Antibody-conjugated drug targeting uPARAP and containing avixatecan derivative

Abstract

The present disclosure relates to antibody-conjugated drugs targeting the receptor uPARAP, in particular to antibody-conjugated drugs (ADC) comprising a humanized antibody against uPARAP and an avitecan derivative and their use in delivering active agents to cells and tissues expressing uPARAP. The disclosure further relates to the use of said ADC in the treatment of diseases involving cells expressing uPARAP, such as certain cancers.

Description

Technical Field

[0001] The present disclosure relates to antibody-drug conjugates (ADCs) targeting the receptor uPARAP, particularly antibody-drug conjugates (ADCs) comprising humanized antibodies against uPARAP and exatecan derivatives, and their use in delivering active agents to cells and tissues expressing uPARAP. The present disclosure further relates to the use of such ADCs in treating diseases involving cells expressing uPARAP, such as certain cancers.

[0002] background

[0003] 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 turnover during tissue remodeling, particularly the uptake and intracellular degradation of collagen. The uPARAP receptor is composed of an N-terminal cysteine-rich domain (CysR), a fibronectin type II (FN-II) domain, and eight C-type lectin-like domains (CTLDs 1-8).

[0004] The receptor uPARAP is upregulated in tumor cells of specific cancers, including sarcomas and advanced glioblastomas. In addition, the receptor is most often upregulated in stromal cells surrounding solid tumors, and some literature shows high expression of uPARAP in bone metastases from prostate cancer (Caley et al., 2012, J. Pathol 5:775-783). In healthy adult individuals, the receptor shows a restricted expression pattern (Melander et al., 2015, Int J Oncol 47:1177-1188).

[0005] Antibody-drug conjugates (ADCs) are a class of highly effective biopharmaceuticals designed for targeted therapy, especially for the treatment of cancer. ADCs are composite molecules consisting of an antibody (whole mAb or antibody fragment) connected to an active agent (e.g., a bioactive drug or cytotoxic compound) via a stable chemical linker that may have an unstable bond. By combining the unique targeting ability of antibodies with the cell-killing ability of cytotoxic drugs, antibody-drug conjugates make it possible to sensitively distinguish healthy tissue from diseased tissue based on the expression of antibody antigens. This means that compared to traditional chemotherapeutic agents, antibody-drug conjugates actively target and attack cancer cells, leaving healthy cells with little or no antigen expression less affected. To date, more than 10 ADCs have been approved for the market and several ADCs are currently in clinical trials.

[0006] WO 2010 / 111198 discloses conjugates comprising anti-uPARAP antibodies and suggests the use of such conjugates to deliver therapeutic agents to cells expressing uPARAP.

[0007] WO 2017 / 133745 discloses ADCs directed against uPARAP.

[0008] WO 2022 / 068878 discloses exitecan derivatives and ADCs containing the same.

[0009] Currently, there are treatments for most types of cancer. However, in many cases, the efficacy is unsatisfactory or there are adverse effects due to the high doses of the therapeutic agents. Therefore, there is a need for more effective treatments with increased efficacy. SUMMARY OF THE INVENTION

[0011] Provided herein are antibody-drug conjugates comprising a humanized form of the murine 9b7 antibody targeting the uPARAP receptor and an exotecan derivative. The murine 9b7 antibody was initially described in WO 2017 / 133745. The antibody-drug conjugates described herein are capable of specifically targeting cells and tissues expressing uPARAP. ADCs comprising the humanized 9b7 antibody described herein exhibit enhanced efficacy compared to ADCs comprising the murine 9b7 antibody, as well as enhanced efficacy compared to ADCs comprising other humanized forms of the murine 9b7 antibody.

[0012] Specifically, the present disclosure relates to an antibody-drug conjugate comprising an antibody that binds to uPARAP, the antibody comprising:

[0013] a. an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 3 or consisting of the amino acid sequence of SEQ ID NO: 3; and / or

[0014] b. an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[0015] wherein the antibody-drug conjugate comprises an active agent having a structure selected from one of Formula (IA), Formula (II-A) and Formula (III-A) described below; and

[0016] The antibody-drug conjugate optionally comprises a linker connecting the antibody and the active agent.

[0017] Furthermore, the present disclosure provides a method of making an antibody-drug conjugate as described herein, comprising using a compound according to one selected from the group consisting of Formula (IA), Formula (II-Fx), Formula (II-Fy), and Formula (III-F) as described herein.

[0018] Furthermore, the present disclosure relates to a method for 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 the antibody-drug conjugate as defined herein.

[0019] 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 means and / or instructions for administering the antibody-drug conjugate to a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 In vitro cell viability assay of the U937 cancer cell line exposed to an MMAE-based ADC containing either the LCOHCO antibody (comprising the variable domains of the original murine 9b7 antibody fused to a human IgG constant region) or the humanized LC4HC3 antibody. Aside from the antibodies, the two ADCs were identical and produced by the same method. Cells were incubated for 96 hours and then analyzed by a colorimetric viability assay. Testing of the U937 cell line showed a significantly greater reduction in total cell viability with the LC4HC3-based ADC compared to the LCOHCO ADC.

[0021] Figure 2 : Internalization of humanized antibodies LC4HC3 and LC3HC3 in SAOS-2 osteosarcoma cells. Detailed protocol is presented in Example 2. The data show that in SAOS-2 osteosarcoma cells, LC4HC3 is not only internalized faster than LC3HC3, but also internalized to a greater extent.

[0022] Figure 3: Vedotin-based ADC based on LC4HC3 (LC4HC3-vc-MMAE, Figure 3a) and LC3HC3-based vedotin-type ADC (LC3HC3-vc-MMAE, Figure 3b ) in vivo efficacy. CB17 mice were inoculated with U937 cells to induce tumor growth. Tumor size was closely monitored and once it reached approximately 80-150 mm 3 The two ADCs are identical except for the antibodies and are produced by the same method. Figure 3a and Figure 3b Each line in represents the tumor size of mice administered a 4 mg / kg dose of the mentioned ADC twice daily for 7 days. The data show that ADCs based on the humanized 9b7 antibody LC4HC3 are superior anti-tumor agents to ADCs based on a different humanized 9b7 antibody LC3HC3.

[0023] Figure 4: Tumor size using the formula = {(length * width 2 ) / 2} Tumor size calculated from caliper measurements. Figure 4a : Administer at 3 mg / kg. Figure 4b : Dosed at 10 mg / kg. Data shown are mean ± standard deviation (SD), when 50% or more mice survived, n = 7. Mice were treated IV three times weekly via the tail vein, indicated by the 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 were also compared to treatment with PBS vehicle (triangles).

[0024] Figure 5: Tumor size using the formula = {(length * width 2 ) / 2} Tumor size calculated from caliper measurements. Figure 5a : Administer at 3 mg / kg. Figure 5b : Dosed at 6 mg / kg. Data shown are mean ± SD, when 50% or more mice survived. Mice were treated IV three times weekly via the tail vein, 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 were also compared to treatment with PBS vehicle (triangles). Detailed Description of the Invention

[0026] The ADCs of the present disclosure are internalized after binding to uPARAP receptors at the cell surface, thus allowing the active agent of the antibody-drug conjugate complex to exert its effects inside the cell.

[0027] Anti-uPARAP humanized antibody

[0028] Methods for producing antibodies are well known in the art. For example, antibodies can be produced by any of several methods, such as inducing the in vivo production of antibody molecules, screening immunoglobulin libraries, or producing monoclonal antibody molecules from cultured cell lines. These include, but are not limited to, hybridoma technology, human B cell hybridoma technology, and Epstein-Barr virus (EBV)-hybridoma technology.

[0029] Humanized antibodies are generally preferred in pharmaceuticals intended for use in humans, and methods for humanizing antibodies are well known in the art. Although humanization techniques are known, achieving humanized antibodies that retain the binding properties of the original antibody can be a challenge, and even more challenging is achieving humanized antibodies that have improved characteristics (e.g., improved ligand affinity and efficacy) compared to the original antibody.

[0030] The inventors provide herein an ADC comprising an improved anti-uPARAP antibody that is a humanized form of the 9b7 murine antibody and exhibits improved ligand affinity and efficacy compared to the 9b7 murine antibody and improved internalization and in vivo efficacy compared to other humanized forms of the 9b7 antibody.

[0031] The ADCs of the present disclosure comprising the anti-uPARAP antibodies described herein can be of any immunoglobulin class, including IgG, IgM, IgD, IgE, IgA, and any subclass 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 IgG1κ.

[0032] The anti-uPARAP antibody disclosed herein is a humanized 9b7 antibody that binds to the uPARAP receptor. More specifically, the humanized 9b7 antibody disclosed herein binds to at least the fibronectin type II (FN-II) domain of the uPARAP receptor.

[0033] The humanized 9b7 antibody, also referred to herein as 980.2LC4HC3, comprises a light chain variable region comprising the amino acids of SEQ ID NO: 3, which is the variable region of LC4; and a heavy chain variable region comprising the amino acids of SEQ ID NO: 6, which is the variable region of HC3.

[0034] The humanized 9b7 antibody, also referred to herein as 980.2LC4HC3, may comprise a light chain comprising or consisting of amino acids of SEQ ID NO: 1, which is LC4; and a heavy chain comprising or consisting of amino acids of SEQ ID NO: 4, which is HC3.

[0035] In one embodiment of the present disclosure, the anti-uPARAP antibody as defined herein comprises:

[0036] a. an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 3 or consisting of the amino acid sequence of SEQ ID NO: 3; and

[0037] b. an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6.

[0038] In one embodiment of the present disclosure, the antibody that binds to uPARAP as defined herein comprises:

[0039] a. an immunoglobulin light chain (LC4) comprising the amino acid sequence of SEQ ID NO: 1; and

[0040] b. An immunoglobulin heavy chain (HC3) comprising the amino acid sequence of SEQ ID NO: 4.

[0041] Antibody-drug conjugates (ADCs) containing humanized anti-uPARAP antibodies

[0042] The inventors' data surprisingly showed that ADCs containing the humanized LC4HC3 antibody caused a significantly greater reduction in total cell viability than ADCs based on LCOHC0 (which has the variable domains of the 9b7 murine antibody fused to human IgG constant regions). LC4HC3-based ADCs also exhibited improved internalization and in vivo efficacy compared to ADCs based on LC3HC3 (another humanized 9b7 antibody).

[0043] The antibody-drug conjugates described herein comprise a specific humanized form of the murine 9b7 antibody targeting the uPARAP receptor (more specifically, LC4HC3) and an exotecan derivative. In some embodiments, the ADCs described herein also comprise a linker connecting the exotecan derivative to LC4HC3. The exotecan derivatives disclosed herein, methods for their preparation, and methods for conjugating them to antibodies are described in WO 2022 / 068878; the entire teachings of that application are incorporated by reference.

[0044] One embodiment of the present disclosure is an antibody drug conjugate (ADC) comprising an antibody that binds to uPARAP, the antibody comprising:

[0045] i. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[0046] ii. An immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6 or consisting of the amino acid sequence of SEQ ID NO:6;

[0047] where the antibody-drug conjugate comprises an active agent having a structure selected from one of the following:

[0048] a. Formula (I-A) or a tautomer, meso form, racemic form, enantiomer or diastereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0049]

[0050] where R 1 is selected from: -O-, -(R 2 H )N-, -P(=O)(R 2 )-, -P(R 2 )- and -S-;

[0051] L 2 is -(C(R 3a )(R 3b )) m -R,

[0052] where 0 or no less than 1 methylene unit of L 2 is independently replaced by -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)-;

[0053] L 1 is -(C(R 5a )(R 5b )) n -,

[0054] where 0 or no less than 1 methylene unit of L 1 is independently replaced by -Cy-, -N(R 6 )C(O)-, -C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR6 -, -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)-;

[0055] -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 substituted with at least one substituent R 7 replace;

[0056] Among them, each R 3a , each R 3b , each R 4 , each R 5a , each R 5b and each R 6 are 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each independently optionally forms a ring B together with the atoms therebetween, wherein the ring B is selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or independently substituted with at least one substituent R 8 replace;

[0057] Among them, each R 2 , each R 7 and each R 8 are independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(Ra )(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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0058] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[0059] m and n are each independently selected from an integer ≥ 1; and wherein R 1 directly or optionally through a linker to the antibody;

[0060] b. Formula (II-A) or its tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof

[0061]

[0062] where X 1 Selected from: N, P and saturated or unsaturated C; when X 1 When C is saturated, X 1 R n replace;

[0063] wherein Ring A connects the structure according to Formula II-A to the antibody directly or optionally via a linker;

[0064] When X 1 When C is saturated, ring A is selected from: 3-10 membered saturated or partially unsaturated heterocyclic group and 3-10 membered saturated or partially unsaturated carbocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1a replace;

[0065] Or when X 1When C is an unsaturated group, ring A is selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclic group and 3-10 membered partially unsaturated carbocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1b replace;

[0066] Or when X 1 When N or P, ring A is selected from: 5- to 8-membered heteroaryl and 3- to 10-membered saturated or partially unsaturated heterocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1c replace;

[0067] When ring A is selected from 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclic group, ring A is substituted by p L 2 Substituted, where L 2 Not for R n ;

[0068] Or when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, ring A is surrounded by p L 2 substituted, or ring A contains q ring heteroatoms X 2 , and X 2 For connecting formula (II-A) directly or optionally through a linker to the antibody;

[0069] X 2 Selected from: N and P;

[0070] L 2 -R 2 -L 3 -, and R 2 For connecting formula (II-A) directly or optionally through a linker to the antibody;

[0071] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, L 3 0 or not less than 1 methylene unit is independently replaced by -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)-;

[0072] R 2 Selected from: -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-;

[0073] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, L 1 0 or not less than 1 methylene unit is independently replaced by -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)-;

[0074] Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0075] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[0076] m and n are each independently selected from an integer ≥ 0, and p and q are each independently selected from an integer ≥ 1;

[0077] c. Formula (III-A) or its tautomer, meso-racemate, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof

[0078]

[0079] where R 1 Selected from: -O-, -(R 2 )N-、-P(=O)(R 2 )- and -S-; wherein R 1 linking the structure according to formula (III-A) to the antibody directly or optionally via a linker;

[0080] X is selected from: -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 -;

[0081] L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or not less than 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[0082] L 0 -C(R 2a )(R 2b )-, or L 0-C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[0083] L 2 -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit is replaced by -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)-;

[0084] L 3 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[0085] Among them, 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 R5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0086] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[0087] m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1;

[0088] When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[0089] When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[0090] When R 1 is -O-, X is -L 3 -C(O)- and L 3 has one methylene unit replaced by -NR 8 R 8 is not -CH2-CH2-NH2;

[0091] When R 1 is -NH- and X is -L 3 -C(O)-, L 3 has at least one methylene unit replaced by -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-;

[0092] And

[0093] where the antibody-drug conjugate optionally comprises a linker that connects the antibody to the active agent.

[0094] IA Implementation Plan

[0095] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to formula (I-A) or a tautomer, meso form, racemic form, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0096]

[0097] where R 1 is independently selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-;

[0098] L 2 can be -(C(R 3a )(R 3b )) m -R, and m is independently selected from integers ≥ 1;

[0099] where 0 or at least one methylene unit of L 2 can be independently replaced by -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)-;

[0100] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 1;

[0101] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0102] -Cy- can be selected from: 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 can be independently substituted with at least one substituent R 7 replace;

[0103] Among them, each R 3a , each R 3b , each R 4 , each R 5a , each R 5b and each R 6 can be 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)SO2R or an optionally R-substituted C 1-6 aliphatic group;

[0104] where each R 2 , each R 7 and each R 8 can each independently be 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)SO2R or an optionally R-substituted C 1-6 aliphatic group;

[0105] where each R, each R a and each R b can each independently be 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 aliphatic group.

[0106] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to formula (I-A) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0107]

[0108] where R 1 is independently selected from: -O-, -(R 2 )(N-, -P(=O)(R 2 )(- and -S-;

[0109] L 2Can be -(C(R 3a )(R 3b )) m -R, and m can be selected from integers ≥ 1;

[0110] Among them L 2 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0111] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 1;

[0112] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0113] -Cy- can be selected from: 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 can be independently substituted with at least one substituent R 7 replace;

[0114] Among them, each R 3a , each R 3b , each R4 , each R 5a , each R 5b and each R 6 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0115] Among them, each R 2 , each R 7 and each R 8 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0116] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0117] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0118]

[0119] For example, where R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each of them can be independently optionally taken together with the atoms therebetween to form a ring B, wherein the ring B can be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or can be substituted with not less than 1 substituent R 8 Replacement; each R 3a , each R 3b , each R 4 , each R 5a , each R 5b and each R 6 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each of them can be independently optionally taken together with the atoms therebetween to form a ring B, wherein the ring B can be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or can be substituted with not less than 1 substituent R 8 replace;

[0120] For example, where R 3a and R 5a Together with the atoms therebetween, they may form a ring B, wherein the ring B may be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B may be unsubstituted or may be substituted with at least one substituent R 8 Replacement; each R 3b , each R 4 , each R 5b and each R 6can be 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each of them can be independently optionally taken together with the atoms therebetween to form a ring B, wherein the ring B can be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or can be substituted with not less than 1 substituent R 8 replace;

[0121] For example, where R 4 and R 5a Together with the atoms therebetween, they may form a ring B, wherein the ring B may be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B may be unsubstituted or may be substituted with at least one substituent R 8 Replacement; each R 3a , each R 3b , each R 5b and each R 6 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6or R 4 and R 6 Each of them can be independently optionally taken together with the atoms therebetween to form a ring B, wherein the ring B can be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or can be substituted with not less than 1 substituent R 8 replace;

[0122] For example, where R 3a and R 6 Together with the atoms therebetween, they may form a ring B, wherein the ring B may be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B may be unsubstituted or may be substituted with at least one substituent R 8 Replacement; each R 3b , each R 4 , each R 5a and each R 5b can be 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each of them can be independently optionally taken together with the atoms therebetween to form a ring B, wherein the ring B can be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or can be substituted with not less than 1 substituent R 8 replace;

[0123] For example, where R 4 and R 6 can be independently optionally taken together with the atoms therebetween to form a ring B, wherein the ring B can be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or can be substituted with not less than 1 substituent R 8 Replacement; each R 3a , each R 3b , each R 5a and each R 5bcan be 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each of them can be independently optionally taken together with the atoms therebetween to form a ring B, wherein the ring B can be selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or can be substituted with not less than 1 substituent R 8 replace.

[0124] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0125]

[0126] where R 1 Can be -O-;

[0127] L 2 Can be -(C(R 3a )(R 3b )) m -R, and m can be selected from integers from 1 to 3;

[0128] Among them L 2 0 methylene units of can be replaced;

[0129] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers from 2 to 4;

[0130] Among them L 1 0, 1 or 2 methylene units may be replaced by -N(R 6)C(O)-, -C(O)-, -OC(O)-, -NR 6 -, -O- or -C(=S)- replacement;

[0131] Among them, each R 3a , each R 3b , each R 5a , each R 5b and each R 6 may be each independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a Together with the atoms therebetween, they may form Ring B, wherein Ring B may be selected from a 5-membered saturated heterocyclylene group, and Ring B is unsubstituted;

[0132] R may be hydrogen or halogen.

[0133] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0134]

[0135] Among them, R 1 Can be -O-;

[0136] L 2 Can be -(C(R 3a )(R 3b )) m -R, and m can be selected from the integers 1 and 2;

[0137] Among them L 2 0 methylene units of can be replaced;

[0138] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from the integers 2 and 3;

[0139] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0140] Among them, each R 3a , each R 3b , each R 5a and each R 5b may each independently be hydrogen; or R 3a and R 5aTogether with the atoms therebetween, they may form Ring B, wherein Ring B may be selected from a 5-membered saturated heterocyclylene group having 1 nitrogen heteroatom, and Ring B is unsubstituted;

[0141] R may be hydrogen.

[0142] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0143]

[0144] Among them, R 1 Can be -O-;

[0145] L 2 Can be -(C(R 3a )(R 3b )) m -R, and m can be selected from the integers 1 and 2;

[0146] Among them L 2 0 methylene units of can be replaced;

[0147] L 1 Can be -(C(R 5a )(R 5b ))2-;

[0148] Among them L 1 One methylene unit of can be replaced by -C(O)-;

[0149] Among them, each R 3a , each R 3b , each R 5a and each R 5b may each independently be hydrogen; or R 3a and R 5a Together with the atoms therebetween, they may form Ring B, wherein Ring B may be selected from a 5-membered saturated heterocyclylene group having 1 nitrogen heteroatom, and Ring B is unsubstituted;

[0150] R may be hydrogen.

[0151] In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to any one of Formula (IA-1) to Formula (IA-17) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0152]

[0153]

[0154] Among them, R 1 can be selected from: -O-, -HN-, -P(=O)H- and -S-; and wherein R 1 The structure represented by any one of Formula (IA-1) to Formula (IA-17) is linked directly or through a linker to an antibody described herein.

[0155] II-A Implementation Plan

[0156] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0157]

[0158] Among them, X 1 Can be selected from: n, P and saturated or unsaturated C; when X 1 When it is saturated C, X 1 Can be R n Substitution; Ring A optionally connects the structure represented by formula (II-A) to other molecular parts;

[0159] When X 1 When C is saturated, ring A can be selected from: 3-10 membered saturated or partially unsaturated heterocyclic group and 3-10 membered saturated or partially unsaturated carbocyclic group, wherein ring A can be substituted by 0 or not less than 1 substituent R 1a replace;

[0160] Or when X 1 When the ring A is an unsaturated C, the ring A can be selected from: 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclic group and 3-10 membered partially unsaturated carbocyclic group, wherein the ring A can be substituted by 0 or not less than 1 substituent R 1b replace;

[0161] Or when X 1 When N or P is present, Ring A can be selected from: 5- to 8-membered heteroaryl groups and 3- to 10-membered saturated or partially unsaturated heterocyclic groups, wherein Ring A can be substituted by 0 or not less than 1 substituent R 1c replace;

[0162] When ring A can be selected from 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclic group, ring A may be substituted by p L 2 Substituted, where L 2 Cannot be R n ;

[0163] Or when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, ring A may be 2 substituted, or ring A may contain q ring heteroatoms X 2 , and X 2 Used to connect the structure represented by formula (II-A) to other molecular parts;

[0164] X 2 Can be selected from: N and P;

[0165] L 2 Can be -R 2 -L 3 -, and R 2 Used to connect the structure represented by formula (II-A) to other molecular parts;

[0166] L 3 Can be -(C(R 3a )(R 3b )) m -, where L 3 When methylene units may be included, L 3 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0167] R 2 Can be selected from: -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-;

[0168] L 1 Can be -(C(R 5a )(R 5b )) n -, where L 1 When methylene units may be included, L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0169] Among them, 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 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0170] Among them, each R, each R a and each R b Each of the above may be 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 aliphatic groups;

[0171] m and n may each be independently selected from integers ≥0, and p and q may each be independently selected from integers ≥1.

