Conjugation linkers, cell binding molecule-drug conjugates containing the linkers, methods of making and uses such conjugates with the linkers

Abstract

To provide a linker and a compound for conjugating a cytotoxic agent with a cell binding molecule.SOLUTION: Provided is a linker compound of formula (I) or (II), where Y is a functional group that is reactive with a drug or a cytotoxic agent to form a disulfide, ether, ester, thioether, thioester, peptide, hydrazone, carbamate, carbonate, amine (secondary, tertiary, or quaternary), imine, cycloheteroalkane, heteroaromatic, alkyloxime, or amide bond.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to compounds, particularly linkers having a propiolyl, substituted acrylic (acryloyl), or disubstituted propanoyl group, which are used to conjugate a cytotoxic agent with a cell-binding molecule. The present invention also relates to a method for preparing a cell-binding molecule-drug (cytotoxic agent) conjugate in a specific manner, including modifying a drug with these linkers and reacting it with a cell-binding molecule, or modifying a cell-binding molecule with these linkers and reacting it with a drug, or directly conjugating a synthesized linker-drug assembly with a cell-binding molecule. The present invention also relates to a method for preparing a cell-binding molecule-drug (cytotoxic agent) conjugate in a specific manner, including modifying a drug with these linkers and reacting it with a cell-binding molecule, or modifying a cell-binding molecule with these linkers and reacting it with a drug, or directly conjugating a synthesized linker-drug assembly with a cell-binding molecule. The present invention also relates to a method for preparing a cell-binding molecule-drug (cytotoxic agent) conjugate in a specific manner, including modifying a drug with these linkers and reacting it with a cell-binding molecule, or modifying a cell-binding molecule with these linkers and reacting it with a drug, or directly conjugating a synthesized linker-drug assembly with a cell-binding molecule. The present invention also relates to a method for preparing a cell-binding molecule-drug (cytotoxic agent) conjugate in a specific manner, including modifying a drug with these linkers and reacting it with a cell-binding molecule, or modifying a cell-binding molecule with these linkers and reacting it with a drug, or directly conjugating a synthesized linker-drug assembly with a cell-binding molecule. The present invention also relates to a method for preparing a cell-binding molecule-drug (cytotoxic agent) conjugate in a specific manner, including modifying a drug with these linkers and reacting it with a cell-binding molecule, or modifying a cell-binding molecule with these linkers and reacting it with a drug, or directly conjugating a synthesized linker-drug assembly with a cell-binding molecule. The present invention also relates to a method for preparing a cell-binding molecule-drug (cytotoxic agent) conjugate in a specific manner, including modifying a drug with these linkers and reacting it with a cell-binding molecule, or modifying a cell-binding molecule with these linkers and reacting it with a drug, or directly conjugating a synthesized linker-drug assembly with a cell-binding molecule. The present invention also relates to a method for preparing a cell-binding molecule-drug (cytotoxic agent) conjugate in a specific manner, including modifying a drug with these linkers and reacting it with a cell-binding molecule, or modifying a cell-binding molecule with these linkers and reacting it with a drug, or directly conjugating a synthesized linker-drug assembly with a cell-binding molecule.

Background Art

[0002] In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). In chemotherapy drugs, it is usually impossible to distinguish between normal cells and malignant cells, so the therapeutic concentration range is narrow, and thus it is a major problem to cause side effects that limit the allowable dose below the clinically effective amount. In contrast, immunotherapy, usually in the form of monoclonal antibodies, can specifically bind to specific proteins or molecules of malignant cells, leaving normal cells intact, and thus has fewer side effects and a larger therapeutic concentration range than chemotherapy drugs. Antibody-drug conjugates (ADCs) are a type of immunotherapy that combines a tumor-specific binding monoclonal antibody conjugated with a very potent cytotoxic agent payload for the targeted treatment of cancer. This approach has shown promising activity in the treatment of Hodgkin lymphoma with the US FDA-approved drug "Adcetris" (brentuximab vedotin) and in the treatment of HER-2 positive breast cancer with the US FDA-approved drug "Kadcyla" (ado-trastuzumab emtansine). There is. Over the past 20 years, both the academic and pharmaceutical industries have increased their investment of time and funds in ADCs. . Since more than 50 ADCs are in clinical trials, the pharmaceutical industry anticipates that an additional 8 -10 ADC drugs may be approved on the market within the next two to three years (Non-Patent Documents 1-5). .

[0003] Many important parameters governing the success of the development of antibody-drug conjugates for clinical use include the selection of tumor target antigens with restricted expression on normal cells, antibodies that are highly selective for the target, cytotoxic molecules that are essential for inducing very potent target cell death when internalized and released by the cell, linkers that are stable in circulation but release the cytotoxic agent in target cells, linkers that crosslink the cytotoxic molecule and the antibody, and appropriate conjugation chemistry used for the attachment of the antibody and the cytotoxic molecule. Although there have been many advances in the development of ADCs, the mechanisms underlying the off-target toxicity of ADCs are not yet well understood, and a significant number of ADCs that have ended in the clinical trial phase for the treatment period in the clinic are much narrower than preclinical models, and the dosing regimens are hampered by dose-limiting toxicities (DLTs) that cannot always be predicted based on preclinical data (Non-Patent Document 4). Therefore, research and development regarding the chemistry and design of ADCs is currently expanding beyond the efficacy of the sole payload to the scope of linker-payload components and conjugation chemistry, particularly addressing the linker-payload activity of ADCs against the target / target disease (Non-Patent Documents 1 and 6). Therefore, many pharmaceutical developers and academic institutions are, as well as improving batch-to-batch consistency in ADC manufacturing, aiming for longer circulation half-lives, higher efficacy, reduction of potential off-target toxicity, and a narrow range of ADC pharmacokinetics in vivo. Regarding the research and development of ADCs, it is currently expanding beyond the efficacy of the sole payload to the scope of linker-payload components and conjugation chemistry, particularly addressing the linker-payload activity of ADCs against the target / target disease (Non-Patent Documents 1 and 6). Therefore, many pharmaceutical developers and academic institutions are, as well as improving batch-to-batch consistency in ADC manufacturing, aiming for longer circulation half-lives, higher efficacy, reduction of potential off-target toxicity, and a narrow range of ADC pharmacokinetics in vivo. A new reliable method for site-specific ADC conjugates that appear to have physical dynamics is strongly focused on establishing (Non-Patent Documents 7 to 11).

[0004] There are several approaches developed in recent years for the preparation of site-selective ADCs (Non-Patent Document 12). These include the introduction of unpaired cysteines, such as the engineered reactive cysteine residue called THIOMAB from Genentech (Non-Patent Documents 13 and 14, Patent Documents 2 to 6), the introduction of a glutamine tag genetically introduced by Streptoverticillium mobaraense transglutaminase (mTG) (Non-Patent Documents 10 and 15, Patent Document 7 (Rinat-Pfizer)) or microbial transglutaminase (MTGase) (Non-Patent Document 16, Patent Document 8 (Innate Pharma), Patent Document 9 (Bio-Ker S.r.l. (IT))), the introduction of thiol fucose (Non-Patent Document 17), the introduction of non-natural amino acids by mutagenesis (Non-Patent Documents 18 to 21, Patent Documents 10 to 12 (Sutro Biopharm), Patent Documents 13 to 17 (Ambrx), Patent Documents 18 to 20 (Allozyne)), the introduction of selenocysteine into antibodies (Non-Patent Document 22, Patent Document 21 (US National Cancer Institute)), the conversion of cysteine located in the CXPXR consensus sequence to formylglycine (FGly) by formylglycine-generating enzyme (FGE) (Non-Patent Document 23, Patent Documents 22 to 26 (Redwood Bioscience)), and also the introduction of glycoengineered sialic acid using galactosyl and sialyltransferases (Non-Patent Document 24, Patent Document 27 (Sanofi-Genzyme)). However However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35). However, the above method requires re-optimization of the antibody engineering process and cell culture conditions. Therefore, a simple homogeneous conjugation method was actually used by re-crosslinking the intermolecular disulfide bonds of reduced natural antibodies, such as using bromo or dibromo maleimides called next-generation maleimides (NGMs) (Non-Patent Document; UCL Cancer Institute) or applying bis-alkyl reagents via three carbon crosslinks (Non-Patent Document 26, Patent Documents 28 and 29 (PolyTherics Ltd)). We have disclosed several conjugation methods for re-crosslinking thiol pairs in which the intermolecular disulfide bonds of natural antibodies are reduced, such as using bromomaleimide and dibromomaleimide conjugates (Patent Document 30), 2,3-disubstituted succinic acid / 2-monosubstituted / 2,3-disubstituted fumaric acid or maleic acid conjugates (Patent Documents 31 and 32), acetylenedicarboxylic acid conjugates (Patent Documents 33 and 34), or hydrazine conjugates (Patent Document 35).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

[0006] [Non-Patent Document 1] Lambert, J. M. Ther. Deliv. 2016, 7, 279-82 [Non-Patent Document 2] Jerjian, T. V. et al. Pharmacotherapy 2016, 36, 99-116 [Non-Patent Document 3] Donaghy, H. MAbs 2016, 8, 659-71 [Non-Patent Document 4] de Goeij, B. E. and Lambert, J. M. Curr Opin Immunol 2016, 40, 14-23 [Non-Patent Document 5] Mehrling, T. Future Oncol, 2015, 11, 549 [Non-Patent Document 6] Zhao, R. Y. et al, 2011, J. Med. Chem. 54, 3606-23

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

[0007] In this application, we extend the scope of our previous patent applications. More importantly, the disulfur cross-linked linker of this application achieves a higher DAR (≥4) for conjugating two or more drugs per linker, or conjugating at two or more sites of thiols on a cell-binding molecule or two or more cell-binding molecules. Therefore, the main advantages of the present application regarding immunoconjugates include the following: extending the half-life of the conjugate during targeted delivery. Conjugated at different stages of the cell cycle with two or more different functional molecules / drugs that act at different stages to increase the number of target cells exposed to a specific pharmaceutical or effector. Alternatively, conjugating two or more cell-binding molecules for a dual, triple, or multiple targeting strategy against proliferating cells. Minimizing exposure to non-target cells, tissues, or organs by conjugating functional molecules. Accurately controlling the ratio of the drug payload to the drug at specific sites for a uniform final product. It can be conjugated. The present invention provides a linker comprising a thiol-reactive group of a propiolyl, substituted acrylic (acryloyl), or disubstituted propanoyl group, and further optionally comprising a phosphoric amide, amine, hydrazine, triazole, heteroaromatic, acetylamide, glycoside, and analogs thereof, for conjugation with a drug, and / or a functional molecule, and / or a cell-binding agent (e.g., an antibody). In one aspect of the present invention, the linker is represented by formula (I) and (II): wherein represents a single bond, and when bonded to a single bond or a double bond, represents a single bond or a double bond. The present invention provides a linker for conjugation with a drug, and / or a functional molecule, and / or a cell-binding agent (e.g., an antibody), which comprises a thiol-reactive group of a propiolyl, substituted acrylic (acryloyl), or disubstituted propanoyl group, and further optionally comprises a phosphoric amide, amine, hydrazine, triazole, heteroaromatic, acetylamide, glycoside, and analogs thereof.

[0008] The present invention provides a linker for conjugation with a drug, and / or a functional molecule, and / or a cell-binding agent (e.g., an antibody), which comprises a thiol-reactive group of a propiolyl, substituted acrylic (acryloyl), or disubstituted propanoyl group, and further optionally comprises a phosphoric amide, amine, hydrazine, triazole, heteroaromatic, acetylamide, glycoside, and analogs thereof. represents a single bond or a double bond. In one aspect of the present invention, the linker is represented by formula (I) and (II): wherein represents a single bond, and when bonded to a single bond or a double bond, Means for solving the problems

[0009] In one aspect of the present invention, the linker is represented by formula (I) and (II):

Chemical formula

[0010] In the formula,

Chemical formula

[0011] Lv1 and Lv2 represent the same or different leaving groups that can be substituted with thiols, the leaving groups include, but are not limited to, halides (selected from fluoride, chloride, bromide, and iodide), methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), trifluoromethylsulfonate, nitrophenyloxyl, N-succinimidyloxyl (NHS), phenoxyl; dinitrophenyloxyl; pentafluorophenoxyl, tetrafluorophenoxyl, tri fluorophenoxyl, difluorophenoxyl, monofluorophenoxyl, pentachlorophenoxyl, 1H-imidazol-1-yl, chlorophenoxyl, dichloropheno xyl, trifluoromethylphenoxyl, pentafluorophenyl, tetrafluorophenyl, trifluorophenyl, difluorophenyl, monofluorophenyl, pentachlorophenyl; 1H-imidazol-1-yl, chlorophenoxyl, dichlorophenoxyl, trifluoromethylphenoxyl, pentafluorophenyl, tetrafluorophenyl, trifluorophenyl, difluorophenyl, monofluorophenyl, pentachlorophenyl; Noxyl, trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazolyl)oxyl, 2-ethyl-5-phenylisoxazolium-3'-sulfonyl, phenyl oxadiazole-sulfonyl (-sulfone-ODA), 2-ethyl-5-phenylisoxazolium-yl, phenyl oxadiazole-yl (ODA), oxadiazole-yl, or selected from intermediates generated by a condensing reagent for the Mitsunobu reaction ; Y is a functional group capable of reacting with a cytotoxic agent to form a disulfide, ether, ester, thioether, thioester, peptide, hydrazone, carbamate, carbonate, amine (secondary, tertiary, or quaternary), imine, cycloheteroalkane, heteroaromatic, alkyloxime, or amide bond; Preferably, Y has the following structure:

