may be replaced by In the formula, R 3a , R 3b and R 1c Each of the groups is independently hydrogen or C, such as methyl, which may be optionally substituted with R. 1-6 and R may be an aliphatic group, where R is hydrogen, halogen, —NO, —CN, —OH, —NH, or C. 1-6 It may be an aliphatic group.

[0092] In formula (IV-A), R 1 can be -O- or -HN-, and X is -L 1 may be —CH—C(O)—; In the formula, L 1 is -(C(R 3a )(R 3b ))m wherein m may be selected from the group consisting of 0, 1 and 2, and wherein L 1 wherein zero or one methylene unit may be independently replaced by -C(O)-; In the formula, each R 3a and R 3b are each independently hydrogen or C such as methyl which may be optionally substituted with R 1-6 and R may be an aliphatic group, where R is hydrogen, halogen, —NO, —CN, —OH, —NH, or C. 1-6 It may be an aliphatic group.

[0093] In one embodiment of the above structure of formula (III-A), R 1 X L 1 is chemically bonded to the aforementioned X via the moiety.

[0094] In one embodiment of Formula (IV-A), R 1 can be -O- and X can be -L 1 It can be —CH—C(O)—. 1 Ha-(C(R 3a )(R 3b )) m wherein m may be selected from the group consisting of 0, 1 and 2, and wherein L 1 may be independently replaced by —C(O)—. Preferably, m is L 1 -(C(R 3a )(R 3b )) where each R 3a and R 3b are each independently hydrogen or C 1-6 It may be an aliphatic group, for example, methyl, which may be optionally substituted with R, where R is hydrogen, halogen, —NO, —CN, —OH, —NH, or C 1-6 It may be an aliphatic group.

[0095] Linker A stable bond between an antibody and an active agent is a key aspect of ADC technology. Linkers can be based on chemical motifs, including, for example, disulfides, hydrazones, or peptides (cleavable), or thioethers (non-cleavable), to control the distribution and delivery of the active agent to target cells. Cleavable and non-cleavable linker types have been proven safe in preclinical and clinical trials. For example, brentuximab vedotin contains an enzyme-sensitive cleavable linker that delivers the synthetic anti-cancer drug monomethyl auristatin E (MMAE), a potent and highly toxic anti-microtubule agent, into cells.

[0096] Another approved ADC, trastuzumab emtansine, is a combination of the microtubule inhibitor mertansine (DM-1), a derivative of maytansine, and the antibody trastuzumab (Herceptin™, Genentech / Roche) linked by a stable, non-cleavable linker.

[0097] The type of cleavable or non-cleavable linker confers specific properties to the delivered drug. For example, a cleavable linker can be cleaved, for example, by an enzyme in the target cell, resulting in efficient intracellular release of the active agent, e.g., a cytotoxic drug. In contrast, ADCs containing non-cleavable linkers lack a mechanism for drug release and must rely on mechanisms such as the degradation of the targeting antibody for drug release. Furthermore, as will be appreciated by those skilled in the art, the linker composition can affect important factors such as the solubility and pharmacokinetic properties of the ADC as a whole.

[0098] For both types of linkers, drug release is important for cellular effects: drugs that can diffuse freely across the cell membrane can escape from target cells and attack neighboring cells, such as cancer cells, near uPARAP-expressing target cells in a process called "bystander killing."

[0099] In a preferred embodiment of the present disclosure, the uPARAP-targeting ADCs disclosed herein comprise a linker that connects the antibody to the active agent.

[0100] In one embodiment of the present disclosure, the linker may be cleavable or non-cleavable.

[0101] Cleavable groups include disulfide bonds, amide bonds, substituted amide bonds in the form of peptide bonds, thioamide bonds, ester bonds, thioester bonds, vicinal diol bonds, or hemiacetals. These or other cleavable bonds can include enzymatically cleavable bonds such as peptide bonds (cleaved by peptidases), phosphate bonds (cleaved by phosphatases), nucleic acid bonds (cleaved by endonucleases), and sugar bonds (cleaved by glycosidases).

[0102] In a further embodiment of the present disclosure, the linker is a cleavable linker that allows for intracellular release of the active agent inside the target cell.

[0103] In further embodiments, the linker is a peptide linker. The selection of the peptide sequence is important for the success of the conjugate. In some embodiments, the linker is stable to serum proteases but is cleaved by lysosomal enzymes in the target cell.

[0104] In some embodiments, the linker is an enzyme-cleavable peptide-containing linker, such as a cathepsin-cleavable peptide-containing linker. Cathepsin is one of several types of cathepsins, which are a group of lysosomal proteases.

[0105] In further embodiments of the present disclosure, the linker comprises or consists of a dipeptide, such as valine-citrulline (VC) or valine-alanine (VA).

[0106] In one embodiment, the linker comprises or consists of a dipeptide, such as valine-citrulline (VC) or valine-alanine (VA), which may be further linked to other structural elements via an amide bond. Valine-citrulline-based linkers, in which the citrulline carboxyl functional group is modified to a substituted amide, can be cleaved by lysosomal cathepsins, while valine-alanine-based linkers, in which the alanine carboxyl functional group is modified to a substituted amide, can be cleaved by other lysosomal proteases, including other cathepsins.

[0107] In further embodiments of the present disclosure, the antibody-drug conjugate defined herein further comprises a spacer, for example, a spacer comprising p-aminobenzoic acid (PAB), p-aminobenzylcarbamate (PABC), p-aminobenzoyloxycarbonyl, or polyethylene glycol (PEG).

[0108] In one embodiment of the present disclosure, the antibody drug conjugate defined herein comprises p-aminobenzylcarbamate (PABC).

[0109] In further embodiments of the present disclosure, the antibody-drug conjugates defined herein further comprise a linking group that comprises or consists of a linking group such as maleimide and caproic acid (MC), N-hydroxysuccinimide, reactive linking groups directed to modified or unmodified protein-bound carbohydrates, peptide sequences required for enzymatic reactions, azides or alkynes, or derived therefrom by reaction with an antibody, or chemically or enzymatically generated derivatives thereof.

[0110] In one embodiment of the present disclosure, the ADC of the present disclosure further comprises a linking entity. The linking entity can, for example, connect an antibody to a cleavable linker, and the linking entity is the reaction product of an antibody amino acid side chain in the linker precursor with a reactive linking group. In one embodiment, the reactive linking group comprises or consists of maleimide and caproic acid (MC), with the maleimide preferably reacting with cysteine ​​thiol during coupling. In other embodiments, the linking group comprises or consists of N-hydroxysuccinimide, a reactive linking group directed to modified or unmodified protein-bound carbohydrates, a peptide sequence required for enzymatic reaction, an azide, or an alkyne, or one derived therefrom by reaction with an antibody, or a chemically or enzymatically generated derivative thereof.

[0111] IB In one embodiment, the antibody drug conjugate comprises a structure according to Formula (IB), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X a may be the nitrogen generated by removing two hydrogen atoms from the amino group of exatecan (EXA), L is -L a -L b -L c - in which L attaches the structure of formula (IB) to an antibody as defined herein; -L a -teeth: [ka] wherein W can be selected from the group consisting of -(C(R wa )(R wb )) wn -, and Y is -(OCH2CH2) yn -O yp -, and Z can be -(C(R za )(R zb ))zn It can be, wherein Z connects -La- to -Lb-; wherein wn may be selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; wherein yn can be selected from the group consisting of integers ≧0, yp can be 0 or 1; wherein zn may be selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; -Cyr- may be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx may be replaced by In the formula, each R wa , each R wb , each Rza , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C can be substituted with 1-6 may be an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 may be an aliphatic group, -L b - represents a peptide residue consisting of 2 to 7 amino acids, -L c -teeth: [ka] may be selected from the group consisting of In the formula, R L1 and R L2are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described hereinabove.

[0112] II-Bx, II-By In one embodiment, the antibody drug conjugate comprises a structure according to Formula (II-Bx) or Formula (II-By), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X a may be the nitrogen generated by removing two hydrogen atoms from the amino group of exatecan (EXA), L is -L a -L b -L c wherein L binds a structure of formula (II-Bx) or (II-By) to an antibody as defined herein; -L a -teeth: [ka] may be selected from the group consisting of In the formula, W is -(C(R wa )(R wb )) wn -, and Y is -(OCH2CH2) yn -O yp -, and Z can be -(C(R za )(R zb )) zn It can be, wherein Z connects -La- to -Lb-; wherein wn may be selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; wherein yn can be selected from the group consisting of integers ≧0, yp can be 0 or 1; wherein zn may be selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; -Cyr- may be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx may be replaced by In the formula, each R wa , each R wb , each R za , each Rzb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C can be substituted with 1-6 may be an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 may be an aliphatic group, -L b - represents a peptide residue consisting of 2 to 7 amino acids, -L c -teeth: [ka] may be selected from the group consisting of In the formula, R L1 and R L2are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups, L 2 , p, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, or X 2 , q, ring A, X 1 and L 1 is defined as in any of the embodiments of formula (II-Ay) described hereinabove.

[0113] III-B In one embodiment, the antibody-drug conjugate comprises a structure according to Formula (III-B), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X a may be the nitrogen generated by removing two hydrogen atoms from the amino group of exatecan (EXA), L is -L a -L b -L c wherein L binds a structure of formula (II-Bx) or (II-By) to an antibody as defined herein; -L a -teeth: [ka] may be selected from the group consisting of In the formula, W is -(C(R wa )(R wb )) wn-, and Y is -(OCH2CH2) yn -O yp and Z can be -(C(R za )(R zb )) zn It can be, wherein Z connects -La- to -Lb-; wherein wn may be selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; wherein yn can be selected from the group consisting of integers ≧0, yp can be 0 or 1; wherein zn may be selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; -Cyr- may be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx may be replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C can be substituted with 1-6 may be an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 may be an aliphatic group, -L b - represents a peptide residue consisting of 2 to 7 amino acids, -L c -teeth: [ka] may be selected from the group consisting of In the formula, R L1 and R L2 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 aliphatic groups, In the formula, R 1 and X is defined as in any of the embodiments of formula (III-A) described hereinabove.

[0114] In another embodiment, wn may be selected from the group consisting of integers from 2 to 6, and 0 or 1 methylene unit of W is independently selected from -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -NR wx It may be replaced by - or -O-.

[0115] For example, wn can be 1, 2, 3, or 6, and one methylene unit of W can independently be -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )- or -C(O)-.

[0116] In another embodiment, yn may be selected from the group consisting of integers from 0 to 12, and yp may be 0 or 1.

[0117] For example, yn can be 0, 4, or 8, and yp can be 0 or 1.

[0118] In another embodiment, zn may be selected from the group consisting of integers from 0 to 10, and 0 or 1 methylene unit of Z is independently selected from -Cyr-, -N(R zx)C(O)-, -C(O)N(R zx )- or -C(O)-.

[0119] For example, zn can be 1, 2, or 3, and one methylene unit of Z can be independently selected from -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )- or -C(O)-.

[0120] In another embodiment, -Cyr- may be selected from the group consisting of 6-10 membered arylene and 3-10 membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently contains 1-3 substituents R cx may be substituted with

[0121] For example, -Cyr- can be a 3- to 10-membered saturated carbocyclylene, where -Cyr- is unsubstituted or independently contains 1 to 3 substituents R cx may be substituted with

[0122] In another embodiment, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r, -N(R)SO2R r , or optionally R r C can be substituted with 1-6 may be an aliphatic group, and each R r , each R ra , and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0123] For example, each wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, halogen, -OR r , or optionally R r C can be substituted with 1-6 may be an aliphatic group, and each R r are independently hydrogen, halogen, or C 1-6 It may be an aliphatic group.

[0124] In another embodiment, -L b - represents a peptide residue consisting of 2 to 7 amino acids, and -L b The peptide residue may be a peptide residue formed from an amino acid selected from the group consisting of phenylalanine, glycine, alanine, valine, citrulline, lysine, serine, glutamic acid, and aspartic acid.

[0125] For example, -L b - represents a peptide residue consisting of 2 to 4 amino acids, and -L b The peptide residue of -L may be a peptide residue that may be formed from an amino acid that may be selected from the group consisting of: phenylalanine, glycine, alanine, valine, citrulline, and lysine. bmay comprise or consist of SEQ ID NO: 14 or 15.

[0126] For example, -L b -teeth: [ka] may be selected from the group consisting of:

[0127] For example, -L b -teeth, [ka] It could be.

[0128] In other embodiments, -L c -teeth: [ka] may be selected from the group consisting of:

[0129] For example, -L c -teeth: [ka] may be selected from the group consisting of:

[0130] -L c -teeth, [ka] It could be.

[0131] In other embodiments, R L1 and R L2 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 The alkyl group may be selected from the group consisting of aliphatic groups.

[0132] For example, R L1 and R L2 are each independently hydrogen, halogen, —OH, and C 1-6 The alkyl group may be selected from the group consisting of aliphatic groups.

[0133] In another embodiment, -L a -teeth [ka] It could be.

[0134] In another embodiment, -L b -teeth, [ka] may be selected from the group consisting of:

[0135] For example, -L b -teeth, [ka] may be selected from the group consisting of:

[0136] In one embodiment, -L c -teeth [ka] It could be.

[0137] In one embodiment, -L a -L b -L c -teeth, [ka] may be selected from the group consisting of:

[0138] As used herein, the formula referred to as exatecan (EXA) is: [ka] Exatecan (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]imidazo[1,2-b]quinoline-10,13(9H,15H)-dione) is a camptothecin derivative. Functionally, exatecan is classified as a topoisomerase inhibitor, more specifically a topoisomerase I inhibitor.

[0139] I C. In one embodiment, the antibody drug conjugate comprises Formula (IC), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, L is -L a -L b -L c - may be L a , L b and L c is defined as in any of the embodiments of formula (IB) described hereinabove, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described hereinabove.

[0140] II-Cx, II-Cy In one embodiment, the antibody drug conjugate comprises Formula (II-Cx) or (II-Cy), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, L is -L a -L b -L c - may be L a , L b and L cis defined as in any of the embodiments of formula (II-Bx) described hereinabove, L 2 , p, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, or X 2 , q, ring A, X 1 and L 1 is defined as in any of the embodiments of formula (II-Ay) described hereinabove.

[0141] III-C In one embodiment, the antibody drug conjugate comprises Formula (III-C), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, L is -L a -L b -L c - may be L a , L b and L c is defined as in any of the embodiments of formula (III-B) described hereinabove, In the formula, R 1 and X is defined as in any of the embodiments of formula (III-A) described hereinabove.

[0142] ID In one embodiment, the antibody drug conjugate comprises Formula (ID), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] wherein Ab represents an antibody as defined herein, and the antibody is i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; N a represents the average number of connections, which can be an integer or decimal number between 1 and 10; L is -L a -L b -L c - may be L a , L b and L c is defined as in any of the embodiments of formula (IB) described hereinabove, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described hereinabove.

[0143] II-Dx, II-Dy In one embodiment, the antibody drug conjugate comprises Formula (II-Dx) or Formula (II-Dy), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] wherein Ab represents an antibody as defined herein, and the antibody is i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; N a represents the average number of connections, which can be an integer or decimal number between 1 and 10; L is -L a -L b -L c - may be L a , L b and L cis defined as in either formula (II-Bx) or formula (II-By) of the embodiments described hereinabove, L 2 , Ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, or X 2 , Ring A, X 1 and L 1 is defined as in any of the embodiments of formula (II-Ay) described hereinabove.

[0144] III-D In one embodiment, the antibody drug conjugate comprises Formula (III-D), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] wherein Ab represents an antibody as defined herein, and the antibody is i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; N a represents the average number of connections, which can be an integer or decimal number between 1 and 10; L is -L a -L b -L c - may be L a , L b and L c is defined as in any of the embodiments of formula (III-B) described hereinabove, In the formula, R 1 and X is defined as in any of the embodiments of formula (III-A) described hereinabove.

[0145] In one embodiment, the ADC is according to any one of formulas (ID), (II-Dx), (II-Dy), or (III-D) as defined herein, and Ab is: i) an immunoglobulin light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 1, and ii) An antibody comprising an immunoglobulin heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO:4.

[0146] In one embodiment, the ADC is according to any one of formulas (ID), (II-Dx), (II-Dy), or (III-D) as defined herein, and Ab is: i) an immunoglobulin light chain consisting of the amino acid sequence of SEQ ID NO: 1, and ii) An antibody comprising an immunoglobulin heavy chain consisting of the amino acid sequence of SEQ ID NO:4.

[0147] In one embodiment, the antibody drug conjugate comprises a structure selected from any one of Table 2, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [Table 2] JPEG2026502232000109.jpg210162JPEG2026502232000110.jpg213162JPEG2026502232000111.jpg213162JPEG2026502232000112.jpg194162JPEG2026502232000113.jpg225162JPEG2026502232000114.jpg64162In the formula, Ab represents an antibody that binds to the uPARAP receptor described herein, and n is an integer from 1 to 10.

[0148] In one embodiment, the average number of connections N a can be an integer or decimal number between 2 and 8. For example, the average number of connections N a can be an integer or decimal number between 3 and 8. For example, the average number of connections N acan be an integer or decimal number between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, or 9 and 10.

[0149] IE In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to Formula (IE), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described hereinabove.

[0150] II-Ex, IIEy In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ex), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, L 2 , p, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove.

[0151] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (II-Ey), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X 2 , q, ring A, X 1 and L 1is defined as in any of the embodiments of formula (II-Ay) described hereinabove.

[0152] III-E In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-E), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 and X is defined as in any of the embodiments of formula (III-A) defined herein above.

[0153] Manufacturing methods, IF, II-Fx, II-Fy, and III-F In one aspect, the disclosure provides a method for producing an antibody-drug conjugate described herein, the method comprising reacting a compound selected from the group consisting of Formula (IF), Formula (II-Fx), Formula (II-Fy), and Formula (III-F), as described herein below, with an anti-uPARAP antibody, as defined herein.

[0154] In one embodiment, the method for making an antibody drug conjugate described herein comprises reacting a compound according to formula (IF), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, L x -L ax -L b -L c -can be, -L ax -teeth: [ka] may be selected from the group consisting of In the formula, Rhal can be iodine or bromine; In the formula, W is -(C(R wa )(R wb )) wn -, and Y is -(OCH2CH2) yn -O yp -, and Z can be -(C(R za )(R zb )) zn It can be, wherein wn may be selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; wherein yn can be selected from the group consisting of integers ≧0, yp can be 0 or 1; wherein zn may be selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; -Cyr- may be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx may be replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C can be substituted with 1-6 may be an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 may be an aliphatic group, L b and L cis defined as in any of the embodiments of formula (IB) described hereinabove, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described hereinabove.

[0155] In one embodiment, the method for making an antibody drug conjugate described herein comprises reacting a compound according to Formula (II-Fx) or Formula (II-Fy), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, L x -L ax -L b -L c -can be, -L ax -teeth: [ka] may be selected from the group consisting of In the formula, R hal can be iodine or bromine; In the formula, W is -(C(R wa )(R wb )) wn -, and Y is -(OCH2CH2) yn -O yp -, and Z can be -(C(R za )(R zb )) zn It can be, wherein wn may be selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx)-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; wherein yn can be selected from the group consisting of integers ≧0, yp can be 0 or 1; wherein zn may be selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; -Cyr- may be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx may be replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r, -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C can be substituted with 1-6 may be an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 may be an aliphatic group, L b and L c is defined as in either formula (II-Bx) or formula (II-By) of the embodiments described hereinabove, In the formula, L 2 , p, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, or X 2 , q, ring A, X 1 and L 1 is defined as in any of the embodiments of formula (II-Ay) described hereinabove.