[0172] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0173]

[0174] where X 1 Can be saturated C, and X 1 Can be R n replace;

[0175] Ring A can be selected from: 3- to 10-membered saturated or partially unsaturated heterocyclic groups and 3- to 10-membered saturated or partially unsaturated carbocyclic groups, wherein Ring A may be substituted by 0 or not less than 1 substituent R 1a replace;

[0176] Ring A can be p L 2 Substitution, wherein p can be selected from integers ≥ 1, and L 2 Cannot be R n ;

[0177] L 2 Can be R 2 -L 3 -;

[0178] L 3 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 0;

[0179] When L 3 When methylene units may be included, L 3 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0180] R 2 Can be selected from: -O-, -(R 2a)N-, -S- and -P(=O)(R 2a )-;

[0181] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 0;

[0182] When L 1 When methylene units may be included, L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0183] Among them, 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 n can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0184] Among them, each R, each R a and each R bEach of the above may be 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 Aliphatic group.

[0185] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0186]

[0187] where X 1 Can be saturated C, and X 1 Can be R n replace;

[0188] Ring A may be a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and Ring A may be unsubstituted or may be substituted with at least one substituent R 1a replace;

[0189] Ring A may contain q ring heteroatoms X 2 , and X 2 For optionally connecting to the antibody via a linker; q can be selected from integers ≥ 1, and X 2 Can be selected from: N and P;

[0190] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 0;

[0191] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0192] Among them, each R 1a , each R 5a , each R 5b , each R 6 and each R n can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0193] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0194] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0195]

[0196] where X 1 Can be unsaturated C;

[0197] Ring A can be selected from: 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 10-membered partially unsaturated heterocyclic group and 3- to 10-membered partially unsaturated carbocyclic group, and Ring A may be unsubstituted or may be substituted with at least one substituent R 1b replace;

[0198] Ring A can be p L 2 Substitution, wherein p can be selected from integers ≥ 1;

[0199] L2 Can be -R 2 -L 3 -, and R 2 for attachment to an antibody, optionally via a linker;

[0200] L 3 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 0;

[0201] Among them L 3 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0202] R 2 Can be selected from: -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-;

[0203] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 0;

[0204] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0205] Among them, 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 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0206] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0207] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0208]

[0209] where X 1 Can be unsaturated C;

[0210] Ring A may be a 3- to 10-membered partially unsaturated heterocyclic group, and Ring A may be unsubstituted or may be substituted with at least one substituent R 1b replace;

[0211] Ring A may contain q ring heteroatoms X 2 , and X 2For direct or through linker connection to the antibody; q can be selected from integers ≥ 1, and X 2 Can be selected from: N and P;

[0212] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 0;

[0213] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0214] Among them, each R 1b , each R 5a , each R 5b and each R 6 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0215] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0216] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0217]

[0218] where X 1 Can be N or P;

[0219] Ring A can be selected from: 5- to 8-membered heteroaryl groups and 3- to 10-membered saturated or partially unsaturated heterocyclic groups, and Ring A can be unsubstituted or can be substituted with at least one substituent R 1c replace;

[0220] Ring A can be p L 2 Substitution, wherein p can be selected from integers ≥ 1;

[0221] L 2 Can be -R 2 -L 3 -, and R 2 For attachment to antibodies, either directly or through a linker;

[0222] L 3 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 0;

[0223] Among them L 3 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0224] R 2 Can be selected from: -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-;

[0225] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 0;

[0226] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0227] Among them, 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 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0228] Among them, each R, each R a and each R bEach of the above may be 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 Aliphatic group.

[0229] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0230]

[0231] where X 1 Can be N or P;

[0232] Ring A may be a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and Ring A may be unsubstituted or may be substituted with at least one substituent R 1c replace;

[0233] Ring A may contain q ring heteroatoms X 2 , and X 2 For direct or through linker connection to the antibody; q can be selected from integers ≥ 1, and X 2 Can be selected from: N and P;

[0234] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from integers ≥ 0;

[0235] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -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)-;

[0236] Among them, each R1c , each R 5a , each R 5b and each R 6 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0237] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0238] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0239]

[0240] where X 1 Can be saturated C, and X 1 Can be R n replace;

[0241] Ring A may be selected from: 3- to 6-membered saturated heterocyclic groups and 3- to 6-membered saturated or partially unsaturated carbocyclic groups;

[0242] p can be 1, and L 2 Cannot be R n ;

[0243] L 2 Can be -R 2 -L 3 -;

[0244] L 3 Can be -(C(R3a )(R 3b )) m -, and m can be selected from an integer from 0 to 2, wherein when L 3 When methylene units may be included, L 3 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0245] R 2 Can be selected from -O-;

[0246] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from 0 and 1;

[0247] When L 1 When methylene units may be included, L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0248] Among them, each R 3a , each R 3b , each R 5a , each R 5b and each R n may be each independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0249] wherein each R can independently be hydrogen or halogen.

[0250] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0251]

[0252] where X 1 Can be saturated C, and X 1 Connect to R n , where R n Can be H;

[0253] Ring A may be selected from: a 5-membered saturated heterocyclic group having 1 nitrogen heteroatom and a 4- to 6-membered saturated carbocyclic group;

[0254] P can be 1;

[0255] L 2 Can be -R 2 -L 3 -, and L 3 Directly connected to Ring A;

[0256] L 3 Can be -(C(R 3a )(R 3b )) m -, and m can be 0 or 2;

[0257] R 2 Can be -O-;

[0258] L 1 It may be -C(O)-;

[0259] Among them, each R 3a and each R 3b may each independently be hydrogen.

[0260] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0261]

[0262] where X 1 Can be saturated C, and X 1 Can be R n replace;

[0263] Ring A may be a 3- to 6-membered saturated heterocyclic group;

[0264] Ring A may contain one ring-forming heteroatom N, and N is used to connect to the antibody directly or through a linker;

[0265] L 1 Can be -(C(R 5a )(R 5b )) n -, and n can be selected from 0 and 1;

[0266] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0267] Among them, each R 5a , each R 5b and each R n may be each independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0268] wherein each R can independently be hydrogen or halogen.

[0269] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0270]

[0271] where X 1 Can be saturated C, and X 1 Can be replaced by H;

[0272] Ring A may be a 5-membered saturated heterocyclic group having one heteroatom N;

[0273] Ring A may contain one ring-forming heteroatom N, and N is used to connect to the antibody directly or through a linker;

[0274] L 1 It may be -C(O)-.

[0275] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0276]

[0277] where X 1 Can be unsaturated C;

[0278] Ring A can be selected from: 6-membered aryl, 5- to 8-membered heteroaryl, 3- to 10-membered partially unsaturated heterocyclic group and 3- to 10-membered partially unsaturated carbocyclic group, and Ring A can be unsubstituted or can be substituted independently with one substituent R 1b replace;

[0279] P can be 1;

[0280] L 2 Can be -R 2 -L 3 -, and R 2 For attachment to antibodies, either directly or through a linker;

[0281] L 3 Can be -C(R 3a )(R 3b )-;

[0282] R 2 Can be selected from: -O-, -(R 2a )N- and -S-;

[0283] L 1 Can be -C(R5a )(R 5b )-;

[0284] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0285] Among them, each R 1b , each R 2a , each R 3a , each R 3b , each R 5a and each R 5b may be each independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0286] wherein each R can independently be hydrogen or halogen.

[0287] For example, the compound may comprise a structure represented by formula (II-Ax):

[0288] where X 1 Can be unsaturated C;

[0289] Ring A may be selected from: 6-membered aryl and 5- to 8-membered heteroaryl;

[0290] P can be 1;

[0291] L 2 Can be -R 2 -L 3 -, and for linking to an antibody directly or via a linker;

[0292] L 3 Can be -C(R 3a )(R 3b )-;

[0293] R 2 Can be selected from: -O-, -(R 2a )N- and -S-;

[0294] L 1 Can be -C(R 5a )(R 5b )-;

[0295] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0296] Among them, each R 2a , each R 3a , each R 3b , each R 5a and each R 5b may be each independently hydrogen, halogen or C which may be optionally substituted by R1-6 aliphatic groups;

[0297] wherein each R can independently be hydrogen or halogen.

[0298] For example, the compound may comprise a structure represented by formula (II-Ax):

[0299] where X 1 Can be unsaturated C;

[0300] Ring A may be a 6-membered aryl group;

[0301] P can be 1;

[0302] L 2 Can be -R 2 -L 3 -, and R 2 For attachment to antibodies, either directly or through a linker;

[0303] L 3 Can be -C(R 3a )(R 3b )-;

[0304] R 2 Can be -O-;

[0305] L 1 It may be -C(O)-;

[0306] Among them, each R 3a , each R 3b , each R 5a and each R 5b can be independently hydrogen or C 1-6 Aliphatic group.

[0307] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0308]

[0309] where X 1 Can be unsaturated C;

[0310] Ring A may be a 5-membered partially unsaturated heterocyclic group;

[0311] Ring A may contain one ring-forming heteroatom N, and N is used to connect to the antibody directly or through a linker;

[0312] L 1 Can be -C(R 5a )(R 5b ),

[0313] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0314] Among them, each R 5a and each R 5b may be each independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0315] wherein each R can independently be hydrogen or halogen.

[0316] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0317]

[0318] where X 1 Can be N;

[0319] Ring A may be a 6-membered saturated heterocyclic group;

[0320] P can be 1;

[0321] L 2 Can be -R 2 -L 3 -, and R 2 For attachment to antibodies, either directly or through a linker;

[0322] L 3 Can be -(C(R 3a )(R 3b )) m -, and m can be 1 or 2,

[0323] Among them L 3 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0324] R 2 Can be selected from: -O-, -(R 2a )N- and -S-;

[0325] L 1 Can be -C(R 5a )(R 5b )-,

[0326] Among them L 1 One methylene unit of may be replaced by -C(O)- or -C(=S)-;

[0327] Among them, each R2a , each R 3a , each R 3b , each R 5a and each R 5b may be each independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0328] wherein each R can independently be hydrogen or halogen.

[0329] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0330]

[0331] where X 1 Can be N;

[0332] Ring A may be a 5-membered partially unsaturated heterocyclic group;

[0333] Ring A may contain one ring-forming heteroatom N, and N is used to connect to the antibody directly or through a linker;

[0334] L 1 Can be -C(R 5a )(R 5b ),

[0335] Among them L 1 At least one methylene unit may be replaced by -C(O)- or -C(=S)-;

[0336] Among them, each R 5a and each R 5b may be each independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0337] wherein each R can independently be hydrogen or halogen.

[0338] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to any one of Formula (II-A-1) to Formula (II-A-12) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0339]

[0340] where R 2 Can be selected from: -O-, -HN-, -P(=O)H- and -S-; X 2 Can be selected from N and P; where R2 or X 2 Connect any one of the structures shown in Formulas (II-A-1) to (II-A-12) directly or through a linker to the antibodies described herein.

[0341] III-A Implementation Plan

[0342] In one embodiment, the antibody-drug conjugate comprises an active agent having a structure according to Formula (III-A) or a tautomer, meso form, racemic form, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0343]

[0344] where R 1 is independently selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-;

[0345] X is independently selected from: -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L<00010​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​2 0 or 1 methylene unit may be replaced by -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)-;

[0349] L 3 Can be -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit may be independently replaced by -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 0 or not less than 1 methylene unit can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[0350] Among them, 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 8can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0351] Among them, each R, each R a and each R b Each of the above may be 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 aliphatic groups;

[0352] m may be selected from integers ≥ 0, and n may be selected from integers ≥ 1;

[0353] When R 1 Can be -O- or -HN- and X can be -L 1 -CH2-C(O)-, and when L 1 When methylene units may be included, L 1 At least one methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substitution, or in L 1 Each -C(R 3a )(R 3b )-Middle R 3a and R 3b Cannot be all hydrogen;

[0354] When R 1 Can be -HN-, X can be -L 1 -L 0 - and L 0 When it can be -CH2-, L 1 At least one methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Cannot be all hydrogen;

[0355] When R 1 Can be -O-, X can be -L 3 -C(O)- and L 3 One methylene unit can be replaced by -NR 8 When replacing, R 8 It cannot be -CH2-CH2-NH2;

[0356] When R 1 may be -NH- and X may be -L 3 -C(O)-, L 3 Not less than one methylene unit may be replaced by -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-.

[0357] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0358]

[0359] where R 1 Can be selected from: -O-, -(R 2 )N- and -S-;

[0360] X can be -L 1 -C(R 1a )(R 1b )-C(S)-;

[0361] L 1 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 0;

[0362] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[0363] R 2 Can be halogen, -NO2, -CN, -OR, -SR, -N(Ra )(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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0364] Among them, each R 1a , each R 1b , each R 3a , each R 3b and each R 4b can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0365] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0366] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0367]

[0368] where R 1 Can be -S- or -(R 2 )N-;

[0369] X can be -L 1 -C(R 1a )(R 1b )-C(O)-;

[0370] L 1 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 0;

[0371] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[0372] R 2 Can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0373] Among them, each R 1a , each R 1b , each R 3a , each R 3b and each R 4b can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0374] Among them, each R, each R a and each R bEach of the above may be 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 Aliphatic group.

[0375] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0376]

[0377] where R 1 Can be -O- or -HN-;

[0378] X can be -L 1 -CH2-C(O)-;

[0379] L 1 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 1;

[0380] Among them L 1 At least one methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[0381] Among them, each R 3a , each R 3b and each R 4b can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0382] Among them, each R, each R a and each R bEach of the above may be 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 Aliphatic group.

[0383] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0384]

[0385] where R 1 Can be -O- or -HN-;

[0386] X can be -L 1 -CH2-C(O)-;

[0387] L 1 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 0;

[0388] In each -C(R 3a )(R 3b )-Middle R 3a and R 3b Cannot be all hydrogen or L 1 At least one methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[0389] Among them, each R 3a , each R 3b and each R 4b can be 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)SO2R or C optionally substituted by R1-6 aliphatic groups;

[0390] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0391] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0392]

[0393] where R 1 Can be -O-, -S- or -(R 2 )N-;

[0394] X can be -L 1 -L 0 -;

[0395] L 0 Can be -C(R 2a )(R 2b )-, or L 0 Can be -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[0396] L 1 Can be -(C(R 3a )(R 3b )) m , and m can be selected from integers ≥ 0;

[0397] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[0398] R 2 Can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0399] Among them, each R 2a , each R 2b 、R 3a , each R 3b , each R 4a and each R 4b can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0400] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0401] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0402]

[0403] where R 1 Can be -HN-;

[0404] X can be -L 1 -L0 -;

[0405] L 0 Can be -C(R 2a )(R 2b )-, or L 0 Can be -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[0406] L 1 Can be -(C(R 3a )(R 3b )) m -, m can be selected from integers ≥ 0, and each R 3a and each R 3b Cannot be all hydrogen;

[0407] Among them L 1 0 or not less than 1 methylene unit can be independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[0408] Among them, each R 2a , each R 2b 、R 3a , each R 3b , each R 4a and each R 4b can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0409] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0410] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0411]

[0412] Where X can be -L 3 -L 2 -;

[0413] L 2 Can be -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit may be replaced by -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)-;

[0414] R 1 Can be -S- or -(R 2 )N-; or R 1 Can be -O- and L 2 Cannot be -C(O)-; or R 1 Can be -NH- and L 2 It cannot be -C(O)-;

[0415] L 3 Can be -(C(R 7a )(R 7b )) n -, and n can be selected from integers ≥ 1;

[0416] Among them L 3 At least one methylene unit may be independently replaced by -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 0 or not less than 1 methylene unit can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[0417] R 2 Can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0418] Among them, each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0419] Among them, each R, each R a and each R bEach of the above may be 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 Aliphatic group.

[0420] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0421]

[0422] where R 1 Can be -O-;

[0423] X can be -L 3 -L 2 -;

[0424] Among them L 2 It may be -C(O)-;

[0425] L 3 Can be -(C(R 7a )(R 7b )) n -, and n can be selected from integers ≥ 0;

[0426] Among them L 3 At least one methylene unit may be independently replaced by -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 0 or not less than 1 methylene unit can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[0427] Among them, each R 7a , each R 7b and each R 8can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0428] Among them, R a and R b Each of the above may be 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 aliphatic groups;

[0429] When L 3 One methylene unit can be replaced by -NR 8 When replacing, R 8 Cannot be a C that can be replaced by -NH2 1-6 Aliphatic group.

[0430] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0431]

[0432] where R 1 Can be -HN-;

[0433] X can be -L 3 -L 2 -;

[0434] Among them L 2 It may be -C(O)-;

[0435] L 3 Can be -(C(R 7a )(R 7b )) n -, and n can be selected from integers ≥ 1;

[0436] L 3 Not less than one methylene unit may be replaced by -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 L 3 0 or not less than 1 methylene unit can also be independently replaced by -C(O)N(R 8 )-、-NR 8 - or -O- substitution, and L 3 0 or not less than 1 methylene unit can also be independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[0437] Among them, each R 7a , each R 7b and each R 8 can be 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[0438] Among them, each R, each R a and each R b Each of the above may be 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 Aliphatic group.

[0439] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0440]

[0441] where R 1 Can be -O-, -S- or -(R 2 )N-;

[0442] X can be -L 1 -C(R 1a )(R 1b )-C(S)-;

[0443] L 1 Can be -(C(R 3a )(R 3b )) m -, and m can be 0, 1 or 2;

[0444] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0445] Among them, each R 1a , each R 1b , each R 2 , each R 3a and each R 3b may be each independently hydrogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0446] wherein each R may be hydrogen.

[0447] For example, the compound may comprise a structure represented by formula (III-A):

[0448] where R 1 Can be -O-;

[0449] X can be -L 1 -C(R 1a )(R 1b )-C(S)-;

[0450] L 1 Can be -(CH2) m -, and m can be 1 or 2;

[0451] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0452] Among them, each R 1a and each R1b may be each independently hydrogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0453] wherein each R may be hydrogen.

[0454] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0455]

[0456] where R 1 Can be -S- or -(R 2 )N-;

[0457] X can be -L 1 -C(R 1a )(R 1b )-C(O)-;

[0458] L 1 Can be -(C(R 3a )(R 3b )) m -, and m can be 0, 1 or 2;

[0459] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0460] R 2 Can be C 1-6 aliphatic groups;

[0461] Among them, each R 1a , each R 1b , each R 3a and each R 3b can be independently hydrogen or C 1-6 Aliphatic group.

[0462] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0463]

[0464] where R 1 Can be -S- or -(R 2 )N-;

[0465] X can be -L 1-C(R 1a )(R 1b )-C(O)-;

[0466] L 1 Can be -(C(R 3a )(R 3b )) m -, and m can be 1 or 2;

[0467] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0468] R 2 Can be C 1-6 aliphatic groups;

[0469] Among them, each R 1a , each R 1b , each R 3a and each R 3b can be independently hydrogen or C 1-6 Aliphatic group.

[0470] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0471]

[0472] When R 1 Can be -S- or -(R 2 )N-,

[0473] X can be -L 1 -C(R 1a )(R 1b )-C(O)-,

[0474] L 1 Can be -(C(R 3a )(R 3b )) m -, and m can be 0, 1 or 2,

[0475] L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0476] R 2 Can be C 1-6 aliphatic groups;

[0477] Among them, each R 1a , each R 1b , each R 3a and each R3b can be independently hydrogen or C 1-6 aliphatic groups;

[0478] Or when R 1 Can be -O-,

[0479] X can be -L 1 -CH2-C(O)-, and

[0480] L 1 Can be -(C(R 3a )(R 3b ))2-,

[0481] L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0482] Among them, each R 3a and each R 3b can be independently hydrogen or C 1-6 aliphatic groups;

[0483] Each R 3a and each R 3b Cannot be all hydrogen or L 1 One methylene unit of can be replaced by -C(O)-;

[0484] Among them, each R 3a and each R 3b can be independently hydrogen or C 1-6 Aliphatic group.

[0485] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0486]

[0487] where R 1 Can be -O-;

[0488] X can be -L 1 -CH2-C(O)-;

[0489] L 1 Can be -(C(R 3a )(R 3b ))2-;

[0490] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0491] Among them, each R 3a and each R3b can be independently hydrogen or C 1-6 aliphatic groups;

[0492] Each R 3a and each R 3b Cannot be all hydrogen or L 1 One methylene unit of can be replaced by -C(O)-;

[0493] Among them, each R 3a and each R 3b can be independently hydrogen or C 1-6 Aliphatic group.

[0494] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0495]

[0496] When R 1 Can be -S- or -(R 2 )N-,

[0497] X can be -L 1 -C(R 1a )(R 1b )-C(O)-,

[0498] L 1 Can be -(C(R 3a )(R 3b )) m -, and m can be 0, 1 or 2,

[0499] L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0500] R 2 Can be C 1-6 aliphatic groups;

[0501] Among them, each R 1a , each R 1b , each R 3a and each R 3b can be independently hydrogen or C 1-6 aliphatic groups;

[0502] Or when R 1 Can be -O-, and

[0503] X can be -L 1 -CH2-C(O)-,

[0504] L 1 Can be -C(R 3a )(R 3b )-, and each -C(R 3a )(R 3b )-R 3a and R 3b Cannot be all hydrogen;

[0505] Among them, each R 3a and each R 3b can be independently hydrogen or C 1-6 Aliphatic group.

[0506] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0507]

[0508] where R 1 Can be -O-;

[0509] X can be -L 1 -CH2-C(O)-;

[0510] L 1 Can be -(C(R 3a )(R 3b ))2-;

[0511] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)-;

[0512] Among them, each R 3a and each R 3b can be independently hydrogen or C 1-6 aliphatic groups;

[0513] In each -C(R 3a )(R 3b ) 3a and R 3b Cannot be all hydrogen or L 1 One methylene unit of can be replaced by -C(O)-;

[0514] Among them, each R 3a and each R 3b can be independently hydrogen or C 1-6 Aliphatic group.

[0515] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0516]

[0517] where R 1 Can be -O-;

[0518] X can be -L 1 -CH2-C(O)-;

[0519] L 1 It can be -(CH2)2-;

[0520] Among them L 1 One methylene unit may be replaced by -C(O)-.