[0012]

Chemical formula

[0013]

[0014] TIFF2025093934000009.tif98170 wherein X 1’ is F, Cl, Br, I, or Lv3; X 2’ is O, NH, N(R1 ), or CH2; R3 and R5 are each independently H, R1, aromatic, heteroaromatic, or an aromatic group in which one or more H atoms are substituted with -R1, -halogen, -OR1, -SR1, -NR 1R2, -NO2, -S(O)R1, -S(O)2R1, or -COOR1; Lv3 is nitrophenol; N-hydroxysuccinimide (NHS ); ​); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; phenol; difluorophenol; monofluorophenol; pentachlorophenol; trifulat; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxy xybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, an acid anhydride formed with itself or another acid anhydride (e.g., acetic anhydride, formic anhydride); or a leaving group selected from intermediates formed by a condensing reagent for a peptide coupling reaction or for a Mitsunobu reaction; or; a leaving group selected from intermediates formed by a condensing reagent for a peptide coupling reaction or for a Mitsunobu reaction;

[0015] R1 is absent or is C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or a C2-C8 (number of carbons 2-8) ester, ether, or amide; or a peptide containing 1 to 8 amino acids; or a structural formula (OCH2 CH2) or (OCH2CH(CH3)) (p; an integer from 0 to about 1000) of p poly p ethyleneoxy units, or a combination of the above groups; Additionally, each R1 is a chain of atoms selected from C, N, O, S, Si, and

[0016] P that are commonly bonded to Y and L1, preferably having 0 to 500 atoms. The atoms used to form R1 are alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, Urea, semicarbazide, carbazide, alkoxyamine, alkoxyamine, urethane, amino acid, peptide, acyloxyamine, or hydroxamic acid, or any chemically related combination thereof may be linked in all ways. combined.

[0017] T is CH2, NH, NHNH, N(R3), N(R3)N(R 3’ ), O, S, C2- C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl,; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcyclo alkyl, alkylcarbonyl, heteroaryl; a peptide containing 1 to 4 amino acid units, preferably the amino acid is selected from aspartic acid, glutamic acid, arginine, his tidine, lysine, serine, threonine, asparagine, glutamine, cysteine, sel enocysteine, tyrosine, phenylalanine, glycine, proline, tryptophan, a lanine; or one of the following structures; selected from; or is one of the following structures;

[0018]

Chemical formula

[0019] wherein

Chemical formula

[0020] X1, X2, X3, X4, X5, X6, X 1’ , X 2’ , and X 3’ are each independently and, NH; NHNH; N(R3); N(R3)N(R 3’ ); O; S; C1-C6 alkyl ; C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C 3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkyl cycloalkyl, alkylcarbonyl, heteroaryl; or 1 to 8 amino acids ; wherein, R3 and R 3’ are each independently H; C1-C8 alkyl; C2-C8 hete roalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, a lkylcarbonyl, heteroaryl; C1-C8 ester, ether or amide; or structural formula (OCH2CH2) p or (OCH2CH(CH3)) p (p; 0 to about 1000 integer) of polyethyleneoxy units, or a combination of the above;

[0021] L1 and L2 are each independently the same or different, O, NH, S, NHNH, N( R3), N(R3)N(R 3’ ), formula (OCH2CH2) p OR3, or (OCH2 CH(CH3)) p OR3, or NH(CH2CH2O) p R3, or NH(C H2CH(CH3)O) p R3, or N[(CH2CH2O) p R3][(CH2C H2O) p’ R 3’ , or (OCH2CH2) p COOR3, or CH2CH 2(OCH2CH2) pThe polyethyleneoxy units of COOR3 (wherein p and p' are each independently an integer from 1 to about 1000), or combinations thereof; C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl ; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; wherein R3 and R are each independently H; C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; C1-C8 ester, ether or amide; 1 to 8 amino acids; or the structural formula (OCH2CH2) 3’ or (OCH2CH(CH3)) (p; an integer from 0 to about 100 0) of polyethyleneoxy units, or combinations of the above; L1 or L2 is 6-maleimidocaproyl (MC), maleimidopropanoyl (MP ), valine-citrulline (val-cit or vc), alanine-phenylalanine (a la-phe or af), p-aminobenzyloxycarbonyl (PAB), 4-thio- p pentanoic acid ester (SPP), 4-(N-maleimidomethyl)cyclohexane-1-car p boxylic acid ester (MCC), (4-acetyl)aminobenzoic acid (SIAB), 4-thio -butyric acid ester (SPDB), 4-thio-2-hydroxy-sulfonyl-butyric acid ester (2

[0022] -sulfo-SPDB), or natural or unnatural amino acid units containing 1 to 8 natural or unnatural amino acid units ; ​​​​​It may be composed of one or more linker components selected from non-natural peptides.

[0023] m1, m2, m3, m4, and m5 are each independently an integer from 1 to 10, preferably from 1 to 4;

[0024] In another aspect, the present invention provides a cell-binding agent-drug conjugate of formula (III), (IV), (V), (VI), (VII), (VIII), or (IX), wherein the cell-binding agent Cb and the drug Drug each react at the end of the crosslinking linker:

[0025]

Chemical formula

[0026] wherein Cb, Cb’, Cb’’, Cb’’’ are the same or different and represent a cell-binding agent or a protein for immunotherapy, preferably an antibody or an antibody fragment; In the right parentheses (angle brackets) of formulas (III), (VII), (VIII), and (IX), there is a linker-drug component conjugated to a pair of thiols of the cell-binding agent / molecule. The thiol

[0027] is preferably a pair of sulfur atoms reduced from an intramolecular disulfide bond by a reducing agent selected from dithiothreitol (DTT), dithioerythritol (DTE), L-glutathione (GSH), tris(2-carboxyethyl)phosphine (TCEP) , 2-mercaptoethylamine (β-MEA), or / and β-mercaptoethanol (β -ME, 2-ME). Drug, Drug’, and Drug’’ are the same or different and are cytotoxic agents or therapeutic agents.

[0028] agents. A functional molecule for promoting the binding or stabilization of a drug, or an immunotherapeutic protein, or a cell binding agent, or a cell surface receptor binding ligand, which is bound to the cell binding agent via the cross-linked conjugate of this patent by R1, and R1 is C1-C8 alkane; C2-C8 alkylene, alkenylene, alkynylene, aromatic ring, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semi carbazide, carbazide, alkoxyamine, urethane, amino acid, peptide, acyl o xyamine, hydroxamic acid, disulfide, thioether, thioester, carbamate to, carbonate, heterocyclic ring, heteroalkyl, heteroaromatic ring, or alkoxime, or can include combinations of the above. Drug can also be a cytotoxic molecule, an immunotherapeutic compound, a chemotherapeutic compound, an antibody or antibody fragment, an siRNA or DNA molecule , or a cell surface binding ligand;

[0029]

Chemical formula

[0030] represents a single bond or a double bond; Inside the square brackets, there is a drug conjugated to the cell binding molecule by a pair of sulfur atoms on the cell binding molecule.

[0031] 1’ 1’’ m1, m 1’ m, 1’’ m, 2’ m2, m 2’’ m, 4’ m3, m4, m5, m ’ m, 4’’ m, 5’’ m, 4’’’ m, 5’’’ m,4’’’’ and m 5’’’’ 、 are each independently an integer of 1 to 10, preferably 1 to 4;

[0032] X1, X 1’ 、X 1’’ 、X 1’’’ 、and X 2’’’’ are each independently NH; NHNH; N(R3); N(R3)N(R 3’ ); O; S; C1-C6 alkyl; C2- C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcyclo alkyl, alkylcarbonyl, heteroaryl; an amino acid of 1 to 8; wherein, R3 and and R 3’ are each independently H; C1-C8 alkyl; C2-C8 heteroalkyl, a lkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl 、heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl l, heteroaryl; C1-C8 ester, ether or amide; or the structural formula (O CH2CH2) p or (OCH2CH(CH3)) p (p; an integer of 0 to about 1000) of polyethyleneoxy units, or a combination of the above, and further, X1, X 1’ 、X 1’ ’ 、X 1’’’ 、and X 2’’’’ may each independently be absent;

[0033] R1, R 1’ 、and R 1’ ’ are the same or different and are C1-C8 alkyl; C2-C Heteroalkyl, alkylcycloalkyl, heterocycloalkyl of 8; A of C3-C8 Reel, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloal Kill, alkylcarbonyl, heteroaryl; Ester, ether or Amide of C2-C8; Or structural formula (OCH2CH2) p Or (OCH2CH(CH3)) p (p; (An integer from 0 to about 1000) of polyethyleneoxy units, or a combination of the above groups;

[0034] L1, L 1’ , L 1’’ , L 1’’’ , L2, L 2’ , L 2’’ , and L 2’’’ , are , the same definitions as L1 and L2 of formula (I) and formula (II), and they may not be the same simultaneously either;

[0035] n is from 1 to 20; T is the same as that described previously in formula (I).

[0036] In a further aspect, the present invention provides a modified cell-binding agent of formula (III), where the cell-binding agent Cb reacts with the cross-linking linker through a pair of thiols generated by the reduction of a disulfide bond and has a functional group Y capable of reacting with a drug:

[0037]

Chemical formula

[0038] In the formula,

Chemical formula

[0039] In yet another aspect, the present invention provides modified drugs of formula (XVII) and (XVIII): wherein the drug "Drug" reacts with the linkers of formula (I) and (II) and still A substituted acryl or propionyl group ( It has a thiol-reactive group (propiolic group).

[0040] [ka]

[0041] During the ceremony, [ka] L1, L2, R1, T, m1, m2, m3, m4, m5, X1, Lv1, and Lv2 are The same definition as in formula (I). Drug 1 has the same definition as in formula (II).

[0042] The present invention further relates to a method for preparing the cell-binding molecule-drug conjugates of formulas (III)-(IX). where the drug "Drug" is bound to the cell-binding agent via a cross-linker.

[0043] The present invention also relates to a method for preparing the modified cell-binding molecules of formula (X)-(XVI), The cell-binding molecule reacts with the conjugates of formula (I) and (II).

[0044] The present invention also relates to a method for preparing modified drugs of formula (XVII) and (XVIII), The drug reacts with the cross-linked linkers of formulas (I) and (II).

Brief Description of the Drawings

[0045]

Figure 1

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Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

Figure 32

Figure 33

Figure 34

Figure 35

Figure 36

Figure 37

Figure 38

Figure 39

Figure 40

Figure 41

Figure 42

Figure 43

Figure 44

Figure 45

Mode for Carrying Out the Invention

[0046] Definition

[0047] "Alkyl" refers to an aliphatic hydrocarbon group or a monovalent group derived from an alkane by removing one or two hydrogen atoms from a carbon atom. It may be linear or branched and have C1-C8 (1 to 8 carbon atoms) in the chain. "Branched" refers to the attachment of one or more lower C-number alkyl groups, such as methyl, ethyl, or propyl groups, to a linear alkyl group. Specific examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl, cyclopentyl, cyclohexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl, 3-methylhexyl, 2,2-dimethylhexyl, 2 to 8 carbon atoms), and may be linear or branched. "Branched" means that one or more lower C-number alkyl groups, such as methyl, ethyl, or propyl groups, are attached to a linear alkyl group. Specific examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl, cyclopentyl, cyclohexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethyl pentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl, 3- methylhexyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 3,3-dimethylhexyl, 3,4-dimethylhexyl, 2,3,4-trimethylhexyl, 2,3,5-trimethyl , 4-dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2, 4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl, n-heptyl, iso heptyl, n-octyl, and isooctyl are included. The C1-C8 alkyl group may be unsubstituted or may be substituted with one or more substituents (but not limited to the following substituents) . Examples of the substituents include -C1-C8 alkyl, -O-(C1-C8 alkyl), aryl , -C(O)R’, -OC(O)R’, -C(O)OR’, -C(O)NH2, -C( O)NHR’, -C(O)N(R’)2, -NHC(O)R’, -SR’, -S(O)2 R’, -S(O)R’, -OH, -halogen, -N3, -NH2, -NH(R’), -N (R’)2, and -CN, where R’ is independently selected from C1-C8 alkyl and aryl.

[0048] "Halogen" refers to a fluorine, chlorine, bromine, or iodine atom, with fluorine and chlorine atoms being preferred.

[0049] "Heteroalkyl" refers to C2-C8 alkyl in which 1 to 4 carbon atoms are independently replaced by a heteroatom selected from the group consisting of O, S, and N.

[0050] "Carbocycle" refers to a saturated or unsaturated monocyclic ring having 3 to 8 carbon atoms or a bicyclic ring having 7 to 13 carbon atoms. Monocyclic carbocycles have 3 to 6, more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms and are arranged as bicyclic [4,5], 5,5], [5,6], or [6,6], or have 9 to 10 ring atoms having and arranged as a bicyclic system [5,6] or [6,6]. Representative C3-C8 carbon Cyclic compounds (C3-C8 carbocycles) include, but are not limited to, -cyclopropyl, -cyclobutyl , -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl , -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -cyclohept yl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrieneyl, -cyclo octyl, and -cyclooctadienyl.