[0156] In one embodiment, the method for making an antibody drug conjugate described herein comprises reacting a compound according to Formula (III-F), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, L x -L ax -L b -L c -can be, -L ax -teeth: [ka] may be selected from the group consisting of In the formula, R hal can be iodine or bromine; In the formula, W is -(C(R wa )(R wb )) wn -, and Y is -(OCH2CH2) yn -O yp -, and Z can be -(C(R za )(R zb )) zn It can be, wherein wn may be selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; wherein yn can be selected from the group consisting of integers ≧0, yp can be 0 or 1; wherein zn may be selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx-, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-; -Cyr- may be selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx may be replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C can be substituted with 1-6 may be an aliphatic group, In the formula, each R r , each R ra and each R rbare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 may be an aliphatic group, L b and L c is defined as in any of the embodiments of formula (III-B) described hereinabove, In the formula, R 1 and X is defined as in any of the embodiments of formula (III-A) described hereinabove.

[0157] In one embodiment, L ax -teeth: [ka] may be selected from the group consisting of In the formula, R hal can be iodine or bromine; In the formula, W is -(C(R wa )(R wb )) wn -, and Y is -(OCH2CH2) yn -O yp -, and Z can be -(C(R za )(R zb )) zn It could be.

[0158] In another embodiment, wn may be selected from the group consisting of integers from 2 to 6, and 0 or 1 methylene unit of W is independently selected from -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -NR wx It may be replaced by - or -O-.

[0159] For example, wn can be 1, 2, 3, or 6, and one methylene unit of W can independently be -Cyr-, -N(R wx)C(O)-, -C(O)N(R wx )- or -C(O)-.

[0160] In another embodiment, yn may be selected from the group consisting of integers from 0 to 12, and yp may be 0 or 1.

[0161] For example, yn can be 0, 4, or 8, and yp can be 0 or 1.

[0162] In another embodiment, zn may be selected from the group consisting of integers from 0 to 10, and 0 or 1 methylene unit of Z is independently selected from -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )- or -C(O)-.

[0163] For example, zn can be 1, 2, or 3, and one methylene unit of Z can be independently selected from -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )- or -C(O)-.

[0164] In another embodiment, -Cyr- may be selected from the group consisting of 6-10 membered arylene and 3-10 membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently contains 1-3 substituents R cx may be substituted with

[0165] For example, -Cyr- can be a 3- to 10-membered saturated carbocyclylene, where -Cyr- is unsubstituted or independently contains 1 to 3 substituents R cx may be substituted with

[0166] In another embodiment, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cxare each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r , or optionally R r C can be substituted with 1-6 may be an aliphatic group, and each R r , each R ra , and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 It may be an aliphatic group.

[0167] For example, each wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, halogen, -OR r , or optionally R r C can be substituted with 1-6 may be an aliphatic group, and each R r are independently hydrogen, halogen, or C 1-6 It may be an aliphatic group.

[0168] In one embodiment, L ax -teeth [ka] It could be.

[0169] In one embodiment, L ax -L b -L c -teeth: [ka] may be selected from the group consisting of:

[0170] In one embodiment, the method for making the antibody-drug conjugates described herein comprises reacting a compound according to any one of the structures in Table 3, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, with an anti-uPARAP antibody as defined herein. [Table 3] JPEG2026502232000129.jpg212162JPEG2026502232000130.jpg206162JPEG2026502232000131.jpg218162JPEG2026502232000132.jpg204162JPEG2026502232000133.jpg191162JPEG2026502232000134.jpg184162JPEG2026502232000135.jpg190162JPEG2026502232000136.jpg189162JPEG2026502232000137.jpg225162JPEG2026502232000138.jpg227162JPEG2026502232000139.jpg208162JPEG2026502232000140.jpg187162JPEG2026502232000141.jpg181162JPEG2026502232000142.jpg186162JPEG2026502232000143.jpg208162JPEG2026502232000144.jpg195162JPEG2026502232000145.jpg193162JPEG2026502232000146.jpg221162JPEG2026502232000147.jpg207162JPEG2026502232000148.jpg222162JPEG2026502232000149.jpg198162JPEG2026502232000150.jpg187162JPEG2026502232000151.jpg226162JPEG2026502232000152.jpg184162JPEG2026502232000153.jpg226162JPEG2026502232000154.jpg211162JPEG2026502232000155.jpg225162JPEG2026502232000156.jpg211162JPEG2026502232000157.jpg206162JPEG2026502232000158.jpg196162JPEG2026502232000159.jpg200162

[0171] In one embodiment of the present disclosure, the antibody drug conjugate described herein is of the general formula I-Z, as depicted herein below: Ab-L a -L b -L c -X(IZ) Ab represents LC4HC3 or an immunoglobulin light chain variable region comprising or consisting of the amino acids of SEQ ID NO: 3 and an immunoglobulin heavy chain variable region comprising or consisting of the amino acids of SEQ ID NO: 6; L a but, [ka] In formula (IZ), the wavy line represents a bond.

[0172] Preferably, X is [ka] is selected as.

[0173] In one embodiment of the present disclosure, the linker connecting the antibody to the active agent is It has the following structure: [ka] Contains a maleimidocaproic acid moiety.

[0174] That is, in one embodiment, -L a -L b -L c - can be: [ka]

[0175] In one embodiment of the disclosure, the antibody-drug conjugate has the structure of formula (II-Z): [ka] wherein Ab represents the humanized antibody LC4HC3 or an antibody comprising an immunoglobulin light chain variable region comprising or consisting of SEQ ID NO: 3 and an immunoglobulin heavy chain variable region comprising or consisting of SEQ ID NO: 6. Preferably, Ab represents the humanized antibody LC4HC3. It will be readily apparent to those skilled in the art that the number of cytotoxic agents conjugated to the Ab in formulas (IZ) and (II-Z) may be greater than 1, e.g., the drug-antibody ratio (DAR) may be greater than 1. In one embodiment, the DAR may be 2 or more, for example, 3 or more, for example, 4 or more, for example, 5 or more, for example, 6 or more, for example, 7 or more, for example, 8 or more, for example, 9 or more, or for example, 10 or more.

[0176] In one embodiment of the present disclosure, the antibody-drug conjugate of formula (II-Z) is characterized in that it contains at least one, e.g., two, e.g., three, e.g., four, preferably four, asymmetric carbon atoms in the (S) configuration. Asymmetric carbon atoms, sometimes referred to as chiral carbon atoms, are well known to those skilled in the art of medicinal chemistry.

[0177] therapeutic use The ADCs directed against uPARAP described herein are useful for delivering active agents to cells that express uPARAP and similar proteins, and are therefore useful for treating a variety of diseases and disorders characterized by either expression or overexpression of the protein.

[0178] Thus, one embodiment of the present disclosure is an antibody-drug conjugate as defined herein for use as a drug.

[0179] One embodiment of the present disclosure is a pharmaceutical composition comprising an effective amount of an antibody drug conjugate as defined herein and a pharmaceutically acceptable buffer, diluent, carrier, adjuvant or excipient.

[0180] As used herein, a "therapeutically effective amount" or "effective amount" or "therapeutically effective" refers to an amount that produces a therapeutic effect for a given condition and administration regimen. This is a predetermined quantity of an active substance calculated to produce a desired therapeutic effect in association with necessary additives and diluents, i.e., a carrier or administration vehicle. Furthermore, this is intended to mean an amount sufficient to reduce, and most preferably prevent, a clinically significant deficit in the activity, function, and response of the host. Alternatively, a therapeutically effective amount is sufficient to improve a clinically significant condition in the host. As will be appreciated by those skilled in the art, the amount of a compound may vary depending on its specific activity. An appropriate dosage may comprise a predetermined amount of the active composition calculated to produce a desired therapeutic effect in association with the necessary diluents.

[0181] The ADCs of the disclosure can be formulated into any type of pharmaceutical composition known in the art to be suitable for their administration.

[0182] Pharmaceutical compositions can be prepared by methods known in the art that are sufficiently shelf-stable and suitable for administration to humans and / or animals, for example, pharmaceutical compositions can be lyophilized, for example, by freeze-drying, spray-drying, spray-chilling, or by using particle formation from supercritical particle formation.

[0183] "Pharmaceutically acceptable" means a non-toxic substance that does not reduce the effectiveness of the ADC. Such pharmaceutically acceptable buffers, carriers, or excipients are well known in the art (see Remington's Pharmaceutical Sciences, 18th edition, A.R. Gennaro, Ed., Mack Publishing Company (1990) and Hanbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000), the disclosures of which are incorporated herein by reference).

[0184] The term "buffer" is intended to mean an aqueous solution containing an acid-base mixture for the purpose of stabilizing pH. Pharmaceutically acceptable buffers are well known in the art. The term "diluent" is intended to mean an aqueous or non-aqueous solution intended to dilute an agent in a pharmaceutical product.

[0185] The term "adjuvant" is intended to mean any compound added to a formulation to enhance the biological effect of the agent of the present invention. Adjuvants can be one or more of zinc, copper, or silver salts with different anions, such as, but not limited to, fluoride, chloride, bromide, iodide, thiocyanate, sulfite, hydroxide, phosphate, carbonate, lactate, glycolate, citrate, borate, tartrate, and acetates with different acyl compositions. Adjuvants can also be cationic polymers, such as cationic cellulose ethers, cationic cellulose esters, deacetylated hyaluronic acid, chitosan, cationic dendrimers, poly(vinylimidazole), and other cationic synthetic polymers, as well as cationic polypeptides, such as polyhistidine, polylysine, polyarginine, and peptides containing these amino acids.

[0186] The excipient may be one or more of carbohydrates, polymers, lipids, and minerals. Examples of carbohydrates include lactose, glucose, sucrose, mannitol, and cyclodextrin, which are added to the composition, for example, to facilitate freeze-drying. Examples of polymers include starch, cellulose ether, cellulose carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, alginic acid, carrageenan, hyaluronic acid and its derivatives, polyacrylic acid, polysulfonic acid, polyethylene glycol / polyethylene oxide, polyethylene oxide / polypropylene oxide copolymer, polyvinyl alcohol / polyvinyl acetate with different hydrolysis degrees, and polyvinylpyrrolidone, all with different molecular weights, which are added to the composition, for example, to adjust viscosity, obtain bioadhesion, or protect lipids from chemical and proteolytic degradation. Examples of lipids are fatty acids, phospholipids, mono-, di- and triglycerides, ceramides, sphingolipids and glycolipids (all with different acyl chain lengths and degrees of saturation), egg lecithin, soybean lecithin, hydrogenated egg and soybean lecithin, which are added to the composition for reasons similar to those of polymers. Examples of minerals are talc, magnesium oxide, zinc oxide, and titanium oxide, which are added to the composition for benefits such as reduced fluid accumulation or favorable pigment properties.

[0187] Another embodiment of the present disclosure is a method of treating a disease in a subject characterized by cells expressing uPARAP, the method comprising administering to the subject an antibody-drug conjugate as defined herein.

[0188] The expression and role of uPARAP in cancer has been investigated by several research groups, see the review by Melander et al. (Melander et al., 2015, Int J Oncol 47:1177-1188) and the paper by Engelholm et al. (Engelholm et al., 2016, J. Pathol. 238, 120-133).

[0189] In one embodiment of the present disclosure, the method is a method defined herein, wherein the disease characterized by cells expressing uPARAP is selected from cancer, a bone degradative disease, e.g., osteoporosis, fibrosis, and a macrophage-associated disease or disorder, e.g., atherosclerosis, arthritis, or chronic inflammation.

[0190] In one embodiment of the disclosure, the method is a method defined herein, wherein the arthritis is selected from osteoarthritis, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, lupus, Lyme disease-induced arthritis, e.g., Lyme arthritis, gout or pseudogout, and ankylosing spondylitis.

[0191] In one embodiment of the present disclosure, the method is a method defined herein and the disease is cancer.

[0192] Examples of cancers characterized by overexpression of uPARAP include sarcomas, including osteosarcomas such as giant cell osteosarcoma, osteoblastoma-like osteosarcoma, and fibroblastic osteosarcoma, as well as other sarcomas (Engelholm et al., 2016, J Pathol 238(1):120-33), glioblastoma (Huijbers et al., 2010, PLoS One 5(3):e9808), prostate cancer and bone metastases from prostate cancer (Kogianni et al., 2009, Eur J Cancer 45(4):685-93), breast cancer, particularly "basal-like" breast cancer (Wienke et al., 2007, Cancer Res 1;67(21):10230-40), head and neck cancer (Sulek et al., 2007, J Histochem Cytochem 55(4):347-53), and mesothelioma (Cakilkaya et al., 2021, Int J Mol Sci 22(21):11452).

[0193] In one embodiment of the present disclosure, the method is a method defined herein, wherein the cancer is selected from sarcoma, glioblastoma, mesothelioma, colon cancer, prostate cancer, bone metastasis from prostate cancer, breast cancer, head and neck cancer, ovarian cancer, endometrial cancer, lymphoma, and leukemia.

[0194] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is breast cancer, such as breast adenocarcinoma and / or ductal carcinoma and / or invasive ductal carcinoma of the breast.

[0195] In one embodiment of the present disclosure, the method is a method defined herein, wherein the cancer is ovarian cancer, such as ovarian adenocarcinoma.

[0196] In one embodiment of the present disclosure, the method is as defined herein, and the cancer is endometrial cancer, such as endometrial adenocarcinoma.

[0197] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is a lymphoma, such as a histiocytic lymphoma.

[0198] In one embodiment of the present disclosure, the method is a method defined herein, and the cancer is leukemia, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML), or a subtype thereof.

[0199] In one embodiment of the present disclosure, the method is a method defined herein, wherein the cancer is a sarcoma, such as osteosarcoma or soft tissue sarcoma (STS), or a subtype thereof.

[0200] In one embodiment of the present disclosure, the method is a method defined herein, wherein the soft tissue sarcoma (STS) is selected from epithelioid sarcoma, clear cell sarcoma, alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, inflammatory myofibroblastic tumor, undifferentiated embryonal sarcoma, alveolar soft part sarcoma (ASPS), angiosarcoma, chondrosarcoma, dermatofibrosarcoma protuberances (DFSP), desmoid sarcoma, Ewing's sarcoma, fibrosarcoma, myxofibrosarcoma, adult fibrosarcoma, gastrointestinal stromal tumor (GIST), non-uterine leiomyosarcoma, uterine leiomyosarcoma, liposarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, myxoid round cell liposarcoma, well-differentiated liposarcoma, malignant fibrous histiocytoma (MFH), malignant peripheral nerve sheath tumor (MPNST), rhabdomyosarcoma, synovial sarcoma, and / or leiomyosarcoma (LMS).

[0201] In one embodiment of the present disclosure, the method is as defined herein and the cancer is metastatic cancer.

[0202] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is a solid tumor.

[0203] In one embodiment of the present disclosure, the method is as defined herein, and the cancer is glioblastoma.

[0204] In one embodiment of the present disclosure, the cancer is not a solid tumor. For example, the ADCs of the present disclosure may be used to treat, for example, uPARAP-expressing leukemias derived from, for example, a macrophage-monocyte cell line.

[0205] In other embodiments of the present disclosure, the disease or disorder characterized by cells that express uPARAP is not cancer.

[0206] uPARAP is involved in bone growth and homeostasis (Madsen et al., 2013, PLoS One 5;8(8):e71261). Thus, in one embodiment, the ADCs of the present disclosure can be used to treat diseases characterized by bone degradation, where the bone degradation is mediated by non-malignant cells, such as osteoporosis.

[0207] Due to its role in collagen accumulation, a role for uPARAP has also been demonstrated in fibrosis (Madsen et al., 2012, J Pathol 227(1):94-105). Thus, in one embodiment, the ADCs of the present disclosure may be used to treat fibrosis, e.g., in the kidney, lung, and liver.

[0208] In one embodiment of the present disclosure, the ADCs of the present disclosure may be used to treat macrophage-associated diseases and disorders, including atherosclerosis, arthritis, and chronic inflammation. The ADCs of the disclosure or pharmaceutical compositions comprising the ADCs can be administered by any suitable route known to those of skill in the art. Possible routes of administration include parenteral (intravenous, subcutaneous, and intramuscular), topical, ocular, nasal, pulmonary, buccal, buccal, vaginal, and rectal. Administration via implants is also possible.

[0209] In a preferred embodiment, pharmaceutical compositions can be administered parenterally, for example, intravenously, intracerebroventricularly, intraarticularly, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly, or subcutaneously, or by infusion techniques.They are conveniently used in the form of a sterile aqueous solution, which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood.The aqueous solution should be suitably buffered, if necessary.

[0210] In one embodiment of the disclosure, the method is a method defined herein, wherein the antibody drug conjugate is administered parenterally, e.g., intravenously, intracerebroventricularly, intraarticularly, intraarterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or by infusion techniques.

[0211] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0212] In one embodiment of the present disclosure, the method is as defined herein, wherein the antibody drug conjugate is administered intravenously.

[0213] In one embodiment of the present disclosure, the method is as defined herein, wherein the antibody drug conjugate is administered subcutaneously.

[0214] In one embodiment of the disclosure, the method is a method defined herein, wherein the antibody drug conjugate is administered in combination with one or more additional agents, such as one or more additional therapeutic agents.

[0215] In one embodiment of the present disclosure, the ADCs of the present disclosure are administered in combination with additional reagents and / or therapeutic agents that may increase the functional efficiency of the ADC, for example, established or novel agents that increase lysosomal membrane permeability, thereby facilitating entry of molecules from inside the lysosome into the cytoplasm, or agents that increase the permeability of the blood-brain barrier.

[0216] In one embodiment of the disclosure, the ADCs or antibodies described herein may be administered in combination with a variety of anti-cancer agents, such as antimetabolites, alkylating agents, anthracyclines and other cytotoxic antibiotics, vinca alkaloids, antimicrotubule / antimitotic agents, histone deacetylase inhibitors, kinase inhibitors, peptide antibiotics, immune checkpoint inhibitors, platinum-based anti-neoplastic agents, etoposide, taxanes, topoisomerase inhibitors, antiproliferative immunosuppressants, corticosteroids, sex hormones and hormone antagonists, cytotoxic antibiotics, and other therapeutic agents.

[0217] Thus, in one embodiment of the present disclosure, the method is a method as defined herein, wherein the cells expressing uPARAP exhibit uPARAP overexpression.

[0218] In one embodiment of the present disclosure, the method is as defined herein, wherein the cells expressing uPARAP are tumor cells.

[0219] In one embodiment of the present disclosure, the method is as defined herein, wherein the cells expressing uPARAP are tumor-associated cells.

[0220] Tumor-associated cells include, but are not limited to, activated fibroblasts, myofibroblasts, angiogenic and infiltrating cells of the macrophage-monocyte lineage or other leukocyte cell types, and cells of the stromal tissue surrounding the tumor.

[0221] In one embodiment of the disclosure, the method is a method as defined herein, wherein the antibody drug conjugate induces cell death and / or inhibits the growth and / or proliferation of uPARAP-expressing cells.