[0521] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0522]

[0523] where R 1 Can be -O-;

[0524] X can be -L 1 -CH2-C(O)-;

[0525] L 1 Can be -C(R 3a )(R 3b )- m -, m can be selected from an integer of 1 to 5, and in each -C(R 3a )(R 3b )-Middle R 3a and R 3b Cannot be all hydrogen;

[0526] Among them, each R 3a and each R 3b may be independently hydrogen, halogen or C which may be optionally substituted by R 1-6 aliphatic groups;

[0527] Each R can be hydrogen or halogen.

[0528] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0529]

[0530] where R 1 Can be -O-;

[0531] X can be -L 1 -CH2-C(O)-;

[0532] L 1 Can be -C(R 3a )(R 3b )-, and R 3a and R 3b Cannot be all hydrogen;

[0533] Among them, each R 3a and each R 3b can be independently hydrogen or C 1-6 Aliphatic group.

[0534] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0535]

[0536] where R 1 Can be -O- or -(R 2 )N-;

[0537] X can be -L 1 -L 0 -;

[0538] L 0 Can be -CH2-, or L 0 Can be -C(=S)-;

[0539] L 1 Can be -(CH2) m -, and m can be selected from integers from 0 to 2;

[0540] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-;

[0541] R 2 Can be C 1-6 Aliphatic group.

[0542] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0543]

[0544] where R 1 It can be -NH-;

[0545] X can be -L 1 -L 0 -;

[0546] L 0 Can be -CH2-, or L 0 Can be -C(=S)-;

[0547] L 1 Can be -(CH2) m -, and m can be selected from integers from 0 to 2;

[0548] Among them L 1 0 or 1 methylene unit may be replaced by -C(O)- or -C(=S)-.

[0549] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0550]

[0551] where R 1 Can be -S- or -(R 2 )N-;

[0552] X can be -L 3 -L 2 -;

[0553] Among them L 2 It may be -C(O)-;

[0554] L 3 Can be -(CH2) n -, and n can be 4 or 5;

[0555] Among them L 3 One methylene unit can be replaced by -NR 8 -, -O-, -S-, or -SO- substitution;

[0556] R2 Can be C 1-6 Aliphatic group.

[0557] For example, the compound may comprise a structure represented by formula (III-A):

[0558] where R 1 Can be -S- or -(R 2 )N-;

[0559] X can be -L 3 -L 2 -;

[0560] Among them L 2 It may be -C(O)-;

[0561] L 3 Can be -(CH2) n -, and n can be 4 or 5;

[0562] Among them L 3 One methylene unit of can be replaced by -O-;

[0563] R 2 Can be C 1-6 Aliphatic group.

[0564] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0565]

[0566] where R 1 Can be -O-;

[0567] X can be -L 3 -L 2 -;

[0568] Among them L 2 It may be -C(O)-;

[0569] L 3 Can be -(C(R 7a )(R 7b )) n -, and n can be 4 or 5;

[0570] Among them L 3 One methylene unit can be replaced by -NR 8 - or -O- substitution, and L 3 0 or 1 methylene unit may also be independently replaced by -C(O)- or -C(=S)-;

[0571] Among them, each R 7a , each R 7b and each R 8 can be independently hydrogen or C 1-6 Aliphatic group.

[0572] For example, the compound may comprise a structure represented by formula (III-A):

[0573] where R 1 Can be -O-;

[0574] X can be -L 3 -L 2 -;

[0575] Among them L 2 It may be -C(O)-;

[0576] L 3 Can be -(C(R 7a )(R 7b ))4-;

[0577] Among them L 3 One methylene unit can be replaced by -NR 8 - or -O- substitution;

[0578] Among them, each R 7a , each R 7b and each R 8 can be independently hydrogen or C 1-6 Aliphatic group.

[0579] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0580]

[0581] where R 1 Can be -O-;

[0582] X can be -L 3 -L 2 -;

[0583] Among them L 2 It may be -C(O)-;

[0584] L 3 Can be -(C(R 7a )(R 7b ))4-;

[0585] Among them L 3One methylene unit can be replaced by -NR 8 - Replacement;

[0586] Among them, each R 7a , each R 7b and each R 8 can be independently hydrogen or C 1-6 Aliphatic group.

[0587] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0588]

[0589] where R 1 It can be -NH-;

[0590] X can be -L 3 -L 2 -;

[0591] Among them L 2 It may be -C(O)-;

[0592] L 3 Can be -(CH2) n -, and n can be 4 or 5;

[0593] Among them L 3 One methylene unit of may be replaced by -S-.

[0594] In one embodiment, the antibody drug conjugate comprises an active agent having a structure according to any one of Formula (III-A-1) to Formula (III-A-17) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0595]

[0596]

[0597] where R 2 C may be optionally substituted by R 1-6 Aliphatic groups, wherein R can be 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 1-6an aliphatic group, or one in which R 2 It can be 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 an aliphatic group; wherein the wavy line represents the connection of the structure represented by any one of Formula (III-A-1) to Formula (III-A-17) to the antibody defined herein, directly or through a linker.

[0598] For example, R 2 It may be methyl, which may be optionally replaced by one or more 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 For example, R 2 It may be an ethyl radical, which may be optionally replaced by 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 For example, R 2 It may be a propyl group, which may be optionally substituted with 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 Aliphatic substitution.

[0599] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0600] Table 1

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624] One or more drug units may be present per antibody molecule. The ratio between the number of drug molecules / antibody is expressed as the drug-to-antibody ratio (DAR). In one embodiment, the DAR is 1 to 10, such as 2 to 8, such as 2 to 6, such as 2 or 4.

[0625] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0626]

[0627] where R 1 Can be -O- or -(R 2 )N- or -S-; and

[0628] X can be -L 1 -CH2-C(O)-, or -AC(O)-;

[0629] When X is -L 1 -CH2-C(O)-, L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 1 0 or 1 methylene unit of can be independently replaced by -C(O)- or -C(S)-;

[0630] When X is -AC(O)-, A may be a ring structure selected from phenyl, pyridyl, cyclohexyl, cyclopentyl and cyclobutyl, wherein A may be unsubstituted or may be substituted by one or more substituents R 1c replace;

[0631] where R 2 、R 3a 、R 3b and R 1c Each of them can be 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)SO2R or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein each R, each R a and each R bEach of the above may be 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 Aliphatic group.

[0632] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0633]

[0634] where R 1 may be -O- or -HN-; and

[0635] X can be -L 1 -CH2-C(O)-, or -AC(O)-;

[0636] When X is -L 1 -CH2-C(O)-, L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 1 0 or 1 methylene unit of may be independently replaced by -C(O)-;

[0637] Wherein when X is -AC(O)-, A may be a ring moiety selected from phenyl, pyridyl, cyclohexyl, cyclopentyl and cyclobutyl, wherein A may be unsubstituted or may be substituted by one or more substituents R 1c replace;

[0638] where R 3a 、R 3b and R 1c Each of them can be independently hydrogen, protium, deuterium, tritium, halogen, -NO2, -CN, -OR, -SR, -N(R a )(R b ), -C(O)R or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein each R, each R a and each R bEach of the above may be 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 Aliphatic group.

[0639] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0640]

[0641] where R 1 may be -O- or -HN-; and

[0642] X can be -L 1 -CH2-C(O)-, or -AC(O)-;

[0643] When X is -L 1 -CH2-C(O)-, L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 1 0 or 1 methylene unit of may be independently replaced by -C(O)-;

[0644] Wherein when X is -AC(O)-, A may be a ring moiety selected from phenyl, pyridyl, cyclohexyl, cyclopentyl and cyclobutyl, wherein A may be unsubstituted or may be substituted by one or more substituents R 1c replace;

[0645] where R 3a 、R 3b and R 1c Each of which can be independently hydrogen or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein R may be hydrogen, halogen, -NO2, -CN, -OH, -NH2 or C 1-6 Aliphatic group.

[0646] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0647]

[0648] where R 1 may be -O- or -HN-; and

[0649] X can be -L 1 -CH2-C(O)-;

[0650] Among them L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 1 0 or 1 methylene unit of may be independently replaced by -C(O)-;

[0651] where R 3a and R 3b Each of which can be independently hydrogen or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein R may be hydrogen, halogen, -NO2, -CN, -OH, -NH2 or C 1-6 Aliphatic group.

[0652] In one embodiment of the structure of Formula (III-A) described above, R 1 L via X 1 The moiety is chemically bonded to X described above.

[0653] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0654]

[0655] Wherein in formula (IV-A), R 1 Can be -O- or -(R 2 )N- or -S-; and

[0656] X can be -L 1 -CH2-C(O)-, or -AC(O)-;

[0657] When X is -L 1 -CH2-C(O)-, L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 10 or 1 methylene unit of can be independently replaced by -C(O)- or -C(S)-;

[0658] When X is -AC(O)-, A may be a ring structure selected from phenyl, pyridyl, cyclohexyl, cyclopentyl and cyclobutyl, wherein A may be unsubstituted or may be substituted by one or more substituents R 1c replace;

[0659] where R 2 、R 3a 、R 3b and R 1c Each of them can be 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)SO2R or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein each R, each R a and each R b Each of the above may be 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 an aliphatic group; or

[0660] Wherein in formula (IV-A), R 1 may be -O- or -HN-; and

[0661] X can be -L 1 -CH2-C(O)-, or -AC(O)-;

[0662] When X is -L 1 -CH2-C(O)-, L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 1 0 or 1 methylene unit of may be independently replaced by -C(O)-;

[0663] Wherein when X is -AC(O)-, A may be a ring moiety selected from phenyl, pyridyl, cyclohexyl, cyclopentyl and cyclobutyl, wherein A may be unsubstituted or may be substituted by one or more substituents R 1c replace;

[0664] where R 3a 、R 3b and R 1c Each of which can be independently hydrogen or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein R may be hydrogen, halogen, -NO2, -CN, -OH, -NH2 or C 1-6 an aliphatic group; or

[0665] Wherein in formula (IV-A), R 1 may be -O- or -HN-; and

[0666] X can be -L 1 -CH2-C(O)-;

[0667] Among them L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 1 0 or 1 methylene unit of may be independently replaced by -C(O)-;

[0668] where R 3a and R 3b Each of which can be independently hydrogen or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein R may be hydrogen, halogen, -NO2, -CN, -OH, -NH2 or C 1-6 Aliphatic group.

[0669] In one embodiment of the structure of Formula (III-A) described above, R 1 L via X 1 The moiety is chemically bonded to X described above.

[0670] In one embodiment of Formula (IV-A), R 1 may be -O-; and X may be -L 1 -CH2-C(O)-. In another embodiment, L 1 Can be -(C(R 3a )(R 3b )) m , where m can be selected from 0, 1 and 2, where L 1 0 or 1 methylene unit of L can be independently replaced by -C(O)-. Preferably, m is 1, so that L1 Can be -(C(R 3a )(R 3b )), where R 3a and R 3b Each of which can be independently hydrogen or C 1-6 An aliphatic group, such as a methyl group, may be optionally substituted with R, wherein R may be hydrogen, halogen, -NO2, -CN, -OH, -NH2 or C 1-6 Aliphatic group.

[0671] connector

[0672] The stable connection between the antibody and the active agent is an important aspect of ADC technology. The linker can be, for example, based on a chemical motif, including a disulfide, a hydrazone or a peptide (cleavable) or a thioether (non-cleavable), and controls the distribution and delivery of the active agent to the target cell. Cleaving and non-cleavable types of linkers have been shown to be safe in preclinical and clinical trials. For example, Brentuximab Vedotin includes an enzyme-sensitive cleavable linker that delivers the potent and highly toxic anti-microtubule agent monomethyl auristatin E (MMAE; MMAE) (a synthetic anti-tumor agent) to cells.

[0673] Trastuzumab Emtansine, another approved ADC, is a combination of the microtubule formation inhibitor mertansine (DM-1), a derivative of maytansine, and the antibody trastuzumab. TM , Genentech / Roche) connected by a stable non-cleavable linker.

[0674] The type of linker (cleavable or non-cleavable) imparts specific properties to the active agent being delivered. 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 agent). In contrast, ADCs containing non-cleavable linkers do not have a drug release mechanism and must rely on mechanisms such as targeted antibody degradation to release the drug. In addition, as will be appreciated by those skilled in the art, the linker composition can affect key factors such as the solubility and pharmacokinetic properties of the ADC as a whole.

[0675] For both types of linkers, drug release is crucial to achieving a cellular effect. Drugs that are able to freely diffuse across the cell membrane can escape from the target cell and, in a process known as "bystander killing," also attack neighboring cells, such as cancer cells near the target cell expressing uPARAP.

[0676] In a preferred embodiment of the present disclosure, the uPARAP-targeted ADC disclosed herein comprises a linker connecting the antibody to the active agent.

[0677] In one embodiment of the present disclosure, the linker may be cleavable or non-cleavable.

[0678] Cleavable groups include disulfide bonds, amide bonds, substituted amide bonds in the form of peptide bonds, sulfamide bonds, ester bonds, thioester bonds, vicinal diol bonds, or hemiacetals. These or other cleavable bonds may 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).

[0679] In another embodiment of the present disclosure, the linker is a cleavable linker that allows for intracellular release of the active agent within the target cell.

[0680] In another embodiment, the linker is a peptide linker. The choice of peptide sequence is crucial 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.

[0681] In another embodiment, the linker is a linker comprising an enzyme-cleavable peptide, such as a linker comprising a cathepsin-cleavable peptide. The cathepsin can be one of several types of cathepsins, which are one of a group of lysosomal proteases.

[0682] In another embodiment of the present disclosure, the linker comprises or consists of a dipeptide, such as valine-citrulline (VC) or valine-alanine (VA).

[0683] In one embodiment, the linker comprises or consists of a dipeptide, such as valine-citrulline (VC) or valine-alanine (VA), which can be further linked to other structural elements via amide bonds. Valine-citrulline-based linkers (wherein the carboxyl functional group of citrulline is modified to a substituted amide) can be cleaved by lysosomal cathepsins, while valine-alanine-based linkers (wherein the carboxyl functional group of alanine is modified to a substituted amide) can be cleaved by other lysosomal proteases, including other cathepsins.

[0684] In another embodiment 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).

[0685] In one embodiment of the present disclosure, the antibody-drug conjugate as defined herein comprises p-aminobenzylcarbamate (PABC).

[0686] In another embodiment of the present disclosure, the antibody-drug conjugate defined herein further comprises a linker group, for example, a linker group comprising or consisting of maleimide and caproic acid (MC), N-hydroxysuccinimide, a reactive linker group for modified or unmodified protein-bound carbohydrates, a peptide sequence required for an enzymatic reaction, an azide or an alkyne, or a group derivatized with these groups by reaction with an antibody or a chemically or enzymatically produced derivative thereof.

[0687] In one embodiment of the present disclosure, the ADC of the present disclosure further comprises a connecting entity. The connecting entity can, for example, connect an antibody to a cleavable linker, wherein the connecting entity is a reaction product between an antibody amino acid side chain and a reactive linking group in a linker precursor. In one embodiment, this reactive linking group comprises or consists of maleimide and hexanoic acid (MC), wherein the maleimide preferably reacts with cysteine thiol during coupling. In other embodiments, the linking group comprises or consists of: N-hydroxysuccinimide, a reactive linking group for modified or unmodified protein-bound carbohydrates, a peptide sequence required for an enzymatic reaction, an azide or an alkyne, or a group derived from these groups by reacting with an antibody or its chemically or enzymatically produced derivatives.

[0688] IB

[0689] In one embodiment, the antibody drug conjugate comprises a structure according to Formula (IB) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0690]

[0691] where X a may be nitrogen generated by removing two hydrogen atoms from the amino group of exatecan (EXA);

[0692] L can be -L a -L b -L c -; wherein L connects the structure of formula (IB) to the antibody defined herein;

[0693] -L a -Can be selected from:

[0694] and Where W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, and Z may be -(C(R za )(R zb )) zn ;

[0695] wherein Z connects -La- to -Lb-;

[0696] where wn can be selected from integers ≥ 0, and

[0697] 0 or more than 1 methylene unit of W may be independently replaced by -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)-;

[0698] Where yn can be selected from integers ≥ 0, and yp can be 0 or 1;

[0699] Where zn can be selected from integers ≥ 0, and

[0700] 0 or more than 1 methylene unit of Z may be independently replaced by -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)-;

[0701] -Cyr- can be selected from: 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 can be independently substituted with at least one substituent R cx replace;

[0702] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx can be 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[0703] Among them, each R r , each R ra and each R rb Each of the above may be 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 1-6aliphatic groups;

[0704] -L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0705] -L c -Can be selected from:

[0706] and

[0707] where R L1 and R L2 Each of the following may be independently selected from the group consisting of 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;

[0708] R 1 、L 1 and L 2 As defined in any of Formula (IA) in the embodiments described above.

[0709] II-Bx, II-By

[0710] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0711]

[0712] where X a may be nitrogen generated by removing two hydrogen atoms from the amino group of exitecan (EXA);

[0713] L can be -L a -L b -L c -; wherein L connects the structure of Formula (II-Bx) or Formula (II-By) to the antibody defined herein;

[0714] -L a -Can be selected from:

[0715] and

[0716] Where W can be -(C(R wa)(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, and Z may be -(C(R za )(R zb )) zn ;

[0717] wherein Z connects -La- to -Lb-;

[0718] where wn can be selected from integers ≥ 0, and

[0719] 0 or more than 1 methylene unit of W may be independently replaced by -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)-;

[0720] Where yn can be selected from integers ≥ 0, and yp can be 0 or 1;

[0721] Where zn can be selected from integers ≥ 0, and

[0722] 0 or more than 1 methylene unit of Z may be independently replaced by -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)-;

[0723] -Cyr- can be selected from: 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 can be independently substituted with at least one substituent R cx replace;

[0724] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx can be 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[0725] Among them, each R r , each R ra and each R rb Each of the above may be 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 aliphatic groups;

[0726] -L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0727] -L c -Can be selected from:

[0728] and

[0729] where R L1 and R L2 Each of the following may be independently selected from the group consisting of 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;

[0730] L 2 , p, ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above;

[0731] or X 2 ,q,ring A,X 1 and L 1 As defined in any of Formula (II-Ay) in the embodiments described above.

[0732] III-B

[0733] In one embodiment, the antibody drug conjugate comprises a structure according to formula (III-B) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0734]

[0735] where X a may be nitrogen generated by removing two hydrogen atoms from the amino group of exitecan (EXA);

[0736] L can be -L a -L b -L c -; wherein L links the structure shown in Formula (II-Bx) or Formula (II-By) to the antibody defined herein;

[0737] -L a -Can be selected from:

[0738] and

[0739] Where W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn-O yp , and Z may be -(C(R za )(R zb )) zn ;

[0740] wherein Z connects -La- to -Lb-;

[0741] where wn can be selected from integers ≥ 0, and

[0742] 0 or more than 1 methylene unit of W may be independently replaced by -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)-;

[0743] Where yn can be selected from integers ≥ 0, and yp can be 0 or 1;

[0744] Where zn can be selected from integers ≥ 0, and

[0745] 0 or more than 1 methylene unit of Z may be independently replaced by -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)-;

[0746] -Cyr- can be selected from: 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 can be independently substituted with at least one substituent R cx replace;

[0747] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx can be 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[0748] Among them, each R r , each R ra and each R rb Each of the above may be 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 aliphatic groups;

[0749] -L b - represents a peptide residue consisting of 2 to 7 amino acids;

[0750] -L c -Can be selected from:

[0751] and

[0752] where R L1 and R L2Each of the following may be independently selected from the group consisting of 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;

[0753] where R 1 and X is as defined in any of Formula (III-A) in the embodiments described above.

[0754] In another embodiment, wn may be selected from an integer of 2 to 6, and 0 or 1 methylene unit of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-、-C(O)-、-NR wx -or -O- substitution.

[0755] For example, wn may be 1, 2, 3 or 6, and one methylene unit of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )- or -C(O)- replacement.

[0756] In another embodiment, yn may be selected from an integer from 0 to 12, and yp may be 0 or 1.

[0757] For example, yn may be 0, 4, or 8, and yp may be 0 or 1.

[0758] In another embodiment, zn can be selected from an integer from 0 to 10, and 0 or 1 methylene unit of Z can be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )- or -C(O)- replacement.

[0759] For example, zn may be 1, 2 or 3, and one methylene unit of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )- or -C(O)- replacement.

[0760] In another embodiment, -Cyr- can be selected from: 6- to 10-membered arylene and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein -Cyr- is unsubstituted or can be substituted independently with 1 to 3 substituents R cx replace.

[0761] For example, -Cyr- can be a 3- to 10-membered saturated carbocyclyl group, wherein -Cyr- is unsubstituted or can be substituted independently with 1 to 3 substituents R cx replace.

[0762] 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 can be 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)CH2C(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 by R r Substituted C 1-6 Aliphatic group; each R r , each R ra and each R rb Each of the above may be 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 Aliphatic group.

[0763] For example, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx can be independently hydrogen, halogen, -OR r or optionally by R r Substituted C 1-6Aliphatic group; each R r can be independently hydrogen, halogen or C 1-6 Aliphatic group.

[0764] In another embodiment, -L b - represents a peptide residue consisting of 2 to 7 amino acids, and -L b The peptide residue of - may be a peptide residue that can be formed by amino acids, and the amino acid may be selected from the group consisting of phenylalanine, glycine, alanine, valine, citrulline, lysine, serine, glutamic acid and aspartic acid.

[0765] For example, -L b - represents a peptide residue consisting of 2 to 4 amino acids, and -L b - can be a peptide residue formed by amino acids, and the amino acids can be selected from: phenylalanine, glycine, alanine, valine, citrulline and lysine. In one embodiment of the present disclosure, -L b - may comprise or consist of SEQ ID NO 14 or 15.

[0766] For example, -L b -Can be selected from:

[0767] and

[0768] For example, -L b -Can be

[0769]

[0770] In another embodiment, -L c -Can be selected from:

[0771] and

[0772] For example, -L c -Can be selected from:

[0773] and

[0774] -L c -Can be

[0775]

[0776] In another embodiment, R L1 and R L2Each of the following may be independently selected from the group consisting of 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 group.

[0777] For example, R L1 and R L2 Can be independently selected from: hydrogen, halogen, -OH and C 1-6 In another embodiment, -L a -Can be In another embodiment, -L b -Can be selected from: and

[0778] For example, -L b -Can be selected from: and In one embodiment, -L c -Can be In one embodiment, -L a -L b -L c -Can be selected from: and

[0779] As used herein, the formula referred to as exitecan (EXA) is

[0780]

[0781] Exitecan (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, exitecan is classified as a topoisomerase inhibitor, more specifically, a topoisomerase I inhibitor.