[0051] A C3-C8 carbocycle refers to a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or unsaturated non-aromatic carbocyclic compound. The C3-C8 carbocycle may be unsubstituted or substituted with one or more substituents. The substituents include, but are not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl -OH, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C (O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -S(O)R (O)NHR', -C(O)N(R')2, -NHC(O)R', -SR', -S(O)R ', -S(O)2R', -OH, -halogen, -N3, -NH2, -NH(R'), -N (R')2, and -CN, where each R' is independently selected from C1-C8 alkyl and aryl.

[0052] "Alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having 2-8 carbon atoms in the chain and containing a carbon-carbon double bond. Alkenyl groups include, for example, ethenyl, prop enyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl , hexenyl, heptenyl, octenyl. ​

[0053] "Alkynyl" refers to an aliphatic hydrocarbon group having 2 to 8 carbon atoms in the chain and containing a carbon-carbon triple bond, which may be linear or branched. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, 5-pentynyl, n- pentynyl, hexynyl, heptynyl, and octynyl.

[0054] "Alkylene" refers to a saturated, linear or branched or cyclic hydrocarbon group having 1 to 18 carbon atoms and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include methylene ( -CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH 2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc., but are not limited to these.

[0055] "Alkenylene" refers to an unsaturated, linear or branched or cyclic hydrocarbon group having 2 to 18 carbon atoms and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene. A typical alkenylene group includes 1, 2-ethylene (-CH=CH-), but is not limited to these.

[0056] "Alkynylene" refers to an unsaturated, linear or branched or cyclic hydrocarbon group having 2 to 18 carbon atoms and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. Typical alkynylene groups include ace It includes, but is not limited to, thylenyl, propargyl, and 4-pentynyl.

[0057] "Aryl" or Ar refers to an aromatic or heteroaromatic group consisting of one or several rings containing 3 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The term "heteroaromatic group" refers to those in which some carbon atoms, preferably 1, 2, 3, or 4 carbon atoms, on the aromatic group are replaced by O , N, Si, Se, P, or S, preferably O, S, and N. The term aryl or Ar also means that one or several H atoms are independently replaced by -R', -halogen, -OR', or -SR', -NR'R'', -N=NR', -N=R', -NR'R'' , -NO2, -S(O)R', -S(O)2R', -S(O)2OR', -OS(O)2 OR', -PR'R'', -P(O)R'R'', -P(OR')(OR''), -P( O)(OR')(OR''), or -OP(O)(OR')(OR''). The above R' and R'' are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, arylalkyl, carbonyl, or a pharmaceutical salt.

[0058] "Heterocycle" refers to a ring system in which 1 to 4 ring carbon atoms are independently replaced by heteroatoms from the group of O, N , S, Se, B, Si, and P. Preferred heteroatoms are O, N, and S. The heterocycle is described in The Handbook of Chemistry and Ph ysics, 78th Edition, CRC Press, Inc., 1997 - 1998, pages 225 - 226, the disclosure of which is incorporated herein by reference. Preferred non-aromatic heterocycles include, but are not limited to, these However, epoxy, aziridinyl, thiranil, pyrrolidinyl, pyrazolidinyl, imidazo lidinyl, oxiranyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyran yl, dioxanyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, pyran yl, imidazolinyl, pyrrolinyl, pyrazolinyl, thiazolidinyl, tetrahydropyran yl, dihydropyranyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrimi dinyl, dihydrothiopyranyl, azepanyl, and condensed systems resulting from condensation with a phenyl group are included.

[0059] The term "heteroaryl" or aromatic heterocycle refers to an aromatic hetero, monocyclic, bicyclic, or polycyclic ring having 3 to 14 members, preferably 5 to 10 members. Examples thereof include pyrrolyl, pyridyl , pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quino linyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl , benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazolyl, tet razolyl, isoquinolinyl, benzothienyl, isobenzofuranyl, pyrazolyl, carbazol yl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide, and condensed systems resulting from condensation with a phenyl group are included.

[0060] For "alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl" , "heteroaryl", "heterocyclic", etc., the corresponding "alkylene", "cycloalkylene ", "alkenylene", "alkynylene", "arylene", "heteroarylene", " ", which are formed by removing two hydrogen atoms, are included. ​​​It also refers to "heterocyclene" and the like.

[0061] "Arylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms, typically a terminal or sp 3 hydrogen atom bonded to the carbon atom is substituted with an aryl group. Typical aryl alkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl , 2-phenylethene-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2 -naphthylethene-1-yl, naphthobenzyl, 2-naphthophenyl-ethane-1-yl, etc. are included.

[0062] "Heteroarylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms, typically a terminal or sp 3 hydrogen atom bonded to the carbon atom is substituted with a heteroaryl group. Typical heteroaryl alkyl groups include 2-benzimidazolylmethyl and 2-furylethyl .

[0063] Examples of "hydroxy protecting groups" include methoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, benzyl ether, p-methoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, t-butyldimethylsilyl ether, triphenylmethylsilyl ether , acetate ester, substituted acetate ester, pivaloate, benzoate, methanesulfonate , and p-toluenesulfonate.

[0064] "Leaving group" refers to a functional group that can be substituted by another functional group. Thus Leaving groups are well known in the art and include, for example, halides (e.g., chlorides , bromides, and iodides), methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl) , trifluoromethylsulfonyl (triflate), and trifluoromethylsulfonate. Preferred leaving groups include nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5 -phenylisoxazolium-3'-sulfonate, acid anhydrides formed with itself or other acid anhydrides (e.g., acetic anhydride, formic anhydride); or selected from intermediates generated by condensation reagents for peptide coupling reactions or Mitsunobu reactions.

[0065] The following abbreviations can be used in this specification and have the definitions shown below: Boc, tert-butoxycarbonyl; BroP, bromotrispyrrolidinophosphonium hexa fluorophosphate; CDI, 1,1'-carbonyldiimidazole; DCC, dicyclo hexylcarbodiimide; DCE, 1,2-dichloroethane; DCM, dichloromethane ; DIAD, diisopropyl azodicarboxylate; DIBAL-H, diisobutylaluminum hydride; DIPEA, diisopropylethylamine; DEPC, diethyl phosphoramidite ; DMA, N,N-dimethylacetamide; DMAP, 4-(N,N-dimethyl L-aminopyridine; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide DTT, dithioester; EDC, 1-(3-dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride; ESI-MS, electrospray mass spectrometry; HATU , O-(7-azabenzotriazol-1-yl)-N,N,N’-N’-tetramethyl uronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; H PLC, high performance liquid chromatography; NHS, N-hydroxysuccinimide; MMP , 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate buffered saline (pH 7.0 to 7.5); PEG, polyethylene glycol; SEC, size exclusion chromatography TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine The "amino acid" can be a natural and / or non-natural amino acid, preferably an α-amino acid

[0066] The "amino acid" can be a natural and / or non-natural amino acid, preferably an α-amino acid . Natural amino acids are those encoded by the genetic code and are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine isoleucine, leucine, lysine, methionine, phenylalanine, proline , serine, threonine, tyrosine, tryptophan, and valine. Non-natural amino acids are derivatives of protein-forming amino acids. For example, hydroxyproline, lanthionine , 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid (neurotransmitter), ornithine , citrulline, β-alanine (3-aminopropanoic acid), γ-carboxyglutamic acid Trp, selenocysteine (which exists in most eukaryotes but is not directly encoded by DNA), pyrroline (found only in some archaea and one bacterium), N-formylmethionine (often the first amino acid of proteins in bacteria, mitochondria, and chloroplasts), 5-hydroxytryptophan, L-dihydroxyphenylalanine, tryptophan, L-3,4-dihydroxyphenylalanine (DOPA), and O-phosphoserine are included. The term amino acid includes amino acid analogs and mimetics. An analog is a compound having the same general H2N(R)CHCO2H structure as a natural amino acid, except that the R group is not found among the natural amino acids. Examples of analogs include homoserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. Preferably, an amino acid mimetic is a compound having a structure different from the general chemical structure of an α-amino acid but functioning similarly. The term unnatural amino acid is intended to represent the "D" stereochemical form, while natural amino acids are in the "L" form. When 1 to 8 amino acids are used in this application, the amino acid sequence is preferably a protease cleavage recognition sequence. Many cleavage recognition sequences are known in the art, for example, Matayoshi et al. Science 247: 954 (1990); Dunn et al. Meth. Enzymol. 241: 254 (1994); Seidah et al. Meth. Enzymol. 244: 175 (1994); Thornberry, Meth. Enzymol. 244: 615 (1994); Weber et al. Meth. Enzymol. 244: 595 (1994); Smith et al. Me -oded), pyrroline (found only in some archaea and one bacterium), N-formyl methionine (often the first amino acid of proteins in bacteria, mitochondria, and chloroplasts), 5-hydroxytryptophan, L-dihydroxyphenylalanine, trypto phan, L-3,4-dihydroxyphenylalanine (DOPA), and O-phospho serine are included. The term amino acid includes amino acid analogs and mimetics. An analog is a compound having the same general H2N(R)CHCO2H structure as a natural amino acid, except that the R group is not found among the natural amino acids. Examples of analogs include ho moserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. Preferably, an amino acid mimetic is a compound having a structure different from the general chemical structure of an α-amino acid but functioning similarly. The term unnatural amino acid is intended to represent the "D" stereochemical form, while natural amino acids are in the "L" form. When 1 to 8 amino acids are used in this application, the amino acid sequence is preferably a protease cleavage recognition sequence. Many cleavage recognition sequences are known in the art, for example, Matayoshi et al. Science 247: 954 (1990); Dunn et al. Meth. Enzymol. 241: 254 (1994); Seidah et al. Meth. Enzymol. 244: 175 (1994); Thornberry, Meth. Enzymo l. 244: 615 (1994); Weber et al. Meth. Enzymol. 244: 595 (1994); Smith et al. Me th. Enzymol. 244: 595 (1994); Smith et al. Me thionine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. Preferably, an amino acid mimetic is a compound having a structure different from the general chemical structure of an α-amino acid but functioning similarly. The term unnatural amino acid is intended to represent the "D" stereochemical form, while natural amino acids are in the "L" form. When 1 to 8 amino acids are used in this application, the amino acid sequence is preferably a protease cleavage recognition sequence. Many cleavage recognition sequences are known in the art, for example, Matayoshi et al. Science 247: 954 (1990); Dunn et al. Meth. Enzymol. 241: 254 (1994); Seidah et al. Meth. Enzymol. 244: 175 (1994); Thornberry, Meth. Enzymo l. 244: 615 (1994); Weber et al. Meth. Enzymol. 244: 595 (1994); Smith et al. Me th. Enzymol. 244: 595 (1994); Smith et al. Me thionine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. Preferably, an amino acid mimetic is a compound having a structure different from the general chemical structure of an α-amino acid but functioning similarly. The term unnatural amino acid is intended to represent the "D" stereochemical form, while natural amino acids are in the "L" form. When 1 to 8 amino acids are used in this application, the amino acid sequence is preferably a protease cleavage recognition sequence. Many cleavage recognition sequences are known in the art, for example, Matayoshi et al. Science 247: 954 (1990); Dunn et al. Meth. Enzymol. 241: 254 (1994); Seidah et al. Meth. Enzymol. 244: 175 (1994); Thornberry, Meth. Enzymo l. 244: 615 (1994); Weber et al. Meth. Enzymol. 244: 595 (1994); Smith et al. Me th. Enzymol. 244: 595 (1994); Smith et al. Me th. Enzymol. 244: 595 (1994); Smith et al. Me th. Enzymol. 244: 595 (1994); Smith et al. Me th. Enzymol. 244: 595 (1994); Smith et al. Me th. Enzymol. 244: 412 (1994); and Bouvier et al. Meth. Enzymol. 248: 614 (1995) See; the disclosure of which is incorporated herein by reference. In particular, the sequences are Val-Cit, Ala-Val , Ala-Ala, Val-Val, Val-Ala-Val, Lys-Lys, Ala-Asn-Val, Val-Leu-Lys, Cit-Cit, Val -Lys, Ala-Ala-Asn, Lys, Cit, Ser, and Glu are selected from the group consisting of

[0067] A "glycoside" is a molecule in which a sugar group is glycosidically linked to another group via its anomeric carbon bond. Glycosides can be linked by O-(O-glycoside), N-(glycosylamine ), S-(thioglycoside), or C-(C-glycoside) glycosidic bonds . The empirical formula of the nucleus is C m (H2O) n (where m is different from n, and m and n are <36), and here the glycosides include glucose (dextrose ), fructose (levulose) allose, altrose, mannose, gulose, idose , galactose, talose, galactosamine, glucosamine, sialic acid, N-ace tylglucosamine, sulfoquinovose (6-deoxy-6-sulfo-D-glucopyrano se), ribose, arabinose, xylose, lyxose, sorbitol, mannitol , sucrose, lactose, maltose, trehalose, maltodextrin, raffino se, glucuronic acid (glucuronide), and stachyose are included. It is of the D-form or the L-form, the 5-atom cyclic furanose form, the 6-atom cyclic pyranose form, or the acyclic form, the α-isomer (-OH of the anomeric carbon below the plane of the carbon atoms in the Haworth projection), or the β-isomer (the -OH of the anomeric carbon above the plane of the Haworth projection). It may also be. It is used herein as a monosaccharide, disaccharide, polyol, or oligosaccharide containing 3 to 6 sugar units. It may also be. It is used herein as a monosaccharide, disaccharide, polyol, or oligosaccharide containing 3 to 6 sugar units. It may also be. It is used herein as a monosaccharide, disaccharide, polyol, or oligosaccharide containing 3 to 6 sugar units.