[0222] In one embodiment of the present disclosure, the method is a method defined herein, wherein the antibody-drug conjugate induces the release of a cytotoxin released from uPARAP-expressing cells, resulting in cell death and / or inhibiting the growth and / or proliferation of adjacent cancer cells.

[0223] In one embodiment of the present disclosure, the method is a method as defined herein, wherein the treatment is ameliorative or curative.

[0224] A further embodiment of the present disclosure is a method for inhibiting tumor progression in a subject, comprising administering to said subject an antibody drug conjugate, or pharmaceutical composition as defined herein.

[0225] A further embodiment of the present disclosure is a method for inhibiting, reducing or eliminating the metastatic potential of a tumor in a subject, comprising administering to the subject an antibody drug conjugate, or pharmaceutical composition as defined herein.

[0226] Yet another embodiment of the present disclosure is a kit comprising an antibody-drug conjugate, or pharmaceutical composition as defined herein, and optionally further comprising a means for administering the antibody-drug conjugate or pharmaceutical composition to a subject and / or instructions for use.

[0227] In one embodiment, the disclosure relates to an antibody-drug conjugate described herein, or a pharmaceutical composition described herein, for use in the manufacture of a medicament for the treatment of a disease characterized by cells that express uPARAP, e.g., cancer.

[0228] In one embodiment, the present disclosure relates to an antibody-drug conjugate, or a pharmaceutical composition comprising the antibody-drug conjugate, for use in the manufacture of a medicament for the treatment of a disease characterized by cells that express uPARAP, e.g., cancer, wherein the antibody-drug conjugate is as described herein.

[0229] In one embodiment, the present disclosure relates to an antibody-drug conjugate, or a pharmaceutical composition comprising said antibody-drug conjugate, for use in the manufacture of a medicament for the treatment of a disease characterized by cells that express uPARAP, e.g., cancer, wherein said antibody-drug conjugate is as defined herein. [Example]

[0230] Example 1: Humanization of the murine 9b7 antibody and efficacy of ADCs based thereon Materials and Methods Humanization of the murine antibody 9b7 directed against uPARAP The amino acid sequence of murine antibody 9b7 and data regarding its CDR regions are available in published patent application WO2017 / 133745.

[0231] Humanized variants of the 9b7 antibody were constructed by a third party (Fusion Antibodies, Belfast, UK). Briefly, the murine parent antibody (clone 9b7) was sequenced and the consensus CDR sequences were grafted in silico onto the human donor sequences.

[0232] For this purpose, a number of human framework sequences (see search procedure below) were used as acceptor frameworks for the CDR sequences. All of these acceptor sequences were derived from mature human IgG of human origin, not from phage display or other techniques. The humanized variant generated from the antibody 9b7 sequence is a light and heavy chain combination designated Ab980.2 LCXHCX (light chain X, heavy chain X), where LCOHC0 refers to a chimeric antibody in which the variable regions of the original murine antibody are fused to the same human IgG constant region used in the humanized antibody. The mature humanized antibody is a complete IgG molecule of the IgG1κ type.

[0233] For the heavy chain, an online database of human IgG sequences was searched for comparison with the mouse VH domain using the BLAST search algorithm, and candidate human variable regions selected from the top 200 BLAST results were selected. These were reduced to four candidates based on a combination of framework homology, maintaining critical framework residues and canonical loop structures.

[0234] For the light chain, an online database of human IgK sequences was searched for comparison with the mouse VL domain using the BLAST search algorithm, and candidate human variable regions were selected from the top 200 BLAST results. These were reduced to four candidates based on a combination of framework homology, maintaining critical framework residues and canonical loop structures.

[0235] Thus, DNA sequences encoding four humanized light chains and four humanized heavy chains were selected. All 16 resulting light and heavy chain combinations were used for protein expression in CHO cells. To enable protein expression, each variable light chain domain was placed in frame with a human IgK isotype constant domain sequence, while each variable heavy chain domain was placed in frame with a human IgG1 isotype constant domain sequence. For comparison, a chimeric antibody, LC0HC0, in which the variable domains of the mouse protein were fused to the same human IgG constant region, was expressed.

[0236] For protein expression (performed by a third party (Fusion Antibodies, Belfast, UK)), mammalian expression vectors encoding each variant were transfected into CHO cells, and batch cultures of each variant were grown for up to 7 days. Expressed antibodies were then purified from cell culture supernatants by affinity chromatography. The concentration and purity of the purified antibody products were determined.

[0237] The resulting sequence was cloned into the mammalian transient expression plasmid pD2610-v13(ATUM). The humanized antibody variants were expressed using a CHO-based transient expression system, and the resulting antibody-containing cell culture supernatant was clarified by centrifugation and filtration. The humanized variants were then purified from the cell culture supernatant by affinity chromatography (using a conventional AKTA chromatography device). The purified antibody was dialyzed / buffer exchanged into phosphate-buffered saline. The purity of the antibody was assessed by sodium dodecyl sulfate polyacrylamide gel and determined to be greater than 95%.

[0238] Among the 16 resulting humanized antibodies, a combination designated LC4HC3 was selected for further experiments based on favorable protein expression yield and antigen-binding properties. Another humanized antibody designated LC3HC3 was selected for comparison with LC4HC3 on important parameters such as manufacturability, internalization, and in vivo efficacy.

[0239] SPR analysis for determination of antibody-ligand affinity Once suitable antibodies are obtained, they can be tested for antigen specificity, for example, by surface plasmon resonance (SPR) or ELISA. When a soluble recombinant protein consisting of the three N-terminal domains of uPARAP (CysR, FN-II, and CTLD-1) is immobilized in a BIAcore setup, mAb 9b7 binds to this construct.

[0240] SPR analysis was performed to determine the affinity of the resulting antibodies for uPARAP. These analyses were performed using a Biacore 2000 instrument (Biaffin GmbH, Kassel, Germany) with a CM5 sensor chip with an anti-human Fc capture surface for antibody binding. The analysis temperature was set at 25°C. After antibody binding to this surface, soluble full-length uPARAP was passed over the chip, and the association and dissociation rates were derived from the resulting binding curves. For kinetic interaction analysis, a flow rate of 30 μL / min was used, and the analysis buffer consisted of 10 mM HEPES (pH 7.4), 150 mM NaCl, 3 mM EDTA, and 0.05% Tween 20.

[0241] Preparation and evaluation of antibody drug conjugates (ADCs) The ADCs used in these experiments were generated using well-established conjugation methods. Briefly, the target antibody was conjugated to a "vedotin"-type payload (MC-VC-PABC-MMAE) via mild reduction of the interchain disulfides, followed by conjugation to excess payload via the maleimide group, resulting in a moderate average drug-to-antibody ratio (DAR) of approximately 4. The ADCs were then purified using a PD-10 desalting column (GE Healthcare).

[0242] cell line The U937 cell line was obtained from ATCC and maintained in RPMI (10% fetal bovine serum, 1% penicillin / streptomycin) in a 37°C incubator under a 5% CO 2 atmosphere.

[0243] In vitro cytotoxicity of ADCs – cell viability assay U937 cells were seeded at low density (20% confluence, 2 x 10 cells per well) in 90 µL of medium in flat-bottom 96-well plates and incubated overnight. The following day, MMAE-based ADCs of the LC4HC3 and LC0HC0 antibodies, synthesized using the method described above, were prepared as serial dilutions (1:4) in PBS and added to each well in a volume of 10 µL for a final maximum ADC concentration (mAb component) of 0.1 µg / mL. Cells were incubated for 96 hours, after which 12 µL of Cell Titer 96 AQueous One Solution Cell Proliferation Assay (MTS, Promega) was added and incubated for a time appropriate for color development (approximately 60 minutes). Plates were then read at 490 nm with background subtraction at 630 nm using a plate reader to obtain viability estimates. Cells treated with PBS alone served as the untreated control, and the ADC-treated wells were normalized to their viability.

[0244] result Manufacturability and expression of LC4HC3 and LC3HC3: The humanized antibodies designated LC4HC3 and LC3HC3 were expressed in CHO cells and purified as described above. The same procedure was followed for both antibodies. The results are summarized in Table 4 below. The results clearly demonstrate that LC4HC3 can be produced in significantly larger quantities with sufficient purity. [Table 4]

[0245] SPR analysis: LC4HC3 and LC0HC0 were analyzed by SPR as described in Materials and Methods above. In particular, the binding kinetics of LC4HC3 were compared to those of LC0HC0 (Table 5). These analyses reveal a low K for antibody LC4HC3. D exhibits approximately 1.7-fold higher ligand affinity than the parent antibody LC0HC0. [Table 5]

[0246] In vitro potency analysis of ADC: MMAE-containing ADCs containing either the LC4HC3 or LC0HC0 antibody were prepared as described above. The in vitro cytotoxicity of these ADCs was tested against uPARAP-positive U937 cells using a concentration series of the ADC (Figure 1). The viability curve obtained from treatment with LC4HC3-vc-MMAE was shifted several-fold to lower concentrations compared to the curve obtained from treatment with LC0HC0-vc-MMAE, demonstrating that the amount of ADC required for cell eradication was lower for the LC4HC3-based ADC than for the LC0HC0-based ADC.

[0247] conclusion The humanized antibody 980.2 LC4HC3 was developed from the murine monoclonal antibody mAb 9b7. The properties of this novel antibody can be directly compared to those derived from the parent variable sequences by comparing it to the chimeric antibody 980.2 LC0HC0, in which the entire murine variable sequence is otherwise retained in the setting of a human IgG. This comparison reveals that 1) humanized 980.2 LC4HC3 has higher ligand affinity than 980.2 LC0HC0, and 2) ADCs based on 980.2 LC4HC3 are more efficient in terms of cytotoxicity than comparable ADCs based on 980.2 LC0HC0.

[0248] Example 2: Internalization of humanized variants of the murine 9b7 antibody, LC3HC3, and LC4HC3 Materials and Methods antibody labeling Iodogen (Thermo Fischer) was dissolved in chloroform at 120 μg / ml and used to coat the bottom of glass tubes by vapor deposition. In the coated tubes, 200 μg / ml of humanized antibody (either LC3HC3 or LC4HC3) was reacted with 588 ng / ml I-125 (Perkin Elmer) in 0.1 M Tris buffer at pH 7.6 for 10 minutes. The reaction was stopped by adding a nine-fold excess of 0.1 M Tris pH 8.1 buffer containing 0.01% Tween-80. Unbound iodine was separated from the collagen using a PD-10 column, and the labeled antibody was eluted in 0.1 M Tris / HCl buffer at pH 8.1 containing 0.01% Tween-80. Assuming all antibody elutes in this buffer, the resulting concentration would be 8 μg / ml. The integrity and radioactivity of the labeled collagen was routinely confirmed by SDS-PAGE followed by Coomassie staining and phosphorimaging.

[0249] Cell culture and antibody internalization procedures SAOS-2 osteosarcoma cells (Finsenlab, 98.7% viability, density 1.07 x 10^6 / ml) were diluted to 1 x 10^5 / ml and seeded at 1 ml per 24-well plate for experiments. Cells were allowed to adhere overnight. At least 30 minutes before the addition of the radiolabeled antibody, this medium was replaced with internalization medium consisting of DMEM / F12 containing 1.5% FBS and 20 mM HEPES. Internalization medium without cells was seeded in separate wells as a control. Radioactivity from these samples is considered to represent the amount of radiolabeled protein that adhered to the plastic and was recovered upon trypsinization. These measurements can be considered "baseline levels" and can be subtracted from those of cell-containing samples. 5 μl of LC4HC3 or LC3HC3, estimated to be slightly less than 40 ng based on the above assumptions, was added to each well. After 1 or 4 hours, the medium was removed by aspiration, and the cells were washed three times with 500 μl of ice-cold PBS. 500 μl of trypsin-EDTA containing 50 μg / ml proteinase K was added to each well for 2 minutes. The cells were harvested, transferred to an Eppendorf tube, and spun at 1000 g for 1 minute at 4°C. The supernatant (containing cell-bound antibody) and pellet were collected separately and analyzed in a gamma counter. 2 μl of labeled antibody stock was also analyzed simultaneously to assess labeling efficiency.

[0250] result The results shown in Figure 2 clearly demonstrate that humanized antibody LC4HC3 is not only internalized significantly faster but also more extensively than humanized antibody LC3HC3.

[0251] conclusion The humanized antibody LC4HC3 was internalized to the greatest extent by SAOS-2 osteosarcoma cells in a time-dependent manner. LC3HC3 was also internalized, but to a much lesser extent and not as rapidly as LC4HC3. The two reference antibodies contain the same heavy chain, and the difference in internalization can only be attributed to differences in the amino acid sequence of the light chain.

[0252] Example 3: In vivo efficacy of ADCs based on humanized murine 9b7 antibodies LC3HC3 and LC4HC3 Materials and Methods Cell culture and preparation U937 cells (described above) were passaged according to standard procedures until sufficient cells were obtained for this experiment. Cells were spun down at 150 g for 5 minutes and washed three times in cold PBS (Gibco). The cell concentration was adjusted to 3.6 x 10 cells / ml. This translates to approximately 3 million viable cells per 100 μl of intended inoculation volume.

[0253] Xenograft tumor inoculation Recipient CB17 mice were anesthetized with Zoletil (AEM), administered Viscotears eye drops, and ear-tagged. The right flank was shaved and disinfected with 70% ethanol. 100 μl of resuspended U937 cells were injected into the subcutaneous space using a 25G needle (no incision or sutures were required). Mice were allowed to recover from anesthesia in their cages. Recovery was monitored until the mice were mobile. Mice were monitored again the next day, and tumor size was closely monitored until treatment began.

[0254] Treatment was initiated as soon as tumors reached an appropriate size (approximately 80–150 mm ).

[0255] ADC Treatment and Monitoring Vedotin-type (MMAE) ADCs containing LC3HC3 or LC4HC3 humanized antibodies were prepared as described above. Mice were divided into groups with 3-5 animals (N=3-5) per group, and the groups varied based on the ADC or dose of the ADC used. One cohort of mice was tested with 2 mg / kg, 4 mg / kg, or 6 mg / kg of LC3HC3 ADC, while another cohort was tested with the same concentration range of LC4HC3 ADC.

[0256] For each group, mice were administered a controlled amount of ADC intravenously (tail vein) once a week for a total of two injections (qd7 x 2), and tumor growth was closely monitored after treatment. Illustratively, Figures 3a and 3b show tumor growth in groups treated with 4 mg / kg doses of LC4HC3 and LC3HC3 ADC, respectively.

[0257] Monitoring consisted of inspecting the animals for general health and measuring the tumor width and length dimensions using digital calipers. All observations and measurements were recorded manually and transferred to a digital data sheet after examination. Animals were euthanized if tumor size exceeded 12 mm in one dimension, if tumor volume (calculated as (length × width) / 2) exceeded 1000 mm3, or if a severe effect on general health was observed. Animals were euthanized by cervical dislocation.

[0258] result U937 tumor volumes after treatment with LC4HC3- and LC3HC3-based ADCs are shown in Figures 3a and 3b, respectively. Figure 3a shows the tumor volumes for a group of four mice (N=4), each administered the LC4HC3 ADC at 4 mg / kg once weekly for a total of two injections (qd7 x 2), and Figure 3b shows the tumor volumes for a different group of four mice (N=4), each administered the LC3HC3 ADC at 4 mg / kg once weekly for a total of two injections (qd7 x 2).

[0259] conclusion As can be seen from a comparison of Figures 3a and 3b, LC4HC3 ADC-based treatment completely cured all mice without tumor regrowth during the post-treatment period, particularly at all doses tested. In contrast, the same LC3HC3-based treatment failed to kill all tumor cells, e.g., aggressive tumor growth was observed during the post-treatment monitoring period.

[0260] The data demonstrate that the humanized antibody LC4HC3 and ADCs containing this humanized antibody are potent antitumor agents with improved in vivo efficacy compared to another humanized antibody, LC3HC3. The two reference antibodies contain the same heavy chain, and the difference in efficacy can only be attributed to differences in the amino acid sequence of the light chain.

[0261] Example 4: Synthesis of Compounds and ADCs The exatecan derivatives disclosed herein can be prepared as described in WO2022 / 068878. Specifically, compounds P-III-30, P-III-1, P-III-2, P-III-20, P-III-21, P-III-22, P-III-28, and P-III-29 may be prepared according to the reference examples shown in the table below. It will be apparent to those skilled in the art that other examples from WO2022 / 068878 regarding the synthesis of the compounds disclosed herein are also incorporated by reference. [Table 6]

[0262] Antibody-drug conjugates comprising an exatecan derivative and the humanized antibody (LC4HC3) that binds to uPARAP described herein can be prepared using standard methods for conjugating a payload to an antibody known to those skilled in the art. For example, they can be prepared in a manner similar to that used for preparing the ADC described in the Examples of WO2022 / 068878.

[0263] Example 5: Efficacy of compounds and ADCs Test Example 5.1. Testing the Inhibition of In Vitro Growth of Tumor Cells by Compounds the purpose The inhibitory activity of pharmaceutical compounds against the in vitro proliferation of NCI-N87, JIMT-1, and MBA-MB-231 tumor cells is tested. The cells are treated with different concentrations of compounds in vitro, and after 6 days of culture, cell proliferation is detected using CTG (Cell Titer-Glo® Luminescent Cell Viability Assay, Promega, Cat. No. G7558) reagent. The in vitro activity of compounds is measured using IC 50 was evaluated according to the value.

[0264] procedure The following example illustrates the method of the present application for testing the inhibitory activity of the compounds of the present application on the in vitro proliferation of tumor cells, taking the test on the inhibition of the in vitro proliferation of NCI-N87 cells as an example. The method is also applicable to, but not limited to, testing the inhibitory activity on the in vitro proliferation of other tumor cells.

[0265] 1. Cell culture: NCI-N87 cells were cultured in RPMI-1640 medium containing 10% FBS.

[0266] 2. Cell preparation: Log-phase NCI-N87 cells were harvested, washed once with PBS, and digested with 2-3 mL of trypsin for 2-3 minutes. After the cells were completely digested, 10-15 mL of cell culture was added to elute the digested cells. The eluate was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The resulting cells were resuspended in 10-20 mL of cell culture to obtain a single cell suspension.

[0267] 3. Cell plating: Mix the NCI-N87 single cell suspension thoroughly and plate 6 × 10 cells in cell culture. 4 The viable cell density was adjusted to 1000 cells / mL. The density-adjusted cell suspension was mixed well and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator (37°C, 5% CO2) for 18 hours.

[0268] 4. Compound preparation: Compounds were dissolved in DMSO to give stock solutions with an initial concentration of 10 mM. For small molecule compounds, there were a total of eight concentrations: 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM.

[0269] 5. Addition of samples: The prepared samples to be detected at different concentrations were added to the culture plate, and two wells for each sample were set up in duplicate. The culture plate was incubated in an incubator (37°C, 5% CO2) for 6 days.

[0270] 6. Color development: A 96-well cell culture plate was taken out, and 50 μL of CTG reagent was added per well, followed by incubation at room temperature for 10 minutes.

[0271] 7. Plate reading: The 96-well cell culture plate was taken out and placed into a microplate reader, and the chemiluminescence was measured using the microplate reader.

[0272] Data analysis Data were processed and analyzed using Microsoft Excel and GraphPad Prism 5. [Table 7]

[0273] Conclusion: According to the results shown in Table 6, the small molecule fragments of the present application have significant inhibitory activity against the proliferation of NCI-N87 cells and JIMT-1 cells. All compounds of the present application have similar inhibitory activity against tumor growth.