[0782] IC

[0783] In one embodiment, the antibody drug conjugate comprises formula (IC) or a tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0784]

[0785] Wherein L can be -L a -L b -L c -, and L a 、L b and L c As defined in any of the embodiments of formula (IB) described above;

[0786] R 1 、L 1 and L 2 As defined in any of Formula (IA) in the embodiments described above.

[0787] II-Cx, II-Cy

[0788] In one embodiment, the antibody conjugate comprises formula (II-Cx) or (II-Cy) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof

[0789]

[0790] Wherein L can be -L a -L b -L c -, and L a 、L b and L c As defined in any of Formula (II-Bx) in the embodiments described above;

[0791] L 2 , p, ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above;

[0792] or X 2 ,q,ring A,X 1 and L 1 As defined in any of Formula (II-Ay) in the embodiments described above.

[0793] III-C

[0794] In one embodiment, the antibody-drug conjugate comprises formula (III-C) or a tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0795]

[0796] Wherein L can be -L a -L b -L c -, and L a 、L b and L c As defined in any of Formula (III-B) in the embodiments described above;

[0797] where R 1 and X is as defined in any of Formula (III-A) in the embodiments described above.

[0798] ID

[0799] In one embodiment, the antibody drug conjugate comprises formula (ID) or a tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0800]

[0801] wherein Ab represents an antibody as defined herein, comprising:

[0802] i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[0803] ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[0804] N a Indicates the average number of connections and can be an integer or decimal from 1 to 10;

[0805] L can be -L a -L b -L c -, and L a 、L b and L c As defined in any of Formula (IB) in the embodiments described above,

[0806] R 1 、L 1 and L 2 As defined in any of Formula (IA) in the embodiments described above.

[0807] II-Dx, II-Dy

[0808] In one embodiment, the antibody-drug conjugate comprises Formula (II-Dx) or Formula (II-Dy) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0809]

[0810] wherein Ab represents an antibody as defined herein, comprising:

[0811] i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[0812] ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[0813] N a Indicates the average number of connections and can be an integer or decimal from 1 to 10.

[0814] L can be -L a -L b -L c -, and L a 、L b and L c As defined in any of Formula (II-Bx) or Formula (II-By) in the embodiments described above;

[0815] L 2 , Ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above;

[0816] or X 2 , Ring A, X 1 and L 1 As defined in any of Formula (II-Ay) in the embodiments described above.

[0817] III-D

[0818] In one embodiment, the antibody-drug conjugate comprises formula (III-D) or a tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0819]

[0820] wherein Ab represents an antibody as defined herein, comprising:

[0821] i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[0822] ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[0823] N a Indicates the average number of connections and can be an integer or decimal from 1 to 10.

[0824] L can be -L a -L b -L c -, and L a 、L b and L c As defined in any of Formula (III-B) in the embodiments described above;

[0825] where R 1 and X is as defined in any of Formula (III-A) in the embodiments described above.

[0826] In one embodiment, the ADC is according to any one of formula (ID), (II-Dx), (II-Dy) or (III-D) as defined herein, wherein Ab represents an antibody comprising:

[0827] i) an immunoglobulin light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 1; and

[0828] ii) an immunoglobulin heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 4.

[0829] In one embodiment, the ADC is according to any one of formula (ID), (II-Dx), (II-Dy) or (III-D) as defined herein, wherein Ab represents an antibody comprising:

[0830] i) an immunoglobulin light chain consisting of the amino acid sequence of SEQ ID NO: 1; and

[0831] ii) an immunoglobulin heavy chain consisting of the amino acid sequence of SEQ ID NO: 4.

[0832] In one embodiment, the antibody-drug conjugate is selected from any one of the structures in Table 2 or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0833] Table 2

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841] wherein Ab represents an antibody described herein that binds to a uPARAP receptor, and wherein n is an integer from 1 to 10.

[0842] In one embodiment, the average number of connections N a It can be an integer or decimal from 2 to 8. For example, the average number of connections N a It can be an integer or decimal from 3 to 8. For example, the average number of connections N a It can be an integer or decimal of 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9 or 9 to 10.

[0843] IE

[0844] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0845]

[0846] where R 1 、L 1 and L 2 As defined in any of the above defined embodiments.

[0847] II-Ex、IIEy

[0848] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0849]

[0850] Among them L 2 , p, ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above.

[0851] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0852]

[0853] where X 2 ,q,ring A,X 1 and L 1 As defined in any of Formula (II-Ay) in the embodiments defined above.

[0854] III-E

[0855] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0856]

[0857] where R 1 and X is as defined in any of Formula (III-A) in the embodiments defined above.

[0858] Manufacturing methods, IF, II-Fx, II-Fy and III-F

[0859] In one aspect, the present disclosure provides a method for making an antibody-drug conjugate described herein, the method comprising reacting a compound according to one selected from the group consisting of Formula (IF), Formula (II-Fx), Formula (II-Fy), and Formula (III-F) described below with an anti-uPARAP antibody as defined herein.

[0860] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0861]

[0862] Among them Lx Can be -L ax -L b -L c -;

[0863] -L ax -Can be selected from:

[0864] and

[0865] where R hal Can be iodine or bromine;

[0866] Where W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, and Z may be -(C(R za )(R zb )) zn ;

[0867] where wn can be selected from integers ≥ 0, and

[0868] 0 or more than 1 methylene unit of W may be independently replaced by -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)-;

[0869] Where yn can be selected from integers ≥ 0, and yp can be 0 or 1;

[0870] Where zn can be selected from integers ≥ 0, and

[0871] 0 or more than 1 methylene unit of Z may be independently replaced by -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)-;

[0872] -Cyr- can be selected from: 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 can be independently substituted with at least one substituent R cx replace;

[0873] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx can be 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[0874] Among them, each R r , each R ra and each R rb Each of the above may be 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 1-6aliphatic groups;

[0875] L b and L c As defined in any of formula (IB) in the embodiments described above;

[0876] R 1 、L 1 and L 2 As defined in any of Formula (IA) in the embodiments described above.

[0877] In one embodiment, a 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0878] 、

[0879] Among them L x Can be -L ax -L b -L c -;

[0880] -L ax -Can be selected from:

[0881] and

[0882] where R hal Can be iodine or bromine;

[0883] Where W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, and Z may be -(C(R za )(R zb )) zn ;

[0884] where wn can be selected from integers ≥ 0, and

[0885] 0 or more than 1 methylene unit of W may be independently replaced by -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)-;

[0886] Where yn can be selected from integers ≥ 0, and yp can be 0 or 1;

[0887] Where zn can be selected from integers ≥ 0, and

[0888] 0 or more than 1 methylene unit of Z may be independently replaced by -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)-;

[0889] -Cyr- can be selected from: 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 can be independently substituted with at least one substituent R cx replace;

[0890] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx can be 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[0891] Among them, each R r , each R ra and each R rb Each of the above may be 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 aliphatic groups;

[0892] L b and L c As defined in any of Formula (II-Bx) or Formula (II-By) in the embodiments described above;

[0893] Among them L 2 , p, ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above;

[0894] or X 2 ,q,ring A,X 1 and L 1 As defined in any of Formula (II-Ay) in the embodiments described above.

[0895] 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0896]

[0897] Among them L x Can be -L ax -L b -L c -;

[0898] -L ax-Can be selected from:

[0899] and

[0900] where R hal Can be iodine or bromine;

[0901] Where W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, and Z may be -(C(R za )(R zb )) zn ;

[0902] where wn can be selected from integers ≥ 0, and

[0903] 0 or more than 1 methylene unit of W may be independently replaced by -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)-;

[0904] Where yn can be selected from integers ≥ 0, and yp can be 0 or 1;

[0905] Where zn can be selected from integers ≥ 0, and

[0906] 0 or more than 1 methylene unit of Z may be independently replaced by -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)-;

[0907] -Cyr- can be selected from: 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 can be independently substituted with at least one substituent R cx replace;

[0908] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx can be 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[0909] Among them, each R r , each R ra and each R rb Each of the above may be 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 aliphatic groups;

[0910] L b and L c As defined in any of Formula (III-B) in the embodiments described above;

[0911] where R 1 and X is as defined in any of Formula (III-A) in the embodiments described above.

[0912] In one embodiment, L ax -Can be selected from:

[0913] and

[0914] where R hal Can be iodine or bromine;

[0915] Where W can be -(C(R wa )(R wb )) wn -, Y can be -(OCH2CH2) yn -O yp -, and Z may be -(C(R za )(R zb )) zn .

[0916] In another embodiment, wn may be selected from an integer of 2 to 6, and 0 or 1 methylene unit of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )-、-C(O)-、-NR wx -or -O- substitution.

[0917] For example, wn may be 1, 2, 3 or 6, and one methylene unit of W may be independently replaced by -Cyr-, -N(R wx )C(O)-、-C(O)N(R wx )- or -C(O)- replacement.

[0918] In another embodiment, yn may be selected from an integer from 0 to 12, and yp may be 0 or 1.

[0919] For example, yn may be 0, 4, or 8, and yp may be 0 or 1.

[0920] In another embodiment, zn can be selected from an integer from 0 to 10, and 0 or 1 methylene unit of Z can be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx )- or -C(O)- replacement.

[0921] For example, zn may be 1, 2 or 3, and one methylene unit of Z may be independently replaced by -Cyr-, -N(R zx )C(O)-、-C(O)N(R zx)- or -C(O)- replacement.

[0922] In another embodiment, -Cyr- can be selected from: 6- to 10-membered arylene and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein -Cyr- is unsubstituted or can be substituted independently with 1 to 3 substituents R cx replace.

[0923] For example, -Cyr- can be a 3- to 10-membered saturated carbocyclyl group, wherein -Cyr- is unsubstituted or can be substituted independently with 1 to 3 substituents R cx replace.

[0924] 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 can be 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)CH2C(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 by R r Substituted C 1-6 Aliphatic group; each R r , each R ra and each R rb Each of the above may be 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 Aliphatic group.

[0925] For example, each R wa , each Rwb , each R za , each R zb , each R wx , each R zx and each R cx can be independently hydrogen, halogen, -OR r or optionally by R r Substituted C 1-6 Aliphatic group; each R r can be independently hydrogen, halogen or C 1-6 Aliphatic group.

[0926] In one embodiment, L ax -Can be

[0927] In one embodiment, L ax -L b -L c -Can be selected from:

[0928] and

[0929] In one embodiment, a method for making an antibody drug conjugate described herein comprises reacting a compound according to any one of the structures in Table 3 or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, with an anti-uPARAP antibody as defined herein.

[0930] Table 3

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965] In one embodiment of the present disclosure, the antibody-drug conjugates described herein have the general formula IZ depicted below.

[0966] Ab-L a -L b -L c -X(IZ)

[0967] wherein Ab represents LC4HC3 or an antibody comprising: an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3 and an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6,

[0968] L a for

[0969] L b for

[0970] L c for and

[0971] X is selected from:

[0972]

[0973] and The wavy lines represent bonds in formula (IZ).

[0974] Preferably, X is selected as

[0975] In one embodiment of the present disclosure, the linker connecting the antibody to the active agent has the following structure:

[0976] and contains a maleimidocaproic acid moiety.

[0977] In other words, in one embodiment, -L a -L b -L c -Can be:

[0978]

[0979] In one embodiment of the present disclosure, the antibody-drug conjugate has the structure of formula (II-Z)

[0980]

[0981] wherein Ab represents a humanized antibody LC4HC3 or an antibody comprising an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3 and an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6. Preferably, Ab represents the humanized antibody LC4HC3. It will be readily apparent to one skilled in the art that the number of cytotoxic agents attached to 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 greater, e.g., 3 or greater, e.g., 4 or greater, e.g., 5 or greater, e.g., 6 or greater, e.g., 7 or greater, e.g., 8 or greater, e.g., 9 or greater, e.g., 10 or greater.

[0982] In one embodiment of the present disclosure, the antibody-drug conjugate of formula (II-Z) is characterized in that it comprises at least one, such as two, such as three, such as four, preferably four asymmetric carbon atoms in the (S) configuration. Asymmetric carbon atoms are sometimes also referred to as chiral carbon atoms and are well known to those skilled in the art of medicinal chemistry.

[0983] Therapeutic uses

[0984] The ADCs directed against uPARAP described herein can be used to deliver active agents to cells expressing uPARAP and similar proteins, and are therefore useful in treating a range of diseases and disorders characterized by the expression or overexpression of such proteins.

[0985] Thus, one embodiment of the present disclosure is an antibody-drug conjugate as defined herein for use as a medicament.

[0986] 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.

[0987] As used herein, "therapeutically effective amount" or "effective amount" or "therapeutically effective" refers to an amount that provides a therapeutic effect for a given condition and dosing regimen. This is a predetermined amount of active substance calculated to produce the desired therapeutic effect in combination with the required additives and diluents (i.e., carriers or administration vehicles). In addition, it 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 cause an improvement in the clinically significant condition of the host. As will be appreciated by those skilled in the art, the amount of a compound may vary depending on its specific activity. A suitable dose may contain a predetermined amount of the active composition calculated to produce the desired therapeutic effect in combination with the required diluents.

[0988] The ADCs of the present disclosure can be formulated into any type of pharmaceutical composition known in the art suitable for their delivery.

[0989] The pharmaceutical composition can be prepared in a manner known in the art that is sufficiently storage stable and suitable for administration to humans and / or animals. For example, the pharmaceutical composition can be lyophilized, for example by freeze drying, spray drying, spray cooling or by particle formation using supercritical particle formation.

[0990] "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, edited by AR Gennaro, Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, edited by A. Kibbe, Pharmaceutical Press (2000), the disclosures of which are incorporated herein by reference).

[0991] The term "buffer" is intended to mean an aqueous solution containing a mixture of acids and bases, the purpose of which is to stabilize the pH. Pharmaceutically acceptable buffers are well known in the art.

[0992] The term "diluent" is intended to mean an aqueous or non-aqueous solution whose purpose is to dilute an agent in a pharmaceutical formulation.

[0993] The term "adjuvant" is intended to mean any compound added to a formulation to increase the biological effect of the agent of the invention. The adjuvant may 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 acetate with different acyl group compositions. The adjuvant may also be a cationic polymer, such as a cationic cellulose ether; a cationic cellulose ester; deacetylated hyaluronic acid; chitosan; a cationic dendrimer; a cationic synthetic polymer, such as poly(vinylimidazole); and a cationic polypeptide, such as polyhistidine, polylysine, polyarginine, and peptides containing these amino acids.

[0994] Excipients can be one or more of carbohydrates, polymers, lipids, and minerals. Examples of carbohydrates include lactose, glucose, sucrose, mannitol, and cyclodextrins, which are added to the composition, for example, to facilitate lyophilization. Examples of polymers are starch, cellulose ethers, cellulose carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, alginates, carrageenan, hyaluronic acid and its derivatives, polyacrylic acid, polysulfonates, polyethylene glycol / polyethylene oxide, polyethylene oxide / polypropylene oxide copolymers, polyvinyl alcohol / polyvinyl acetate of varying degrees of hydrolysis, and polyvinyl pyrrolidone, all of varying molecular weights, which are added to the composition, for example, for viscosity control, for achieving bioadhesion, or for protecting lipids from chemical and protein degradation. Examples of lipids are fatty acids, phospholipids, monoglycerides, diglycerides, and triglycerides, ceramides, sphingolipids, and glycolipids, all of varying acyl chain lengths and degrees of saturation; egg yolk lecithin, soy lecithin, hydrogenated egg yolk lecithin, and soy lecithin, which are added to the composition for similar reasons as polymers. Examples of minerals are talc, magnesium oxide, zinc oxide and titanium oxide, which are added to the composition to obtain benefits such as reduced fluid buildup or favorable pigment properties.

[0995] Another embodiment of the present disclosure is a method for 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.

[0996] The expression and role of uPARAP in cancer has been studied by several groups; see the review by Melander et al. (Melander et al., 2015, Int J Oncol 47: 1177-1188) and the article by Engelholm et al. (Engelholm et al., 2016, J. Pathol. 238, 120-133).

[0997] In one embodiment of the present disclosure, the method is a method as defined herein, wherein the disease characterized by cells expressing uPARAP is selected from cancer, bone degradation diseases (such as osteoporosis), fibrosis, and macrophage-related diseases or disorders (such as atherosclerosis, arthritis, or chronic inflammation).

[0998] In one embodiment of the present disclosure, the method is as 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.

[0999] In one embodiment of the present disclosure, the method is as defined herein, wherein the disease is cancer.

[1000] Examples of cancers characterized by overexpression of uPARAP include, but are not limited to, sarcomas, including osteosarcomas (Engelholm et al., 2016, J Pathol 238(1):120-33), such as giant cell-rich osteosarcoma, osteoblastoma-like osteosarcoma, and fibroblastic osteosarcoma, among others; 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, and 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 ( et al., 2021, Int J Mol Sci 22(21):11452).

[1001] In one embodiment of the present disclosure, the method is as 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.

[1002] 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 breast ductal carcinoma and / or invasive ductal carcinoma of the breast.

[1003] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is ovarian cancer, such as ovarian adenocarcinoma.

[1004] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is endometrial cancer, such as endometrial adenocarcinoma.

[1005] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is lymphoma, such as histiocytic lymphoma.

[1006] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is a leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML), or a subtype of these.

[1007] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is a sarcoma, such as osteosarcoma or soft tissue sarcoma (STS), or a subtype of these.

[1008] In one embodiment of the present disclosure, the method is as defined herein, and the soft tissue sarcoma (STS) is selected from the group consisting of epithelioid sarcoma, clear cell sarcoma, alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, inflammatory myofibroblastic tumor, undifferentiated embryonal sarcoma, alveolar soft parts sarcoma (ASPS), angiosarcoma, chondrosarcoma, dermatofibrosarcoma protuberens (DFSP), desmoid sarcoma, Ewing's sarcoma, and fibrosarcoma. sarcoma), fibrosarcoma, myxofibrosarcoma, adult-type fibrosarcoma, gastrointestinal stromal tumor (GIST), non-uterine leiomyosarcoma, uterine leiomyosarcoma, liposarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, myxoid round cell liposarcoma, well-differentiated liposarcoma, malignant fibrohistiocytoma (MFH), malignant peripheral nerve sheath tumor;MPNST), rhabdomyosarcoma, synovial sarcoma, and / or leiomyosarcoma (LMS).

[1009] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is a metastatic cancer.

[1010] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is a solid tumor.

[1011] In one embodiment of the present disclosure, the method is as defined herein, wherein the cancer is glioblastoma.

[1012] 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, for example, to treat leukemias that express uPARAP, such as leukemias from the macrophage-monocyte lineage.

[1013] In other embodiments of the present disclosure, the disease or disorder characterized by cells expressing uPARAP is not cancer.

[1014] uPARAP is involved in bone growth and homeostasis (Madsen et al., 2013, PLoS One 5; 8(8): e71261). Therefore, in one embodiment, the ADCs of the present disclosure can be used to treat diseases characterized by bone degradation, where bone degradation is mediated by non-malignant cells, such as osteoporosis.

[1015] Since uPARAP plays a role in collagen accumulation, it has also been shown to play a role in fibrosis (Madsen et al., 2012, J Pathol 227(1):94-105). Therefore, in one embodiment, the ADCs of the present disclosure can be used to treat fibrosis, such as fibrosis of the kidney, lung, and liver.

[1016] In one embodiment of the present disclosure, the ADCs of the present disclosure can be used to treat diseases and disorders associated with macrophages, including atherosclerosis, arthritis, and chronic inflammation.

[1017] The ADC of the present disclosure or the pharmaceutical composition comprising the ADC can be administered via any suitable route known to those skilled in the art. Thus, possible routes of administration include parenteral (intravenous, subcutaneous and intramuscular), topical, ocular, nasal, pulmonary, buccal, oral, vaginal and rectal. In addition, administration can also be performed via implants.

[1018] In a preferred embodiment, the pharmaceutical compositions are administered parenterally, for example, intravenously, intraventricularly, intraarticularly, intraarterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are preferably used in the form of sterile aqueous solutions which may contain other substances, for example, sufficient salts or glucose to render the solution isotonic with the blood. If necessary, the aqueous solution should be suitably buffered.

[1019] In one embodiment of the present disclosure, the method is as 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.

[1020] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations may be present in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Ready-to-use injection solutions and suspensions can be prepared from the aforementioned types of sterile powders, granules, and tablets.

[1021] In one embodiment of the present disclosure, the method is as defined herein, wherein the antibody-drug conjugate is administered intravenously.

[1022] In one embodiment of the present disclosure, the method is as defined herein, wherein the antibody-drug conjugate is administered subcutaneously.

[1023] In one embodiment of the present disclosure, the method is a method as defined herein, wherein the antibody drug conjugate is administered in combination with one or more other agents, such as one or more other therapeutic agents.

[1024] In one embodiment of the present disclosure, the ADCs of the present disclosure are administered in combination with additional agents and / or therapeutic agents that can increase the functional efficiency of the ADC (e.g., existing or novel drugs that increase the permeability of the lysosomal membrane, thereby facilitating the entry of molecules from the interior of the lysosome into the cytoplasm) or drugs that increase the permeability of the blood-brain barrier.

[1025] In one embodiment of the present disclosure, the ADCs or antibodies described herein can be administered in combination with a range of anticancer 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 antineoplastic drugs, etoposide, taxanes, topoisomerase inhibitors, antiproliferative immunosuppressants, corticosteroids, sex hormones and hormone antagonists, cytotoxic antibiotics and other therapeutic agents.

[1026] Thus, in one embodiment of the present disclosure, the method is a method as defined herein, wherein the uPARAP-expressing cell shows uPARAP overexpression.

[1027] In one embodiment of the present disclosure, the method is a method as defined herein, wherein the cell expressing uPARAP is a tumor cell.

[1028] In one embodiment of the present disclosure, the method is a method as defined herein, wherein the cell expressing uPARAP is a tumor-associated cell.

[1029] Tumor-associated cells include, but are not limited to, activated fibroblasts, myofibroblasts, new blood vessels, infiltrating cells of the macrophage-monocyte lineage or other leukocyte types, and cells of the stromal tissue surrounding the tumor.

[1030] In one embodiment of the present disclosure, the method is as defined herein, wherein the antibody drug conjugate induces cell death and / or inhibits growth and / or proliferation of cells expressing uPARAP.