[0068] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecules and compositions that do not cause harmful, allergic, or other adverse reactions when administered to animals or humans in a suitable manner. "Pharmaceutically" or "pharmaceutically acceptable" refers to molecules and compositions that do not cause harmful, allergic, or other adverse reactions when administered to animals or humans in a suitable manner.

[0069] "Pharmaceutically acceptable solvate" or "solvate" refers to the association of a compound disclosed with one or more solvent molecules. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. "Pharmaceutically acceptable solvate" or "solvate" refers to the association of a compound disclosed with one or more solvent molecules. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. "Pharmaceutically acceptable solvate" or "solvate" refers to the association of a compound disclosed with one or more solvent molecules. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. "Pharmaceutically acceptable solvate" or "solvate" refers to the association of a compound disclosed with one or more solvent molecules. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0070] Pharmaceutically acceptable auxiliary materials include all carriers, diluents, aids, or molding agents, for example, preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, it is a common method to add these auxiliary materials to the active drug component. Except when the auxiliary material is incompatible with the drug active component, it is reasonable to add the auxiliary material to the drug component. To obtain good results, an active auxiliary material may be added to the drug component. Pharmaceutically acceptable auxiliary materials include all carriers, diluents, aids, or molding agents, for example, preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, it is a common method to add these auxiliary materials to the active drug component. Except when the auxiliary material is incompatible with the drug active component, it is reasonable to add the auxiliary material to the drug component. To obtain good results, an active auxiliary material may be added to the drug component. Pharmaceutically acceptable auxiliary materials include all carriers, diluents, aids, or molding agents, for example, preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, it is a common method to add these auxiliary materials to the active drug component. Except when the auxiliary material is incompatible with the drug active component, it is reasonable to add the auxiliary material to the drug component. To obtain good results, an active auxiliary material may be added to the drug component. Pharmaceutically acceptable auxiliary materials include all carriers, diluents, aids, or molding agents, for example, preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, it is a common method to add these auxiliary materials to the active drug component. Except when the auxiliary material is incompatible with the drug active component, it is reasonable to add the auxiliary material to the drug component. To obtain good results, an active auxiliary material may be added to the drug component. Pharmaceutically acceptable auxiliary materials include all carriers, diluents, aids, or molding agents, for example, preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, it is a common method to add these auxiliary materials to the active drug component. Except when the auxiliary material is incompatible with the drug active component, it is reasonable to add the auxiliary material to the drug component. To obtain good results, an active auxiliary material may be added to the drug component. Pharmaceutically acceptable auxiliary materials include all carriers, diluents, aids, or molding agents, for example, preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, it is a common method to add these auxiliary materials to the active drug component. Except when the auxiliary material is incompatible with the drug active component, it is reasonable to add the auxiliary material to the drug component. To obtain good results, an active auxiliary material may be added to the drug component. Pharmaceutically acceptable auxiliary materials include all carriers, diluents, aids, or molding agents, for example, preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersing media, coating agents, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, etc. In the pharmaceutical field, it is a common method to add these auxiliary materials to the active drug component. Except when the auxiliary material is incompatible with the drug active component, it is reasonable to add the auxiliary material to the drug component. To obtain good results, an active auxiliary material may be added to the drug component.

[0071] In the present invention, "pharmaceutically acceptable salts" refers to salt derivatives of the compounds of the present invention. By appropriate modification, the compounds according to the present invention can be formed into corresponding acid salts or alkali salts. Pharmaceutically In the present invention, "pharmaceutically acceptable salts" refers to salt derivatives of the compounds of the present invention. By appropriate modification, the compounds according to the present invention can be formed into corresponding acid salts or alkali salts. Pharmaceutically Possible salts include common non-toxic salts or quaternary ammonium, and these salts can be prepared by corresponding non-toxic inorganic or organic acids with the compounds according to the present invention. For example, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and organic acids include acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, lactic acid, etc. These acids can be used for pharmaceutically acceptable salts. Other salts include ammonium salts such as tromethamine, meglumine, pyrrolidinoethanol, etc., and metal salts such as sodium, potassium, calcium, zinc, magnesium, etc. In the present invention, pharmaceutically acceptable salts can be prepared from parent compounds containing acidic or basic residues by conventional chemical methods. Generally, these salts can be obtained by reacting the free acid or free base form of these compounds with a stoichiometric amount of an appropriate salt-forming base or acid in water, an organic solvent, or a mixed solvent of both. As a non-aqueous reaction solvent, generally, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. A list of suitable salts is given in "Remington’s Pharmaceutical Sciences", 17th Edition, Mack Publishing Company, Easton, PA, 1985, page 1418, and the disclosure is incorporated by reference. As inorganic acids, it includes hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and as organic acids, it includes acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, lactic acid, etc. These acids can be used for pharmaceutically acceptable salts. Other salts include ammonium salts such as tromethamine, meglumine, pyrrolidinoethanol, etc., and metal salts such as sodium, potassium, calcium, zinc, magnesium, etc. In the present invention, pharmaceutically acceptable salts can be prepared from parent compounds containing acidic or basic residues by conventional chemical methods. Generally, these salts can be obtained by reacting the free acid or free base form of these compounds with a stoichiometric amount of an appropriate salt-forming base or acid in water, an organic solvent, or a mixed solvent of both. As a non-aqueous reaction solvent, generally, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. A list of suitable salts is given in "Remington’s Pharmaceutical Sciences", 17th Edition, Mack Publishing Company, Easton, PA, 1985, page 1418, and the disclosure is incorporated by reference. In the present invention, pharmaceutically acceptable salts can be prepared from parent compounds containing acidic or basic residues by conventional chemical methods.

[0072] In the present invention, pharmaceutically acceptable salts can be prepared from parent compounds containing acidic or basic residues by conventional chemical methods. Generally, these salts can be obtained by reacting the free acid or free base form of these compounds with a stoichiometric amount of an appropriate salt-forming base or acid in water, an organic solvent, or a mixed solvent of both. As a non-aqueous reaction solvent, generally, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. A list of suitable salts is given in "Remington’s Pharmaceutical Sciences", 17th Edition, Mack Publishing Company, Easton, PA, 1985, page 1418, and the disclosure is incorporated by reference. In the present invention, pharmaceutically acceptable salts can be prepared from parent compounds containing acidic or basic residues by conventional chemical methods. Generally, these salts can be obtained by reacting the free acid or free base form of these compounds with a stoichiometric amount of an appropriate salt-forming base or acid in water, an organic solvent, or a mixed solvent of both. As a non-aqueous reaction solvent, generally, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. A list of suitable salts is given in "Remington’s Pharmaceutical Sciences", 17th Edition, Mack Publishing Company, Easton, PA, 1985, page 1418, and the disclosure is incorporated by reference. In the present invention, pharmaceutically acceptable salts can be prepared from parent compounds containing acidic or basic residues by conventional chemical methods.

[0073] "Administering" or "Administrat" "Delivery" refers to any mode of transferring, delivering, introducing, or transporting a pharmaceutical or other agent. Such modes include oral administration, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, nasal cavity, subcutaneous, or intracavitary administration. Also contemplated by the present invention is the use of devices or instruments in administering the agent. Such devices can utilize active or passive transport and can be slow-release or fast-release delivery devices.

[0074] The novel conjugates disclosed herein utilize a cross-linking linker. Examples of some suitable cross- linking linkers and their synthesis are shown in FIGS. 1-34.

[0075] Cross-linking linker

[0076] Similar to the preparation of the conjugate of the cell-binding molecule and the agent of the present invention, the synthetic routes for obtaining the cross-linking linker are shown in FIGS. 1-20. The cross-linking linker has two elements: a) a substituent that is a substituted acrylic or propiol group and can react with one or more thiols to form a thioether bond; and b) a group capable of reacting with the agent, including but not limited to disulfide, maleimide, haloacetyl, aldehyde, ketone, azide, amine, alkoxyamine, hydrazide, ethenesulfonyl, acyl halide (acid halide), acrylyl (acryloyl), and / or acid anhydride groups, etc. Cross-linking substituents of the substituted acrylic or propiol group containing an amine, alcohol, or thiol group for forming an amide, ester, or thioester bond. The synthesis of these cross-linking linkers and their application to conjugation with antibodies are illustrated in FIGS. 1-20. ~20.

[0077] Preferably, the cross-linking linker is a compound of the following formulas (I) and (II): [Chemical formula]

[0078] In the formula, [Chemical formula] represents a single bond, and when it is bonded to a single bond or a double bond, [Chemical formula] may be an enantiomeric or stereoisomeric bond; [Chemical formula] represents either a single bond, a double bond, or a triple bond; [Chemical formula] when represents a single bond, both Lv1 and Lv2 are not H; [Chemical formula] when represents a double bond, either Lv1 or Lv2 can be H, but not simultaneously become H; [Chemical formula] when represents a triple bond, Lv1 does not exist and Lv2 may optionally be H;

[0079] Lv1 and Lv2 represent the same or different leaving groups that can be substituted with thiols, the leaving groups include, but are not limited to, halides (selected from fluoride, chloride, bromide, and iodide), methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), trifluoromethylsulfonate Trinitrophenoxyl, N-Succinimidyl Oxyl (NHS), Phenoxyl; Di Nitrophenoxyl; Pentafluorophenoxyl, Tetrafluorophenoxyl, Tri Fluorophenoxyl, Difluorophenoxyl, Monofluorophenoxyl, Pentac hlorophenoxyl, 1H-Imidazol-1-yl, Chlorophenoxyl, Dichloropheno xyl, Trichlorophenoxyl, Tetrachlorophenoxyl, N-(Benzotriazol yl)oxyl, 2-Ethyl-5-Phenylisoxazolium-3'-Sulfonyl, Phenyloxadiazole-Sulfonyl (-Sulfone-ODA), 2-Ethyl-5-Phe nylisoxazolium-yl, Phenyloxadiazole-yl (ODA), Oxadiaz ole-yl, or selected from intermediates generated by a condensation reagent for Mitsunobu reaction ;

[0080] Y is a functional group capable of reacting with a drug or a cytotoxic agent to form a disulfide, ether, ester, thioether , thioester, peptide, hydrazone, carbamate, carbonate, amine (secondary , tertiary, or quaternary), imine, cycloheteroalkane, heteroaromatic, alkyloxime , or amide bond; preferably, Y has the following structure :

[0081]

Chemical formula

[0082] In the formula, X 1’ is F, Cl, Br, I, or Lv3; X 2’ is O, NH, N(R1 )、or CH2; R3 and R5 are each independently H, R1, aromatic, heteroaromatic, or an aromatic group in which one or more H atoms are substituted with -R1, -halogen, -OR1, -SR1, -NR1R2, -NO2, -S(O)R1, -S(O)2R1, or -COOR1; Lv3 is nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; trichlorofluoromethane; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, an acid anhydride formed with itself or another acid anhydride (e.g., acetic anhydride, formic anhydride); or a leaving group selected from intermediates generated by a condensing reagent for a peptide coupling reaction or for a Mitsunobu reaction; R1 is absent or is C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or a C2-C8 (2 to 8 carbon atoms) ester, ether, or amide; or a peptide containing 1 to 8 amino acids; or a polyethyleneoxy unit of the structural formula (OCH2CH2) or (OCH2CH(CH3)) (p; an integer from 0 to about 1000), or a combination of the above groups;

[0083] p p

[0084] ​​​​​​​​​​​​​​​​​​Additionally, R1 is a chain of atoms selected from C, N, O, S, Si, and P, preferably having 0 to 500 atoms and covalently bonding to Y and L1. The atoms used to form R1 are alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, alkoxyamine, urethane, amino acid, peptide, acyloxyamine, or hydroxamic acid, or may be bonded in all chemically related ways such as to form a combination thereof.