[0274] Test Example 5.2. Testing the Inhibition of In Vitro Growth of Tumor Cells by Compounds the purpose The inhibitory activity of pharmaceutical compounds against the in vitro proliferation of NCI-N87, JIMT-1, and MBA-MB-231 tumor cells is tested. The cells are treated with different concentrations of compounds in vitro, and after 6 days of culture, cell proliferation is detected using CTG (Cell Titer-Glo® Luminescent Cell Viability Assay, Promega, Cat. No. G7558) reagent. The in vitro activity of compounds is measured using IC 50 was evaluated according to the value.

[0275] 1. Cell culture: NCI-N87 / JIMT-1 / MBA-MB-231 cells were cultured in RPMI-1640 medium containing 10% FBS.

[0276] 2. Cell preparation: Log-phase NCI-N87 / JIMT-1 / MBA-MB-231 cells were harvested, washed once with PBS, and digested with 2-3 mL of trypsin for 2-3 minutes. After the cells were completely digested, 10-15 mL of cell culture was added to elute the digested cells. The eluate was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The resulting cells were resuspended in 10-20 mL of cell culture to obtain a single cell suspension.

[0277] 3. Cell plating: NCI-N87 / JIMT-1 / MBA-MB-231 single cell suspension was mixed thoroughly and plated in cell culture at 6 × 10 4 The viable cell density was adjusted to 1000 cells / mL. The density-adjusted cell suspension was mixed well and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator (37°C, 5% CO2) for 18 hours.

[0278] 4. Compound preparation: Compounds were dissolved in DMSO to give stock solutions with an initial concentration of 10 mM.

[0279] For small molecule compounds, there were a total of eight concentrations: 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM.

[0280] 5. Addition of samples: The prepared samples to be detected at different concentrations were added to the culture plate, and two wells for each sample were set up in duplicate. The culture plate was incubated in an incubator (37°C, 5% CO2) for 6 days.

[0281] 6. Color development: A 96-well cell culture plate was taken out, and 50 μL of CTG reagent was added per well, followed by incubation at room temperature for 10 minutes.

[0282] 7. Plate reading: The 96-well cell culture plate was taken out and placed into a microplate reader, and the chemiluminescence was measured using the microplate reader.

[0283] Data analysis: Data were processed and analyzed using Microsoft Excel and GraphPad Prism 5. [Table 8]

[0284] Conclusion: According to the results shown in Table 7, the small molecule fragments of the present application have significant inhibitory activity against the proliferation of NCI-N87, JIMT-1 and MDA-MB-231 cells. All compounds of the present application have similar inhibitory activity against tumor growth.

[0285] Test Example 5.3. Testing the Inhibition of In Vitro Growth of Tumor Cells by Compounds the purpose The inhibitory activity of pharmaceutical compounds against the in vitro proliferation of NCI-N87, JIMT-1, and MBA-MB-231 tumor cells is tested. The cells are treated with different concentrations of compounds in vitro, and after 6 days of culture, cell proliferation is detected using CTG (Cell Titer-Glo® Luminescent Cell Viability Assay, Promega, Cat. No. G7558) reagent. The in vitro activity of compounds is measured using IC 50 was evaluated according to the value.

[0286] 1. Cell culture: NCI-N87 / JIMT-1 / MBA-MB-231 cells were cultured in RPMI-1640 medium containing 10% FBS.

[0287] 2. Cell preparation: Log-phase NCI-N87 / JIMT-1 / MBA-MB-231 cells were harvested, washed once with PBS, and digested with 2-3 mL of trypsin for 2-3 minutes. After the cells were completely digested, 10-15 mL of cell culture was added to elute the digested cells. The eluate was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The resulting cells were resuspended in 10-20 mL of cell culture to obtain a single cell suspension.

[0288] 3. Cell plating: NCI-N87 / JIMT-1 / MBA-MB-231 single cell suspension was mixed thoroughly and plated in cell culture at 6 × 10 4 The viable cell density was adjusted to 1000 cells / mL. The density-adjusted cell suspension was mixed well and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator (37°C, 5% CO2) for 18 hours.

[0289] 4. Compound preparation: Compounds were dissolved in DMSO to give stock solutions with an initial concentration of 10 mM. For small molecule compounds, there were a total of eight concentrations: 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM.

[0290] 5. Addition of samples: The prepared samples to be detected at different concentrations were added to the culture plate, and two wells for each sample were set up in duplicate. The culture plate was incubated in an incubator (37°C, 5% CO2) for 6 days.

[0291] 6. Color development: A 96-well cell culture plate was taken out, and 50 μL of CTG reagent was added per well, followed by incubation at room temperature for 10 minutes.

[0292] 7. Plate reading: The 96-well cell culture plate was taken out and placed into a microplate reader, and the chemiluminescence was measured using the microplate reader.

[0293] Data analysis: Data were processed and analyzed using Microsoft Excel and GraphPad Prism 5. [Table 9]

[0294] Conclusion: According to the results shown in Table 8, the small molecule fragments of the present application have significant inhibitory activity against the proliferation of NCI-N87, JIMT-1 and MDA-MB-231 cells. All compounds of the present application have similar inhibitory activity against tumor growth.

[0295] Test Example 5.4. Testing the Inhibition of In Vitro Growth of Tumor Cells by Compounds the purpose The inhibitory activity of pharmaceutical compounds against the in vitro proliferation of NCI-N87 and Colo205 tumor cells is tested. The cells are treated with different concentrations of compounds in vitro, and after 6 days of culture, cell proliferation is detected using CTG (Cell Titer-Glo® Luminescent Cell Viability Assay, Promega, Cat. No. G7558) reagent. The in vitro activity of compounds is evaluated using IC 50 was evaluated according to the value.

[0296] 1. Cell culture: NCI-N87 / Colo205 cells were cultured in RPMI-1640 medium containing 10% FBS.

[0297] 2. Cell preparation: Log-phase NCI-N87 / Colo205 cells were harvested, washed once with PBS, and digested with 2–3 mL of trypsin for 2–3 minutes. After the cells were completely digested, 10–15 mL of cell culture medium was added to elute the digested cells. The eluate was centrifuged at 1,000 rpm for 5 minutes, and the supernatant was discarded. The resulting cells were resuspended in 10–20 mL of cell culture medium to obtain a single cell suspension.

[0298] 3. Cell plating: Mix the NCI-N87 / Colo205 single cell suspension thoroughly and incubate at 6 × 10 cells in cell culture. 4 The viable cell density was adjusted to 1000 cells / mL. The density-adjusted cell suspension was mixed well and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator (37°C, 5% CO2) for 18 hours.

[0299] 4. Compound preparation: Compounds were dissolved in DMSO to give stock solutions with an initial concentration of 10 mM.

[0300] For small molecule compounds, there were a total of eight concentrations: 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM.

[0301] 5. Addition of samples: The prepared samples to be detected at different concentrations were added to the culture plate, and two wells for each sample were set up in duplicate. The culture plate was incubated in an incubator (37°C, 5% CO2) for 6 days.

[0302] 6. Color development: A 96-well cell culture plate was taken out, and 50 μL of CTG reagent was added per well, followed by incubation at room temperature for 10 minutes.

[0303] 7. Plate reading: The 96-well cell culture plate was taken out and placed into a microplate reader, and the chemiluminescence was measured using the microplate reader.

[0304] Data analysis: Data were processed and analyzed using Microsoft Excel and GraphPad Prism 5. [Table 10]

[0305] Conclusion: According to the results shown in Table 9, the small molecule fragments of the present application have significant inhibitory activity against the proliferation of NCI-N87 cells and Colo205 cells. All compounds of the present application have similar inhibitory activity against tumor growth.

[0306] Test Example 5.5. Pharmacokinetic and Toxicity Test of ADC in Single Administration the purpose To investigate the pharmacokinetic properties of the drug in monkeys and to observe the occurrence of animal toxicity after a single intravenous infusion of the ADC in monkeys.

[0307] Test Method Pharmacokinetics: After a single intravenous infusion of ADC drugs at different doses in monkeys, blood samples were collected at multiple consecutive time points and blood drug concentrations were detected by appropriate specific methods.

[0308] Toxicity study: After a single intravenous infusion of ADC drugs at different doses in monkeys, the animal tolerance and manifestations of drug-related toxicity were investigated in multiple aspects, including clinical observation, body weight and food intake, hematology, blood biochemistry, urinary and gross anatomy.

[0309] Test results After a single intravenous infusion of the ADC in monkeys, the concentration of free toxin was very low, and the pharmacokinetic properties of the whole antibody and the ADC were similar, suggesting that the ADC is slowly released in monkeys, has a stable conjugation mode, and can be used at the clinically planned dosing frequency.

[0310] After a single intravenous infusion of the ADC in monkeys, the animals tolerated it well and showed no serious or unacceptable drug-related toxicity, suggesting that the ADC has a manageable safety profile and may be further clinically tested. All ADCs in this application have similar safety profiles.

[0311] Example 6: In vivo efficacy of ADCE-D01 ADCE-D01 is an antibody-drug conjugate with a theoretical molecular weight of 156 kDa. The drug-to-antibody ratio (DAR) is 8. ADCE-D01 has the following structure: [ka]

[0312] This structure is derived from the linker-payload combination L-III-30 described on page 162 of this specification. Maleimide conjugation to the humanized monoclonal antibody LC4HC3 (Ab in the structure) is achieved by complete conjugation to the two interchain heavy-light chain cysteines and the two interchain heavy chain cysteines. ADCE-D01 thereby contains the exatecan derivative P-III-30 shown hereinabove. Conjugation of the antibody to the antibody-drug conjugate drug substance (DS) is achieved by well-established TCEP reduction chemistry known to those skilled in the art of antibody-drug conjugates, where TCEP refers to tris(2-carboxyethyl)phosphine.

[0313] ADCE-D01 formulation (DP) is presented as a powder for solution for injection in 20 mL vials with a plastic cap and aluminum seal.

[0314] In vivo pharmacology The in vivo efficacy of the uPARAP-directed ADC ADCE-D01 was evaluated in two cell lines.

[0315] Leiomyoma is a subtype of soft tissue sarcoma derived from smooth muscle cells. The SK-LMS-1 cell line was established from a vaginal metastasis in a 43-year-old Caucasian woman (Fogh 1975c). CB17-SCID immunodeficient mice were inoculated subcutaneously with human SK-LMS-1 cells into the right flank. The mean tumor volume of the group was approximately 120 mm. 3 Treatment was initiated when the mice reached 3 mg / kg and 10 mg / kg of vehicle control (PBS), control ADC, and ADCE-D01.

[0316] Treatment was administered intravenously (IV) via the tail vein on days 0, 7, and 14 (q1wk x3). The control ADC (ADCE-D51) was an isotype-matched (IgG1) antibody against HIV gp120 (B12) (Parren et al. 1995) conjugated to L-III-30 (containing the payload P-III-30) at a DAR of 8. ADCE-D51 is therefore identical to ADCE-D01 in all respects except the antibody. Tumor size was monitored by caliper measurements three times weekly for up to 90 days. Tumor volume versus time data are shown in Figures 4a and 4b.

[0317] Dose-dependent antitumor activity was observed with ADCE-D01 at 3 mg / kg and 10 mg / kg when compared with PBS. Tumor growth inhibition by ADCE-D01 on day 14 was 62% and 94% at 3 mg / kg and 10 mg / kg, respectively. Tumor regression was observed at 10 mg / kg and persisted until day 28, two weeks after the last dose. Tumor growth resumed after day 28, but tumor size at that time was too large (800 mm 3 ), both the control ADC-treated group and the PBS-treated group were terminated.

[0318] Rhabdomyosarcoma is a type of soft tissue sarcoma that arises from skeletal (striatal) muscle cells. The RD cell line was derived directly from a human biopsy specimen with refractory RMS (McAllister et al. 1969).

[0319] CB17-SCID immunodeficient mice were inoculated subcutaneously with human RD cells in the right flank. The mean tumor volume of the group was approximately 150 mm 3 Treatment was initiated when the mice reached 3 mg / kg and 6 mg / kg of vehicle control (PBS), control ADC, and ADCE-D01.

[0320] Treatment was administered IV via the tail vein on days 0, 7, and 14 (q1wk x3). The control ADC was ADCE-D51 as described above for leiomyosarcoma. Tumor size was monitored by caliper measurements three times per week for up to 90 days. Tumor volume versus time data are shown in Figures 5a and 5b.

[0321] In the RD rhabdomyosarcoma model, dose-dependent antitumor activity was observed with ADCE-D01 at all doses tested when compared with PBS. Tumor growth inhibition at day 22 was 87% and 89% at 3 mg / kg and 6 mg / kg, respectively. Tumor regression was observed at 6 mg / kg and persisted until day 42, four weeks after the last dose. Although tumor growth resumed after day 42, the mean tumor volume at 6 mg / kg remained smaller than both the control ADC-treated group (6 mg / kg) and the PBS-treated group. [Table 11] JPEG2026502232000174.jpg222162JPEG2026502232000175.jpg225162JPEG2026502232000176.jpg227162JPEG2026502232000177.jpg58162

[0322] References J. Fogh and G. Trempe, “New Human Tumor Cell Lines,” In: J. Fogh, Ed., Human Tumor Cells in Vitro, Plenum Publishing Corp., New York, 1975, pp. 115-159. Parren PW, Ditzel HJ, Gulizia RJ, Binley JM, Barbas CF 3rd, Burton DR, Mosier DE. Protection against HIV-1 infection in hu-PBL-SCID mice by passive immunization with a neutralizing human monoclonal antibody against the gp120 CD4-binding site. AIDS. 1995 Jun;9(6):F1-6. doi: 10.1097 / 00002030-199506000-00001. PMID:7662189. McAllister, RM, Melnyk, J., Finklestein, JZ, Adams, EC, Jr. and Gardner, MB (1969), Cultivation in vitro of cells derived from a human rhabdomyosarcoma. Cancer, 24: 520-526. https: / / doi.org / 10.1002 / 1097-0142(196909)24:3<520::AID-CNCR2820240313>3.0.CO;2-M

[0323] item 1. An antibody-drug conjugate (ADC) comprising: i. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:3, and ii. an antibody that binds to uPARAP, comprising an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; the antibody-drug conjugate comprising: a. Formula (IA), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )-, -P(R 2)-, and -S-; L 2 is -(C(R 3a )(R 3b )) m -R, L 2 and 0 or 1 or more methylene units are independently -Cy-, -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, L 1 is -(C(R 5a )(R 5b )) n - and In the formula, L 1 and 0 or 1 or more methylene units are independently -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, -Cy- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cy- is unsubstituted or independently represents one or more substituents R 7 is replaced by In the formula, each R3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 , or R 4 and R 6 are each independently optionally joined together with the atoms therebetween to form ring B, wherein ring B is selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and ring B is unsubstituted or independently contains one or more substituents R 8 is replaced by In the formula, each R 2 , each R 7 , and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each Ra and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m and n are each independently selected from the group consisting of integers ≧1; R 1 binds the structure of formula (IA) to the antibody, optionally via a linker); b. Formula (II-A), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, X 1 is selected from the group consisting of N, P, and saturated or unsaturated C; X 1 If C is saturated, then X 1 But R n is replaced by Ring A attaches the structure according to formula II-A to the antibody, optionally via a linker; X 1 is a saturated C, then ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R 1a is replaced by or X 1 is an unsaturated C, then ring A is selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclyl, and 3-10 membered partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R 1b is replaced by or X 1is N or P, then ring A is selected from the group consisting of 5-8 membered heteroaryl and 3-10 membered saturated or partially unsaturated heterocyclyl, wherein ring A contains zero or more substituents R 1c is replaced by When ring A is selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, ring A is preferably selected from the group consisting of pL 2 wherein L 2 is R n Instead, Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl, ring A is pL 2 or ring A is substituted with q ring-forming heteroatom X 2 Contains X 2 is used to attach formula (II-A) to the antibody, optionally via a linker, X 2 is selected from the group consisting of N and P; L 2 -R 2 -L 3 - and R 2 is used to attach formula (II-A) to the antibody, optionally via a linker, L 3 Ha-(C(R 3a )(R 3b )) m - in which L 3 If contains a methylene unit, L 3 and 0 or 1 or more methylene units of -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, R 2 is -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-, L 1 is -(C(R 5a )(R 5b )) n - in which L 1 If contains a methylene unit, L 1 and 0 or 1 or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, In the formula, each R 1a , each R 1b , each R 1c , each R 2a , each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , each R 6 and each R n are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R aand each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m and n are each independently selected from the group consisting of integers > 0, and p and q are each independently selected from the group consisting of integers > 1, and c. Formula (III-A), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-; R 1 attaches a structure according to formula (III-A) to the antibody, optionally via a linker; X is -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 - and -L 3 -L 2 - selected from the group consisting of L 1 is -(C(R 3a )(R 3b )) m - in which L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, L 0 is -C(R 2a )(R 2b)- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 2 is -C(R 5a )(R 5b )-, wherein L 2 0 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, L 3 is -(C(R 7a )(R 7b )) n - and L 3 one or more methylene units independently represent -N(R 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- can also be substituted, In the formula, each R 1a , each R 1b , each R 2 , each R 2a , each R 2b , each R 3a , each R 3b , each R4a , each R 4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -HN- and X is -L 1 -L 0 - and L 0 If is -CH2-, L 1one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -O- and X is -L 3 -C(O)- and L 3 One methylene unit is -NR 8 If replaced by R 8 is not -CH2-CH2-NH2, R 1 is -NH- and X is -L 3 -C(O)-, L 3 One or more methylene units of -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-), wherein -N=N-, -C=N-, or -N=C- is replaced by -N=N-, -C=N-, or -N=C-.

[0324] 2. In formula (IA), each R 3a , each R 3b , each R 4 , each R 5a , each R 5b , and each R 6 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6and / or in formula (IA), R 3a and R 5a , R 4 and R 5a , R 3a and R 6 , or R 4 and R 6 are each independently and optionally taken together with the atoms therebetween to form ring B, wherein ring B is selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and ring B is unsubstituted or contains one or more substituents R 8 2. The antibody-drug conjugate of item 1, wherein

[0325] 3. In formula (IA), m is 1 or 2, and optionally, m is 1 and L 2 is -C(R 3a )(R 3b )-R, or optionally, m is 2 and L 2 is -(C(R 3a )(R 3b ))2-R and L 2 0 or 1 methylene unit is -Cy-, -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S -, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, preferably -C(O)- or -Cy-, for example, L 2 is -C(O)-C(R 3a )(R 3b )-R or -C(R 3a )(R 3b 3. The antibody-drug conjugate according to any one of items 1 to 2, wherein the antibody-drug conjugate is )-Cy-R.

[0326] 4. In formula (IA), L 2 0 or 1 methylene unit is -Cy-, -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, for example, L 2 wherein one methylene unit is replaced by -C(O)- or -Cy-.

[0327] 5. The antibody-drug conjugate according to any one of items 1 to 4, wherein in formula (IA), n is 2, 3, or 5.