[1031] In one embodiment of the present disclosure, the method is as defined herein, wherein the antibody drug conjugate induces the release of free cytotoxins from cells expressing uPARAP, causing cell death and / or inhibiting the growth and / or proliferation of adjacent cancer cells.

[1032] In one embodiment of the disclosure, the method is as defined herein, wherein the treatment is ameliorative or curative.

[1033] Another embodiment of the present disclosure is a method for inhibiting tumor progression in a subject, comprising administering to the subject the antibody-drug conjugate or pharmaceutical composition defined herein.

[1034] Another embodiment of the present disclosure is a method for inhibiting, reducing or eliminating the metastatic ability of a tumor in a subject, comprising administering to the subject the antibody-drug conjugate or pharmaceutical composition defined herein.

[1035] Yet another embodiment of the present disclosure is a kit comprising the antibody-drug conjugate or pharmaceutical composition defined herein, optionally further comprising means and / or instructions for administering the antibody-drug conjugate or pharmaceutical composition to a subject.

[1036] 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 treating a disease characterized by cells expressing uPARAP, such as cancer.

[1037] In one embodiment, the present disclosure relates to an antibody-drug conjugate or a pharmaceutical composition comprising the same for the manufacture of a medicament for treating a disease characterized by cells expressing uPARAP, such as cancer, wherein the antibody-drug conjugate is as described herein.

[1038] In one embodiment, the present disclosure relates to an antibody-drug conjugate or a pharmaceutical composition comprising the same for the manufacture of a medicament for treating a disease characterized by cells expressing uPARAP, such as cancer, wherein the antibody-drug conjugate is as defined herein. Example

[1039] Example 1: Humanization of murine 9b7 antibody and efficacy of ADC based thereon

[1040] Materials and methods

[1041] Humanization of the murine antibody 9b7 targeting uPARAP

[1042] Data regarding the amino acid sequence of the murine antibody 9b7 and its CDR regions are available in published patent application WO 2017 / 133745.

[1043] A humanized variant of the 9b7 antibody was 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 into the human donor sequence by computer simulation.

[1044] For this purpose, a variety of human framework sequences (see search procedure below) were used as the acceptor framework for the CDR sequences. These acceptor sequences were all derived from mature human IgG of human origin, rather than from phage display or other technologies. The humanized variants generated from the antibody 9b7 sequence were a combination of light and heavy chains, referred to as Ab980.2LCXHCX (light chain X, heavy chain X), with the exception of LCOHC0, which refers to a chimeric antibody in which the variable domains of the original murine antibody are fused to the same human IgG constant regions used in the humanized antibody. The mature humanized antibody is an IgG1κ type complete IgG molecule.

[1045] For the heavy chain, an online database of human IgG sequences was searched using the BLAST search algorithm to compare with the murine VH domain, and candidate human variable domains were selected from the top 200 BLAST results. These were reduced to four candidates based on a combination of framework homology, maintenance of key framework residues, and canonical loop structure.

[1046] For the light chain, an online database of human IgK sequences was searched using the BLAST search algorithm to compare with the murine VL domain, and candidate human variable domains were selected from the top 200 BLAST results. These were reduced to four candidates based on a combination of framework homology, maintenance of key framework residues, and canonical loop structure.

[1047] In summary, 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 achieve protein expression, each variable light chain domain was placed in frame with a human Igκ 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, LCOHCO, was expressed in which the variable domains of the murine protein were fused to the same human IgG constant region.

[1048] 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 seven days. The expressed antibodies were then purified from the cell culture supernatant via affinity chromatography. The concentration and purity of the purified antibody products were determined.

[1049] 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 cell culture supernatant containing the antibody was clarified by centrifugation and filtration. The humanized variants were then purified from the cell culture supernatant via affinity chromatography (using advanced AKTA chromatography equipment). The purified antibody was dialyzed / buffered into phosphate-buffered saline solution. The antibody purity was determined to be >95% by sodium dodecyl sulfate polyacrylamide gel analysis.

[1050] Of the 16 humanized antibodies obtained, a combination designated LC4HC3 was selected for further study based on favorable protein expression yield and antigen binding properties. Another humanized antibody designated LC3HC3 was selected to compare key parameters with LC4HC3, such as manufacturability, internalization, and in vivo efficacy.

[1051] SPR analysis for determining antibody-ligand affinity

[1052] 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) was immobilized in a BIAcore device, mAb 9b7 bound to the construct.

[1053] 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) using a CM5 sensor chip with an anti-human Fc capture surface for antibody binding. The assay temperature was set to 25°C. The antibodies were bound to this surface, and soluble full-length uPARAP was then passed over the chip, and the resulting 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 assay buffer consisted of 10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, and 0.05% Tween 20.

[1054] Preparation and evaluation of antibody-drug conjugates (ADCs)

[1055] The ADCs used in these studies were generated using a well-established coupling method. Briefly, the targeted antibody was coupled to a "vedotin" type payload (MC-VC-PABC-MMAE) by mild reduction of the interchain disulfide, followed by coupling to excess payload via the maleimide group, achieving a moderate average drug / antibody ratio (DAR) of approximately 4. The ADCs were subsequently purified using a PD-10 desalting column (GE Healthcare).

[1056] cell lines

[1057] The U937 cell line was obtained from ATCC and maintained in RPMI, 10% fetal bovine serum, 1% penicillin / streptomycin in a 37° C. incubator in a 5% CO 2 atmosphere.

[1058] In vitro cytotoxicity-cell viability assays of ADCs

[1059] U937 cells were grown at low density (20% confluence, 2 × 10 3Cells were plated in 90 μL of culture medium in a flat-bottomed 96-well plate and incubated overnight. The next day, ADCs based on MMAE of the LC4HC3 and LCOHC0 antibodies synthesized comparably 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, with a final maximum ADC concentration of 0.1 μg / mL ADC (mAb component). The cells were incubated for 96 hours, followed by the addition of 12 μL CellTiter96 AQueous One Solution cell proliferation detection reagent (MTS, Promega) and incubated for an appropriate time to develop color (approximately 60 minutes). The plate was then read using a plate reader at 490 nm, and 630 nm was used as background subtraction to obtain an estimated value of viability. Cells treated with PBS alone were used as untreated controls, and the viability of the ADC-treated wells was normalized relative to that of the control.

[1060] result

[1061] Manufacturability and Expression of LC4HC3 and LC3HC3:

[1062] Humanized antibodies designated LC4HC3 and LC3HC3 were expressed in CHO cells and purified as described above. The same procedure was performed on both antibodies. The results are summarized in Table 4 below, clearly showing that LC4HC3 can be produced in significantly higher quantities with sufficient purity:

[1063] Table 4 - Manufacturability data of humanized antibodies LC3HC3 and LC4HC3

[1064] Antibody ID Concentration (mg / ml) Volume (ml) Total amount (mg) Estimated purity (%) LC4HC3 3.69 3.02 11.14 >95％ LC3HC3 2.42 3.06 7.41 >95％

[1065] SPR analysis:

[1066] LC4HC3 and LCOHCO were analyzed by SPR as described in the Materials and Methods above. Specifically, the binding kinetics of LC4HC3 were compared with those of LCOHCO (Table 5). From these analyses, it is clear that the lower K of antibody LC4HC3 D Indicates approximately 1.7-fold higher ligand affinity than the parent antibody LCOHCO.

[1067] Table 5 - Summary of results from kinetic interaction analysis based on SPR measurements

[1068]

[1069] ADC in vitro potency analysis:

[1070] ADCs containing MMAE were prepared as described above, including either of the antibodies LC4HC3 and LC0HC0. These ADCs were tested for in vitro cytotoxicity against uPARAP-positive U937 cells using a range of ADC concentrations. Figure 1 It is evident that lower amounts of ADC are required for cell eradication with the LC4HC3-based ADC compared to the LCOHCO-based ADC, as the viability curve generated by treatment with LC4HC3-vc-MMAE is shifted several-fold towards lower concentrations compared to the viability curve generated by treatment with LCOHCO-vc-MMAE.

[1071] in conclusion

[1072] A humanized antibody, 980.2LC4HC3, has been developed from the murine monoclonal antibody mAb 9b7. By comparing this novel antibody to the chimeric antibody 980.2LC0HC0 (in which all murine variable sequences are retained, with the remainder in a human IgG configuration), the properties of this novel antibody can be directly compared to those of the antibody generated from the parental variable sequences. This comparison revealed that 1) humanized 980.2LC4HC3 has a higher ligand affinity than 980.2LC0HC0, and 2) ADCs based on 980.2LC4HC3 are more potent in terms of cytotoxicity than otherwise identical ADCs based on 980.2LC0HC0.

[1073] Example 2: Internalization of humanized variants LC3HC3 and LC4HC3 of the murine 9b7 antibody

[1074] Materials and methods

[1075] Antibody labeling

[1076] Iodogen (Thermo Fischer) was dissolved in chloroform at 120 μg / ml and used to coat the bottom of a glass tube by evaporation. In the coated tube, 200 μg / ml of humanized antibody (LC3HC3 or LC4HC3) was reacted with 588 ng / ml I-125 (Perkin Elmer) in 0.1 M Tris buffer, pH 7.6, for 10 minutes. The reaction was stopped by adding a nine-fold excess of 0.1 M Tris buffer, pH 8.1, 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, pH 8.1, containing 0.01% Tween-80. Assuming that all antibody was eluted in this buffer, a concentration of 8 μg / ml was obtained. The integrity and radioactivity of labeled collagen were routinely confirmed by running on SDS-PAGE followed by Coomassie staining and phosphor imaging.

[1077] Cell culture and antibody internalization procedures

[1078] SAOS-2 osteosarcoma cells (Finsenlab; viability 98.7%, density 1.07×10^6 cells / ml) were diluted to 1×10^5 cells / ml and 1 ml was seeded per 24 wells for the experiment. The cells were allowed to adhere overnight. At least 30 minutes before adding the radiolabeled antibody, the culture medium was replaced with an internalization medium consisting of DMEM / F12 with 1.5% FBS and 20mM HEPES. Internalization medium without cells was seeded in separate wells as a control. It was assumed that the radioactivity from these samples represented the amount of radiolabeled protein adhered to the plastic and obtained after trypsin treatment. These measurements can be considered "baseline levels" and can be subtracted from the measurements of samples that do contain cells. 5 μl of LC4HC3 or LC3HC3 (based on the assumptions mentioned above, it is estimated to be slightly less than 40 ng) was added to each well. After 1 hour or 4 hours, the culture medium was removed by aspiration and the cells were washed three times with 500 μl of ice-cold PBS. 500 μl of trypsin-EDTA with 50 μg / ml proteinase K was added to each well for 2 minutes. The cells were harvested, transferred to Eppendorf tubes and spun at 1000 g for 1 minute at 4°C. The supernatant (containing cell-bound antibody) and the pellet were collected separately and analyzed on a gamma counter. 2 μl of labeled antibody stock solution was analyzed simultaneously to assess labeling efficiency.

[1079] result

[1080] Figure 2 The results presented in clearly demonstrate that the humanized antibody LC4HC3 is not only internalized significantly faster than the humanized antibody LC3HC3, but also internalized to a greater extent.

[1081] in conclusion

[1082] 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 mentioned antibodies contain the same heavy chain, so the difference in internalization can be attributed solely to differences in the amino acid sequence of the light chain.

[1083] Example 3: In vivo efficacy of ADCs based on humanized murine 9b7 antibodies LC3HC3 and LC4HC3

[1084] Materials and methods

[1085] Cell culture and preparation

[1086] U937 cells (as described above) were passaged according to standard procedures until sufficient cells were obtained for this experiment. Cells were centrifuged at 150 g for 5 minutes and washed three times in cold PBS (Gibco). The cell concentration was adjusted to 3.6 × 10 6 This translates to approximately 3 million viable cells per 100 μl, the intended inoculation volume.

[1087] Xenograft tumor inoculation

[1088] Recipient CB17 mice were anesthetized with Zoletil (AEM), Viscotears eye drops were applied, and ear markings were performed. 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 suturing required). The mice were allowed to recover from anesthesia in their cages. Recovery was monitored until the mice were able to move. The mice were monitored again the next day, and tumor size was closely monitored until treatment began.

[1089] Once the tumor reaches an appropriate size (approximately 80-150 mm 3 ), then start treatment.

[1090] ADC treatment and monitoring

[1091] Vedotin-type (MMAE) ADCs containing LC3HC3 or LC4HC3 humanized antibodies were prepared as previously described above. Mice were divided into groups of 3-5 animals per group (N=3-5), with each group differing in the ADC used or the dose of the ADC administered. One cohort of mice was tested with the LC3HC3 ADC in groups receiving concentrations of 2, 4, or 6 mg / kg, while another cohort was tested with the LC4HC3 ADC in groups receiving the same concentration range.

[1092] For each group, mice were intravenously administered a controlled amount of ADC (tail vein) once a week for a total of two injections (qd7×2), and tumor progression was also closely monitored after treatment. Figure 3a and Figure 3b Tumor progression is shown for the groups treated with 4 mg / kg dose of LC4HC3 and LC3HC3 ADC, respectively.

[1093] Monitoring consisted of checking overall health and measuring the width and length of the tumor using a digital caliper. All observations and measurements were recorded manually and transcribed to a spreadsheet after the examination. If the tumor size exceeded 12 mm in one dimension, the tumor volume (calculated as (length × width)) was increased. 2 ) / 2 calculation) exceeds 1000mm 3 Animals were euthanized by cervical dislocation.

[1094] result

[1095] The U937 tumor volumes after treatment with LC4HC3- and LC3HC3-based ADCs were Figure 3a and Figure 3b . Figure 3a Shown are the tumor volumes of a group of four mice (N=4), each of which was administered 4 mg / kg LC4HC3 ADC once a week for a total of two injections (qd7×2); Figure 3b Shown are the tumor volumes of four mice (N=4) from different groups, each mouse receiving a 4 mg / kg dose of LC3HC3 ADC once a week for a total of two injections (qd7×2).

[1096] in conclusion

[1097] If compared Figure 3a and Figure 3b As seen in the study, LC4HC3 ADC-based treatment completely cured all mice, with no 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, and in some cases, aggressive tumor growth was observed during the post-treatment monitoring period.

[1098] The data show that the humanized antibody LC4HC3 and ADCs containing the humanized antibody are potent anti-tumor agents with improved in vivo efficacy compared to another humanized antibody, LC3HC3. Since the two mentioned antibodies contain the same heavy chain, the difference in efficacy can be attributed solely to changes in the amino acid sequence of the light chain.

[1099] Example 4: Synthesis of compounds and ADCs

[1100] The exitecan derivatives disclosed herein can be prepared as described in WO 2022 / 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 can be prepared according to the reference examples given in the table below. It will be apparent to those skilled in the art that other examples from WO 2022 / 068878 regarding the synthesis of the compounds disclosed herein are also incorporated by reference.

[1101]

[1102] Antibody-drug conjugates comprising an exitecan derivative and a humanized antibody (LC4HC3) that binds uPARAP as described herein can be prepared using standard methods known to those skilled in the art for conjugating payloads to antibodies. For example, they can be prepared in a manner similar to the ADC preparations described in the examples of WO 2022 / 068878.

[1103] Example 5: Efficacy of Compounds and ADCs

[1104] Test Example 5.1. Test of the compound's inhibition of tumor cell proliferation in vitro

[1105] Target

[1106] The inhibitory activity of pharmaceutical compounds on the proliferation of NCI-N87, JIMT-1 and MBA-MB-231 tumor cells in vitro was tested. Cells were treated with different concentrations of the compounds in vitro and, after 6 days of culture, were treated with CTG ( Cell proliferation was detected by luminescence cell viability assay (Promega, catalog number G7558) and the IC 50 The in vitro activity of the compounds was evaluated.

[1107] program

[1108] Hereinafter, the method of the present application for testing the inhibitory activity of the present compounds on the in vitro proliferation of tumor cells is described using the test of inhibiting the in vitro proliferation of NCI-N87 cells as an example. This method is also applicable to (but not limited to) testing the inhibitory activity on the in vitro proliferation of other tumor cells.

[1109] 1. Cell culture: NCI-N87 cells were cultured in RPMI-1640 medium containing 10% FBS.

[1110] 2. Cell Preparation: Take logarithmic-phase NCI-N87 cells, wash once with PBS, and digest with 2-3 mL of trypsin for 2-3 minutes. After complete digestion, add 10-15 mL of cell culture medium to elute the digested cells. Centrifuge the eluate at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the resulting cells in 10-20 mL of cell culture medium to obtain a single-cell suspension.

[1111] 3. Cell plating: Mix the NCI-N87 single cell suspension thoroughly and adjust the viable cell density to 6×10 4 The density-adjusted cell suspension was thoroughly mixed and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator for 18 hours (37°C, 5% CO2).

[1112] 4. Preparation of compounds: Compounds were dissolved in DMSO to obtain a stock solution with an initial concentration of 10 mM.

[1113] There are a total of 8 concentrations of small molecule compounds: 300nM, 100nM, 30nM, 10nM, 3nM, 1nM, 0.3nM and 0.1nM.

[1114] 5. Sample addition: Add the prepared samples to be tested at different concentrations to the culture plate, and set up two replicate wells for each sample. Incubate the culture plate in an incubator for 6 days (37° C., 5% CO 2 ).

[1115] 6. Color development: Remove the 96-well cell culture plate, add 50 μL / well of CTG reagent, and incubate at room temperature for 10 minutes.

[1116] 7. Plate Reading: Take out the 96-well cell culture plate, place it in a microplate reader, and measure the chemiluminescence using a microplate reader.

[1117] Data Analysis

[1118] Data were processed and analyzed using Microsoft Excel and GraphpadPrism 5.

[1119] Table 6. IC values of the small molecule fragments of the present invention for inhibiting the proliferation of NCI-N87 and JIMT-1 cells in vitro 50 value.

[1120]

[1121]

[1122] Conclusion: According to the results shown in Table 6, the small molecule fragments of the present application have significant inhibitory activity on the proliferation of NCI-N87 cells and JIMT-1 cells. The compounds of the present application all have similar inhibitory activity on tumor proliferation.

[1123] Test Example 5.2. Test of the compound's inhibition of tumor cell proliferation in vitro

[1124] Target

[1125] The inhibitory activity of pharmaceutical compounds on the proliferation of NCI-N87, JIMT-1 and MBA-MB-231 tumor cells in vitro was tested. Cells were treated with different concentrations of the compounds in vitro and, after 6 days of culture, were treated with CTG ( Cell proliferation was detected by luminescence cell viability assay (Promega, catalog number G7558) and the IC 50 The in vitro activity of the compounds was evaluated.

[1126] 1. Cell culture: NCI-N87 / JIMT-1 / MBA-MB-231 cells were cultured in RPMI-1640 medium containing 10% FBS.

[1127] 2. Cell Preparation: Take logarithmic-phase NCI-N87 / JIMT-1 / MBA-MB-231 cells, wash once with PBS, and digest with 2-3 mL of trypsin for 2-3 minutes. After complete digestion, add 10-15 mL of cell culture medium to elute the digested cells. Centrifuge the eluate at 1000 rpm for 5 minutes, and discard the supernatant. Resuspend the resulting cells in 10-20 mL of cell culture medium to obtain a single-cell suspension.

[1128] 3. Cell plating: NCI-N87 / JIMT-1 / MBA-MB-231 single cell suspension was thoroughly mixed and adjusted to a viable cell density of 6×10 4 The density-adjusted cell suspension was thoroughly mixed and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator for 18 hours (37°C, 5% CO2).

[1129] 4. Preparation of compounds: Compounds were dissolved in DMSO to obtain a stock solution with an initial concentration of 10 mM.

[1130] There are a total of 8 concentrations of small molecule compounds: 300nM, 100nM, 30nM, 10nM, 3nM, 1nM, 0.3nM and 0.1nM.

[1131] 5. Sample addition: Add the prepared samples to be tested at different concentrations to the culture plate, and set up two replicate wells for each sample. Incubate the culture plate in an incubator for 6 days (37° C., 5% CO 2 ).

[1132] 6. Color development: Remove the 96-well cell culture plate, add 50 μL / well of CTG reagent, and incubate at room temperature for 10 minutes.

[1133] 7. Plate reading: Take out the 96-well cell culture plate, place it in a microplate reader, and measure the chemiluminescence using a microplate reader.

[1134] Data analysis: Microsoft Excel and Graphpad Prism 5 were used to process and analyze data.

[1135] Table 7. IC values of the small molecule fragments of the present invention for inhibiting tumor cell proliferation in vitro 50 value.

[1136]

[1137] “-”: Not detected

[1138] Conclusion: According to the results shown in Table 7, the small molecule fragments of the present application have significant inhibitory activity on the proliferation of NCI-N87, JIMT-1 and MDA-MB-231 cells. The compounds of the present application all have similar inhibitory activity on tumor proliferation.

[1139] Test Example 5.3. Test of the compound's ability to inhibit tumor cell proliferation in vitro

[1140] Target

[1141] The inhibitory activity of pharmaceutical compounds on the proliferation of NCI-N87, JIMT-1 and MBA-MB-231 tumor cells in vitro was tested. Cells were treated with different concentrations of the compounds in vitro and, after 6 days of culture, were treated with CTG ( Cell proliferation was detected by luminescence cell viability assay (Promega, catalog number G7558) and the IC 50 The in vitro activity of the compounds was evaluated.

[1142] 1. Cell culture: NCI-N87 / JIMT-1 / MBA-MB-231 cells were cultured in RPMI-1640 medium containing 10% FBS.

[1143] 2. Cell Preparation: Take logarithmic-phase NCI-N87 / JIMT-1 / MBA-MB-231 cells, wash once with PBS, and digest with 2-3 mL of trypsin for 2-3 minutes. After complete digestion, add 10-15 mL of cell culture medium to elute the digested cells. Centrifuge the eluate at 1000 rpm for 5 minutes, and discard the supernatant. Resuspend the resulting cells in 10-20 mL of cell culture medium to obtain a single-cell suspension.

[1144] 3. Cell plating: NCI-N87 / JIMT-1 / MBA-MB-231 single cell suspension was thoroughly mixed and adjusted to a viable cell density of 6×10 4 The density-adjusted cell suspension was thoroughly mixed and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator for 18 hours (37°C, 5% CO2).

[1145] 4. Preparation of compounds: Compounds were dissolved in DMSO to obtain a stock solution with an initial concentration of 10 mM.

[1146] There are a total of 8 concentrations of small molecule compounds: 300nM, 100nM, 30nM, 10nM, 3nM, 1nM, 0.3nM and 0.1nM.