[0085] T is CH2, NH, NHNH, N(R3), N(R3)N(R 3’ ), O, S, C2- C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl,; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcyclo alkyl, alkylcarbonyl, heteroaryl; a peptide containing 1 to 4 amino acid units, preferably the amino acids are selected from aspartic acid, glutamic acid, arginine, his tidine, lysine, serine, threonine, asparagine, glutamine, cysteine, seleno nocytosine, tyrosine, phenylalanine, glycine, proline, tryptophan, ala nine; or is one of the following structures;

[0086]

Chemical formula

[0087] wherein,

Chemical formula

[0088] X1, X2, X3, X4, X5, X6, X 1’ , X 2’ , and X 3’ are each independently NH; NHNH; N(R3); N(R3)N(R 3’ ); O; S; C1-C6 alkyl ; C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C 3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkyl cycloalkyl, alkylcarbonyl, heteroaryl; or 1 to 8 amino acids ; wherein, R3 and R 3’ are each independently H; C1-C8 alkyl; C2-C8 hete roalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, a lkylcarbonyl, heteroaryl; C1-C8 ester, ether or amide; or structural formula (OCH2CH2) p or (OCH2CH(CH3)) p (p; 0 to about 1 000 integer) of polyethyleneoxy units, or a combination of the above;

[0089] m, m1, m2, m3, m4, and m5 are each independently an integer from 1 to 10, preferably 1 to 4;

[0090] L1 and L2 are each independently the same or different, O, NH, S, NHNH, N( R3), N(R3)N(R 3’ ), formula (OCH2CH2) p OR3, or (OCH2 CH(CH3)) p OR3, or NH(CH2CH2O)p R3, or NH(C H2CH(CH3)O) p R3, or N[(CH2CH2O) p R3][(CH2C H2O) p’ R 3’ , or (OCH2CH2) p COOR3, or CH2CH 2(OCH2CH2) p polyethyleneoxy units of COOR3 (wherein p and p’ are each independently an integer from 1 to about 1000), or combinations thereof; C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl ; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; wherein R3 and R are each independently H; C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; C1-C8 ester, ether or amide; 1 to 8 amino acids; or the structural formula (OCH2CH2) 3’ or (OCH2CH(CH3)) (p; an integer from 0 to about 100 0), or a combination of the above;

[0091] 0), or a polyethyleneoxy unit of the above combination;

[0091] L1 or L2 may contain a self-destructive or non-self-destructive component, a peptide unit, a hydrazone bond, a disulfide bond, an ester bond, an oxime bond, an amide bond, or a thioether bond. The self-destructive unit is not limited to these, but 2-aminoimidazole-​​ 5 - methanol derivatives, heterocyclic PAB analogs, β - glucuronide, and o - or p - am inobenzyl acetal and other para - aminobenzyl carbamoyl (PAB) groups electronically similar to aromatic compounds containing;

[0092] Preferably, the self - destructing linker component has one of the following structures:

Chemical formula

[0093] wherein the atom labeled with ( * ) is a binding point with an additional spacer or releasable linker unit, a cell disrupting agent, and / or a cell adhesion molecule (CBA); X 1 , Y 1 , Z 2 , and Z 3 is independently NH, O or S; Z 1 is independently H, NHR1, OR1, SR1, COX1R1, wherein the definitions of X1 and R1 are as described above; v is 0 or 1 ; U 1 is independently H, OH, C1 - C6 alkyl, (OCH2CH2) n , F, Cl, Br, I, OR5, SR5, NR5R5’, N = NR5, N = R5, NR5R5’, NO 2, SOR5R5’, SO2R5, SO3R5, OSO3R5, PR5R5’, POR5 R5’, PO2R5R5’, OPO(OR5)(OR5’), or OCH2PO(OR5 )(OR5’), wherein R5 and R5’ are each independently H, C1 - C8 al kyl; C2 - C8 alkenyl, alkynyl, heteroalkyl, or amino acid; C3 - C8 aryl group, heterocycle, carbocycle, cycloalkyl, heterocycloalkyl, hetero Selected from an aralkyl group, an alkylcarbonyl, or a glycosyl group; or a medicinal cationic salt ;

[0094] The non-cleavable linker component is any of the following structures:

Chemical formula

[0095] In the formula, the atom labeled with ( * ) is a binding point with an additional spacer or releasable linker unit, a cell disrupting agent, and / or a cell adhesion molecule (CBA); X 1 , Y 1 , U 1 , R5 , and the definitions of R5’ are as described above; r is 0 to 100; m and n are each independently 0 to 6.

[0096] More preferably, L1 or L2 may be composed of one or more linker components as shown below :

Chemical formula

[0097] Even more preferably, L1 or L2 may be a releasable linker. The term releasable linker refers to a linker containing at least one bond that can break under physiological conditions, for example, a pH-labile , acid-labile, alkali-labile, oxidation-labile, metabolism-labile, biochemical-labile, , or enzyme-labile bond. The physiological conditions for cleaving such a bond are ​、It is not necessarily required to involve a biochemical or metabolic process. Instead, hydrolysis or a substitution reaction, for example, a reaction in an endosome with a pH lower than the cytosolic pH, and / or a general chemical reaction condition such as a disulfide exchange reaction of intracellular thiols (glutathione at mmol concentration in malignant cells) may be understood.

[0098] Examples of releasable linkers (L, L1, or L2 ) include, but are not limited to: -(CR5R6) m (Aa) r (CR7R8) n (OCH2CH2) t 、-( CR5R6) m (CR7R8) n (Aa) r (OCH2CH2) t 、-(Aa) r (CR 5R6) m (CR7R8) n (OCH2CH2) t 、-(CR5R6) m (CR7R8) n (OCH2CH2) r (Aa) t 、-(CR5R6) m (CR7=R8)(CR9R1 0) n (Aa) t (OCH2CH2) r 、-(CR5R6) m (NR 11 CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r 、-(CR5R6) m (Aa) t (NR 11 CO)(CR9R 10 ) n (OCH2CH2)​r , -(CR5R6) m (OCO)(Aa ) t (CR9R 10 ) n (OCH2CH2) r , -(CR5R6) m (OCNR7)(A a) t (CR9R 10 ) n (OCH2CH2) r , -(CR5R6) m (CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r , -(CR5R6) m (NR 11 CO)(A a) t (CR9R 10 ) n (OCH2CH2) r , -(CR5R6) m (OCO)(Aa ) t (CR9R 10 ) n (OCH2CH2) r , -(CR5R6) m (OCNR7)(A a) t (CR9R 10 ) n (OCH2CH2) r , -(CR5R6) m (CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r , -(CR5R6) m , -phenyl-(CO) (Aa) t (CR7R8) n , -(CR5R6) m , -furyl-(CO)(Aa) t (CR 7R8) n , -(CR5R6) m-oxazolyl-(CO)(Aa) t (CR7R8) n 、-(CR5R6) m -thiazolyl-(CO)(Aa) t (CR7R8) n 、-(CR5 R6) t -thienyl-(CO)(CR7R8) n 、-(CR5R6) t -imidazolyl- (CO)(CR7R8) n 、-(CR5R6) t -morpholino-(CO)(Aa) t (C R7R8) n 、-(CR5R6) t -piperazino-(CO)(Aa) t (CR7R8) n 、-(CR5R6) t -N-methylpiperazino-(CO)(Aa) t (CR7R8) n 、 -(CR5R) m -(Aa) t phenyl-、-(CR5R6) m -(Aa) t furyl-、 -(CR5R6) m -oxazolyl(Aa) t -、-(CR5R6) m -thiazolyl(A a) t -、-(CR5R6) m -thienyl(Aa) t -、-(CR5R6) m -imidazo ryl(Aa) t -、-(CR5R6) m -morpholino-(Aa) t 、-(CR5R6) m -piperazino-(Aa) t 、-(CR5R6) m -N-methylpiperazino-(Aa) t 、 -K(CR5R6) m (Aa) r (CR7R8) n (OCH2CH2) t 、-K(CR5 R6) m (CR7R8) n (Aa) r (OCH2CH2) t 、-K(Aa) r (CR5R 6) m (CR7R8) n (OCH2CH2) t 、-K(CR5R6) m (CR7R8) n (OCH2CH2) r (Aa) t 、-K(CR5R6) m (CR7=R8)(CR9R1 0) n (Aa) t (OCH2CH2) r 、-K(CR5R6) m (NR 11 CO)(Aa ) t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m (Aa) t (NR 11 CO)(CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m (OCO) (Aa) t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m (OCNR 7)(Aa) t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m (CO )(Aa)t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m (NR1 1CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m ( OCO)(Aa) t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m ( OCNR7)(Aa) t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m (CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r 、-K(CR5R6) m -phenyl-(CO)(Aa) t (CR7R8) n 、-K(CR5R6) m -furyl-( CO)(Aa) t (CR7R8) n 、-K(CR5R6) m -oxazolyl-(CO)( Aa) t (CR7R8) n 、-K(CR5R6) m -thiazolyl-(CO)(Aa) t ( CR7R8) n 、-K(CR5R6) t -thienyl-(CO)(CR7R8) n 、-K( CR5R6) t -imidazolyl-(CO)(CR7R8) n 、-K(CR5R6) t -mo L-holinyl-(CO)(Aa) t (CR7R8) n -K(CR5R6) t -piperazino- (CO)(Aa) t (CR7R8) n -K(CR5R6) t -N-methylpiperazino- (CO)(Aa) t (CR7R8) n -K(CR5R) m -(Aa) t phenyl-,- K(CR5R6) m -(Aa) t furyl-,-K(CR5R6) m -oxazolyl(Aa ) t -,-K(CR5R6) m -thiazolyl(Aa) t -,-K(CR5R6) m -thie nyl(Aa) t -,-K(CR5R6) m -imidazolyl(Aa) t -,-K(CR5R 6) m -morpholino-(Aa) t -,-K(CR5R6) m -piperazino-(Aa) t - K(CR5R6) m -N-methylpiperazino-(Aa) t 。 (In the formula, the definitions of m, Aa, m, n, R3, R4, and R5 are the same as those in formula (I) ; t and r are integers from 0 to 100; R6, R7, and R8 are each independently H , halogen, C1-C8 alkyl group, aryl group, alkenyl group, alkynyl group, ether yl, ester, amine or amide (these may have one or more halogens, CN, NR1R2, CF 3, OR1, aryl group, heterocycle, S(O)R1, SO2R1, -CO2H, -SO3H , -OR1, -CO2R1, -CONR1, -PO2R1R2, -PO3H, or P(O )R1R2R3, which may be optionally substituted.); K is selected from NR1, -SS- , -C(=O)-, -C(=O)NH-, -C(=O)O-, -C=NH-O-, -C= N-NH-, -C(=O)NH-NH-, O, S, Se, B, a C3-C8 heterocyclic ring or a he teroaromatic ring, or a peptide containing 1 to 20 amino acids.).

[0099] Furthermore, L1, L2, X1, X2, X3, X 1’ , X 2’ , and X 3’ each independently may not be present.

[0100] In formula (I) or (II), the substituted acrylic group or propiol group can react with the thiol of a cell-binding agent, preferably a pair of thiols; the pair of thiols is preferably a pair of sulfur atoms reduced from the intramolecular disulfide bond of the cell-binding agent by a reducing agent such as dithiothreitol (DTT), dithioerythritol (DTE), L-gl utathione (GSH), tris(2-carboxyethyl)phosphine (TCEP), 2- mercaptoethylamine (β-MEA), or / and β-mercaptoethanol (β-ME , 2-ME), etc.

[0101] Examples of the functional group Y that enables the binding of a drug or a cytotoxic agent include disulfide, thioeth er, thioester, peptide, hydrazone, ester, carbamate, carbonate, alkoxime, or a group that enables binding via an amide bond. Such functional groups include thiol, disulfide, amino, carboxyl, aldehyde, ketone, ma ​​Examples include, but are not limited to, a lenimid, haloacetyl, hydrazine, alkoxyamino, and / or hydroxy. These are not limited thereto.

[0102] Examples of the functional group Y capable of reacting with the terminal of the amine of the agent / cytotoxic agent include, but are not limited to, N-hydroxysuccinimide ester, p-nitrophenyl ester, di nitrophenyl ester, pentafluorophenyl ester, carboxylic acid chloride, or carboxylic anhydride. Those capable of reacting with the terminal of a thiol include, but are not limited to, pyridyl disulfide, nitropyridyl disulfide, maleimide haloacetic acid, methylsulfonylphenyloxadiazole (ODA), carboxylic acid chloride, and carboxylic anhydride. Those capable of reacting with the terminal of a ketone or aldehyde include, but are not limited to, amine, alkoxyamine, hydrazine, or acyloxylamine. Those capable of reacting with the terminal of an azide include, but are not limited to, alkyne.

[0103] In a preferred embodiment, each of R1, L1, or L2 is independently a straight-chain alkyl having 1 to 6 carbon atoms, or a polyethyleneoxy unit of the structural formula (OCH2CH2) (p; an integer from 1 to 100 p ), or a peptide containing 1 to 4 units of amino acid (L or D), or a combination thereof.