[0328] 6. In formula (IA), n is 2 and L 1 But -(C(R 5a )(R 5b 6. The antibody-drug conjugate according to any one of items 1 to 5, wherein

[0329] 7. In formula (IA), L 1 is -(C(R 5a )(R 5b ))2- and L 1 0 methylene units are Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6)-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, or L 1 One methylene unit of -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, for example, L 1 is -(C(R 5a )(R 5b ))2- and L 1 one methylene unit is replaced by -C(O)- or -C(=S)-, for example, L 1 is -C(R 5a )(R 5b )-C(O)-, or L 1 is -C(R 5a )(R 5b 7. The antibody-drug conjugate according to any one of items 1 to 6, wherein R is —C(═S)—.

[0330] 8. In formula (IA), n is 3 and L 1 is -(C(R 5a )(R 5b 6. The antibody-drug conjugate according to any one of items 1 to 5, wherein

[0331] 9. In formula (IA), L 1 is -(C(R 5a )(R 5b ))3- and L 1 0 methylene units are -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, or L 1 One methylene unit of -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, for example, L 1 is -(C(R 5a )(R 5b 9. The antibody-drug conjugate of item 8, wherein the aryl group is 2-C(O)-.

[0332] 10. In formula (IA), n is 5 and L 1 But -(C(R 5a )(R 5b 6. The antibody-drug conjugate according to any one of items 1 to 5, wherein

[0333] 11. In formula (IA), L 1 is -(C(R 5a )(R 5b ))5- and L 1 One methylene unit of -NR 6 -, for example, in which L 1 is -(C(R 5a )(R 5b ))2-NR 6 -(C(R 5a )(R 5b ))2- or replaced by -O-, e.g., L 1 is (C(R5a )(R 5b ))2-O-(C(R 5a )(R 5b ))2- or In formula (IA), L 1 is -(C(R 5a )(R 5b ))5- and L 1 two methylene units are each independently -C(O)-, -NR 6 - or -O-, e.g., L 1 is selected from the group: -C(R 5a )(R 5b )-C(O)-NR 6 -(C(R 5a )(R 5b ))2-, -(C(R 5a )(R 5b ))2-NR 6 -C(O)-C(R 5a )(R 5b )-, and L 1 But -(C(R 5a )(R 5b ))2-OC(R 5a )(R 5b )-C(O)-, or In formula (IA), L 1 is -(C(R 5a )(R 5b )) 5- and L 1 wherein the three methylene units are each independently —C(O)— or —NR 6 - is replaced by, for example, L 1 is -(C(R 5a )(R 5b ))2-NR 6 11. The antibody-drug conjugate of item 10, wherein the C(O)-C(O)- moiety is -C(O)-C(O)-.

[0334] 12. In formula (IA), L 1 0 methylene units are -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6)-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, or in formula (IA), L 1 One methylene unit of -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, for example, -C(O)-, -C(=S)-, -NR 6 - or -O-, more preferably -C(O)-, or In formula (IA), L 1 two methylene units are each independently -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, for example, each independently -C(O)-, -NR 6 - or -O-, preferably -C(O)- or -NR 6replaced with -, or In formula (IA), L 1 three methylene units are each independently -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, for example, each independently -C(O)- or -NR 6 5. The antibody-drug conjugate of any one of items 1 to 4, wherein - is replaced by

[0335] 13. In formula (IA), R 3a and R 5a independently, optionally together with the atoms therebetween form ring B, and ring B is optionally a 3- to 10-membered saturated or partially unsaturated heterocyclylene, for example, ring B is a 3- to 6-membered saturated or partially unsaturated heterocyclylene, for example, ring B is a 5-membered saturated or partially unsaturated heterocyclylene, or In formula (IA), R 4 and R 5a and optionally, independently, together with the atom(s) therebetween, form ring B, and ring B is optionally a 3- to 10-membered saturated or partially unsaturated heterocyclylene, for example, ring B is a 6-membered saturated or partially unsaturated heterocyclylene. The antibody-drug conjugate of any one of items 1 to 2,

[0336] 14. In formula (IA), L 2 is -C(R 3a )(R 3b )-R or -(C(R 3a )(R 3b ))2-R and L 1is -(C(R 5a )(R 5b ))2-, -(C(R 5a )(R 5b ))3-, or -(C(R 5a )(R 5b 2. The antibody-drug conjugate of claim 1, wherein

[0337] 15. In formula (IA), L 2 is -(C(R 3a )(R 3b ))2-R and L 1 is -(C(R 5a )(R 5b ))2-, and optionally, L 1 One methylene unit of -C(O)-, -C(=S)-, -NR 6 - or -O-, e.g., L 2 is -(C(R 3a ))(R 3b ))2-R and L 1 is -C(R 5a )(R 5b )—C(O)—, and optionally, in formula (IA), R 3a and R 5a are independently, optionally taken together with the atoms between them, to form ring B, and ring B is optionally a 3- to 10-membered saturated or partially unsaturated heterocyclylene, for example, ring B is a 5-membered saturated heterocyclylene, or In formula (IA), L 2 is -C(R 3a )(R 3b )-R and L 1 is -(C(R 5a )(R 5b ))2-, and optionally, L 1 One methylene unit is -C(O)-, -C(=S)-, -NR 6 - or -O-, e.g., L 2 is -C(R 3a )(R 3b )-R and L 1 is -C(R 5a )(R 5b15. The antibody-drug conjugate of item 14, wherein the R is —C(O)—.

[0338] 16. In formula (IA), R 1 However, -O-, -(R 2 16. The antibody-drug conjugate according to any one of items 1 to 15, wherein the aryl group is selected from the group consisting of -N-, -N-, and -S-.

[0339] 17. In formula (IA), R 1 is -O- or R 1 is -(R 2 )N- and optionally R 2 is a hydrogen such as -HN-, or C 1-6 17. The antibody-drug conjugate according to any one of items 1 to 16, wherein the group is an aliphatic group.

[0340] 18. The antibody-drug conjugate according to any one of items 1 to 17, wherein in formula (IA), -Cy- is a 6- to 10-membered arylene, for example, phenylene.

[0341] 19. In formula (IA), R 7 19. The antibody-drug conjugate according to any one of items 1 to 18, wherein is hydrogen.

[0342] 20. In formula (IA), R 3a and R 3b are independently hydrogen, or R 3a and R 5a are independently, optionally taken together with the atoms therebetween, to form ring B, and ring B is optionally a 3- to 10-membered saturated or partially unsaturated heterocyclylene, for example, ring B is a 5-membered saturated heterocyclylene, or in formula (IA), R 4 is hydrogen, or R 4 and R 5a and optionally, independently, together with the atom(s) therebetween, form ring B. The antibody-drug conjugate of any one of items 1 to 2.

[0343] 21. In formula (IA), R 8is hydrogen.

[0344] 22. In formula (IA), R, R a and R b and each independently represents hydrogen.

[0345] 23. Formula (IA) is one of the formulas (IA-1) to (IA-17): [ka] In the formula, R 1 may be selected from the group consisting of -O-, -HN-, -P(=O)H-, and -S-, wherein R 1 The antibody-drug conjugate according to item 1, wherein the structure represented by any one of formulas (IA-1) to (IA-17) is bound to the antibody, optionally via a linker.

[0346] 24. In formula (II-A), X 1 is saturated C.

[0347] 25. The antibody-drug conjugate of any one of items 1 or 24, wherein, in formula (II-A), ring A is selected from the group consisting of 3- to 10-membered saturated heterocyclyl and 3- to 10-membered saturated carbocyclyl.

[0348] 26. The antibody-drug conjugate of any one of items 1 or 24 to 25, wherein, in formula (II-A), ring A is a 3- to 10-membered saturated carbocyclyl, for example, a 3- to 6-membered saturated carbocyclyl, for example, a 4-membered saturated carbocyclyl, or a 6-membered saturated carbocyclyl, or ring A is a 3- to 10-membered saturated heterocyclyl, for example, a 3- to 6-membered saturated heterocyclyl, for example, a 3-membered saturated heterocyclyl.

[0349] 27. The antibody-drug conjugate according to any one of items 1 or 24 to 26, wherein in formula (II-A), ring A contains one heteroatom, for example, one nitrogen atom.

[0350] 28. The antibody-drug conjugate of any one of items 1 or 24 to 26, wherein in formula (II-A), ring A is a 5-membered saturated heterocyclyl, and optionally, ring A contains one heteroatom, for example one nitrogen atom.

[0351] 29. In the formula (II-A), ring A is 0 substituents R 1a 29. The antibody-drug conjugate of any one of items 24 to 28, wherein

[0352] 30. In formula (II-A), X 1 is an unsaturated C.

[0353] 31. The antibody-drug conjugate of item 30, wherein in formula (II-A), ring A is selected from the group consisting of 6- to 10-membered aryl and 5- to 8-membered heteroaryl, and optionally, the 6- to 10-membered aryl is phenyl.

[0354] 32. In the formula (II-A), ring A is 0 substituents R 1b 32. The antibody-drug conjugate according to any one of items 30 to 31, wherein

[0355] 33. In formula (II-A), X 1 is N or P, preferably N.

[0356] 34. The antibody-drug conjugate according to any one of items 1 and 33, wherein in formula (II-A), ring A is selected from the group consisting of 5- to 8-membered heteroaryl and 3- to 10-membered saturated carbocyclyl.

[0357] 35. The antibody-drug conjugate according to any one of items 1 and 33 to 34, wherein, in formula (II-A), ring A is a 3- to 10-membered saturated heterocyclyl, for example, a 3- to 6-membered saturated heterocyclyl, for example, a 6-membered saturated heterocyclyl, and optionally, ring A independently contains two heteroatoms, for example, two nitrogen atoms.

[0358] 36. In the formula (II-A), ring A is 0 substituents R 1c 36. The antibody-drug conjugate of any one of items 33 to 35, wherein

[0359] 37. The formula (II-A) has a structure shown as formula (II-Ax): [ka] When ring A is selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, ring A is preferably selected from the group consisting of pL 2 is replaced by Or when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl, ring A is pL 2 2. The antibody-drug conjugate of item 1, wherein

[0360] 38. The formula (II-A) is a structure shown as formula (II-Ay): [ka] In the formula, ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl, and ring A is a ring-forming heteroatom X 2 Contains X 2 is used to bind to the antibody, optionally via a linker.

[0361] 39. The antibody-drug conjugate according to item 1, wherein in formula (II-A), ring A is selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated carbocyclyl.

[0362] 40. The antibody-drug conjugate of any one of items 1 and 39, wherein, in formula (II-A), ring A is selected from the group consisting of phenyl and 3- to 6-membered saturated carbocyclyl, for example, 4-membered saturated carbocyclyl or 6-membered saturated carbocyclyl, for example, ring A is phenyl.

[0363] 41. In formula (II-A), ring A is one or more L 2 , for example, one L 2 41. The antibody-drug conjugate according to any one of items 1 and 39 to 40, wherein

[0364] 42. The antibody-drug conjugate of any one of items 1 and 39, wherein in formula (II-A), ring A is a 3- to 10-membered saturated heterocyclyl, for example, a 3- to 6-membered saturated heterocyclyl, optionally a 3-membered saturated heterocyclyl or a 5-membered saturated heterocyclyl or a 6-membered saturated heterocyclyl.

[0365] 43. In formula (II-A), ring A is one or more L 2 , for example, one L 2 43. The antibody-drug conjugate of item 42, wherein

[0366] 44. In formula (II-A), m is 0, 1, or 2, and optionally, m is 0 and L 3 is a covalent bond, or m is 1 and L 3 But -C(R 5a )(R 5b )- and optionally, L 3 0 methylene units in -N(R 4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, or m is 2 and L 3 is -(C(R 3a )(R 3b ))2-, and optionally, L 3 0 methylene units in -N(R4 )C(O)-, -C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-, -P(=O)(R 4 )-, -N(R 4 )SO2-, -SO2N(R 4 )-, -C(=S)-, -C(=NR 4 2. The antibody-drug conjugate of item 1, wherein N is substituted with -N=N-, -C=N-, -N=C-, or -C(=N2)-.

[0367] 45. Ring A has one or more ring-forming heteroatoms X 2 , e.g., one X 2 Contains X 2 is optionally used to bind to the antibody via a linker, and optionally X 2 is N.

[0368] 46. ​​n is 0 or 1, and optionally, n is 0 and L 1 is a covalent bond, or Optionally, n is 1 and L 1 is -C(R 5a )(R 5b )- and optionally, L 1 One or more methylene units of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 46. ​​The antibody-drug conjugate of any one of items 1 to 45, wherein the substituted or unsubstituted N is replaced by -N=N-, -C=N-, -N=C-, or -C(=N2)-, such as C(O)-.

[0369] 47.R 2 However, -O-, -(R 2a 47. The antibody-drug conjugate according to any one of items 1 to 46, wherein the aryl group is selected from the group consisting of -N-, -N-, and -S-.

[0370] 48.R 2 is -O- or R 2 is -(R 2A )N- and optionally R 2a 48. The antibody-drug conjugate according to any one of items 1 to 47, wherein is hydrogen, such as -HN-.

[0371] 49.R 1a 30. The antibody-drug conjugate according to any one of items 1 to 29, wherein is hydrogen.

[0372] 50.R 1b 34. The antibody-drug conjugate according to any one of items 1 and 30 to 33, wherein is hydrogen.

[0373] 51.R 1c 37. The antibody-drug conjugate according to any one of items 1 and 33 to 36, wherein is hydrogen.

[0374] 52.R 3a and R 3b are each independently hydrogen, and / or R 4 is hydrogen, and / or R 5a and R 5b are each independently hydrogen, and / or R 6 are hydrogen, and / or R, R a and R b and each independently represent hydrogen.

[0375] 53. Formula II-A is according to any one of formulas (II-A-1) to (II-A-12): [ka] In the formula, R 2 is selected from the group consisting of -O-, -HN-, -P(=O)H-, and -S-; X 2 is selected from the group consisting of N and P, and R 2 or X 2 The antibody-drug conjugate according to item 1, wherein any one of the structures shown in formulae (II-A-1) to (II-A-12) is linked to the antibody, optionally via a linker.

[0376] 54. In formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)- and R 1 is -S- or -(R 2 )N- and R 2 is not hydrogen.

[0377] 55. In formula (III-A), L 1 is -(C(R 3a )(R 3b )) m - and L 1 0 or 1 methylene unit is -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, e.g., L 1 55. The antibody-drug conjugate of any one of items 1 to 54, wherein one methylene unit of the formula (I) is replaced with -C(O)-.

[0378] 56. In formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)- and R 1 is -O- or -HN-, m is not 0, and L 1 one or more methylene units are -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, for example replaced by one methylene unit, and optionally, in formula (III-A), L 1 2. The antibody-drug conjugate of item 1, wherein one methylene unit of

[0379] 57. In formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)- and R 1 is -O- or -HN-, and L 1 is -(C(R 3a )(R 3b )) m - and m is not 0, L 1 The 0 methylene units are -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, and each R 3a and each R 3b Both are hydrogen, and R 1a and R 1b is hydrogen.

[0380] 58. In formula (III-A), X is -L 1 -C(R 1a )(R 1b 2. The antibody-drug conjugate of item 1, wherein m is 0, 1, or 2.

[0381] 59. In formula (III-A), m is 0 and L 1 is a covalent bond, and optionally further, in formula (III-A), R 1 (R 2 )N- or -S-, R 2 59. The antibody-drug conjugate of any one of items 1 and 58, wherein

[0382] 60. In formula (III-A), m is 1 and L 1 is -C(R 3a )(R 3b )- and optionally, L 1 The 0 methylene units are -C(O)-, -C(=S)-, -C(=NR 4b 59. The antibody-drug conjugate of any one of items 1 and 58, wherein -C(=N)- or -C(=N2)- is replaced by -C(=N)-.

[0383] 61. In formula (III-A), R1 is (R 2 )N- or -S-, R 2 is not hydrogen and optionally, R 1 is -S- and / or R 1 is -S- and R 1a and R 1b is hydrogen, or R 1a and R 1b are each independently -N(R a )(R b ), for example, R 1a is -N(R a )(R b 61. The antibody-drug conjugate of any one of items 1, 58, and 60, wherein

[0384] 62. The antibody-drug conjugate according to any one of items 1, 58, and 60 to 61, wherein in formula (III-A), R is hydrogen.

[0385] 63. In formula (III-A), R 1 is -(R 2 )N- and R 2 is C such as methyl 1-6 63. The antibody-drug conjugate according to any one of items 1 to 62, wherein the group is an aliphatic group.

[0386] 64. In formula (III-A), L 1 is -C(R 3a )(R 3b )- and R 1 is -O- or -HN-, and L 1 The 0 methylene units are -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, and R 3a and R 3b and optionally, R 1 is -O- and / or R 3a is C 1-6 an aliphatic group, optionally R 3a is C 1-6 is an aliphatic group, R 3b is hydrogen or C 1-6is an aliphatic group, e.g., R 3a is C 1-6 is an aliphatic group, R 3b 63. The antibody-drug conjugate according to any one of items 1 to 62, wherein is hydrogen.

[0387] 65. In formula (III-A), R 3a is methyl and R 3b 65. The antibody-drug conjugate according to any one of items 1 to 62 and 64, wherein is hydrogen.

[0388] 66. In formula (III-A), R 3a is C 1-6 is an aliphatic group, R 3b is C 1-6 is an aliphatic group, e.g., R 3a is methyl and R 3b is C 1-6 is an aliphatic group, such as R 3a is methyl and R 3b is methyl.

[0389] 67. In formula (III-A), m is 2 and L 1 is -(C(R 3a )(R 3b ))2-, and optionally, in formula (III-A), L 1 One methylene unit of -C(O)-, -C(=S)-, -C(=NR 4b 59. The antibody-drug conjugate of any one of items 1 and 58, wherein -C(═N)- or -C(═N)- is replaced by -C(O)-, for example, -C(O)-.

[0390] 68. In formula (III-A), R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 68. The antibody-drug conjugate of any one of items 1, 58 and 67, wherein the R is selected from the group consisting of -R-, -S ...

[0391] 69. In formula (III-A), R 1 is -O-, or R1 is -S- or R 1 is -(R 2 )N- and optionally R 2 is C such as methyl 1-6 69. The antibody-drug conjugate according to any one of items 1, 58, and 67 to 68, wherein the group is an aliphatic group.

[0392] 70. In formula (III-A), X is -L 1 -L 0 - and R 1 is -O-, -S- or -(R 2 )N- and R 2 is not hydrogen, and optionally, L 1 is -C(R 3a )(R 3b ) and L 1 0 or 1 methylene unit is -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, for example, replaced by -C(O)-, or In formula (III-A), X is -L 1 -L 0 - and R 1 is -HN-, m is not 0, L 0 -C(=S)-, -C(=NR 4a )-, or -C(=N2)-, or In formula (III-A), X is -L 1 -L 0 - and R 1 is -HN-, m is not 0, L 0 -C(R 2a )(R 2b )- and L 1 is -(C(R 3a )(R 3b )) m - and each R 3a and each R 3b and n are not hydrogen.

[0393] 71. In formula (III-A), X is -L 1 -L 0-, m is 1 or 2, optionally, wherein m is 1 and L 1 is -C(R 3a )(R 3b )- and optionally, L 1 The 0 methylene units are -C(O)-, -C(=S)-, -C(=NR 4b 2. The antibody-drug conjugate of item 1, wherein the R is substituted with —C(═N)—, or —C(═N)—.

[0394] 72. In formula (III-A), R 1 is (R 2 )N- or -S-, R 2 is not hydrogen and optionally, R 1 72. The antibody-drug conjugate of any one of items 1 and 71, wherein is -S-.