[1147] 5. Sample addition: Add the prepared samples to be tested at different concentrations to the culture plate, and set up two replicate wells for each sample. Incubate the culture plate in an incubator for 6 days (37° C., 5% CO 2 ).

[1148] 6. Color development: Remove the 96-well cell culture plate, add 50 μL / well of CTG reagent, and incubate at room temperature for 10 minutes.

[1149] 7. Plate reading: Take out the 96-well cell culture plate, place it in a microplate reader, and measure the chemiluminescence using a microplate reader.

[1150] Data analysis: Microsoft Excel and Graphpad Prism 5 were used to process and analyze data.

[1151] Table 8. IC values of the small molecule fragments of the present invention for inhibiting the proliferation of NCI-N87, JIMT-1 and MDA-MB-231 cells in vitro 50 value.

[1152]

[1153]

[1154] “-”: Not detected

[1155] Conclusion: According to the results shown in Table 8, the small molecule fragments of the present application have significant inhibitory activity on the proliferation of NCI-N87, JIMT-1 and MDA-MB-231 cells. All compounds of the present application have similar inhibitory activity on tumor proliferation.

[1156] Test Example 5.4. Test of the compound's inhibition of tumor cell proliferation in vitro

[1157] Target

[1158] The inhibitory activity of pharmaceutical compounds on the proliferation of NCI-N87 and Colo205 tumor cells in vitro was tested. Cells were treated with different concentrations of compounds in vitro and cultured for 6 days. Cell proliferation was detected by luminescence cell viability assay (Promega, catalog number G7558) and the IC 50 The in vitro activity of the compounds was evaluated.

[1159] 1. Cell culture: NCI-N87 / Colo205 cells were cultured in RPMI-1640 medium containing 10% FBS.

[1160] 2. Cell Preparation: Take logarithmic-phase NCI-N87 / Colo205 cells, wash once with PBS, and digest with 2-3 mL of trypsin for 2-3 minutes. After complete digestion, add 10-15 mL of cell culture medium to elute the digested cells. Centrifuge the eluate at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the resulting cells in 10-20 mL of cell culture medium to obtain a single-cell suspension.

[1161] 3. Cell plating: Mix the NCI-N87 / Colo205 single cell suspension thoroughly and adjust the viable cell density to 6×10 4 The density-adjusted cell suspension was thoroughly mixed and added to a 96-well cell culture plate at 50 μL / well. The culture plate was incubated in an incubator for 18 hours (37°C, 5% CO2).

[1162] 4. Preparation of compounds: Compounds were dissolved in DMSO to obtain a stock solution with an initial concentration of 10 mM.

[1163] There are a total of 8 concentrations of small molecule compounds: 300nM, 100nM, 30nM, 10nM, 3nM, 1nM, 0.3nM and 0.1nM.

[1164] 5. Sample addition: Add the prepared samples to be tested at different concentrations to the culture plate, and set up two replicate wells for each sample. Incubate the culture plate in an incubator for 6 days (37° C., 5% CO 2 ).

[1165] 6. Color development: Remove the 96-well cell culture plate, add 50 μL / well of CTG reagent, and incubate at room temperature for 10 minutes.

[1166] 7. Plate reading: Take out the 96-well cell culture plate, place it in a microplate reader, and measure the chemiluminescence using a microplate reader.

[1167] Data analysis: Microsoft Excel and Graphpad Prism 5 were used to process and analyze data.

[1168] Table 9. IC values of the small molecule fragments of the present invention for inhibiting the proliferation of NCI-N87 and Colo205 cells in vitro 50 value.

[1169]

[1170] Conclusion: According to the results shown in Table 9, the small molecule fragments of the present application have significant inhibitory activity on the proliferation of NCI-N87 cells and Colo205 cells. All compounds of the present application have similar inhibitory activity on tumor proliferation.

[1171] Test Example 5.5. Pharmacokinetics and toxicity studies of ADC upon single administration

[1172] Target

[1173] The pharmacokinetic properties of the drug in monkeys were studied, and the toxicity of the animals was observed after a single intravenous infusion of ADC in monkeys.

[1174] Test Method

[1175] Pharmacokinetics: After a single intravenous infusion of ADC drugs at different doses in monkeys, blood samples were collected at multiple serial time points and the drug concentration in the blood was measured by appropriate specific detection methods.

[1176] Toxicity studies: Following a single intravenous infusion of the ADC at various doses in monkeys, the tolerability and drug-related toxicity profiles were evaluated in multiple areas, including clinical observations, body weight and food intake, hematology, blood biochemistry, urine, and gross anatomy.

[1177] Test results

[1178] After a single intravenous infusion of ADC in monkeys, the concentration of free toxin was extremely low, and the pharmacokinetic properties of total antibody and ADC were similar, indicating that the ADC was slowly released in monkeys, had a stable conjugation pattern, and could be used at the clinically planned administration frequency.

[1179] After a single intravenous infusion of the ADC in monkeys, the animals were well tolerated and showed no severe or intolerable drug-related toxicity, indicating that the ADC has a manageable safety profile and can be further studied clinically. All ADCs in this application have similar safety profiles.

[1180] Example 6: In vivo efficacy of ADCE-D01

[1181] ADCE-D01 is an antibody-drug conjugate with a theoretical molecular weight of 156 kDa and a drug-to-antibody ratio (DAR) of 8. ADCE-D01 has the following structure:

[1182]

[1183] This structure is derived from the linker payload combination L-III-30 described on page 162 of this article, in which the maleimide is coupled to the humanized monoclonal antibody LC4HC3 (Ab in this structure) via complete coupling with two interchain heavy chain-light chain cysteines and two interchain heavy chain-heavy chain cysteines. ADCE-D01 thus comprises the exitecan derivative L-III-30 represented above. The antibody is coupled to the drug substance (DS) of the antibody-drug conjugate via well-established TCEP reduction chemistry known to those skilled in the art of antibody-drug conjugates, where TCEP refers to tris(2-carboxyethyl)phosphine.

[1184] ADCE-D01 finished drug product (DP) is presented as a powder for solution for infusion in 20 mL vials with plastic caps and aluminum seals.

[1185] In vivo pharmacology

[1186] The in vivo efficacy of ADCADCE-D01 against uPARAP was evaluated in two cell lines.

[1187] Leiomyosarcoma is a subtype of soft tissue sarcoma derived from smooth muscle cells. The SK-LMS-1 cell line was established from a vulvar metastasis in a 43-year-old Caucasian woman (Fogh 1975c). CB17-SCID immunodeficient mice were inoculated subcutaneously in the right flank with human SK-LMS-1 cells. The mean tumor volume in the group was approximately 120 mm. 3 Treatment was initiated at 4 hr. Mice were treated with vehicle control (PBS), 3 and 10 mg / kg of control ADC, and ADCE-D01.

[1188] Treatment was administered intravenously (IV) via the tail vein on days 0, 7, and 14 (q1 wk x 3). The control ADC (ADCE-D51) was a conjugate of an isotype-matched (IgG1) antibody (B12) to HIV gp120 (Parren et al., 1995) and L-III-30 (containing the payload P-III-30) with a DAR of 8. Thus, ADCE-D51 was identical to ADCE-D01 in all respects except the antibody. Tumor size was monitored three times per week for up to 90 days by caliper measurement. Tumor volume versus time data are presented in Figure 4a and Figure 4b middle.

[1189] Dose-dependent antitumor activity was observed at 3 and 10 mg / kg of ADCE-D01 compared to PBS. Tumor growth inhibition on day 14 was 62% and 94% for 3 and 10 mg / kg of ADCE-D01, 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 by this time, both the control ADC and PBS treatment groups had already reached a plateau due to the large size of the tumors (800 mm). 3 ) and terminated.

[1190] Rhabdomyosarcoma is a type of soft tissue sarcoma that arises from skeletal (striated) muscle cells. The RD cell line was derived directly from a human biopsy specimen of refractory RMS (McAllister et al., 1969).

[1191] CB17-SCID immunodeficient mice were inoculated with human RD cells subcutaneously on the right flank. The average tumor volume in the group was approximately 150 mm 3 Treatment was initiated at 4 hr. Mice were treated with vehicle control (PBS), 3 and 6 mg / kg of control ADC, and ADCE-D01.

[1192] Treatment was administered IV via the tail vein on days 0, 7, and 14 (q1 wk x 3). The control ADC was ADCE-D51 described above for leiomyosarcoma. Tumor size was monitored 3 times per week by caliper measurement for up to 90 days. Tumor volume versus time data are presented in Figure 5a and Figure 5b middle.

[1193] When compared to PBS in the RD rhabdomyosarcoma model, dose-dependent antitumor activity was observed at all doses of ADCE-D01 tested. Tumor growth inhibition on day 22 was 87% and 89% at 3 and 6 mg / kg, respectively. Tumor regression was observed at 6 mg / kg and persisted until day 42, four weeks after the last dose. Tumor growth resumed after day 42, but the mean tumor volume at 6 mg / kg was still smaller than that of the control ADC (6 mg / kg) and PBS-treated groups.

[1194] Sequence Overview

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201] References

[1202] 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.

[1203] ParrenPW,Ditzel HJ,GuliziaRJ,Binley JM,Barbas CF 3rd,Burton DR,MosierDE.

[1204] Protection against HIV-1infection inhu-PBL-SCID micebypassiveimmunization with aneutralizing humanmonoclonal antibody against the gp120CD4-binding site.AIDS.1995Jun;9(6):F1-6.doi:10.1097 / 00002030-199506000-00001.PMID:7662189.

[1205] McAllister,RM,Melnyk,J.,Finklestein,JZ,Adams,EC,Jr.and Gardner,MB(1969),Cultivation invitro ofcells derived fromahumanrhabdomyosarcoma.Cancer,24:520-526.https: / / doi.org / 10.1002 / 1097-0142(196909)24:3<520::AID-CNCR2820240313>3.0.CO;2-M

[1206] project

[1207] 1. An antibody-drug conjugate (ADC) comprising an antibody that binds to uPARAP, the antibody comprising:

[1208] i. An immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:3 or consisting of the amino acid sequence of SEQ ID NO:3; and

[1209] ii. An immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:6 or consisting of the amino acid sequence of SEQ ID NO:6;

[1210] where the antibody conjugate drug comprises an active agent having a structure selected from one of the following:

[1211] a. Formula (I-A) or a tautomer, meso form, racemic form, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[1212]

[1213] where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )-, -P(R 2 )- and -S-;

[1214] L 2 is -(C(R 3a )(R 3b )) m -R,

[1215] where 0 or no less than 1 methylene unit of L 2 is independently replaced by -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)-;

[1216] L 1 is -(C(R 5a )(R 5b )) n -,

[1217] where L 10 or not less than 1 methylene unit is independently replaced by -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)-;

[1218] -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 substituted with at least one substituent R 7 replace;

[1219] Among them, each R 3a , each R 3b , each R 4 , each R 5a , each R 5b and each R 6 are 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each independently optionally forms a ring B together with the atoms therebetween, wherein the ring B is selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or independently substituted with at least one substituent R 8 replace;

[1220] Among them, each R 2 , each R 7 and each R 8 are 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[1221] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[1222] m and n are each independently selected from an integer ≥ 1; and wherein R 1 connecting the structure represented by formula (IA) to an antibody, optionally via a linker;

[1223] b. Formula (II-A) or its tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof

[1224]

[1225] where X 1 Selected from: N, P and saturated or unsaturated C; when X 1 When C is saturated, X 1 R n replace;

[1226] wherein Ring A is linked to the antibody according to the structure of Formula II-A, optionally via a linker;

[1227] When X 1 When C is saturated, ring A is selected from: 3-10 membered saturated or partially unsaturated heterocyclic group and 3-10 membered saturated or partially unsaturated carbocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1a replace;

[1228] Or when X 1 When C is an unsaturated group, ring A is selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclic group and 3-10 membered partially unsaturated carbocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1b replace;

[1229] Or when X 1 When N or P, ring A is selected from: 5- to 8-membered heteroaryl and 3- to 10-membered saturated or partially unsaturated heterocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1c replace;

[1230] When ring A is selected from 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclic group, ring A is substituted by p L 2 Substituted, where L 2 Not for R n ;

[1231] Or when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, ring A is surrounded by p L 2 substituted, or ring A contains q ring heteroatoms X 2 , and X 2 For linking the compound of formula (II-A) to an antibody, optionally via a linker;

[1232] X 2 Selected from: N and P;

[1233] L 2 -R 2 -L 3 -, and R 2 For linking the compound of formula (II-A) to an antibody, optionally via a linker;

[1234] L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, L 3 0 or not less than 1 methylene unit is independently replaced by -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)-;

[1235] R 2 Selected from: -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-;

[1236] L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, L 1 0 or not less than 1 methylene unit is independently replaced by -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)-;

[1237] Among them, 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 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)SO2R or C optionally substituted by R1-6 aliphatic groups;

[1238] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[1239] m and n are each independently selected from integers ≥ 0, and p and q are each independently selected from integers ≥ 1; and

[1240] c. Formula (III-A) or its tautomer, meso-racemate, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof

[1241]

[1242] where R 1 Selected from: -O-, -(R 2 )N-、-P(=O)(R 2 )- and -S-; wherein R 1 linking the structure according to formula (III-A) to an antibody, optionally via a linker;

[1243] X is selected from: -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 -;

[1244] L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or not less than 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement;

[1245] L 0 -C(R 2a )(R 2b)-, or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[1246] L 2 -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit is replaced by -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)-;

[1247] L 3 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[1248] Among them, 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 R4b , each R 5a , each R 5b , each R 6 , each R 7a , each R 7b and each R 8 are 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[1249] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[1250] m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1;

[1251] When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1252] When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R3b Not all are hydrogen;

[1253] When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2;

[1254] When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-.

[1255] 2. The antibody-drug conjugate according to item 1, wherein in formula (IA), each R 3a , each R 3b , each R 4 , each R 5a , each R 5b and each R 6 are 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)SO2R or C optionally substituted by R 1-6 aliphatic group, and / or wherein in formula (IA), R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6Each independently optionally forms a ring B together with the atoms therebetween, wherein the ring B is selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or substituted with at least one substituent R 8 replace.

[1256] 3. The antibody-drug conjugate according to any one of items 1 to 2, wherein in formula (IA), m is 1 or 2, optionally m is 1, and L 2 -C(R 3a )(R 3b )-R, or optionally m is 2, and L 2 -(C(R 3a )(R 3b ))2-R, and L 2 0 or 1 methylene unit is replaced by -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 -C(O)-C(R 3a )(R 3b )-R or -C(R 3a )(R 3b )-Cy-R.

[1257] 4. The antibody-drug conjugate according to items 1 to 3, wherein in formula (IA), L 2 0 or 1 methylene unit is replaced by -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 One methylene unit is replaced by -C(O)- or -Cy-.

[1258] 5. The antibody-drug conjugate according to any one of items 1 to 4, wherein in formula (IA), n is 2, 3 or 5.

[1259] 6. The antibody-drug conjugate according to any one of items 1 to 5, wherein in formula (IA), n is 2, and L 1 -(C(R 5a )(R 5b ))2-.

[1260] 7. The antibody-drug conjugate according to any one of items 1 to 6, wherein in formula (IA), L 1 -(C(R 5a )(R 5b ))2-, and L 1 The 0 methylene units are replaced by -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 is replaced by -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 -(C(R 5a )(R 5b ))2-, and L1 One methylene unit of L is replaced by -C(O)- or -C(=S)-, for example 1 -C(R 5a )(R 5b )-C(O)- or L 1 -C(R 5a )(R 5b )-C(=S)-.

[1261] 8. The antibody-drug conjugate according to any one of items 1 to 5, wherein in formula (IA), n is 3, and L 1 -(C(R 5a )(R 5b ))3-.

[1262] 9. The antibody-drug conjugate according to item 8, wherein in formula (IA), L 1 -(C(R 5a )(R 5b ))3-, and L 1 The 0 methylene units are replaced by -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 is replaced by -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, wherein L 1 -(C(R 5a )(R 5b))2-C(O)-.

[1263] 10. The antibody-drug conjugate according to any one of items 1 to 5, wherein in formula (IA), n is 5, and L 1 -(C(R 5a )(R 5b ))5-.

[1264] 11. The antibody-drug conjugate according to item 10, wherein in formula (IA), L 1 -(C(R 5a )(R 5b ))5-, and L 1 One methylene unit is replaced by -NR 6 - substitution, for example, where L 1 -(C(R 5a )(R 5b ))2-NR 6 -(C(R 5a )(R 5b ))2-, or replaced by -O-, for example, wherein L 1 -(C(R 5a )(R 5b ))2-O-(C(R 5a )(R 5b ))2-; or

[1265] Wherein in formula (IA), L 1 -(C(R 5a )(R 5b ))5-, and L 1 The two methylene units are each independently replaced by -C(O)-, -NR 6 - or -O- substitution, such as L 1 Selected from:

[1266] -C(R 5a )(R 5b )-C(O)-NR 6 -(C(R 5a )(R 5b ))2-;

[1267] -(C(R 5a )(R 5b ))2-NR 6 -C(O)-C(R 5a )(R 5b )-;and

[1268] L 1 -(C(R 5a )(R 5b ))2-OC(R5a )(R 5b )-C(O)-; or

[1269] Wherein in formula (IA), L 1 -(C(R 5a )(R 5b ))5-, and L 1 The three methylene units are each independently replaced by -C(O)- or -NR 6 - substitution, for example, where L 1 -(C(R 5a )(R 5b ))2-NR 6 -C(O)-C(O)-.

[1270] 12. The antibody-drug conjugate according to any one of items 1 to 4, wherein in formula (IA), L 1 The 0 methylene units are replaced by -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 wherein in formula (IA), L 1 One methylene unit is replaced by -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

[1271] Wherein in formula (IA), L 1 The two methylene units are each independently replaced by -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 replaced by -C(O)-, -NR 6 - or -O-, preferably replaced by -C(O)- or -NR 6 - Replacement; or

[1272] Wherein in formula (IA), L 1 The three methylene units are each independently replaced by -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 replaced by -C(O)- or -NR 6 - Replacement.

[1273] 13. The antibody-drug conjugate according to any one of items 1 to 2, wherein in formula (IA), R 3a and R 5a independently and optionally together with the atoms therebetween form ring B, optionally ring B is 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

[1274] Wherein in formula (IA), R 4 and R 5aIndependently, optionally together with the atoms therebetween, form ring B, optionally ring B is a 3- to 10-membered saturated or partially unsaturated heterocyclylene group, for example, ring B is a 6-membered saturated or partially unsaturated heterocyclylene group.

[1275] 14. The antibody-drug conjugate according to item 1, wherein in formula (IA), L 2 -C(R 3a )(R 3b )-R or -(C(R 3a )(R 3b ))2-R, and L 1 -(C(R 5a )(R 5b ))2-、-(C(R 5a )(R 5b ))3-or-(C(R 5a )(R 5b ))5-.

[1276] 15. The antibody-drug conjugate according to item 14, wherein in formula (IA), L 2 -(C(R 3a )(R 3b ))2-R, and L 1 -(C(R 5a )(R 5b ))2-, optionally L 1 One methylene unit is replaced by -C(O)-, -C(=S)-, -NR 6 - or -O- substitution, such as L 2 -(C(R 3a )(R 3b ))2-R, and L 1 -C(R 5a )(R 5b )-C(O)-, optionally wherein in formula (IA), R 3a and R 5a and independently, optionally together with the atoms therebetween, form ring B, optionally ring B is a 3- to 10-membered saturated or partially unsaturated heterocyclylene, for example, ring B is a 5-membered saturated heterocyclylene; or

[1277] Wherein in formula (IA), L 2 -C(R 3a )(R 3b )-R, and L 1 -(C(R 5a )(R 5b ))2-, optionally L 1 One methylene unit is replaced by -C(O)-, -C(=S)-, -NR 6 - or -O- substitution, such as L2 is -C(R 3a )(R 3b )-R, and L 1 is -C(R 5a )(R 5b )-C(O)-.

[1278] 16. The antibody-drug conjugate according to any one of Items 1 to 15, wherein in formula (I-A), R 1 is selected from: -O-, -(R 2 )N-, and -S-.

[1279] 17. The antibody-drug conjugate according to any one of Items 1 to 16, wherein in formula (I-A), R 1 is -O-; or R 1 [[ID=2S]]is -(R 2 )N-, optionally wherein R 2 is hydrogen, such as -HN-, or is C 1-6 aliphatic group.

[1280] 18. The antibody-drug conjugate according to any one of Items 1 to 17, wherein in formula (I-A), -Cy- is a 6- to 10-membered arylene group, such as phenylene.

[1281] 19. The antibody-drug conjugate according to any one of Items 1 to 18, wherein in formula (I-A), R 7 is hydrogen.

[1282] 20. The antibody-drug conjugate according to any one of Items 1 to 2, wherein in formula (I-A), R 3a and R 3b are independently hydrogen, or R 3a and R 5a independently and optionally together with the atoms therebetween form ring B, optionally ring B is a 3- to 10-membered saturated or partially unsaturated heterocyclene group, such as ring B is a 5-membered saturated heterocyclene group; or wherein in formula (I-A), R 4 is hydrogen, or R 4 and R 5a independently and optionally together with the atoms therebetween form ring B.

[1283] 21. The antibody-drug conjugate according to Item 1, wherein in formula (I-A), R 8 is hydrogen.

[1284] 22. The antibody-drug conjugate according to Item 1, wherein in formula (I-A), R, R a and R b are each independently hydrogen.

[1285] 23. The antibody-drug conjugate according to item 1, wherein Formula (IA) is according to any one of Formula (IA-1) to Formula (IA-17):

[1286]

[1287]

[1288] where R 1 Can be selected from: -O-, -HN-, -P(=O)H- and -S-, wherein R 1 The structure represented by any one of Formula (IA-1) to Formula (IA-17) is optionally linked to an antibody via a linker.

[1289] 24. The antibody-drug conjugate according to item 1, wherein in formula (II-A), X 1 is saturated C.

[1290] 25. The antibody-drug conjugate according to any one of items 1 or 24, wherein in formula (II-A), Ring A is selected from: a 3- to 10-membered saturated heterocyclic group and a 3- to 10-membered saturated carbocyclic group.

[1291] 26. The antibody-drug conjugate according to 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.

[1292] 27. The antibody-drug conjugate according to any one of items 1 or 24 to 26, wherein in formula (II-A), ring A contains 1 heteroatom, for example, 1 nitrogen atom.