[0104] In a preferred embodiment, Lv1 and Lv2 are the same or each independently is OG ;F;Cl;Br;I; nitrophenol; N-hydroxysuccinimide (NHS); Phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triphenyl phosphate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxy benzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium -3'-sulfonate, acetic anhydride, formic anhydride, etc., acid anhydrides formed with self or other acid anhydrides; or leaving groups selected from intermediates generated by condensation reagents for peptide coupling reactions or for Mitsunobu reactions; examples of condensation reagents include EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide), DCC (dicyclohexyl-carbodiimide), N,N'-diisopropylcarbodiimide (DIC), N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methanesulfonate-p-toluenesulfonate (CMC, or CME-CDI), 1,1'-carbonyldiimidazole (CDI), TBTU (O-(benzotriazol-1-yl)-N,N ,N',N'-tetramethyluronium tetrafluoroborate), N,N,N',N' -tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol -1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diethyl cyanophosphonate (DEPC), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-[bis(dimethylamino) imidazole (CDI), TBTU (O-(benzotriazol-1-yl)-N,N ,N',N'-tetramethyluronium tetrafluoroborate), N,N,N',N' -tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol -1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diethyl cyanophosphonate (DEPC), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-[bis(dimethylamino) phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diethyl cyanophosphonate (DEPC), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-[bis(dimethylamino) phosphonium hexafluorophosphate (PyBOP), diethyl cyanophosphonate (DEPC), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-[bis(dimethylamino) phosphonium hexafluorophosphate (PyBOP), diethyl cyanophosphonate (DEPC), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-[bis(dimethylamino) formamidinium hexafluorophosphate, 1-[bis(dimethylamino) Methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide Hexafluorophosphate (HATU), 1-[(dimethylamino)(morpholino)meth ylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium-3- oxide hexafluorophosphate (HDMA), 2-chloro-1,3-dimethylimi dazolidinium hexafluorophosphate (CIP), chlorotripyrrolidinophosphoni um hexafluorophosphate (PyCloP), fluoro-N,N,N’,N’-bi s(tetramethylene)formamidinium hexafluorophosphate (BTFFH), N,N,N’,N’-tetramethyl-S-(1-oxide-2-pyridyl)thiuronium hexafluorophosphate, O-(2-oxo-1(2H)pyridyl)-N,N,N’ ,N’-tetramethylthiuronium tetrafluoroborate (TPTU), S-(1-oxo ide-2-pyridyl)-N,N,N’,N’-tetramethylthiuronium tetrafluoro robate, O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N’,N ’-tetramethyluronium hexafluorophosphate (HOTU), (1-cyano- 2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-car benium hexafluorophosphate (COMU), O-(benzotriazol-1-yl l)-N,N,N’,N’-bis(tetramethylene)uronium hexafluorophosphate ate (HBPyU), N-benzyl-N’-cyclohexylcarbodiimide (polymer-bound with, or without), dipyrrolidino(N-succinimidyl oxy)-carbenium Hexafluorophosphate (HSPyU), chlorodipyrrolidinocarbenium hexafluoro rophosphate (PyCIU), 2-chloro-1,3-dimethylimidazolinium tetra fluoroborate (CIB), (benzotriazol-1-yloxy)dipiperidino carbenium hexafluorophosphate (HBPipU), O-(6-chlorobenzo triazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoro borate (TCTU), bromotris(dimethylamino)phosphonium hexafluoro phosphate (BroP), propylphosphonic anhydride (PPACA, T3P (registered trademark )), 2-morpholinoethyl isocyanide (MEI), N,N,N’,N’-tetramethyl -O-(N-succinimidyl)uronium hexafluorophosphate (HSTU) ), 2-bromo-1-ethyl-pyridinium tetrafluoroborate (BEP), O-[( ethoxycarbonyl)cyanomethyleneamino]-N,N,N’,N’-tetramethyluro nium tetrafluoroborate (TOTU), 4-(4,6-dimethoxy-1,3,5- triazin-2-yl)-4-methylmorpholinium chloride (MMTM, DMTMM) ), N,N,N’,N’-tetramethyl-O-(N-succinimidyl)uronium tetra fluoroborate (TSTU), O-(3,4-dihydro-4-oxo-1,2,3-benzo triazin-3-yl)-N,N,N’,N’-tetramethyluronium tetrafluoro borate (TDBTU), 1,1’-(azodicarbonyl)dipiperidine (ADD) ), di-(4-chlorobenzyl) azodicarboxylate (DCAD), di-tert-but yl azodicarboxylate (DBAD), diisopropyl azodicarboxylate (DIAD), or diethyl azodicarboxylate (DEAD). Further, L v1 and Lv2 may be acid anhydrides formed with itself or another C1-C8 acid anhydride as well.

[0105] In a preferred embodiment, formula (I) or (II) has the following structure:

Chemical formula

[0106] Detailed examples of the synthesis of the cross-linked linker are shown in FIGS. 1 to 33. Usually, the cross-linking substituent of propiolyl, or a substituted acrylyl (acryloyl) group, or a disubstituted propanoyl group, can be condensed with a linker component containing a functional group capable of reacting with the desired conjugate drug substance. The cross-linking substituent of propiolyl, or a substituted acrylyl (acryloyl) group, or a disubstituted propanoyl group, can be condensed with a linker component containing a functional group capable of reacting with the desired conjugate drug

[0107] Cell-binding agent-drug conjugate

[0108] The conjugate of the present invention can be represented by a cell-binding agent-drug conjugate compound of the following formula (III), (IV), (V), (VI), (VII), (VIII), or (IX):

Chemical formula

[0109] In the formula, n is 1 to 20. T has the same definition as formula (I) above. Cb, Cb’, C b’’, Cb’’’ are the same or different and represent a cell-binding agent / molecule or a protein for immunotherapy , preferably an antibody or an antibody fragment.

[0110] Inside the right parentheses (angle brackets) of Formulas (III), (VII), (VIII), and (IX) is a linker-drug component conjugated with a thiol pair of a cell-binding agent / molecule. The said thio ol is preferably a pair of sulfur atoms reduced from an inter-chain disulfide bond of a cell-binding agent by a reducing agent selected from dithiothreitol (DTT), dithioerythritol (DTE), dithiobutyl amine (DTBA), L-glutathione (GSH), tris(2-carboxyethyl)phosphine (TCEP), 2-mercaptoethylamine (β-MEA), or / and β-mer captoethanol (β-ME, 2-ME). Drug, Drug’, and Drug’’ represent the same or different cytotoxic agents, or therapeutic drugs, or immunotherapeutic proteins, or functional molecules for promoting the binding or stabilization of cell-binding agents, or cell surface receptor-binding ligands, and are bound to the said cell-binding agent via the cross-linking linker of this patent by R1. R1 is C1-C8 alkane; C2-C8

[0111] alkylene, alkenylene, alkynylene, aromatic ring, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semi carbazide, carbazide, alkoxyamine, urethane, amino acid, peptide, acylo xyamine, hydroxamic acid, disulfide, thioether, thioester, carbamate , carbonate, heterocyclic ring, heteroalkyl, heteroaromatic ring, or alkoxime, or can include the above combinations. Drug, Drug’, and Drug’’ are also immunotherapy compounds, chemotherapy compounds, antibodies or antibody fragments, siRNA, or can be the above combinations. Drug, Drug’, and Drug’’ are also immunotherapy compounds, chemotherapy compounds, antibodies or antibody fragments, siRNA, or It may also be a DNA molecule or a cell surface binding ligand.

[0112]

Chem.

[0113] Inside the angular brackets, there is a drug conjugated with the cell binding molecule by a pair of sulfur atoms on the cell binding molecule. on the cell binding molecule.

[0114] m1, m 1’ , m 1’’ , m2, m 2’ , m 2’’ , m3, m4, m5, m 4’ , m5 ’ , m 4’’ , m 5’’ , m 4’’’ , m 5’’’ , m 4’’’’ , and m 5’’’’ , are each independently an integer from 1 to 10, preferably from 1 to 4.

[0115] X1, X 1’ , X 1’’ , X 1’’’ , and X 2’’’’ are each independently NH; NHNH; N(R3); N(R3)N(R 3’ ); O; S; C1-C6 alkyl; C2- C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl alkyl, alkylcarbonyl, heteroaryl; or 1 to 8 amino acids; wherein R 3 and R 3’ are each independently H; C1-C8 alkyl; C2-C8 heteroalkyl , alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, Ar-alkyl Kill, complex ring, carbon ring, cycloalkyl, heteroalkyl cycloalkyl, alkyl car bonyl, heteroaryl; C1-C8 ester, ether or amide; or structural formula (OCH2CH2) p or (OCH2CH(CH3)) p (p; an integer from 0 to about 1000 of polyethyleneoxy units, or a combination of the above, and further, X1, X 1’ , X 1’’ , X 1’’’ , and X 2’’’’ may each independently be absent.

[0116] R1, R2, R 1’ , and R 1’’ are the same or different and are C1-C8 alkyl; C 2-C8 heteroalkyl, alkyl cycloalkyl, heterocycloalkyl; C3-C 8 aryl, Ar-alkyl, complex ring, carbon ring, cycloalkyl, heteroalkyl cyclo alkyl, alkyl carbonyl, heteroaryl; or C2-C8 ester, ether or amide; or structural formula (OCH2CH2) p or (OCH2CH(CH3) ) p (p; an integer from 0 to about 1000) of polyethyleneoxy units, or a combination of the above groups is.

[0117] L1, L 1’ , L 1’’ , L 1’’’ , L2, L 2’ , L 2’’ , and L 2’’’ , are , the same definition as L1 and L2 of formulas (I) and (II), and may be the same or different.

[0118] L1, L 1’ , L 1’’ , L 1’’’, L2, L 2’ , L 2’’ , and L 2’’’ , is , may be composed of one or more linker components. Examples of such linker components include, for example, 6-maleyl midocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (va l-cit or vc), alanine-phenylalanine (ala-phe or af), p- aminobenzyloxycarbonyl (PAB), 4-thio-pentanoic acid ester (SPP) , 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid ester (MCC), (4-acetyl)aminobenzoic acid (SIAB), 4-thio-butyric acid ester (SPDB), 4-thio-butyric acid ester (SPDB), 4-thio-2-hydroxy-sulfonyl-butyric acid es ter (2-sulfo-SPDB), ethyleneoxy-C as one or more repeating units H2CH2O-(EO or PEO) is included. Further linker components are known in the art and some are described herein.

[0119] Exemplary structures of the components of the linker contained are as follows:

Chemical formula

[0120] As described in more detail below, Drug, Drug’, or Drug’’ can be any of many small molecule drugs, including, but not limited to, tubulysins, calicheamicins, auristatins, maytansinoids, CC -1065 analogs, morpholinos, doxorubicins, taxanes, cryptophycins -1065 analogs, morpholinos, doxorubicins, taxanes, cryptophycins , amatoxins (amanitins), epothilones, geldanamycins, duocarmycins, daunomycins, methotrexate, vindesines, vincristines, and benzodiazepine dimers (e.g., pyrrolobenzodiazepine (PBD), tomamycin, indolobenzodiazepines, imidazobenzothiadiazepine, or oxazolidinobenzodiazepine dimers) are included.

[0121] Generally, formulas (III), (IV), (V), (VI), (VII), (VIII), and (IX) are generated from formulas (I) and (II), where "Drug" and "Cb" react with formulas (I) and (II), respectively or simultaneously. Further, when two or more thiols react with a substituted acrylic or propiol group by an addition reaction to form formula (III), (IV), (V ), or (VI), UV light in the range of 190 - 390 nm, preferably 340 - 380 nm, more preferably 365 nm, is preferably used to promote the reaction. Therefore, the photochemical reaction is carried out in a temperature-controlled environment in a quartz or Pyrex (registered trademark) flask, or in a liquid immersion well reactor containing an ultraviolet lamp, preferably in a continuous flow quartz tube or in a Pyrex (registered trademark) tube where the ultraviolet irradiation is maximized (simultaneously enabling efficient cooling, which reduces the thermal damage to the cell-binding molecule). In the formation of formula (VII), (VIII), or (IX), when two or more thiols react with two or more substituted acrylic or propiol groups of formulas (I) and (II), UV light is optionally not necessary.