[0395] 73. In formula (III-A), m is 2 and L 1 is -(C(R 3a )(R 3b ))2-, and optionally, in formula (III-A), L 1 The 0 methylene units are -C(O)-, -C(=S)-, -C(=NR 4b 72. The antibody-drug conjugate of any one of items 1 and 71, wherein the R is replaced by —C(═N)—, or —C(═N)—.

[0396] 74. In formula (III-A), R 1 is -O-, -S-, or (R 2 )N- and R 2 is not hydrogen and optionally, R 1 is -(R 2 )N- and R 2 is not hydrogen and optionally, R 2 is C 1-6 an aliphatic group, for example methyl; or the antibody-drug conjugate of any one of items 1, 71 and 73.

[0397] 75. In formula (III-A), R 1 The antibody-drug conjugate according to any one of items 1, 71, and 73 to 74, wherein is -O-.

[0398] 76. In formula (III-A), R 3a is C 1-6 is an aliphatic group, and / or R 3a is C 1-6 is an aliphatic group, R 3b is hydrogen or C 1-6 and / or in formula (III-A), R 3a is C 1-6 is an aliphatic group, R 3b is C 1-6 and / or in formula (III-A), R 3a is methyl and R 3b is C 1-6 and / or in formula (III-A), R 3a is methyl and R 3b is methyl.

[0399] 77. In formula (III-A), L 1 is -C(R 3a )(R 3b 77. The antibody-drug conjugate according to any one of items 1, 71, and 73 to 76, wherein the carboxyl group is —C(CH3)2—.

[0400] 78. In formula (III-A), X is -L 3 -L 2 -, and in formula (III-A), L 2 is -C(R 5a )(R 5b )- and L 3 is -(C(R 7a )(R 7b )) n - and R 1 is -S- or -(R 2 )N- and R 2 is not hydrogen.

[0401] 79. In formula (III-A), X is -L 3 -L 2-, and in formula (III-A), L 2 is -C(O)- and R 1 is -O- and L 3 is -(C(R 7a )(R 7b )) n - and L 3 One methylene unit is -NR 8 If replaced by R 8 is replaced by -NH2 1-6 2. The antibody-drug conjugate of item 1, wherein the group is not an aliphatic group.

[0402] 80. In formula (III-A), L 3 One methylene unit of -NR 8 80. The antibody-drug conjugate of any one of items 1 and 79, wherein -, -O-, or -SO- is replaced by -.

[0403] 81. In formula (III-A), R 8 is C 1-6 is an aliphatic group, R 8 is hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Optionally substituted with aliphatic groups, e.g., R 8 is C 1-3 is an aliphatic group, R 8 is unsubstituted.

[0404] 82. In formula (III-A), X is -L 3 -L 2 -, and in formula (III-A), L 2 is -C(O)- and R 1 is -HN- and L 3 -(C(R 7a )(R 7b )) n -If L 3At least one methylene unit of -N(R 8 )C(O)-, -OC(O))-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 2. The antibody-drug conjugate of item 1, wherein -N=N-, -C=N-, or -N=C- is replaced by -N=N-, -C=N-, or -N=C-.

[0405] 83. In formula (III-A), X is -L 3 -L 2 -, n is 4, and L 3 is -(C(R 7a )(R 7b 2. The antibody-drug conjugate of claim 1, wherein

[0406] 84. In formula (III-A), L 2 is -C(R 5a )(R 5b )-, and in formula (III-A), L 2 One methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C-, or -C(=N2)-, for example, in formula (III-A), L 2 One methylene unit of is replaced by -C(O)-, and L 2 84. The antibody-drug conjugate of any one of items 1 and 83, wherein is —C(O)—.

[0407] 85. In formula (III-A), L 3 One methylene unit of -N(R 8)C(O)-, -C(O))N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, preferably -NR 8 -, -O- or -SO-, more preferably -NR 8 -, where R 8 is C 1-6 85. The antibody-drug conjugate according to any one of items 1 and 83 to 84, wherein the group is an aliphatic group, for example, methyl.

[0408] 86. In formula (III-A), X is -(C(R 7a )(R 7b ))2-N(CH3)-C(R 7a )(R 7b 86. The antibody-drug conjugate according to any one of items 1 and 83 to 85, wherein the carboxyl group is —C(O)—.

[0409] 87. In formula (III-A), L 3 86. The antibody-drug conjugate according to any one of items 1 and 83 to 85, wherein one methylene unit of the formula (I) is replaced with -SO-.

[0410] 88. In formula (III-A), X is -(C(R 7a )(R 7b ))2-SO-C(R 7a )(R 7b 88. The antibody-drug conjugate according to items 1 and 87, wherein the carboxyl group is —C(O)—.

[0411] 89. In formula (III-A), L 3 2. The antibody-drug conjugate of item 1, wherein one methylene unit of

[0412] 90. In formula (III-A), X is -(C(R 7a )(R7b ))2-OC(R 7a )(R 7b 90. The antibody-drug conjugate of any one of items 1 and 89, wherein R is —C(O)—.

[0413] 91. In formula (III-A), R 1a and R 1b are each independently hydrogen or -N(R a )(R b ) and / or In formula (III-A), R 2 is C 1-6 Aliphatic groups, e.g., C 1-3 is an aliphatic group, such as R 2 is methyl, and / or In formula (III-A), R 3a and R 3b are each independently hydrogen or C 1-6 is an aliphatic group, such as R 3a and R 3b are each independently C 1-3 is an aliphatic group, e.g., R 3a and R 3b is methyl, and / or In formula (III-A), R 4a and R 4b is hydrogen, and / or In formula (III-A), R 5a and R 5b is hydrogen, and / or In formula (III-A), R 6 is hydrogen, and / or In formula (III-A), R 7a and R 7b is hydrogen, and / or In formula (III-A), R 8 is C 1-6 Aliphatic groups, e.g., C 1-3 is an aliphatic group, such as R 8 is methyl.

[0414] 92. R, R aand R b is hydrogen.

[0415] 93. Formula (III-A) is one of the formulas (III-A-1) to (III-A-17): [ka] Item 1, wherein the wavy line represents a bond between the antibody and the structure represented by any one of formulas (III-A-1) to (III-A-17), optionally via a linker.

[0416] 94. The antibody-drug conjugate comprises the structure shown in formula (IC): [ka] L binds the structure represented by formula (IC) to the antibody, and L is -L a -L b -L c - and L a , L b , and L c each has the meaning defined in any of formula (IB) herein, and R 1 , L 1 and L 2 wherein each of the formulas (IA) is defined as in any of the embodiments described hereinabove.

[0417] 95. The antibody-drug conjugate is represented by the formula (II-C x ) or formula (II-C y ) including the structure shown in: [ka] In the formula, L is -L a -L b -L c - may be L a , L b and L cis defined as in any of the embodiments of formula (II-Bx) described hereinabove, L 2 , p, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, or X 2 , q, ring A, X 1 and L 1 is defined as in any of the embodiments of formula (II-Ay) described herein above.

[0418] 96. The antibody-drug conjugate comprises the structure shown in formula (III-C): [ka] In the formula, L is -L a -L b -L c -, and L binds the structure of formula (III-C) to the antibody, -L a -teeth: [ka] is selected from the group consisting of In the formula, W is -(C(R wa )(R wb )) wn - and Y is -(OCH2CH2) yn -O yp and Z is -(C(R za )(R zb )) zn and Z connects -La- to -Lb-, wherein wn is selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(Rwx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, wherein yn is selected from the group consisting of integers ≧0, and yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx is replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r, -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C replaced by 1-6 is an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 is an aliphatic group, -L b - represents a peptide residue consisting of 2 to 7 amino acids, -L c -teeth: [ka] is selected from the group consisting of In the formula, R L1 and R L2 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 is selected from the group consisting of aliphatic groups; In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is -L 1 -C(R 1a )(R1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 - and -L 3 -L 2 - selected from the group consisting of L 1 is -(C(R 3a )(R 3b )) m - in which L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, L 0 is -C(R 2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 2 is -C(R 5a )(R 5b )-, wherein L 2 0 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, L 3 is -(C(R 7a )(R 7b )) n - and L 3 one or more methylene units independently represent -N(R 8 )C(O)-, -C(O)N(R 8)-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- can also be substituted, In the formula, each R 1a , each R 1b , each R 2 , each R 2a , each R 2b , each R 3a , each R 3b , each R 4a , each R 4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -HN- and X is -L 1 -L 0 - and L 0 If is -CH2-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -O- and X is -L 3 -C(O)- and L 3 One methylene unit is -NR 8 If replaced by R 8 is not -CH2-CH2-NH2, R 1 is -NH- and X is -L 3 -C(O)-, L 3 One or more methylene units of -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 2. The antibody-drug conjugate of item 1, wherein -N=N-, -C=N-, or -N=C- is replaced by -N=N-, -C=N-, or -N=C-.

[0419] 97. The antibody-drug conjugate comprises the structure shown in formula (ID): [ka] wherein Ab is the antibody that binds to uPARAP, and the antibody is: i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; N a is an integer or decimal number between 1 and 10, L is -L a -L b -L c - may be L a , L b and L c is defined as in any of the embodiments of formula (IB) described hereinabove, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described herein above.

[0420] 98. The antibody-drug conjugate comprises a structure shown in formula (II-Dx) or formula (II-Dy): [ka] wherein Ab is the antibody that binds to uPARAP, and the antibody is: i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; N a is an integer or decimal number between 1 and 10, L is -L a -L b -L c - may be L a, L b and L c is defined as in either formula (II-Bx) or formula (II-By) of the embodiments described hereinabove, L 2 , Ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, or X 2 , Ring A, X 1 and L 1 is defined as in any of the embodiments of formula (II-Ay) described herein above.

[0421] 99. The antibody-drug conjugate comprises the structure shown in formula (III-D): [ka] wherein Ab is the antibody that binds to uPARAP, and the antibody is: i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; N a is an integer or decimal number between 1 and 10, L is -L a -L b -L c and L binds the structure of formula (III-D) to the antibody; -L a -teeth: [ka] is selected from the group consisting of In the formula, W is -(C(R wa )(R wb )) wn - and Y is -(OCH2CH2) yn -O yp and Z is -(C(R za)(R zb )) zn and Z connects -La- to -Lb-, wherein wn is selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, wherein yn is selected from the group consisting of integers ≧0, and yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx is replaced by In the formula, each R wa , each R wb , each Rza , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C replaced by 1-6 is an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 is an aliphatic group, -L b - represents a peptide residue consisting of 2 to 7 amino acids, -L c -teeth: [ka] is selected from the group consisting of In the formula, R L1 and R L2are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 is selected from the group consisting of aliphatic groups; In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 - and -L 3 -L 2 - selected from the group consisting of L 1 is -(C(R 3a )(R 3b )) m - in which L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, L 0 is -C(R 2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 2 is -C(R 5a )(R 5b )-, wherein L 2 0 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, L 3 is -(C(R 7a )(R 7b )) n - and L 3 one or more methylene units independently represent -N(R 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- can also be substituted, In the formula, each R 1a , each R 1b , each R 2 , each R 2a , each R 2b , each R 3a , each R 3b , each R 4a , each R 4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(Rb ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -HN- and X is -L 1 -L 0 - and L 0 If is -CH2-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -O- and X is -L 3 -C(O)- and L 3 One methylene unit is -NR 8 If replaced by R 8 is not -CH2-CH2-NH2, R 1is -NH- and X is -L 3 -C(O)-, L 3 One or more methylene units of -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 2. The antibody-drug conjugate of item 1, wherein -N=N-, -C=N-, or -N=C- is replaced by -N=N-, -C=N-, or -N=C-.

[0422] 100. The antibody-drug conjugate according to any one of items 1 and 94 to 99, wherein the antibody-drug conjugate is according to any one of the structures shown in Table 2, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0423] 101. An antibody-drug conjugate (ADC), a. i. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:3, and ii. An antibody that binds to uPARAP, comprising an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; b. i. Formula (IE), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described hereinabove), ii. Formula (II-Ex) or Formula (II-Ey), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (For formula (II-Ex), L 2 , p, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, and for formula (II-Ey), X 2 , q, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ay) described hereinabove), and iii. Formula (III-E), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 - and -L 3 -L 2 - selected from the group consisting of L 1 is -(C(R 3a )(R 3b )) m - in which L 1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b)- or -C(=N2)-, L 0 is -C(R 2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 2 is -C(R 5a )(R 5b )-, wherein L 2 0 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, L 3 is -(C(R 7a )(R 7b )) n - and L 3 one or more methylene units independently represent -N(R 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- can also be substituted, In the formula, each R 1a , each R 1b , each R2 , each R 2a , each R 2b , each R 3a , each R 3b , each R 4a , each R 4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -HN- and X is -L1 -L 0 - and L 0 If is -CH2-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -O- and X is -L 3 -C(O)- and L 3 One methylene unit is -NR 8 If replaced by R 8 is not -CH2-CH2-NH2, R 1 is -NH- and X is -L 3 -C(O)-, L 3 One or more methylene units of -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-), and c. The antibody-drug conjugate, optionally comprising a linker connecting a) to b).

[0424] 102. The antibody-drug conjugate of any one of items 1 or 101, wherein the active agent is selected from any one of the structures in Table 1, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof.

[0425] 103. A method for producing an antibody-drug conjugate according to any one of the preceding paragraphs, comprising: a. Formula (IF), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, L x L ax -L b -L c - and L ax -teeth: [ka] is selected from the group consisting of In the formula, R hal is iodine or bromine, In the formula, W is -(C(R wa )(R wb )) wn - and Y is -(OCH2CH2) yn -O yp - and Z is -(C(R za )(R zb )) zn and wherein wn is selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, wherein yn is selected from the group consisting of integers ≧0, and yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx is replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C replaced by 1-6 is an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 is an aliphatic group, L b and L c is defined as in any of the embodiments of formula (IB) described hereinabove, R 1 , L 1 , and L 2 is defined as in any of the embodiments of formula (IA) described hereinabove), b.Formula (II-F x ) or (II-F y ), or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, L x L ax -L b -L c - and L ax -teeth: [ka] is selected from the group consisting of In the formula, R hal is iodine or bromine, In the formula, W is -(C(R wa )(R wb )) wn - and Y is -(OCH2CH2) yn -O yp- and Z is -(C(R za )(R zb )) zn and wherein wn is selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, wherein yn is selected from the group consisting of integers ≧0, and yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx is replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zxand each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C replaced by 1-6 is an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 is an aliphatic group, L b and L c is defined as in either formula (II-Bx) or formula (II-By) of the embodiments described hereinabove, In the formula, L 2 , p, ring A, X 1 , and L 1 is defined as in any of the embodiments of formula (II-Ax) described hereinabove, or X 2 , q, ring A, X 1 and L 1 is defined as in any of the embodiments of formula (II-Ay) described hereinabove), and c. Formula (III-F), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof [ka] (In the formula, L x L ax -L b -L c - and L ax -teeth: [ka] is selected from the group consisting of In the formula, R hal is iodine or bromine, In the formula, W is -(C(R wa )(R wb )) wn - and Y is -(OCH2CH2) yn -O yp - and Z is -(C(R za )(R zb )) zn and wherein wn is selected from the group consisting of integers ≧0; The zero or more methylene units of W are independently -Cyr-, -N(R wx )C(O)-, -C(O)N(R wx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR wx -, -O-, -S-, -SO-, -SO2-, -P(R wx )-, -P(=O)(R wx )-, -N(R wx )SO2-, -SO2N(R wx )-, -C(=S)-, -C(=NR wx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, wherein yn is selected from the group consisting of integers ≧0, and yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R zx )C(O)-, -C(O)N(R zx )-, -C(O)-, -OC(O)-, -C(O)O-, -NR zx -, -O-, -S-, -SO-, -SO2-, -P(R zx )-, -P(=O)(R zx )-, -N(R zx )SO2-, -SO2N(R zx )-, -C(=S)-, -C(=NR zx )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently represents one or more substituents R cx is replaced by In the formula, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO2R r , -C(O)C(O)R r , -C(O)CHC(O)R r , -S(O)R r , -S(O)2R r , -C(O)N(R ra )(R rb ), -SO2N(R ra )(R rb ), -OC(O)R r , -N(R)SO2R r or optionally R r C replaced by 1-6 is an aliphatic group, In the formula, each R r , each R ra and each R rb are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H or C 1-6 is an aliphatic group, -L b - represents a peptide residue consisting of 2 to 7 amino acids, -L c -teeth: [ka] is selected from the group consisting of In the formula, R L1 and R L2 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, and C 1-6 is selected from the group consisting of aliphatic groups; In the formula, R 1 is -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 - and -L 3 -L 2 - selected from the group consisting of L 1 is -(C(R 3a )(R 3b )) m - in which L1 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, C(=NR 4b )- or -C(=N2)-, L 0 is -C(R 2a )(R 2b )- or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-, L 2 is -C(R 5a )(R 5b )-, wherein L 2 0 or 1 methylene unit of -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-, -P(=O)(R 6 )-, -N(R 6 )SO2-, -SO2N(R 6 )-, -C(=S)-, -C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-, L 3 is -(C(R 7a )(R 7b )) n - and L 3 one or more methylene units independently represent -N(R 8 )C(O)-, -C(O)N(R 8 )-, -OC(O)-, -C(O)O-, -NR 8 -, -O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-, and L 3 wherein 0 or 1 or more methylene units are independently -C(O)-, -C(=S)-, -C(=NR 8)- or -C(=N2)- can also be substituted, In the formula, each R 1a , each R 1b , each R 2 , each R 2a , each R 2b , each R 3a , each R 3b , each R 4a , each R 4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a )(R b ), -SO2N(R a )(R b ), -OC(O)R, -N(R)SOR, or C optionally substituted with R 1-6 is an aliphatic group, In the formula, each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, or each R 3aand each R 3b are not both hydrogen, R 1 is -HN- and X is -L 1 -L 0 - and L 0 If is -CH2-, L 1 one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b are not both hydrogen, R 1 is -O- and X is -L 3 -C(O)- and L 3 One methylene unit is -NR 8 If replaced by R 8 is not -CH2-CH2-NH2, R 1 is -NH- and X is -L 3 -C(O)-, L 3 One or more methylene units of -N(R 8 )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -P(R 8 )-, -P(=O)(R 8 )-, -N(R 8 )SO2-, -SO2N(R 8 )-, -N=N-, -C=N-, or -N=C-), reacting a compound selected from the group consisting of: -N=N-, -C=N-, or -N=C- with the antibody defined in item 1.

[0426] 104.L ax -teeth, [ka] Item 104. The method according to Item 103, wherein

[0427] 105.L ax -L b -L c -teeth: [ka] 105. The method according to any one of items 103 to 104, selected from the group consisting of:

[0428] 106. The method according to any one of items 103 to 105, wherein the compound is selected from any one of the structures in Table 3, or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof.

[0429] 107. The antibody: a. an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 1, and b. The antibody-drug conjugate of any one of items 1 to 106, comprising an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 4.

[0430] 108. The antibody is: a. an immunoglobulin light chain consisting of the amino acid sequence of SEQ ID NO: 1, and b. The antibody-drug conjugate according to any one of items 1 to 107, comprising an immunoglobulin heavy chain consisting of the amino acid sequence of SEQ ID NO: 4.