[1293] 28. The antibody-drug conjugate according to any one of items 1 or 24 to 26, wherein in formula (II-A), Ring A is a 5-membered saturated heterocyclic group, optionally wherein Ring A contains 1 heteroatom, such as 1 nitrogen atom.

[1294] 29. The antibody-drug conjugate according to any one of items 24 to 28, wherein in formula (II-A), ring A is substituted with 0 substituents R 1a replace.

[1295] 30. The antibody-drug conjugate according to item 1, wherein in formula (II-A), X 1 It is unsaturated C.

[1296] 31. The antibody-drug conjugate according to item 30, wherein in formula (II-A), ring A is selected from: a 6- to 10-membered aryl group and a 5- to 8-membered heteroaryl group, optionally wherein the 6- to 10-membered aryl group is a phenyl group.

[1297] 32. The antibody-drug conjugate according to any one of items 30 to 31, wherein in formula (II-A), ring A is substituted with 0 substituents R 1b replace.

[1298] 33. The antibody-drug conjugate according to item 1, wherein in formula (II-A), X 1 It is N or P, preferably N.

[1299] 34. The antibody-drug conjugate according to any one of items 1 and 33, wherein in formula (II-A), Ring A is selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated heterocyclic group.

[1300] 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, such as a 3- to 6-membered saturated heterocyclyl, such as a 6-membered saturated heterocyclyl, optionally wherein ring A independently contains 2 heteroatoms, such as 2 nitrogen atoms.

[1301] 36. The antibody-drug conjugate according to any one of items 33 to 35, wherein in formula (II-A), ring A is substituted with 0 substituents R 1c replace.

[1302] 37. The antibody-drug conjugate according to item 1, wherein Formula (II-A) is a structure represented by Formula (II-Ax):

[1303]

[1304] Wherein when ring A is selected from: 6 to 10 membered aryl, 5 to 8 membered heteroaryl and 3 to 10 membered saturated or partially unsaturated carbocyclic group, ring A is surrounded by p L 2 replace;

[1305] Or when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, ring A is surrounded by p L 2 replace.

[1306] 38. The antibody-drug conjugate according to item 1, wherein Formula (II-A) is a structure represented by Formula (II-Ay):

[1307]

[1308] wherein Ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, and Ring A contains q ring-forming heteroatoms X 2 , and X 2 For attachment to an antibody, optionally via a linker.

[1309] 39. The antibody-drug conjugate according to item 1, wherein in formula (II-A), Ring A is selected from the group consisting of a 6- to 10-membered aryl group, a 5- to 8-membered heteroaryl group, and a 3- to 10-membered saturated carbocyclic group.

[1310] 40. The antibody-drug conjugate according to any one of items 1 and 39, wherein in formula (II-A), Ring A is selected from: phenyl and a 3- to 6-membered saturated carbocyclyl, such as a 4-membered saturated carbocyclyl or a 6-membered saturated carbocyclyl, for example, Ring A is phenyl.

[1311] 41. The antibody-drug conjugate according to any one of items 1 and 39 to 40, wherein in formula (II-A), ring A is replaced by not less than 1 L 2 , for example, 1 L 2 replace.

[1312] 42. The antibody-drug conjugate according to any one of items 1 and 39, wherein in formula (II-A), Ring A is a 3- to 10-membered saturated heterocyclic group, such as a 3- to 6-membered saturated heterocyclic group, optionally a 3-membered saturated heterocyclic group, a 5-membered saturated heterocyclic group, or a 6-membered saturated heterocyclic group.

[1313] 43. The antibody-drug conjugate according to item 42, wherein in formula (II-A), ring A is replaced by not less than 1 L 2 Replaced, for example, by 1 L 2 replace.

[1314] 44. The antibody-drug conjugate according to item 1, wherein in formula (II-A), m is 0, 1 or 2, optionally wherein m is 0, and L 3 is a covalent bond; or

[1315] m is 1, and L 3 -C(R 5a )(R 5b )-, optionally wherein L 3 The 0 methylene units are replaced by -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

[1316] m is 2, and L 3 -(C(R3a )(R 3b ))2-, optionally wherein L 3 The 0 methylene units are replaced by -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)-.

[1317] 45. The antibody-drug conjugate according to any one of items 1 and 38, wherein Ring A contains at least one ring heteroatom X 2 , for example, 1 X 2 , and X 2 for attachment to an antibody, optionally via a linker, optionally wherein X 2 is N.

[1318] 46. The antibody-drug conjugate according to any one of items 1 to 45, wherein n is 0 or 1, optionally wherein n is 0, and L 1 is a covalent bond; or

[1319] Optionally, wherein n is 1, and L 1 -C(R 5a )(R 5b )-, and optionally L 1 One methylene unit is replaced by -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, substituted by -C(O)-.

[1320] 47. The antibody-drug conjugate according to any one of items 1 to 46, wherein R2 Selected from: -O-, -(R 2a )N- and -S-.

[1321] 48. An antibody-drug conjugate according to any one of Items 1 to 47, wherein R 2 is -O-; or R 2 is -(R 2A )N-, optionally wherein R 2a is hydrogen, such as -HN-.

[1322] 49. An antibody-drug conjugate according to any one of Items from 1 to 29, wherein R 1a is hydrogen.

[1323] 50. An antibody-drug conjugate according to Item 1 and any one of Items 30 to 33, wherein R 1b is hydrogen.

[1324] 51. An antibody-drug conjugate according to Item 1 and any one of Items 33 to 36, wherein R 1c is hydrogen.

[1325] 52. An antibody-drug conjugate according to Item 1, wherein 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 is hydrogen, and / or R, R a and R b are each independently hydrogen.

[1326] 53. An antibody-drug conjugate according to Item 1, wherein Formula II-A is any one of Formulae (II-A-1) to (II-A-12):

[1327]

[1328]

[1329] wherein R 2 is selected from: -O-, -HN-, -P(=O)H- and -S-; X 2 is selected from N and P; wherein R 2 or X 2 optionally connects any one of the structures shown in Formulae (II-A-1) to (II-A-12) to the antibody via a linker.

[1330] 54. An antibody-drug conjugate according to Item 1, wherein in Formula (III-A), X is -L 1 -C(R 1a )(R1b )-C(O)-,R 1 -S- or -(R 2 )N-, and R 2 Not hydrogen.

[1331] 55. The antibody-drug conjugate according to any one of items 1 to 54, wherein in formula (III-A), L 1 -(C(R 3a )(R 3b )) m -, and L 1 0 or 1 methylene unit is replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- substitution, such as L 1 One methylene unit is replaced by -C(O)-.

[1332] 56. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)-,R 1 is -O- or -HN-, m is not 0, and L 1 Not less than one methylene unit, for example, one methylene unit is replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, optionally wherein in formula (III-A), L 1 One methylene unit is replaced by -C(O)-.

[1333] 57. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)-,R 1 -O- or -HN-, L 1 -(C(R 3a )(R 3b )) m -, m is not 0, L 1 The 0 methylene units are replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, each R 3a and each R 3b Not all are hydrogen, and R 1a and R 1b For hydrogen.

[1334] 58. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L1 -C(R 1a )(R 1b )-C(O)-, and m is 0, 1 or 2.

[1335] 59. The antibody-drug conjugate according to any one of items 1 and 58, wherein in formula (III-A), m is 0, and L 1 is a covalent bond, optionally further wherein in formula (III-A), R 1 (R 2 )N- or -S-, and R 2 Not hydrogen.

[1336] 60. The antibody-drug conjugate according to any one of items 1 and 58, wherein in formula (III-A), m is 1, and L 1 -C(R 3a )(R 3b )-, optionally L 1 The 0 methylene units are replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement.

[1337] 61. The antibody-drug conjugate according to any one of items 1, 58 and 60, wherein in formula (III-A), R 1 (R 2 )N- or -S-, and R 2 is not hydrogen; optionally wherein R 1 -S-; and / or R 1 is -S-, and R 1a and R 1b is hydrogen or R 1a and R 1b Each is independently -N(R a )(R b ), for example, where R 1a -N(R a )(R b ).

[1338] 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.

[1339] 63. The antibody-drug conjugate according to any one of items 1 to 62, wherein in formula (III-A), R 1 For -(R 2 )N-, and R 2 C 1-6 Aliphatic groups, such as methyl.

[1340] 64. The antibody-drug conjugate according to any one of items 1 to 62, wherein in formula (III-A), L 1 -C(R 3a )(R 3b )-,R 1 -O- or -HN-, L 1 The 0 methylene units are replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, and R 3a and R 3b are not all hydrogen; optionally wherein R 1 -O- and / or R 3a C 1-6 aliphatic group; optionally R 3a C 1-6 aliphatic group, and R 3b is hydrogen or C 1-6 Aliphatic groups, such as those in which R 3a C 1-6 aliphatic group, and R 3b For hydrogen.

[1341] 65. The antibody-drug conjugate according to any one of items 1 to 62 and 64, wherein in formula (III-A), R 3a is methyl and R 3b For hydrogen.

[1342] 66. The antibody-drug conjugate according to item 1, wherein in formula (III-A), R 3a C 1-6 Aliphatic group and R 3b C 1-6 Aliphatic groups, such as those in which R 3a is methyl and R 3b C 1-6 Aliphatic groups, such as those in which R 3a is methyl and R 3b It is a methyl group.

[1343] 67. The antibody-drug conjugate according to any one of items 1 and 58, wherein in formula (III-A), m is 2, and L 1 -(C(R 3a )(R 3b ))2-; optionally wherein in formula (III-A), L 1 One methylene unit is replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, for example, by -C(O)-.

[1344] 68. The antibody-drug conjugate according to any one of Items 1, 58, and 67, wherein in formula (III-A), R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-.

[1345] 69. The antibody-drug conjugate according to any one of Items 1, 58, and 67 to 68, wherein in formula (III-A), R 1 is -O-; or R 1 is -S-; or R 1 is -(R 2 )N-, optionally wherein R 2 is an aliphatic group, such as methyl. 1-6

[1346] 70. The antibody-drug conjugate according to Item 1, wherein in formula (III-A), X is -L<00032xx> 1 -L 0 -, R 1 is -O-, -S-, or -(R 2 )N-, and R s 2 is not hydrogen, optionally wherein L 1 is -C(R 3a )(R 3b ), and 0 or 1 methylene unit of L 1 is replaced by -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-, such as being replaced by -C(O)-; or

[1347] wherein in formula (III-A), X is -L 1 -L 0 -, R 1 is -HN-, m is not 0, and L 0 is -C(=S)-, -C(=NR 4a )-, or -C(=N2)-; or

[1348] wherein in formula (III-A), X is -L 1 -L 0 -, R 1 is -HN-, m is not 0, L 0 is -C(R 2a )(R 2b ), L 1 is -(C(R 3a )(R 3b )) m -, and each R 3a and each R 3b is not hydrogen. It should be noted that there are some tags like <00032xx> in the original text which seem to be incomplete or incorrect in the provided format. I've translated as much as possible based on the clear parts. If there are specific corrections or clarifications for those tags, the translation can be adjusted accordingly.

[1349] 71. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L 1 -L 0 -, and m is 1 or 2; optionally wherein m is 1, and L 1 -C(R 3a )(R 3b )-; optionally wherein L 1 The 0 methylene units are replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement.

[1350] 72. The antibody-drug conjugate according to any one of items 1 and 71, wherein in formula (III-A), R 1 (R 2 )N- or -S-, and R 2 is not hydrogen; optionally wherein R 1 For -S-.

[1351] 73. The antibody-drug conjugate according to any one of items 1 and 71, wherein in formula (III-A), m is 2, and L 1 -(C(R 3a )(R 3b ))2-; Optionally, wherein in formula (III-A), L 1 The 0 methylene units are replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement.

[1352] 74. The antibody-drug conjugate according to any one of items 1, 71 and 73, wherein in formula (III-A), R 1 -O-, -S- or (R 2 )N-, and R 2 is not hydrogen; optionally wherein R 1 For -(R 2 )N-, and R 2 is not hydrogen, optionally R 2 C 1-6 an aliphatic group, for example, a methyl group; or

[1353] 75. The antibody-drug conjugate according to any one of items 1, 71 and 73 to 74, wherein in formula (III-A), R 1 It is -O-.

[1354] 76. The antibody-drug conjugate according to any one of items 1, 71, and 73 to 75, wherein in formula (III-A), R 3a C 1-6aliphatic; and / or wherein R 3a C 1-6 aliphatic group, and R 3b is hydrogen or C 1-6 aliphatic group; and / or wherein in formula (III-A), R 3a C 1-6 aliphatic group, and R 3b C 1-6 aliphatic group; and / or wherein in formula (III-A), R 3a is methyl, and R 3b C 1-6 aliphatic group; and / or wherein in formula (III-A), R 3a is methyl, and R 3b It is a methyl group.

[1355] 77. The antibody-drug conjugate according to any one of items 1, 71, and 73 to 76, wherein in formula (III-A), L 1 -C(R 3a )(R 3b )-C(CH3)2-.

[1356] 78. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L 3 -L 2 -, wherein in formula (III-A), L 2 -C(R 5a )(R 5b )-,L 3 -(C(R 7a )(R 7b )) n -, R 1 -S- or -(R 2 )N-, and R 2 Not hydrogen.

[1357] 79. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L 3 -L 2 -, wherein in formula (III-A), L 2 -C(O)-, R 1 -O-, L 3 -(C(R 7a )(R 7b )) n -, and when L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 C not substituted by -NH2 1-6 Aliphatic group.

[1358] 80. The antibody-drug conjugate according to any one of items 1 and 79, wherein in formula (III-A), L 3 One methylene unit is replaced by -NR 8 -, -O- or -SO- replacement.

[1359] 81. The antibody-drug conjugate according to any one of items 1 and 79 to 80, wherein in formula (III-A), R 8 C 1-6 aliphatic group, and R 8 Optionally, 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 Aliphatic substitution, for example, where R 8 C 1-3 aliphatic group, and R 8 Not replaced.

[1360] 82. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L 3 -L 2 -, wherein in formula (III-A), when L 2 -C(O)-, R 1 -HN- and L 3 -(C(R 7a )(R 7b )) n -When, L 3 At least one methylene unit is replaced by -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-.

[1361] 83. The antibody-drug conjugate according to item 1, wherein in formula (III-A), X is -L 3 -L 2 -, n is 4, and L 3 -(C(R 7a )(R 7b ))4-.

[1362] 84. The antibody-drug conjugate according to any one of items 1 and 83, wherein in formula (III-A), L 2 -C(R 5a )(R 5b )-, wherein in formula (III-A), L 2 One methylene unit is replaced by -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 L is replaced by -C(O)-, and L 2 It is -C(O)-.

[1363] 85. The antibody-drug conjugate according to any one of items 1 and 83 to 84, wherein in formula (III-A), L 3 One methylene unit is replaced by -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 replaced by -NR 8 -, -O- or -SO-, more preferably -NR 8 - permutation, where R 8 C 1-6 Aliphatic groups, such as methyl.

[1364] 86. The antibody-drug conjugate according to any one of items 1 and 83 to 85, wherein in formula (III-A), X is -(C(R 7a )(R 7b ))2-N(CH3)-C(R 7a )(R 7b )-C(O)-.

[1365] 87. The antibody-drug conjugate according to any one of items 1 and 83 to 85, wherein in formula (III-A), L 3 One methylene unit is replaced by -SO-.

[1366] 88. The antibody-drug conjugate according to any one of items 1 and 87, wherein in formula (III-A), X is -(C(R 7a )(R 7b ))2-SO-C(R 7a )(R 7b )-C(O)-.

[1367] 89. The antibody-drug conjugate according to item 1, wherein in formula (III-A), L 3 One methylene unit is replaced by -O-.

[1368] 90. The antibody-drug conjugate according to any one of items 1 and 89, wherein in formula (III-A), X is -(C(R 7a )(R 7b ))2-OC(R 7a )(R 7b )-C(O)-.

[1369] 91. The antibody-drug conjugate according to item 1, wherein in formula (III-A), R 1a and R 1b are each independently hydrogen or -N(R a )(R b ); and / or

[1370] Wherein in formula (III-A), R 2 C 1-6 Aliphatic groups, such as C 1-3 Aliphatic groups, such as R 2 is methyl; and / or

[1371] Wherein in formula (III-A), R 3a and R 3b are each independently hydrogen or C 1-6 Aliphatic groups, such as R 3a and R 3b Each independently is C 1-3 Aliphatic groups, such as R 3a and R 3b is methyl; and / or

[1372] Wherein in formula (III-A), R 4a and R 4b is hydrogen; and / or

[1373] Wherein in formula (III-A), R 5a and R 5b is hydrogen; and / or

[1374] Wherein in formula (III-A), R 6 is hydrogen; and / or

[1375] Wherein in formula (III-A), R 7a and R 7b is hydrogen; and / or

[1376] Wherein in formula (III-A), R 8 C 1-6 Aliphatic groups, such as C 1-3 Aliphatic groups, such as R 8 It is a methyl group.

[1377] 92. The antibody-drug conjugate according to item 1, wherein R, R a and R b For hydrogen.

[1378] 93. The antibody-drug conjugate according to item 1, wherein Formula (III-A) is any one of Formula (III-A-1) to Formula (III-A-17):

[1379]

[1380]

[1381] The wavy line indicates that the structure represented by any one of Formula (III-A-1) to Formula (III-A-17) is optionally connected to the antibody via a linker.

[1382] 94. The antibody-drug conjugate according to item 1, wherein the antibody-drug conjugate comprises a structure represented by formula (IC):

[1383]

[1384] wherein L connects the structure of formula (IC) to the antibody, and wherein L is -L a -L b -L c -, L a , L b and L c Each of has the meaning as defined herein in any Formula (IB), and R 1 , L 1 and L 2 Each of is as defined in any of Formula (IA) described above.

[1385] 95. The antibody-drug conjugate according to item 1, wherein the antibody-drug conjugate comprises formula (II-C x ) or formula (II-C y ) shows the structure:

[1386]

[1387] Wherein L can be -L a -L b -L c -, and L a 、L b and L c As defined in any of Formula (II-Bx) in the embodiments described above;

[1388] L 2 , p, ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above;

[1389] or X 2 ,q,ring A,X 1 and L 1 As defined in any of Formula (II-Ay) in the embodiments described above.

[1390] 96. The antibody-drug conjugate according to item 1, wherein the antibody-drug conjugate comprises a structure represented by formula (III-C):

[1391]

[1392] Where L is -L a -L b -L c -; wherein L connects the structure represented by formula (III-C) to the antibody;

[1393] -L a -Selected from:

[1394] and

[1395] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp , and Z is -(C(R za )(R zb )) zn ;

[1396] where Z connects -La- to -Lb-

[1397] where wn is selected from integers ≥ 0, and

[1398] 0 or more than 1 methylene unit of W is independently replaced by -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)-;

[1399] Wherein yn is selected from an integer ≥ 0, and yp is 0 or 1;

[1400] wherein zn is selected from integers ≥ 0, and

[1401] 0 or more than 1 methylene unit of Z is independently replaced by -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)-;

[1402] -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 substituted with at least one substituent R cx replace;

[1403] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cxare 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[1404] Among them, each R r , each R ra and each R rb Each is 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 aliphatic groups;

[1405] -L b - represents a peptide residue consisting of 2 to 7 amino acids;

[1406] -L c -Selected from:

[1407] and

[1408] where R L1 and R L2 Each independently selected from: 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;

[1409] where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-;

[1410] X is selected from: -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 -;

[1411] L 1 is -(C(R 3a )(R 3b )) m -, where 0 or not less than 1 methylene unit of L 1 is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-;

[1412] L 0 is -C(R 2a )(R 2b )-, or L 0 is -C(=S)-, -C(=NR 4a )-, or -C(=N2)-;

[1413] L 2 is -C(R 5a )(R 5b )-, where 0 or 1 methylene unit of L 2 is replaced by -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)-;

[1414] L 3 is -(C(R7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[1415] Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[1416] Among them, each R, each R a and each R bEach is 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 aliphatic groups;

[1417] m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1;

[1418] When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1419] When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1420] When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2;

[1421] When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-.

[1422] 97. The antibody-drug conjugate according to item 1, wherein the antibody-drug conjugate comprises a structure represented by formula (ID):

[1423]

[1424] Wherein Ab is an antibody that binds to uPARAP, comprising:

[1425] i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[1426] ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[1427] N a An integer or decimal from 1 to 10;

[1428] L can be -L a -L b -L c -, and L a , L b and L c As defined in any of Formula (IB) in the embodiments described above,

[1429] R 1 , L 1 and L 2 As defined in any of Formula (IA) in the embodiments described above.

[1430] 98. The antibody-drug conjugate according to item 1, wherein the antibody-drug conjugate comprises a structure represented by formula (II-Dx) or formula (II-Dy):

[1431]

[1432] Wherein Ab is an antibody that binds to uPARAP, comprising:

[1433] i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[1434] ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[1435] N aAn integer or decimal from 1 to 10;

[1436] L can be -L a -L b -L c -, and L a , L b and L c As defined in any of Formula (II-Bx) or Formula (II-By) in the embodiments described above;

[1437] L 2 , Ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above;

[1438] or X 2 , Ring A, X 1 and L 1 As defined in any of Formula (II-Ay) in the embodiments described above.

[1439] 99. The antibody-drug conjugate according to item 1, wherein the antibody-drug conjugate comprises a structure represented by formula (III-D):

[1440]

[1441] Wherein Ab is an antibody that binds to uPARAP, comprising:

[1442] i) an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[1443] ii) an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[1444] N a An integer or decimal from 1 to 10;

[1445] L is -L a -L b -L c -; wherein L connects the structure shown in formula (III-D) to the antibody;

[1446] -L a -Selected from:

[1447] and

[1448] Where W is -(C(R wa )(R wb)) wn -, Y is -(OCH2CH2) yn -O yp , and Z is -(C(R za )(R zb )) zn ;

[1449] where Z connects -La- to -Lb-

[1450] where wn is selected from integers ≥ 0, and

[1451] 0 or more than 1 methylene unit of W is independently replaced by -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)-;

[1452] Wherein yn is selected from an integer ≥ 0, and yp is 0 or 1;

[1453] wherein zn is selected from integers ≥ 0, and

[1454] 0 or more than 1 methylene unit of Z is independently replaced by -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)-;

[1455] -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 substituted with at least one substituent Rcx replace;

[1456] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[1457] Among them, each R r , each R ra and each R rb Each is 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 aliphatic groups;

[1458] -L b - represents a peptide residue consisting of 2 to 7 amino acids;

[1459] -L c -Selected from:

[1460] and

[1461] where R L1 and R L2Each independently selected from: 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 an aliphatic group;

[1462] where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-;

[1463] X is selected from: -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 -;

[1464] L 1 is -(C(R 3a )(R 3b )) m -, where 0 or no less than 1 methylene unit of L 1 is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-;

[1465] L 0 is -C(R 2a )(R 2b )-, or L 0 is -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[1466] L 2 is -C(R 5a )(R 5b )-, where 0 or 1 methylene unit of L 2 is replaced by -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)(R6 )-、-N(R 6 )SO2-、-SO2N(R 6 )-、-C(=S)-、-C(=NR 6 )-, -N=N-, -C=N-, -N=C- or -C(=N2)-;

[1467] L 3 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[1468] Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[1469] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[1470] m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1;

[1471] When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1472] When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1473] When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2;

[1474] When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-.