[0122] To synthesize the conjugate, first, a drug or cytotoxic molecule is reacted with a linker of formula (I) or (II) in a chemical solvent or an aqueous medium to form formula (XVII) or (XVIII). Then, formula (XVII) or (XVIII) can optionally be isolated, or immediately, simultaneously, or sequentially, in an aqueous medium with or without addition of 0 - 30% of a water-miscible organic solvent such as DMA, DMF, ethanol, methanol, acetone, acetonitrile, THF, isopropanol, dioxane, propylene glycol, or ethylene glycol at 25 - 38 °C and pH 5 - 9, it is reacted with a pair of free thiols generated through reduction of the disulfide bond of the cell-binding molecule to obtain formula (III), (IV), (V), or (VI). At this time, the assistance of UV light at 365 nm is preferably or necessarily used, or for forming formula (XVII), (XVIII), or (IX). The UV light is optionally unnecessary. Alternatively, with the assistance of UV light at 365 nm to form a modified cell-binding molecule of formula (X), (XI), (XII), or (XIII), or optionally without the assistance of UV light to form formula (XIV), (XV), or (XVI), the conjugates of formula (III), (IV), (V), (VI), (VII), (VIII), and (IX) can also be obtained by first reacting a linker of formula (I) or (II) with a pair of thiols on a cell-binding agent in an aqueous medium at 0 - 38 °C with or without addition of 0 - 30% of a water-miscible organic solvent at pH 5 - 9. The thiol pair is in an aqueous medium at pH 4 - 9 with or without addition of 0 - 30% of a water-miscible organic solvent, and dithiothreitol (DTT)

[0123] ​​​​​​​​​​​​​​​​​ T), dithioerythritol (DTE), L - glutathione (GSH), tris(2 - carboxyethyl)phosphine (TCEP), 2 - mercaptoethylamine (β - MEA) , or / and β - mercaptoethanol (β - ME, 2 - ME), and a pair of sulfur atoms reduced from the inter - chain disulfide bond of the cell - binding agent is preferred. After purification , to obtain formulas (III), (IV), (V), (VI), (VII), (VIII), and (IX ), disulfide, maleimide, haloacetyl, azide, 1 - in, ketone , aldehyde, alkoxyamino, triflate, carbonylimidazole, tosylate , mesylate, 2 - ethyl - 5 - phenylisoxazolium - 3’ - sulfonate, or , nitrophenol, N - hydroxysuccinimide (NHS), carboxyl ester of phenol; dinitrophenol, pentafluorophenol, tetrafluorophenol , difluorophenol, monofluorophenol, pentachlorophenol, dichlorophenol , tetrachlorophenol, 1 - hydroxybenzotriazole, anhydride , or hydrazide group, or other acid ester derivatives may be included in formula (X) , (XI), (XII), (XIII), (XIV), (XV), or (XVI). The reactive group Y, with or without the addition of 0 - 30% of a water - soluble (miscible) organic solvent, simultaneously or sequentially , in an aqueous medium at pH 4 - 9.5 and at 15 - 38 °C, can react with the drug / cytotoxic agent D rug, Drug’, Drug’’. The reactive group of the drug / cytotoxic agent reacts with the modified cell - binding molecule in a corresponding different way. For example, disulfide , in an aqueous medium at pH 4 - 9.5 and at 15 - 38 °C, can react with the drug / cytotoxic agent D , in an aqueous medium at pH 4 - 9.5 and at 15 - 38 °C, can react with the drug / cytotoxic agent D rug, Drug’, Drug’’. The reactive group of the drug / cytotoxic agent reacts with the modified cell - binding molecule in a corresponding different way. For example, disulfide group Y, with or without the addition of 0 - 30% of a water - soluble (miscible) organic solvent, simultaneously or sequentially Synthesis of a cell-binding agent-drug conjugate linked via a Fido linkage is achieved by disulfide exchange between a modified cell-binding agent containing disulfide bonds and a drug containing free thiol groups. Synthesis of a cell-binding agent-drug conjugate linked via a thioether is achieved by reaction of a maleimide or haloacetyl or ethylsulfonyl modified cell-binding agent with a drug containing free thiol groups. Synthesis of a conjugate having an acid-labile hydrazone can be achieved by reaction of a carbonyl group with a hydrazide residue in the linker by methods known in the art (e.g., P. Hamann et al., Hinman, L. M., et al, Cancer Res. 53, 3336-334 , 1993; B. Laguzza et al., J. Med. Chem., 32; 548-555, 1959; P. Trail et al., Ca ncer Res., 57; 100-105, 1997). Synthesis of a conjugate having a triazole linkage can be achieved by reaction of an azide residue in the linker with a 1-yn group in the drug via click chemistry (Huisgen cycloaddition) (Lutz, J-F. et al, 2008, Adv. Drug Del. Rev. 60, 958-970; Sletten, E. M. et al 2011, Acc Chem. Research 44, 666-676). Synthesis of a cell-binding agent-drug conjugate linked via an oxime is achieved by reaction of a modified cell-binding agent containing a ketone or aldehyde with a drug containing an oxyamine group. To obtain a cell-binding molecule-drug conjugate via a thioether bridge, a thiol-containing drug is reacted with maleimide, haloacetyl, or ethylsulfonyl in an aqueous buffer at pH 5.5 to 9.0 (Lutz, J-F. et al, 2008, Adv. Drug Del. Rev. 60, 958-970; Sletten, E. M. et al 2011, Acc Chem. Research 44, 666-676). Synthesis of a cell-binding agent-drug conjugate linked via an oxime is achieved by reaction of a modified cell-binding agent containing a ketone or aldehyde with a drug containing an oxyamine group. To obtain a cell-binding molecule-drug conjugate via a thioether bridge, a thiol-containing drug is reacted with maleimide, haloacetyl, or ethylsulfonyl in an aqueous buffer at pH 5.5 to 9.0 ​​​A modified cell-binding molecule conjugate of formula (X), (XI), (XII), (XIII), (XIV), (XV) , or (XVI) can be reacted. To obtain a conjugate with a disulfide bridge , a thiol-containing agent can undergo disulfide exchange with a modified cross-link conjugate of formula ( X), (XI), (XII), (XIII), (XIV), (XV), or (XVI). To obtain a modified drug with an ether or thioether bond, a drug having a hydroxyl group or a thiol group can react with a modified cross-link conjugate of formula (X), (XI), (XII), (XIII), (XIV), (XV), or (XVI) having a carboxylic acid α-halide, in the presence of a mild base, for example, at pH 8.0 - 9.5. To obtain an ester bridge , a drug containing a hydroxyl group can be condensed with a cross-link conjugate of formula (I) having a carboxyl group in the presence of a dehydrating agent such as EDC or DCC, and then a conjugate of the target drug modified cross-link conjugate with a cell binding molecule can be formed. To obtain a conjugate via an amide bond bridge, a drug containing an amino group can be reacted on a cell-binding molecule-conjugate of formula (X), (XI), (XII), (XIII), (XIV), ( XV), or (XVI) with carboxyl esters of NHS, imidazole, nitrophenol; N-hydroxysuccinimide (NHS); phenol ; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluoro rophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3 A drug containing an amino group can be reacted on a cell-binding molecule-conjugate of formula (X), (XI), (XII), (XIII), (XIV), ( XV), or (XVI) with carboxyl esters of NHS, imidazole, nitrophenol; N-hydroxysuccinimide (NHS); phenol ; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluoro rophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3 imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3 ; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3 It can be condensed with '-sulfonate.

[0124] The conjugate can be purified by standard biochemical methods, such as gel filtration using Sephadex G25 or Sephac ryl S300 column, adsorption chromatography, ion exchange, or dialysis. In some cases, when a small molecule (e.g., folic acid, melanocyte-stimulating hormone, EGF, etc.) is conjugated to a small molecule drug as a cell-binding molecule, it can be purified by chromatography, such as HPLC, medium-pressure column chromatography, or ion exchange chromatography. For example, when folic acid, melanocyte-stimulating hormone, EGF, etc.) is conjugated to a small molecule drug as a cell-binding molecule, it can be purified by chromatography, such as HPLC, medium-pressure column chromatography, or ion exchange chromatography. chromatography, such as HPLC, medium-pressure column chromatography, or ion exchange chromatography. It can be purified by chromatography, such as HPLC, medium-pressure column chromatography, or ion exchange chromatography.

[0125] In a preferred embodiment, formula (III), (IV), (V), (VI), (VII), ( VIII), or (IX) has the following structure:

Chemical formula

[0126] Modified cell-binding agent / molecule

[0127] The cell-binding agent modified by reaction with the conjugate of the present invention is preferably represented by formula (X), (XI ), (XII), (XIII), (XIV), (XV), or (XVI):

Chemical formula

[0128] In the formula, R1, R 1’ , R 1’’ , R2, X1, X 1’ , X 1’’ , L1, L 1’ , L1 ’’ , L2, L 2’ , L 2’’ ,

Chemical

[0129] In the formula,

Chemical

[0130] In the formula, Y, Y’, and Y’’ have the same definitions as in formulas (I) and (II).

[0131] In a preferred embodiment, Y, Y’, and Y’’ are each independently a disulfide substitution group, maleimide, haloacetyl, alkoxyamine, azide, ketone, aldehyde, hyd razine, alkyne, N-hydroxysuccinimide ester, or carboxyl ester formed with phenol; dinitrophenol; pentafluorophenol; tetraflu orophenol; difluorophenol; monofluorophenol; pentachlorophen ol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1 -hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenyl ​ It is isoxazolium-3'-sulfonate. Y, Y', and Y'' are each independent and can react independently with the cytotoxic agent via a disulfide, thioether, hydrazone, amide, alkoxime, carbamate , ester, ether bond, or heteroaromatic ring. The modified cell-binding agent can be prepared via a reaction between the cell-binding agent and the linker of formula (I) or (II) as described in formula (III) above.

[0132] To achieve a higher yield of the conjugate reaction between a pair of free thiols on a cell-binding molecule, preferably an antibody, and the substituted acrylic or propiol group of formula (I) or (II), it may be required to add a small proportion of an organic co-solvent to the reaction mixture , and similarly, it may be required to add it to the post-reaction solution to maintain the solubility of formulas (I II)-(IX) in an aqueous solution. To modify the cell-binding agent, first, a cross-linking reagent (cross-linking linker ) of formula (I) or (II) is dissolved in a polar organic solvent miscible with water, such as methanol , at a high concentration, for example, 1 - 500 mM, in different alcohols such as ethanol, propanol, etc., acetone, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), or dimethyl sulfoxide (DMSO). On the other hand, a cell-binding molecule such as an antibody dissolved at a concentration of 1 - 35 mg / ml in an aqueous buffer at pH 4 - 9.5, preferably 6 - 8.5, is treated with 1 - 20 equivalents of TCEP or DTT for 20 minutes to 48 hours. After reduction, DTT can be removed by SEC chromatography purification . TCEP can also, if desired, be removed by SEC chromatography . It can be removed, or retained in the reaction mixture for the next step reaction without purification. Furthermore, to achieve cross - conjugation of cell - binding molecules simultaneously with TCEP reduction, the reduction of the antibody or other cell - binding agent by TCEP can be carried out together with the cross - linker of formula (I) or (II). As described above, the formation of the modified cell - binding molecules of formula (X), (XI), (XII), or (XIII) is carried out with the aid of UV light at 340 - 380 nm. And the formation of the modified cell - binding molecules of formula (XIV), (XV), or (XVI) is carried out optionally without the aid of ultraviolet light.

[0133] The aqueous solution for the modification of the cell - binding agent is buffered between pH 4 - 9, preferably between 6.0 - 7.5, and can contain non - nucleophilic buffer salts useful in these pH ranges. Representative buffers include phosphate, acetate, triethanolamine HCl, HEPES, and MOPS buffers, and can further contain additional components such as, for example, dextrin, sucrose, salts (e.g., NaCl, KCl). After adding the cross - linker of formula (I) or (II) to the solution containing the reduced cell - binding molecule, the reaction mixture is incubated at 4 °C - 45 °C, preferably 15 °C - ambient temperature. The progress of the reaction can be monitored by measuring the decrease in absorption at 254 nm or the increase in absorption at 280 nm, or changes at other appropriate wavelengths. After the reaction is complete, the isolation of the modified cell - binding agent can be carried out by conventional methods, such as gel filtration chromatography or adsorption chromatography. The degree of modification is determined by the 2 - nitro - pyridine - thione, dinitro - pyridine released through the UV spectrum.

[0134] ​​​Lysine dithione, pyridine dithione, carboxamidopyridine dithione, and dicarbox It can be evaluated by measuring the absorbance of the thiocarboxamide pyridine dithione group. In a conjugate without a chromophore group, the modification or conjugation reaction can be monitored by LC-MS, preferably UPLC-QTOF mass spectrometry, or capillary electrophoresis-spectroscopic analysis (CEMS). The cross-linked conjugates described herein have various functional groups that can react with any suitable agent, preferably a cytotoxic agent, having appropriate substituents. For example, a modified cell-binding molecule having an amino or hydroxy substituent can react with an agent having an N-hydroxysuccinimide (NHS) ester, and a modified cell-binding molecule having a thiol substituent can react with an agent having a maleimide or haloacetyl group. Further, a modified cell-binding molecule having a carbonyl substituent (ketone or aldehyde) can react with an agent having a hydrazide or alkoxyamine. One skilled in the art can easily determine the linker to be used based on the known reactivity of the available functional groups on the conjugate.

[0135] Modified cytotoxic agent

[0136] The cytotoxic agent modified by reaction with the cross-linked conjugate of the present invention is preferably represented by formulas (XVII) and (XVIII), where the drug "Drug" has reacted with the linker of formulas (I) and (II) and still has a thiol-reactive group of a substituted acrylic or propiol group that can react with a pair of thiols of the cell-binding agent:

Chemical formula

[0137] In the formula, [Chem.] L1, L2, R1, T, m1, m2, m3, m4, m5, X1, Lv1, and Lv2 are defined the same as in formula (I). Drug1 is defined the same as in formula (II).

[0138] Formulas (XVII) and (XVIII) having a functional group of a substituted acrylic group or a propiol group To obtain a modified drug of, through the reaction of a drug with a linker of formulas (I) and (II), the modified drug is prepared. However, for a drug containing a thiol, or a drug that conjugates a cell-binding molecule via a crosslinking agent through a thioether, thioester or disulfide bond, therefore, Drug1 is preferably first bonded to one of the components R1 via a bond of a thioether, thioester, or disulfide bond. Subsequently, a substituted acrylic group or a propiol group is incorporated into the synthesized R1-drug component to form a crosslinking agent-modified drug of formulas (XVII) and (XVIII).