Claims

1. An antibody drug conjugate (ADC) comprising: i. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii. an antibody that binds to uPARAP, comprising an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; the antibody-drug conjugate comprising: a. Formula (III-A), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, R １ is -O-, -(R ２ )N-, -P(=O)(R ２ )- and -S-; R １ attaches a structure according to formula (III-A) to the antibody, optionally via a linker; X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-,-L １ -C(R １ａ ) (R １ｂ )-C(S)-,-L １ -L ０ - and -L ３ -L ２ - selected from the group consisting of L １ is -(C(R ３ａ ) (R ３ｂ )) ｍ -, wherein L １ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, C(=NR ４ｂ )- or -C(=N ２ ) - is replaced by L ０ is -C(R ２ａ ) (R ２ｂ )—, or L ０ is -C(=S)-, -C(=NR ４ａ ) - or -C(=N ２ ) - and L ２ is -C(R ５ａ ) (R ５ｂ )—, wherein L ２ 0 or 1 methylene unit of -N(R ６ )C(O)-, -C(O)N(R ６ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ６ -, -O-, -S-, -SO-, -SO ２ -, -P(R ６ )-, -P(=O)(R ６ ) -, -N(R ６ ) SO ２ -, -SO ２ N (R ６ )-, -C(=S)-, -C(=NR ６ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by L ３ is -(C(R ７ａ ) (R ７ｂ )) ｎ - and L ３ one or more methylene units of ８ )C(O)-, -C(O)N(R ８ )-, -OC(O)-, -C(O)O-, -NR ８ -, -O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ )-, -N=N-, -C=N-, or -N=C-, and L ３ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ８ ) - or -C(=N ２ ) - but replaced, In the formula, each R １ａ , each R １ｂ , each R ２ , each R ２ａ , each R ２ｂ , each R ３ａ , each R ３ｂ , each R ４ａ , each R ４ｂ , each R ５ａ , each R ５ｂ , each R ６ , each R ７ａ , each R ７ｂ and each R ８ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, In the formula, each R, each R ａ and each R ｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R １ is —O— or —HN—, and X is —L １ -CH ２ When —C(O)—, L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ ) - or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -HN- and X is -L １ -L ０ - and L ０ Ga-CH ２ -, then L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ )- or -C(=N ２ ) -, or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -O- and X is -L ３ -C(O)- and L ３ One methylene unit is -NR ８ When replaced by R ８ Ha-CH ２ -CH ２ -NH ２ Instead, R １ is -NH- and X is -L ３ When —C(O)—, L ３ At least one methylene unit of -N(R ８ )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ ) -, -N=N-, -C=N-, or -N=C-), b. Formula (IA), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof 【Chemistry 2】 (In the formula, R １ is -O-, -(R ２ )N-, -P(=O)(R ２ ) -, -P(R ２ )-, and -S-; L ２ is -(C(R ３ａ ) (R ３ｂ )) ｍ -R, L ２ and 0 or 1 or more methylene units independently represent -Cy-, -N(R ４ )C(O)-, -C(O)N(R ４ )-, C(O)-, -OC(O)-, -C(O)O-, -NR ４ -, -O-, -S-, -SO-, -SO ２ -, -P(R ４ )-, -P(=O)(R ４ ) -, -N(R ４ ) SO ２ -, -SO ２ N (R ４ )-, -C(=S)-, -C(=NR ４ )-, -N=N-, -C=N-, -N=C-, or -C(=N ２ ) - is replaced by L １ is -(C(R ５ａ ) (R ５ｂ )) ｎ - and In the formula, L １ and 0 or 1 or more methylene units independently represent -Cy-, -N(R ６ )C(O)-, -C(O)N(R ６ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ６ -, -O-, -S-, -SO-, -SO ２ -, -P(R ６ )-, -P(=O)(R ６ ) -, -N(R ６ ) SO ２ -, -SO ２ N (R ６ )-, -C(=S)-, -C(=NR ６ )-, -N=N-, -C=N-, -N=C-, or -C(=N ２ ) - is replaced by -Cy- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cy- is unsubstituted or independently represents one or more substituents R ７ is replaced by In the formula, each R ３ａ , each R ３ｂ , each R ４ , each R ５ａ , each R ５ｂ , and each R ６ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, or R ３ａ and R ５ａ , R ４ and R ５ａ , R ３ａ and R ６ , or R ４ and R ６ are each independently optionally joined together with the atoms therebetween to form ring B, wherein said ring B is selected from the group consisting of 5- to 8-membered heteroarylene and 3- to 10-membered saturated or partially unsaturated heterocyclylene, and said ring B is unsubstituted or independently contains one or more substituents R ８ is replaced by In the formula, each R ２ , each R ７ , and each R ８ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, In the formula, each R, each R ａ and each R ｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, m and n are each independently selected from the group consisting of integers ≧1; R １ binds the structure of formula (IA) to the antibody, optionally via a linker, and c. Formula (II-A), or a tautomer, mesomers, racemates, enantiomers or diastereoisomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof 【Transformation 3】 (In the formula, X １ is selected from the group consisting of N, P, and saturated or unsaturated C; X １ If is saturated C, then X １ But, R ｎ is replaced by Ring A attaches a structure according to formula II-A to the antibody, optionally via a linker; X １ is a saturated C, then ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R １ａ is replaced by Or X １ is an unsaturated C, then ring A is selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclyl, and 3-10 membered partially unsaturated carbocyclyl, wherein ring A contains zero or more substituents R １ｂ is replaced by Or X １ is N or P, then ring A is selected from the group consisting of 5- to 8-membered heteroaryl and 3- to 10-membered saturated or partially unsaturated heterocyclyl, wherein ring A contains zero or more substituents R １ｃ is replaced by When ring A is selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, ring A is preferably selected from the group consisting of pL ２ wherein L ２ is R ｎ Instead, Alternatively, when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl, ring A is pL ２ or ring A is substituted with q ring-forming heteroatom X ２ Including X ２ is used to attach formula (II-A) to the antibody, optionally via a linker, X ２ is selected from the group consisting of N and P; L ２ is -R ２ -L ３ - and R ２ is used to attach formula (II-A) to the antibody, optionally via a linker, L ３ Ha-(C(R ３ａ ) (R ３ｂ )) ｍ -, wherein L ３ When contains a methylene unit, L ３ and 0 or 1 or more methylene units of the formula (I) are independently -N(R ４ )C(O)-, -C(O)N(R ４ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ４ -, -O-, -S-, -SO-, -SO ２ -, -P(R ４ )-, -P(=O)(R ４ ) -, -N(R ４ ) SO ２ -, -SO ２ N (R ４ )-, -C(=S)-, -C(=NR ４ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by R ２ is -O-, -(R ２ａ )N-, -S- and -P(=O)(R ２ａ )- is selected from the group consisting of L １ is -(C(R ５ａ ) (R ５ｂ )) ｎ -, wherein L １ When contains a methylene unit, L １ and 0 or 1 or more methylene units of the formula (I) are independently -N(R ６ )C(O)-, -C(O)N(R ６ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ６ -, -O-, -S-, -SO-, -SO ２ -, -P(R ６ )-, -P(=O)(R ６ ) -, -N(R ６ ) SO ２ -, -SO ２ N (R ６ )-, -C(=S)-, -C(=NR ６ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by In the formula, each R １ａ , each R １ｂ , each R １ｃ , each R ２ａ , each R ３ａ , each R ３ｂ , each R ４ , each R ５ａ , each R ５ｂ , each R ６ and each R ｎ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, In the formula, each R, each R ａ and each R ｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, wherein m and n are each independently selected from the group consisting of integers ≧0, and p and q are each independently selected from the group consisting of integers ≧1.

2. 2. The antibody-drug conjugate of claim 1, wherein the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A), or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. In formula (III-A), X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-, and R １ is -S- or -(R ２ ) N- and R ２ The antibody-drug conjugate of any one of claims 1 to 2, wherein is not hydrogen.

4. In formula (III-A), L １ is -(C(R ３ａ ) (R ３ｂ )) ｍ - and L １ wherein 0 or 1 methylene unit is -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ 4. The antibody-drug conjugate of claim 1, wherein the substituted aryl group is substituted with aryl.

5. In formula (III-A), L １ The antibody-drug conjugate of any one of claims 1 to 4, wherein one methylene unit of the formula (I) is replaced with -C(O)-.

6. In formula (III-A), X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-, and R １ is —O— or —HN—, m is not 0, and L １ one or more methylene units are -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ 3. The antibody-drug conjugate according to claim 1, wherein the substituted aryl group is substituted with aryl.

7. In formula (III-A), X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-, and R １ is —O— or —HN—, and L １ is -(C(R ３ａ ) (R ３ｂ )) ｍ -, m is not 0, L １ 0 methylene units are -C(O)-, -C(=S)-, -C(=NR ４ｂ )- or -C(=N ２ ) -, and each R ３ａ and each R ３ｂ are not hydrogen, and R １ａ and R １ｂ The antibody-drug conjugate according to any one of claims 1 to 2, wherein is hydrogen.

8. In formula (III-A), X is -L １ -C(R １ａ ) (R １ｂ 8. The antibody-drug conjugate of claim 7, wherein m is —C(O)—, and m is 0, 1, or 2.

9. In formula (III-A), m is 1 and L １ is -C(R ３ａ ) (R ３ｂ 9. The antibody-drug conjugate according to claim 7, wherein

10. In formula (III-A), R １ The antibody-drug conjugate of any one of claims 7 to 9, wherein is -O-.

11. The antibody-drug conjugate of any one of claims 1 to 2, wherein in formula (III-A), R is hydrogen.

12. In formula (III-A), R １ is -(R ２ ) N- and R ２ is C １－６ The antibody-drug conjugate according to any one of claims 1 to 2, wherein the group is an aliphatic group.

13. In formula (III-A), R ２ The antibody-drug conjugate of claim 12, wherein is methyl.

14. In formula (III-A), L １ is -C(R ３ａ ) (R ３ｂ )- and R １ is —O— or —HN—, and L １ 0 methylene units are -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ ) - is replaced by R ３ａ and R ３ｂ The antibody-drug conjugate of any one of claims 1 to 2, wherein neither of

15. In formula (III-A), R １ The antibody-drug conjugate of claim 14, wherein is -O-.

16. In formula (III-A), R ３ａ is C １－６ is an aliphatic group, or R ３ａ is C １－６ is an aliphatic group, and R ３ｂ is hydrogen or C １－６ is an aliphatic group, or R ３ａ is C １－６ is an aliphatic group, and R ３ｂ is hydrogen, or R ３ａ is methyl and R ３ｂ 190. The antibody-drug conjugate of any one of claims 1 to 15 and 188 to 189, wherein is hydrogen.

17. In formula (III-A), m is 2, and L １ is -(C(R ３ａ ) (R ３ｂ )) ２ The antibody-drug conjugate according to any one of claims 1 to 2, wherein

18. In formula (III-A), R ８ is C １－６ is an aliphatic group, R ８ is hydrogen, protium, deuterium, tritium, halogen, -NO ２ , -CN, -OH, -SH, -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ an aliphatic group, preferably C １－６ Aliphatic groups, for example, C １－３ The antibody-drug conjugate of any one of claims 1 to 2, optionally substituted with an aliphatic group, for example, methyl.

19. R, R ａ and R ｂ The antibody-drug conjugate according to any one of claims 1 to 2, wherein is hydrogen.

20. Formula (III-A) is according to any one of formulas (III-A-1) to (III-A-17): 【Chemistry 4】 In the formula, R ２ is C, which may be optionally replaced by R １－６ It may be an aliphatic group, and R is hydrogen, protium, deuterium, tritium, halogen, —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ may be an aliphatic group, or R ２ is halogen, -NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １～６ The antibody-drug conjugate of any one of claims 1 to 2, wherein the wavy line represents a bond between the antibody and the structure represented by any one of formulas (III-A-1) to (III-A-17), optionally via a linker.

21. Formula (III-A) is selected from the group consisting of: 【Transformation 5】 The antibody-drug conjugate according to any one of claims 1 to 2, wherein the wavy line represents a bond between the structure shown in any one of formulas (III-A) and the antibody, optionally via a linker.

22. Formula (IA) is according to any one of formulas (IA-1) to (IA-17): 【Transformation 6】 In the formula, R １ may be selected from the group consisting of —O—, —HN—, —P(═O)H—, and —S—, wherein R １ represents a bond between the structure represented by any one of formulas (IA-1) to (IA-17) and the antibody, optionally via a linker.

23. Formula (II-A) is according to any one of formulas (II-A-1) to (II-A-12): 【Transformation 7】 In the formula, R ２ may be selected from the group consisting of —O—, —HN—, —P(═O)H—, and —S—; X ２ may be selected from the group consisting of N and P, and R ２ or X ２ The antibody-drug conjugate of claim 1, wherein any one of the structures represented by formulas (II-A-1) to (II-A-12) is linked to the antibody described herein directly or via a linker.

24. The antibody-drug conjugate comprises the structure shown in formula (III-C): 【Transformation 8】 In the formula, L is -L ａ -L ｂ -L ｃ -, and L binds the structure shown in formula (III-C) to the antibody, -L ａ -teeth: 【Chemistry 9】 is selected from the group consisting of In the formula, W is -(C(R ｗａ ) (R ｗｂ )) ｗｎ - and Y is -(OCH ２ CH ２ ) ｙｎ -O ｙｐ and Z is -(C(R ｚａ ) (R ｚｂ )) ｚｎ and Z connects -La- to -Lb-; where wn is selected from the group consisting of integers ≧0; 0 or 1 or more methylene units of W are independently -Cyr-, -N(R ｗｘ )C(O)-, -C(O)N(R ｗｘ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ｗｘ -, -O-, -S-, -SO-, -SO ２ -, -P(R ｗｘ )-, -P(=O)(R ｗｘ ) -, -N(R ｗｘ ) SO ２ -, -SO ２ N (R ｗｘ )-, -C(=S)-, -C(=NR ｗｘ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by wherein yn is selected from the group consisting of integers ≧0, yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R ｚｘ )C(O)-, -C(O)N(R ｚｘ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ｚｘ -, -O-, -S-, -SO-, -SO ２ -, -P(R ｚｘ )-, -P(=O)(R ｚｘ ) -, -N(R ｚｘ ) SO ２ -, -SO ２ N (R ｚｘ )-, -C(=S)-, -C(=NR ｚｘ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently contains one or more substituents R ｃｘ is replaced by In the formula, each R ｗａ , each R ｗｂ , each R ｚａ , each R ｚｂ , each R ｗｘ , each R ｚｘ and each R ｃｘ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR ｒ , -SR ｒ , -N(R ｒａ ) (R ｒｂ ), -C(O)R ｒ , -CO ２ R ｒ , -C(O)C(O)R ｒ , —C(O)CH ２ C(O)R ｒ , -S(O)R ｒ , -S(O) ２ R ｒ , -C(O)N(R ｒａ ) (R ｒｂ ), -SO ２ N (R ｒａ ) (R ｒｂ ), -OC(O)R ｒ , -N(R)SO ２ R ｒ or optionally R ｒ C substituted with １－６ is an aliphatic group, In the formula, each R ｒ , each R ｒａ and each R ｒｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, -L ｂ - represents a peptide residue consisting of 2 to 7 amino acids, -L ｃ -teeth: 【Chemistry 10】 is selected from the group consisting of In the formula, R Ｌ１ and R Ｌ２ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H and C １－６ is selected from the group consisting of aliphatic groups; In the formula, R １ is -O-, -(R ２ )N-, -P(=O)(R ２ )- and -S-; X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-,-L １ -C(R １ａ ) (R １ｂ )-C(S)-,-L １ -L ０ - and -L ３ -L ２ - selected from the group consisting of L １ is -(C(R ３ａ ) (R ３ｂ )) ｍ -, wherein L １ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, C(=NR ４ｂ )- or -C(=N ２ ) - is replaced by L ０ is -C(R ２ａ ) (R ２ｂ )—, or L ０ is -C(=S)-, -C(=NR ４ａ ) - or -C(=N ２ ) - and L ２ is -C(R ５ａ ) (R ５ｂ )—, wherein L ２ 0 or 1 methylene unit of -N(R ６ )C(O)-, -C(O)N(R ６ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ６ -, -O-, -S-, -SO-, -SO ２ -, -P(R ６ )-, -P(=O)(R ６ ) -, -N(R ６ ) SO ２ -, -SO ２ N (R ６ )-, -C(=S)-, -C(=NR ６ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by L ３ is -(C(R ７ａ ) (R ７ｂ )) ｎ - and L ３ one or more methylene units of ８ )C(O)-, -C(O)N(R ８ )-, -OC(O)-, -C(O)O-, -NR ８ -, -O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ )-, -N=N-, -C=N-, or -N=C-, and L ３ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ８ ) - or -C(=N ２ ) - but replaced, In the formula, each R １ａ , each R １ｂ , each R ２ , each R ２ａ , each R ２ｂ , each R ３ａ , each R ３ｂ , each R ４ａ , each R ４ｂ , each R ５ａ , each R ５ｂ , each R ６ , each R ７ａ , each R ７ｂ and each R ８ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, In the formula, each R, each R ａ and each R ｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R １ is —O— or —HN—, and X is —L １ -CH ２ When —C(O)—, L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ ) - or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -HN- and X is -L １ -L ０ - and L ０ Ga-CH ２ -, then L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ )- or -C(=N ２ ) -, or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -O- and X is -L ３ -C(O)- and L ３ One methylene unit is -NR ８ When replaced by R ８ Ha-CH ２ -CH ２ -NH ２ Instead, In the formula, R １ is -NH- and X is -L ３ When —C(O)—, L ３ At least one methylene unit of -N(R ８ )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ 2. The antibody-drug conjugate of claim 1, wherein N is substituted with -N=N-, -C=N-, or -N=C-.