[1475] 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, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[1476] 101. An antibody-drug conjugate (ADC), comprising:

[1477] a. An antibody that binds to uPARAP, comprising:

[1478] i. an immunoglobulin light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and

[1479] ii. an immunoglobulin heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 6;

[1480] b. an active agent selected from the group consisting of:

[1481] i. Formula (IE) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[1482]

[1483] where R 1 、L 1 and L 2 As defined in any of the above defined embodiments, formula (IA);

[1484] ii. Formula (II-Ex) or Formula (II-Ey) or its tautomers, meso-racemates, racemates, enantiomers or diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof

[1485] 、

[1486] Wherein for formula (II-Ex), L 2 , p, ring A, X 1and L 1 as defined in any of the formula (II-Ax) in the embodiments described above, and for formula (II-Ey), X 2 , q, ring A, X 1 and L 1 as defined in any of the formula (II-Ay) in the embodiments defined above; and

[1487] iii. formula (III-E) or its tautomer, meso form, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof

[1488]

[1489] where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )-, and -S-;

[1490] X is selected from: -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 -;

[1491] L 1 is -(C(R 3a )(R 3b )) m -, where 0 or no less than 1 methylene unit of L 1 is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )-, or -C(=N2)-;

[1492] L 0 is -C(R 2a )(R 2b ), or L 0 is -C(=S)-, -C(=NR 4a ), or -C(=N2)-;

[1493] L 2 is -C(R 5a )(R 5b ), where 0 or 1 methylene unit of L 2 is replaced by -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)-;

[1494] L 3 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[1495] Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[1496] Among them, each R, each R a and each R b Each is 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 aliphatic groups;

[1497] m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1;

[1498] When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1499] When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1500] When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2;

[1501] When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-;

[1502] as well as

[1503] c. Optionally, connecting a) to the linker of b).

[1504] 102. The antibody-drug conjugate according to any one of items 1 or 101, wherein the active agent is selected from any one of the structures in Table 1 or its tautomers, mesomers, racemates, enantiomers or diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[1505] 103. A method for producing an antibody-drug conjugate according to any one of the preceding items, the method comprising reacting a compound selected from one of the following with the antibody defined in item 1:

[1506] a. Formula (IF) or a tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[1507]

[1508] Among them L x For L ax -L b -L c -;

[1509] L ax -Selected from:

[1510] and

[1511] where R hal is iodine or bromine;

[1512] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp-, and Z is -(C(R za )(R zb )) zn ;

[1513] where wn is selected from integers ≥ 0, and

[1514] 0 or more than 1 methylene unit of W is independently replaced by -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)-;

[1515] Wherein yn is selected from an integer ≥ 0, and yp is 0 or 1;

[1516] wherein zn is selected from integers ≥ 0, and

[1517] 0 or more than 1 methylene unit of Z is independently replaced by -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)-;

[1518] -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 substituted with at least one substituent R cx replace;

[1519] Among them, each R wa , each R wb , each R za , each Rzb , each R wx , each R zx and each R cx are 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[1520] Among them, each R r , each R ra and each R rb Each is 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 aliphatic groups;

[1521] L b and L c As defined in any of formula (IB) in the embodiments described above;

[1522] R 1 , L 1 and L 2 As defined in any of Formula (IA) in the embodiments described above;

[1523] b. Formula (II-F x ) or formula (II-F y ) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[1524] 、

[1525] Among them L x For L ax -L b -L c -;

[1526] L ax -Selected from:

[1527] and

[1528] where R hal is iodine or bromine;

[1529] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp -, and Z is -(C(R za )(R zb )) zn ;

[1530] where wn is selected from integers ≥ 0, and

[1531] 0 or more than 1 methylene unit of W is independently replaced by -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)-;

[1532] Wherein yn is selected from an integer ≥ 0, and yp is 0 or 1;

[1533] wherein zn is selected from integers ≥ 0, and

[1534] 0 or more than 1 methylene unit of Z is independently replaced by -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)-;

[1535] -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 substituted with at least one substituent R cx replace;

[1536] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[1537] Among them, each R r , each R ra and each R rbEach is 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 aliphatic groups;

[1538] L b and L c As defined in any of Formula (II-Bx) or Formula (II-By) in the embodiments described above;

[1539] Among them L 2 , p, ring A, X 1 and L 1 As defined in any of Formula (II-Ax) in the embodiments described above;

[1540] or X 2 ,q,ring A,X 1 and L 1 as defined in any of Formula (II-Ay) in the embodiments described above; and

[1541] c. Formula (III-F) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[1542]

[1543] Among them L x For L ax -L b -L c -;

[1544] L ax -Selected from:

[1545] and

[1546] where R hal is iodine or bromine;

[1547] Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp , and Z is -(C(R za )(R zb )) zn ;

[1548] where wn is selected from integers ≥ 0, and

[1549] 0 or more than 1 methylene unit of W is independently replaced by -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)-;

[1550] Wherein yn is selected from an integer ≥ 0, and yp is 0 or 1;

[1551] wherein zn is selected from integers ≥ 0, and

[1552] 0 or more than 1 methylene unit of Z is independently replaced by -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)-;

[1553] -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 substituted with at least one substituent R cx replace;

[1554] Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cxare 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups;

[1555] Among them, each R r , each R ra and each R rb Each is 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 aliphatic groups;

[1556] -L b - represents a peptide residue consisting of 2 to 7 amino acids;

[1557] -L c -Selected from:

[1558] and

[1559] where R L1 and R L2 Each independently selected from: 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;

[1560] where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-;

[1561] X is selected from: -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 -;

[1562] L 1 is -(C(R 3a )(R 3b )) m -, where 0 or no less than 1 methylene unit of L 1 is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-;

[1563] L 0 is -C(R 2a )(R 2b ), or L 0 is -C(=S)-, -C(=NR 4a )- or -C(=N2)-;

[1564] L 2 is -C(R 5a )(R 5b ), where 0 or 1 methylene unit of L 2 is replaced by -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<00041​​​​​​7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement;

[1566] Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups;

[1567] Among them, each R, each R a and each R bEach is 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 aliphatic groups;

[1568] m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1;

[1569] When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1570] When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen;

[1571] When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2;

[1572] When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-.

[1573] 104. The method according to item 103, wherein L ax -for

[1574] 105. The method according to any one of items 103 to 104, wherein L ax -L b -L c -Selected from:

[1575]

[1576] 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, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[1577] 107. The antibody-drug conjugate according to any one of items 1 to 106, wherein the antibody comprises:

[1578] a. an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 1; and

[1579] b. an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 4.

[1580] 108. The antibody-drug conjugate according to any one of items 1 to 107, wherein the antibody comprises:

[1581] a. an immunoglobulin light chain consisting of the amino acid sequence of SEQ ID NO: 1; and

[1582] b. An immunoglobulin heavy chain consisting of the amino acid sequence of SEQ ID NO: 4.

Claims

1. An antibody-drug conjugate (ADC) comprising an antibody that binds to uPARAP, the antibody comprising: 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; wherein the antibody-drug conjugate comprises an active agent having a structure selected from one of the following: a. Formula (III-A) or its tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof where R 1 Selected from: -O-, -(R 2 )N-、-P(=O)(R 2 )- and -S-; wherein R 1 linking the structure according to formula (III-A) to the antibody, optionally via a linker; X is selected from: -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 -; L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or not less than 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement; L 0 -C(R 2a )(R 2b )-, or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-; L 2 -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit is replaced by -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 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement; Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups; Among them, each R, each R a and each R b Each is 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 aliphatic groups; m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1; When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2; When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-; b. Formula (IA) or a tautomer, mesomer, racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )-, -P(R 2 )- and -S-; L 2 -(C(R 3a )(R 3b )) m -R, Among them L 2 0 or not less than 1 methylene unit is independently replaced by -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 -(C(R 5a )(R 5b )) n -, Among them L 1 0 or not less than 1 methylene unit is independently replaced by -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 substituted with at least one substituent R 7 replace; Among them, each R 3a , each R 3b , each R 4 , each R 5a , each R 5b and each R 6 are 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)SO2R or C optionally substituted by R 1-6 aliphatic group; or R 3a and R 5a 、R 4 and R 5a 、R 3a and R 6 or R 4 and R 6 Each independently optionally forms a ring B together with the atoms therebetween, wherein the ring B is selected from: a 5- to 8-membered heteroaryl group and a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, and the ring B is unsubstituted or independently substituted with at least one substituent R 8 replace; Among them, each R 2 , each R 7 and each R 8 are 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)SO2R or C optionally substituted by R 1-6 aliphatic groups; Among them, each R, each R a and each R b Each is 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 aliphatic groups; m and n are each independently selected from an integer ≥ 1; and wherein R 1 linking the structure shown in formula (IA) to the antibody, optionally via a linker; and c. Formula (II-A) or its tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof where X 1 Selected from: N, P and saturated or unsaturated C; when X 1 When C is saturated, X 1 R n replace; wherein Ring A is connected to the antibody according to the structure of Formula II-A, optionally via a linker; When X 1 When C is saturated, ring A is selected from: 3-10 membered saturated or partially unsaturated heterocyclic group and 3-10 membered saturated or partially unsaturated carbocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1a replace; Or when X 1 When C is an unsaturated group, ring A is selected from the group consisting of 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered partially unsaturated heterocyclic group and 3-10 membered partially unsaturated carbocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1b replace; Or when X 1 When N or P, ring A is selected from: 5- to 8-membered heteroaryl and 3- to 10-membered saturated or partially unsaturated heterocyclic group, wherein ring A is substituted by 0 or not less than 1 substituent R 1c replace; When ring A is selected from 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclic group, ring A is substituted by p L 2 Substituted, where L 2 Not for R n ; Or when ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclic group, ring A is surrounded by p L 2 substituted, or ring A contains q ring heteroatoms X 2 , and X 2 for linking the compound of formula (II-A) to the antibody, optionally via a linker; X 2 Selected from: N and P; L 2 -R 2 -L 3 -, and R 2 for linking the compound of formula (II-A) to the antibody, optionally via a linker; L 3 -(C(R 3a )(R 3b )) m -, where L 3 When containing methylene units, L 3 0 or not less than 1 methylene unit is independently replaced by -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 Selected from: -O-, -(R 2a )N-, -S- and -P(=O)(R 2a )-; L 1 -(C(R 5a )(R 5b )) n -, where L 1 When containing methylene units, L 1 0 or not less than 1 methylene unit is independently replaced by -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)-; Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups; Among them, each R, each R a and each R b Each is 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 aliphatic groups; m and n are each independently selected from integers ≥0, and p and q are each independently selected from integers ≥1.

2. The antibody-drug conjugate according to 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

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

4. The antibody-drug conjugate according to any one of claims 1 to 3, wherein in formula (III-A), L 1 -(C(R 3a )(R 3b )) m -, and L 1 0 or 1 methylene unit is replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement.

5. The antibody-drug conjugate according to any one of claims 1 to 4, wherein in formula (III-A), L 1 One methylene unit is replaced by -C(O)-.

6. The antibody-drug conjugate according to any one of claims 1 to 2, wherein in formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)-,R 1 is -O- or -HN-, m is not 0, and L 1 At least one methylene unit is replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement.

7. The antibody-drug conjugate according to any one of claims 1 to 2, wherein in formula (III-A), X is -L 1 -C(R 1a )(R 1b )-C(O)-,R 1 -O- or -HN-, L 1 -(C(R 3a )(R 3b )) m -, m is not 0, L 1 The 0 methylene units are replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, each R 3a and each R 3b Not all are hydrogen, and R 1a and R 1b For hydrogen.

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

9. The antibody-drug conjugate according to any one of claims 7 to 8, wherein in formula (III-A), m is 1, and L 1 -C(R 3a )(R 3b )-.

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

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

12. The antibody-drug conjugate according to any one of claims 1 to 2, wherein in formula (III-A), R 1 For -(R 2 )N-, and R 2 C 1-6 Aliphatic group.

13. The antibody-drug conjugate according to claim 12, wherein in formula (III-A), R 2 It is a methyl group.

14. The antibody-drug conjugate according to any one of claims 1 to 2, wherein in formula (III-A), L 1 -C(R 3a )(R 3b )-,R 1 -O- or -HN-, L 1 The 0 methylene units are replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, and R 3a and R 3b Not all are hydrogen.

15. The antibody-drug conjugate according to claim 14, wherein in formula (III-A), R 1 It is -O-.

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

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

18. The antibody-drug conjugate according to any one of claims 1 to 2, wherein in formula (III-A), R 8 C 1-6 aliphatic group, and R 8 Optionally, 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 Aliphatic substituted, preferably C 1-6 Aliphatic groups, such as C 1-3 Aliphatic groups, such as methyl.

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

20. The antibody-drug conjugate according to any one of claims 1 to 2, wherein Formula (III-A) is according to any one of Formula (III-A-1) to Formula (III-A-17): where R 2 C may be optionally substituted by R 1-6 Aliphatic groups, wherein R can be 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 an aliphatic group, or one in which R 2 It can be 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 an aliphatic group; and wherein the wavy line represents that the structure represented by any one of Formula (III-A-1) to Formula (III-A-17) is optionally connected to the antibody via a linker.

21. The antibody-drug conjugate according to any one of claims 1 to 2, wherein formula (III-A) is selected from: The wavy line indicates that the structure represented by any one of formula (III-A) is optionally connected to the antibody via a linker.

22. The antibody-drug conjugate according to claim 1, wherein Formula (IA) is any one of Formula (IA-1) to Formula (IA-17): where R 1 can be selected from: -O-, -HN-, -P(=O)H- and -S-; and wherein R 1 The structure represented by any one of Formula (IA-1) to Formula (IA-17) is optionally linked to the antibody via a linker.

23. The antibody-drug conjugate according to claim 1, wherein Formula (II-A) is any one of Formula (II-A-1) to Formula (II-A-12): where R 2 Can be selected from: -O-, -HN-, -P(=O)H- and -S-; X 2 Can be selected from N and P; where R 2 or X 2 Any of the structures shown in Formula (II-A-1) to Formula (II-A-12) is linked directly or through a linker to an antibody described herein.

24. The antibody-drug conjugate according to claim 1, wherein the antibody-drug conjugate comprises a structure represented by formula (III-C): Where L is -L a -L b -L c -; wherein L connects the structure shown in formula (III-C) to the antibody; -L a -Selected from: Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp , and Z is -(C(R za )(R zb )) zn ; where Z connects -La- to -Lb- where wn is selected from integers ≥ 0, and 0 or more than 1 methylene unit of W is independently replaced by -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 an integer ≥ 0, and yp is 0 or 1; wherein zn is selected from integers ≥ 0, and 0 or more than 1 methylene unit of Z is independently replaced by -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 substituted with at least one substituent R cx replace; Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups; Among them, each R r , each R ra and each R rb Each is 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 aliphatic groups; -L b - represents a peptide residue consisting of 2 to 7 amino acids; -L c -Selected from: where R L1 and R L2 Each independently selected from: 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; where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is selected from: -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 -; L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or not less than 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement; L 0 -C(R 2a )(R 2b )-, or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-; L 2 -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit is replaced by -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 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement; Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups; Among them, each R, each R a and each R b Each is 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 aliphatic groups; m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1; When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2; When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-.

25. The antibody-drug conjugate according to claim 1, wherein the antibody-drug conjugate comprises a structure represented by formula (III-D): Wherein Ab is an antibody that binds to uPARAP, comprising: 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 An integer or decimal from 1 to 10; L is -L a -L b -L c -; wherein L connects the structure shown in formula (III-D) to the antibody; -L a -Selected from: Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp , and Z is -(C(R za )(R zb )) zn ; Where Z connects -La- to -Lb-, where wn is selected from integers ≥ 0, and 0 or more than 1 methylene unit of W is independently replaced by -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 an integer ≥ 0, and yp is 0 or 1; wherein zn is selected from integers ≥ 0, and 0 or more than 1 methylene unit of Z is independently replaced by -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 substituted with at least one substituent R cx replace; Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups; Among them, each R r , each R ra and each R rb Each is 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 aliphatic groups; -L b - represents a peptide residue consisting of 2 to 7 amino acids; -L c -Selected from: where R L1 and R L2 Each independently selected from: 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; where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is selected from: -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 -; L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or not less than 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement; L 0 -C(R 2a )(R 2b )-, or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-; L 2 -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit is replaced by -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 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement; Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups; Among them, each R, each R a and each R b Each is 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 aliphatic groups; m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1; When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2; When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-.

26. The antibody-drug conjugate according to 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

27. An antibody-drug conjugate (ADC), comprising: a. An antibody that binds to uPARAP, the antibody comprising: 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; b. an active agent selected from the group consisting of: i. Formula (III-E) or its tautomer, meso-racemate, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is selected from: -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 -; L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or not less than 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement; L 0 -C(R 2a )(R 2b )-, or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-; L 2 -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit is replaced by -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 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement; Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups; Among them, each R, each R a and each R b Each is 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 aliphatic groups; m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1; When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2; When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-; as well as c. Optionally, connecting a) to the linker of b).

28. The antibody-drug conjugate according to any one of claims 1 or 27, wherein the active agent is selected from the group consisting of 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, -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 or P-III-31 or any one thereof, a tautomer, a racemate, a racemate, an enantiomer or a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

29. The antibody-drug conjugate according to any one of claims 1 or 27 to 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 diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

30. A method for producing an antibody-drug conjugate according to any one of the preceding claims, said method comprising reacting a compound selected from one of the following with an antibody as defined in claim 1: a. Formula (III-F) or a tautomer, mesomer, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, Among them L x For L ax -L b -L c -; L ax -Selected from: where R hal is iodine or bromine; Where W is -(C(R wa )(R wb )) wn -, Y is -(OCH2CH2) yn -O yp , and Z is -(C(R za )(R zb )) zn ; where wn is selected from integers ≥ 0, and 0 or more than 1 methylene unit of W is independently replaced by -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 an integer ≥ 0, and yp is 0 or 1; wherein zn is selected from integers ≥ 0, and 0 or more than 1 methylene unit of Z is independently replaced by -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 substituted with at least one substituent R cx replace; Among them, each R wa , each R wb , each R za , each R zb , each R wx , each R zx and each R cx are 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)CH2C(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 by R r Substituted C 1-6 aliphatic groups; Among them, each R r , each R ra and each R rb Each is 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 aliphatic groups; -L b - represents a peptide residue consisting of 2 to 7 amino acids; -L c -Selected from: where R L1 and R L2 Each independently selected from: 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; where R 1 is selected from: -O-, -(R 2 )N-, -P(=O)(R 2 )- and -S-; X is selected from: -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 -; L 1 -(C(R 3a )(R 3b )) m -, where L 1 0 or not less than 1 methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)- replacement; L 0 -C(R 2a )(R 2b )-, or L 0 -C(=S)-, -C(=NR 4a )- or -C(=N2)-; L 2 -C(R 5a )(R 5b )-, where L 2 0 or 1 methylene unit is replaced by -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 -(C(R 7a )(R 7b )) n -, where L 3 At least one methylene unit is independently replaced by -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 0 or not less than 1 methylene unit is also independently replaced by -C(O)-, -C(=S)-, -C(=NR 8 )- or -C(=N2)- replacement; Among them, 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 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)SO2R or C optionally substituted by R 1-6 aliphatic groups; Among them, each R, each R a and each R b Each is 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 aliphatic groups; m is selected from an integer ≥ 0, and n is selected from an integer ≥ 1; When R 1 is -O- or -HN- and X is -L 1 -CH2-C(O)-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -HN-, X is -L 1 -L 0 - and L 0 When it is -CH2-, L 1 At least one methylene unit is independently replaced by -C(O)-, -C(=S)-, -C(=NR 4b )- or -C(=N2)-, or each R 3a and each R 3b Not all are hydrogen; When R 1 is -O-, X is -L 3 -C(O)- and L 3 One methylene unit is replaced by -NR 8 When replacing, R 8 Not -CH2-CH2-NH2; When R 1 is -NH- and X is -L 3 -C(O)-, L 3 Not less than one methylene unit is replaced by -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-.

31. The method according to claim 30, wherein L ax -for 32. The method according to any one of claims 30 to 31, wherein L ax -L b -L c -Selected from:

33. according to the method for any one of claim 30 to 32, wherein the compound is selected from 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-24, L-III-25, L-III-26, L-III-27 ... Any one of I-16, L-III-15, L-III-14, L-III-13, L-III-12, 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, mesoform, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

34. according to the method for 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 in Table 3 or its tautomer, mesoform, racemate, enantiomer or diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

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

4.

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

4.

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

38. 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 as a medicament.

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 the group consisting of: cancer; bone degradative diseases, such as osteoporosis; fibrosis; and macrophage-associated diseases or disorders, such as atherosclerosis, arthritis or chronic inflammation.

40. The antibody-drug conjugate or composition for use according to claim 39, wherein the disease is cancer, for example, wherein 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. The antibody-drug conjugate or composition for use according to claim 40, wherein the cancer is a solid tumor.

42. The antibody-drug conjugate or composition for use according to claim 40, wherein the cancer is leukemia, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid 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. 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. The antibody-drug conjugate or composition for use according to claim 44, wherein the soft tissue sarcoma (STS) is selected from epithelioid sarcoma, clear cell sarcoma, alveolar soft tissue sarcoma, extraskeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, inflammatory myofibroblastic tumor, undifferentiated embryonal sarcoma, alveolar soft tissue sarcoma (ASPS), angiosarcoma, chondrosarcoma, dermatofibrosarcoma protuberans (DFSP), desmoid sarcoma, Ewing sarcoma, fibrosarcoma, myxofibrosarcoma, adult-type 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 metastatic cancer.

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 other agents, such as one or more other therapeutic agents.

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

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

50. 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 in a method of inhibiting tumor progression 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 means and / or instructions for administering the antibody or antibody-drug conjugate to a subject.

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