25. The antibody-drug conjugate comprises the structure shown in formula (III-D): 【Chemistry 11】 wherein Ab is the antibody that binds to uPARAP, and the antibody is: i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO:6; N ａ is an integer or decimal number between 1 and 10, L is -L ａ -L ｂ -L ｃ -, and L binds the structure shown in formula (III-D) to the antibody, -L ａ -teeth: 【Chemistry 12】 is selected from the group consisting of In the formula, W is -(C(R ｗａ ) (R ｗｂ )) ｗｎ - and Y is -(OCH ２ CH ２ ) ｙｎ -O ｙｐ and Z is -(C(R ｚａ ) (R ｚｂ )) ｚｎ and Z connects -La- to -Lb-; where wn is selected from the group consisting of integers ≧0; 0 or 1 or more methylene units of W are independently -Cyr-, -N(R ｗｘ )C(O)-, -C(O)N(R ｗｘ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ｗｘ -, -O-, -S-, -SO-, -SO ２ -, -P(R ｗｘ )-, -P(=O)(R ｗｘ ) -, -N(R ｗｘ ) SO ２ -, -SO ２ N (R ｗｘ )-, -C(=S)-, -C(=NR ｗｘ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by wherein yn is selected from the group consisting of integers ≧0, yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R ｚｘ )C(O)-, -C(O)N(R ｚｘ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ｚｘ -, -O-, -S-, -SO-, -SO ２ -, -P(R ｚｘ )-, -P(=O)(R ｚｘ ) -, -N(R ｚｘ ) SO ２ -, -SO ２ N (R ｚｘ )-, -C(=S)-, -C(=NR ｚｘ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently contains one or more substituents R ｃｘ is replaced by In the formula, each R ｗａ , each R ｗｂ , each R ｚａ , each R ｚｂ , each R ｗｘ , each R ｚｘ and each R ｃｘ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR ｒ , -SR ｒ , -N(R ｒａ ) (R ｒｂ ), -C(O)R ｒ , -CO ２ R ｒ , -C(O)C(O)R ｒ , —C(O)CH ２ C(O)R ｒ , -S(O)R ｒ , -S(O) ２ R ｒ , -C(O)N(R ｒａ ) (R ｒｂ ), -SO ２ N (R ｒａ ) (R ｒｂ ), -OC(O)R ｒ , -N(R)SO ２ R ｒ or optionally R ｒ C substituted with １－６ is an aliphatic group, In the formula, each R ｒ , each R ｒａ and each R ｒｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, -L ｂ - represents a peptide residue consisting of 2 to 7 amino acids, -L ｃ -teeth: 【Chemistry 13】 is selected from the group consisting of In the formula, R Ｌ１ and R Ｌ２ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H and C １－６ is selected from the group consisting of aliphatic groups; In the formula, R １ is -O-, -(R ２ )N-, -P(=O)(R ２ )- and -S-; X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-,-L １ -C(R １ａ ) (R １ｂ )-C(S)-,-L １ -L ０ - and -L ３ -L ２ - selected from the group consisting of L １ is -(C(R ３ａ ) (R ３ｂ )) ｍ -, wherein L １ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, C(=NR ４ｂ )- or -C(=N ２ ) - is replaced by L ０ is -C(R ２ａ ) (R ２ｂ )—, or L ０ is -C(=S)-, -C(=NR ４ａ ) - or -C(=N ２ ) - and L ２ is -C(R ５ａ ) (R ５ｂ )—, wherein L ２ 0 or 1 methylene unit of -N(R ６ )C(O)-, -C(O)N(R ６ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ６ -, -O-, -S-, -SO-, -SO ２ -, -P(R ６ )-, -P(=O)(R ６ ) -, -N(R ６ ) SO ２ -, -SO ２ N (R ６ )-, -C(=S)-, -C(=NR ６ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by L ３ is -(C(R ７ａ ) (R ７ｂ )) ｎ - and L ３ one or more methylene units of ８ )C(O)-, -C(O)N(R ８ )-, -OC(O)-, -C(O)O-, -NR ８ -, -O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ )-, -N=N-, -C=N-, or -N=C-, and L ３ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ８ ) - or -C(=N ２ ) - but replaced, In the formula, each R １ａ , each R １ｂ , each R ２ , each R ２ａ , each R ２ｂ , each R ３ａ , each R ３ｂ , each R ４ａ , each R ４ｂ , each R ５ａ , each R ５ｂ , each R ６ , each R ７ａ , each R ７ｂ and each R ８ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, In the formula, each R, each R ａ and each R ｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R １ is —O— or —HN—, and X is —L １ -CH ２ When —C(O)—, L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ ) - or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -HN- and X is -L １ -L ０ - and L ０ Ga-CH ２ -, then L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ )- or -C(=N ２ ) -, or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -O- and X is -L ３ -C(O)- and L ３ One methylene unit is -NR ８ When replaced by R ８ Ha-CH ２ -CH ２ -NH ２ Instead, R １ is -NH- and X is -L ３ When —C(O)—, L ３ At least one methylene unit of -N(R ８ )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ 2. The antibody-drug conjugate of claim 1, wherein N is substituted with -N=N-, -C=N-, or -N=C-.

26. 26. The antibody-drug conjugate of any one of claims 1 and 25, wherein the antibody-drug conjugate is according to any one of structures D-III-1, D-III-2, D-III-3, D-III-4, D-III-5, D-III-6, or D-III-7 shown in Table 2, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

27. a. i. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and ii. An antibody that binds to uPARAP, comprising an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6; b. i. Formula (III-E), or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof 【Chemistry 14】 (In the formula, R １ is -O-, -(R ２ )N-, -P(=O)(R ２ )- and -S-; X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-,-L １ -C(R １ａ ) (R １ｂ )-C(S)-,-L １ -L ０ - and -L ３ -L ２ - selected from the group consisting of L １ is -(C(R ３ａ ) (R ３ｂ )) ｍ -, wherein L １ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, C(=NR ４ｂ )- or -C(=N ２ ) - is replaced by L ０ is -C(R ２ａ ) (R ２ｂ )—, or L ０ is -C(=S)-, -C(=NR ４ａ ) - or -C(=N ２ ) - and L ２ is -C(R ５ａ ) (R ５ｂ )—, wherein L ２ 0 or 1 methylene unit of -N(R ６ )C(O)-, -C(O)N(R ６ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ６ -, -O-, -S-, -SO-, -SO ２ -, -P(R ６ )-, -P(=O)(R ６ ) -, -N(R ６ ) SO ２ -, -SO ２ N (R ６ )-, -C(=S)-, -C(=NR ６ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by L ３ is -(C(R ７ａ ) (R ７ｂ )) ｎ - and L ３ one or more methylene units of ８ )C(O)-, -C(O)N(R ８ )-, -OC(O)-, -C(O)O-, -NR ８ -, -O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ )-, -N=N-, -C=N-, or -N=C-, and L ３ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ８ ) - or -C(=N ２ ) - but replaced, In the formula, each R １ａ , each R １ｂ , each R ２ , each R ２ａ , each R ２ｂ , each R ３ａ , each R ３ｂ , each R ４ａ , each R ４ｂ , each R ５ａ , each R ５ｂ , each R ６ , each R ７ａ , each R ７ｂ and each R ８ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, In the formula, each R, each R ａ and each R ｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R １ is —O— or —HN—, and X is —L １ -CH ２ When —C(O)—, L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ ) - or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -HN- and X is -L １ -L ０ - and L ０ Ga-CH ２ -, then L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ )- or -C(=N ２ ) -, or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -O- and X is -L ３ -C(O)- and L ３ One methylene unit is -NR ８ When replaced by R ８ Ha-CH ２ -CH ２ -NH ２ Instead, R １ is -NH- and X is -L ３ When —C(O)—, L ３ One or more methylene units of -N(R ８ )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ an active agent selected from the group consisting of: -N=N-, -C=N-, or -N=C-; and c. An antibody-drug conjugate, optionally comprising a linker connecting a) to b).

28. The active agent is selected from the group consisting of the structures P-III-1, P-III-2, P-III-3, P-III-4, P-III-5, P-III-6, P-III-7, P-III-8, P-III-9, P-III-10, P-III-11, P-III-12, P-III-13, P-III-14, P-III-15, P-III-16, P-III-17, P-III-18, P-III-19, P-III-20, P-III-21, P-III-22, P-III-23, P-III-24, P-III-25, P-III-26, P-III-27, P-III-28, P-III-29, P-III-30, P-III-31, P-III-32, P-III-33, P-III-34, P-III-35, P-III-36, P-III-37, P-III-38, P-III-39, P-III-40, P-III-41, P-III-42, P-III-43, P-III-44, P-III-45, P-III-46, P-III-47, P-III-48, P-III-49, P-III-50, P-III-51, P-III-52, P-III-53, P-III-54, P-III-55, P-III-56, P-III-57, P-III-58, P-III-59, P-III-60, P-III-61, P-III-62, P-III-63, P-III-64, P-III-65, P-III-66, P-III-67, P-III-68, P-III-69, P-III-70, P-III-71, P-III-72, P-III- 28. The antibody-drug conjugate of any one of claims 1 or 27, wherein the antibody-drug conjugate is selected from any one of P-III-22, P-III-23, P-III-24, P-III-25, P-III-26, P-III-27, P-III-28, P-III-29, P-III-30, or P-III-31, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

29. 29. The antibody-drug conjugate of any one of claims 1 or 27-28, wherein the active agent is selected from any one of structures P-III-30, P-III-31, P-III-1, P-III-2, P-III-9, P-III-20, P-III-21, P-III-22, P-III-27, P-III-28, or P-III-29 shown in Table 1, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

30. 10. A method for producing an antibody drug conjugate according to any one of the preceding claims, said method comprising: a. Formula (III-F), or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof 【Chemistry 15】 (In the formula, L ｘ Is, L ａｘ -L ｂ -L ｃ - and L ａｘ -teeth: 【Chemistry 16】 is selected from the group consisting of In the formula, R ｈａｌ is iodine or bromine, In the formula, W is -(C(R ｗａ ) (R ｗｂ )) ｗｎ - and Y is -(OCH ２ CH ２ ) ｙｎ -O ｙｐ - and Z is -(C(R ｚａ ) (R ｚｂ )) ｚｎ and where wn is selected from the group consisting of integers ≧0; 0 or 1 or more methylene units of W are independently -Cyr-, -N(R ｗｘ )C(O)-, -C(O)N(R ｗｘ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ｗｘ -, -O-, -S-, -SO-, -SO ２ -, -P(R ｗｘ )-, -P(=O)(R ｗｘ ) -, -N(R ｗｘ ) SO ２ -, -SO ２ N (R ｗｘ )-, -C(=S)-, -C(=NR ｗｘ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by wherein yn is selected from the group consisting of integers ≧0, yp is 0 or 1; wherein zn is selected from the group consisting of integers ≧0; Zero or more methylene units of Z are independently -Cyr-, -N(R ｚｘ )C(O)-, -C(O)N(R ｚｘ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ｚｘ -, -O-, -S-, -SO-, -SO ２ -, -P(R ｚｘ )-, -P(=O)(R ｚｘ ) -, -N(R ｚｘ ) SO ２ -, -SO ２ N (R ｚｘ )-, -C(=S)-, -C(=NR ｚｘ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by -Cyr- is selected from the group consisting of 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsubstituted or independently contains one or more substituents R ｃｘ is replaced by In the formula, each R ｗａ , each R ｗｂ , each R ｚａ , each R ｚｂ , each R ｗｘ , each R ｚｘ and each R ｃｘ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR ｒ , -SR ｒ , -N(R ｒａ ) (R ｒｂ ), -C(O)R ｒ , -CO ２ R ｒ , -C(O)C(O)R ｒ , —C(O)CH ２ C(O)R ｒ , -S(O)R ｒ , -S(O) ２ R ｒ , -C(O)N(R ｒａ ) (R ｒｂ ), -SO ２ N (R ｒａ ) (R ｒｂ ), -OC(O)R ｒ , -N(R)SO ２ R ｒ or optionally R ｒ C substituted with １－６ is an aliphatic group, In the formula, each R ｒ , each R ｒａ and each R ｒｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, -L ｂ - represents a peptide residue consisting of 2 to 7 amino acids, -L ｃ -teeth: 【Chemistry 17】 is selected from the group consisting of In the formula, R Ｌ１ and R Ｌ２ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H and C １－６ is selected from the group consisting of aliphatic groups; In the formula, R １ is -O-, -(R ２ )N-, -P(=O)(R ２ )- and -S-; X is -L １ -C(R １ａ ) (R １ｂ )-C(O)-,-L １ -C(R １ａ ) (R １ｂ )-C(S)-,-L １ -L ０ - and -L ３ -L ２ - selected from the group consisting of L １ is -(C(R ３ａ ) (R ３ｂ )) ｍ -, wherein L １ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, C(=NR ４ｂ )- or -C(=N ２ ) - is replaced by L ０ is -C(R ２ａ ) (R ２ｂ )—, or L ０ is -C(=S)-, -C(=NR ４ａ ) - or -C(=N ２ ) - and L ２ is -C(R ５ａ ) (R ５ｂ )—, wherein L ２ 0 or 1 methylene unit of -N(R ６ )C(O)-, -C(O)N(R ６ )-, -C(O)-, -OC(O)-, -C(O)O-, -NR ６ -, -O-, -S-, -SO-, -SO ２ -, -P(R ６ )-, -P(=O)(R ６ ) -, -N(R ６ ) SO ２ -, -SO ２ N (R ６ )-, -C(=S)-, -C(=NR ６ )-, -N=N-, -C=N-, -N=C- or -C(=N ２ ) - is replaced by L ３ is -(C(R ７ａ ) (R ７ｂ )) ｎ - and L ３ one or more methylene units of ８ )C(O)-, -C(O)N(R ８ )-, -OC(O)-, -C(O)O-, -NR ８ -, -O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ )-, -N=N-, -C=N-, or -N=C-, and L ３ 0 or 1 or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ８ ) - or -C(=N ２ ) - but replaced, In the formula, each R １ａ , each R １ｂ , each R ２ , each R ２ａ , each R ２ｂ , each R ３ａ , each R ３ｂ , each R ４ａ , each R ４ｂ , each R ５ａ , each R ５ｂ , each R ６ , each R ７ａ , each R ７ｂ and each R ８ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OR, -SR, -N(R ａ ) (R ｂ ), -C(O)R, -CO ２ R, -C(O)C(O)R, -C(O)CH ２ C(O)R, -S(O)R, -S(O) ２ R, -C(O)N(R ａ ) (R ｂ ), -SO ２ N (R ａ ) (R ｂ ), -OC(O)R, -N(R)SO ２ R or C optionally substituted with R １－６ is an aliphatic group, In the formula, each R, each R ａ and each R ｂ are each independently hydrogen, protium, deuterium, tritium, a halogen, or —NO ２ , -CN, -OH, -SH, -NH ２ , -C(O)H, -CO ２ H, -C(O)C(O)H, -C(O)CH ２ C(O)H, -S(O)H, -S(O) ２ H, —C(O)NH ２ , -SO ２ NH ２ , -OC(O)H, -N(H)SO ２ H or C １－６ is an aliphatic group, m is selected from the group consisting of integers >= 0 and n is selected from the group consisting of integers >= 1; R １ is —O— or —HN—, and X is —L １ -CH ２ When —C(O)—, L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ ) - or -C(=N ２ ) - or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -HN- and X is -L １ -L ０ - and L ０ Ga-CH ２ -, then L １ one or more methylene units independently represent -C(O)-, -C(=S)-, -C(=NR ４ｂ )- or -C(=N ２ ) -, or each R ３ａ and each R ３ｂ are not both hydrogen, R １ is -O- and X is -L ３ -C(O)- and L ３ One methylene unit is -NR ８ When replaced by R ８ Ha-CH ２ -CH ２ -NH ２ Instead, R １ is -NH- and X is -L ３ When —C(O)—, L ３ One or more methylene units of -N(R ８ )C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO ２ -, -P(R ８ )-, -P(=O)(R ８ ) -, -N(R ８ ) SO ２ -, -SO ２ N (R ８ )-, -N=N-, -C=N-, or -N=C-), reacting one compound selected from the group consisting of with the antibody defined in claim 1.

31. L ａｘ -but, [Chemistry 18] 31. The method of claim 30, wherein:

32. L ａｘ -L ｂ -L ｃ -teeth: 【Chemistry 19】 The method of any one of claims 30 to 31, selected from the group consisting of:

33. The above compounds are L-III-30, L-III-31, L-III-29, L-III-28, L-III-27, L-III-26, L-III-25, L-III-24, L-III-23, L-III-22, L-III-21, L-III-20, L-III-20, L-III-19, L-III-18, L-III-17, L-III-16, L-III-15, L-III-14, L-III-13, L-III-12, L 33. The method of any one of claims 30 to 32, wherein the compound is selected from any one of L-III-11, L-III-10, L-III-9, L-III-8, L-III-7, L-III-6, L-III-5, L-III-4, L-III-3, L-III-2, or L-III-1, or a tautomer, mesomer, racemate, enantiomer, or diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

34. 34. The method of any one of claims 30 to 33, wherein the compound is selected from any one of L-III-30, L-III-31, L-III-22, L-III-21, L-III-20, L-III-7, L-III-6, L-III-4, L-III-3, or L-III-2 of Table 3, or a tautomer, mesomer, racemate, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

35. The antibody: a. an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 1, and b. The antibody-drug conjugate of any one of claims 1 to 34, comprising an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO:

4.

36. The antibody: a. an immunoglobulin light chain consisting of the amino acid sequence of SEQ ID NO: 1, and b. The antibody-drug conjugate of any one of claims 1 to 35, comprising an immunoglobulin heavy chain consisting of the amino acid sequence of SEQ ID NO:

4.

37. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 29 and 35 to 36, and a pharmaceutically acceptable carrier.

38. The antibody-drug conjugate according to any one of claims 1 to 29 and 35 to 36, or the pharmaceutical composition according to claim 37, for use as a drug.

39. The antibody-drug conjugate of any one of claims 1 to 29 and 35 to 36, or the pharmaceutical composition of claim 37, for use in treating a disease characterized by cells expressing uPARAP, optionally wherein the disease characterized by cells expressing uPARAP is selected from cancer, bone degradative diseases such as osteoporosis, fibrosis, and macrophage-related diseases or disorders such as atherosclerosis, arthritis, or chronic inflammation.

40. 40. The antibody drug conjugate or composition for use of claim 39, wherein the disease is cancer, for example, the cancer is selected from sarcoma, glioblastoma, mesothelioma, colon cancer, prostate cancer, bone metastasis from prostate cancer, breast cancer, head and neck cancer, and leukemia.

41. 41. The antibody drug conjugate or composition for use according to claim 40, wherein the cancer is a solid tumor.

42. 41. The antibody drug conjugate or composition for use according to claim 40, wherein the cancer is a leukemia, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).

43. The antibody drug conjugate or composition for use according to any one of claims 39 to 40, wherein the cancer is glioblastoma.

44. 42. The antibody drug conjugate or composition for use according to any one of claims 39 to 41, wherein the cancer is a sarcoma, such as osteosarcoma or soft tissue sarcoma (STS).

45. 45. The antibody-drug conjugate or composition for use of claim 44, wherein the soft tissue sarcoma (STS) is selected from epithelioid sarcoma, clear cell sarcoma, alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, inflammatory myofibroblastic tumor, undifferentiated embryonal sarcoma, alveolar soft part sarcoma (ASPS), angiosarcoma, chondrosarcoma, dermatofibrosarcoma protuberances (DFSP), desmoid sarcoma, Ewing's sarcoma, fibrosarcoma, myxofibrosarcoma, adult fibrosarcoma, gastrointestinal stromal tumor (GIST), non-uterine leiomyosarcoma, uterine leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma (MFH), malignant peripheral nerve sheath tumor (MPNST), rhabdomyosarcoma, synovial sarcoma, and / or leiomyosarcoma (LMS).

46. The antibody drug conjugate or composition for use according to any one of claims 39 to 41, wherein the cancer is a metastatic cancer.

47. 47. The antibody-drug conjugate or composition for use according to any one of claims 38 to 46, wherein the antibody-drug conjugate or composition is administered in combination with one or more additional agents, such as one or more additional therapeutic agents.

48. 48. The antibody-drug conjugate or composition for use according to any one of claims 39 to 47, wherein the uPARAP-expressing cells exhibit uPARAP overexpression, and optionally, the uPARAP-expressing cells are tumor cells and / or tumor-associated cells.

49. The antibody drug conjugate or composition for use according to any one of claims 38 to 48, wherein the treatment is palliative or curative.

50. An antibody-drug conjugate according to any one of claims 1 to 29 and 35 to 36, or a pharmaceutical composition according to claim 37, for use in a method for inhibiting tumor growth in a subject.

51. A kit comprising the antibody-drug conjugate of any one of claims 1 to 29 and 35 to 36, or the pharmaceutical composition of claim 37, optionally further comprising a means for administering the antibody or antibody-drug conjugate to a subject and / or instructions for use.

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