[0139] Regarding the synthesis example, to obtain an R1-Drug component having a thioether bond, a thiol-containing drug can react with the moiety R1 of a linker having a maleimide substituent in an aqueous buffer at neutral pH, and subsequently, it can condense with a substituted acrylic group or a propiol group to obtain a modified drug of formula (XVII) or (XV III) having a thioether bond. To obtain an R1-Drug component having an ether bond, a drug having a hydroxy group can react with the moiety R1 of a linker having a halogen, tosylate, or mesylate in the presence of a mild base, and subsequently, a formula having a thioether bond ( (XVII) or (XVIII) to obtain a modified drug, it can be condensed with a substituted acrylic group or a pro piol group. To obtain a modified drug of formula (XVII) or (XVI II) via an ester bond, a drug containing a hydroxy group can be condensed with a linker of formula (I ) having a carboxyl group in the presence of a dehydrating agent such as EDC or dicyclohexylcarbodiimide (DCC). To obtain an R1-Drug component having a thioether bond , a thiol-containing drug can also be reacted with the moiety R1 of a linker having a maleimide, vinylsulfonyl, or haloacetyl group , and subsequently, to obtain a modified drug of formula (XVII) or (XVIII) having a thioether bond, it can be condensed with a component of an acrylic group or a substituted propionyl group. To obtain a modified drug of formula (XVII) or (XVIII) having an amide bond, a drug having an amino group can likewise be condensed with the carboxyl group on the crosslinked linker of formula (I) or (II). The modified drug can be purified by standard methods such as silica gel or alumina column chromatography, crystallization, preparative thin layer chromatography , ion exchange chromatography, or HPLC. It can be done.

[0140] In a preferred embodiment, formula (XVII) or (XVIII) has the following structure:

[0141]

Chemical formula

[0142] TIFF2025093934000064.tif230161TIFF2025093934000065.tif223146TIFF2025093934000066.tif139155

[0142] In the formula, [Chemical formula] Lv1 and Lv2 have the same definitions as in formula (I); L1, L2, L3, L4, L5, L 6, L7, and L8 are the same as or different from each other and have the same definition as L1 in formula (I); Drug1, Drug2, Drug3, Drug4, Drug5, Drug6, Drug7, and Dr ug8 have the same definition as Drug1 in formula (II).

[0143] Cell-binding agent

[0144] The cell-binding molecule Cb that constitutes the conjugate and the modified cell-binding molecule of the present invention binds, complexes, or reacts with residues of a cell population to be therapeutically or otherwise biologically modified, and may be any molecule known or found to date.

[0145] Examples of cell-binding agents include, but are not limited to, high molecular weight proteins such as whole antibodies (polyclonal or monoclonal), dimers, multimers, multispecific antibodies (e.g., bispecific antibodies); single-chain antibodies; antibody fragments such as Fab, Fab’, F(ab’)2, Fv [Parham, J. Immunol. 131, 2895 - 2902 (1983)], fragments obtained from a Fab expression library, anti-idiotype (anti-Id) antibodies, CDR’s, bispecific antibodies, trispecific antibodies, cancer cell antigens, viral antigens, microbial antigens, or epitope-binding fragments of any of the above substances that specifically recognize, bind to, or can express a desired biological activity and specifically bind immunologically to proteins produced by the immune system; interferons (e.g., types I, II, III); peptides; lymphokines such as, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, GM-CSF, or interferon γ (IFN-γ); hormones such as insulin, TRH (thyrotropin releasing hormone), MSH (melanocyte-stimulating hormone), or steroid hormones such as androgen, estrogen or melanocyte-stimulating hormone (MSH); growth factors and colony-stimulating factors such as epidermal growth factor (EFG), granulocyte macrophage colony stimulating factor (GM-CSF); transforming growth factor (TGF), such as TGF α, TGFβ; insulin and insulin-like growth factors (IGF-I, IGF-II) G -CSF, M-CSF, and GM-CSF [Burgess, Immunology T oday, 5, 155-158 (1984)]; vaccine growth factor (VGF); fibroblast growth factor (FGF); small molecular weight proteins, polypeptides, peptides, and peptide hormones such as bombesin, gastrin, and gastrin-releasing peptide; platelet-derived growth factor; interleukins and cytokines such as interleukin-2 (IL-2 ), interleukin-6 (IL-6), leukemia inhibitory factor, granulocyte macrophage colony stimulating factor (GM-CSF); vitamins such as folic acid; apoproteins and glycoproteins such as transferrin [O’Keefe et al, J. Bio. Chem. 260 , 932-927 (1985)]; lectins and other carbohydrate-binding proteins or lipoproteins; cellular nutrient transport molecules; and small molecule inhibitors such as inhibitors of prostate-specific membrane antigen (PSMA), small molecule tyrosine kinase inhibitors (TKI), non-peptides, or other cell-binding molecules or substances such as bioactive polymers (Dhar, et al, Proc. Natl. A , 932-927 (1985)]; lectins and other carbohydrate-binding proteins or lipoproteins; cellular nutrient transport molecules; and small molecule inhibitors such as inhibitors of prostate-specific membrane antigen (PSMA), small molecule tyrosine kinase inhibitors (TKI), non-peptides, or other cell-binding molecules or substances such as bioactive polymers (Dhar, et al, Proc. Natl. A gent, small molecule tyrosine kinase inhibitor (TKI), non-peptide, or other cell-binding molecule or substance such as bioactive polymer (Dhar, et al, Proc. Natl. A cad. Sci. USA 91, 1994-1998 (1994)]; or a combination of two or more of the foregoing substances.​​ cad.Sci.2008, 105, 17356 - 61), bioactive dendrimers (Le e, et al, Nat. Biotechnol. 2005, 23, 1517 - 26; A lmutairi, et al; Proc. Natl. Acad. Sci. 2009, 1 06, 685 - 90), nanoparticles (Liong, et al, ACS Nano, 200 8, 19, 1309 - 12; Medarova, et al, Nat. Med. 2007 , 13, 372 - 7; Javier, et al, Bioconjugate Chem . 2008, 19, 1309 - 12), liposomes (Medinai, et al, Cu rr. Pharm. Des. 2004, 10, 2981 - 9), virus capsids (Fle nniken, et al, Viruses Nanotechnol. 2009, 32 7, 71 - 93) are included.

[0146] Generally, if a suitable monoclonal antibody is available, the monoclonal antibody is preferred as a cell surface ligand molecule. The antibody may be of mouse, human, humanized, chimeric, or other species origin.

[0147] The production of the antibodies used in the present invention includes in vivo or in vitro production processes or combinations thereof. Methods for preparing anti - receptor peptide polyclonal antibodies are well - known, for example, as shown in U.S. Patent No. 4,493,795 (Nestor et al). A typical method for preparing monoclonal antibodies is to fuse mouse spleen cells isolated from mice immunized with a specific antigen with myeloma cells (Kohler , G; Milstein, C. 1975. Nature 256:495 - 497). Details Regarding a specific operation method, Antibodies - A Laboratory Manual l, Harlow and Lane, eds., Cold Spring Harbor Laboratory Press, New York (1988) is described herein, and the content of this literature is incorporated herein by reference as part of this specification. In particular, by the method of immunizing mice, rats, hamsters, or other mammals with the target antigen, monoclonal antibodies can be obtained, and examples of the target antigen include intact target cells, antigens isolated from target cells, whole viruses, attenuated whole viruses, and virus protein stamps. Spleen cells and myeloma cells are fused using PEG6000. The hybridomas obtained after fusion are screened using their sensitivity to HAT. Hybridomas that produce monoclonal antibodies useful for the practice of the present invention are identified by performing an immune reaction with a specific target cell receptor or suppressing receptor activity. The monoclonal antibodies used in the present invention can be obtained by starting the culture of monoclonal hybridoma cells in a nutrient medium containing hybridoma cells that secrete antibodies having appropriate antigen specificity. In this culture, it is necessary to maintain conditions and time sufficient for the hybridoma cells to secrete antibodies into the culture medium. After collecting the antibody-containing culture supernatant, well-known techniques such as protein A affinity chromatography; anion exchange chromatography, cation exchange chromatography, hydrophobic interaction chromatography, and molecular sieve chromatography (in particular, affinity chromatography using antigen-crosslinked protein A) are used.

[0148] graphy, and molecular sieve chromatography (especially affinity chromatography using antigen-crosslinked protein A) are used. ​​​​​​​​​​Ie chromatography and molecular sieve chromatography); centrifugation, precipitation, or other Antibodies can be isolated by standard methods for purifying proteins.

[0149] Media useful for preparing these compositions are well known in the art and are commercially available and include synthetic media. Exemplary synthetic media is Dulbecco's Minimum Essential Medium (D MEM; Dulbecco et al., Virol. 8:396 (1959)) supplemented with 4.5 g / L glucose, 0-20 mM glutamine, 0-20% fetal bovine serum, ppm amounts of any of several heavy metals (e.g., Cu, Mn, Fe, or Zn) or / and heavy metals added in salt form and an antifoaming agent (e.g., polyoxyethylene-polyoxypropylene block copolymer ).

[0150] In addition to cell fusion technology, cell lines for producing antibodies can also be constructed by the following methods. For example, direct transformation of B lymphocytes with oncogenic DNA or transfection with oncogenic viruses such as Epstein-Barr virus (EBV, also known as human herpesvirus 4 (HHV-4).) or Kaposi's sarcoma-associated virus (KSHV) (see, for example, U.S. Patent Nos. 4341761 ; 4399121; 4427783; 4444887; 4451570; 4466917 ; 4472500; 4491632; 4493890). Monoclonal antibodies can be prepared based on known methods using anti-receptor peptides or peptides containing terminal carboxyl groups (see, for example, Niman et al. Proc. Natl. Acad. Sc ). i. USA, 80:4949 - 4953 (1983); Geysen et al. Proc. Nat l. Acad. Sci. USA, 82:178 - 182 (1985); Lei et al. Bioc hemistry 34(20):6675 - 6688 (1995) (see). Usually, an anti receptor polypeptide or polypeptide analog can be used alone or conjugated to a crosslinked immunogenic carrier as an immunogen for preparing the anti - receptor polypeptide of a monoclonal antibody.

[0151] There are also many other well - known production methods for producing monoclonal antibodies as the binding molecules of the present invention. Among them, the production method of fully human antibodies has attracted particular attention. Phage display technology can obtain fully human antibodies that specifically bind to a known antigen from a fully human antibody library by affinity selection. The literature has detailed descriptions of phage display technology itself, vector construction, and library screening. Specifically, see Dente et al. Gene. 148(1):7 - 13 (1994); Little et al. Biotechnol Adv. 12(3):539 - 55 (1994); Clacks on et al. Nature 352:264 - 628 (1991); Huse et al. Scien ce 246:1275 - 1281 (1989).

[0152] For monoclonal antibodies obtained from other species (e.g., mice) other than humans using hybridoma technology, they can be humanized to avoid human anti - mouse antibodies when administered to humans. Among them, a well - known method for antibody humanization is the complementarity - determining region It is domain transplantation and remodeling. Specifically, see U.S. Patent Nos. 5,859,205 and 6 ,797,492; Liu et al., Immunol Rev. 222:9-27 (2008 ); Almagro et al., Front Biosci. 1; 13:1619-33 (200 8); Lazar et al., Mol Immunol. 44(8):1986-98 (2007 ); Li et al Proc. Natl. Acad. Sci. USA. 103(10):355 7-62 (2006). The disclosures of the above documents are incorporated by reference. Fully human antibodies can be prepared by immunizing transgenic mice, rabbits, monkeys and other mammals that carry most of the human immunoglobulin light and heavy chains with an antigen. Examples of such mice include Xenomouse (Abgenix, Inc.), HuM ab-Mouse (Medarex / BMS), VelociMouse (Regene ron). Specifically, see U.S. Patent Nos. 6,596,541, 6,207,418, 6,150,584, 6,111,166, 6,075,181, 5,922,5 45, 5,661,016, 5,545,806, 5,436,149 and 5, 569,825. During the treatment of humans, the immunogenicity of chimeric antibodies constructed by integrating mouse antibody variable region genes and human antibody constant region genes produced in the human body is much lower than that of mouse antibodies (Kipriyanov et al., Mol Biotech nol. 26:39-60 (2004); Houdebine, Curr Opin B iotechnol. 13:625-9 (2002)). The disclosures of the above documents are incorporated by reference. Furthermore, by site-specific mutagenesis of the antibody variable region, antibody affinity can be further improved. The disclosures of the above documents are incorporated by reference. By introducing site-specific mutations into the antibody variable region, the affinity of the antibody can be further enhanced. (Kipriyanov et al., Mol Biotechnol. 26:39-60 (2004); Houdebine, Curr Opin B iotechnol. 13:625-9 (2002)). The disclosures of the above documents are incorporated by reference. In addition, by introducing site-specific mutations into the antibody variable region, the affinity of the antibody can be further increased. The disclosures of the above documents are incorporated by reference. Additionally, by introducing site-specific mutations into the antibody variable region, the affinity of the antibody can be further improved. The disclosures of the above documents are incorporated by reference. Moreover, by introducing site-specific mutations into the antibody variable region, the affinity of the antibody and specificity can be improved (Brannigan et al., Nat Rev M ol Cell Biol. 3:964-70 (2002); Adams et al., J. Imm unol Methods. 231:249-60 (1999)). By partially replacing the constant region of the antibody and effectively promoting the affinity with immune effector cells, the cytotoxic effect can be enhanced.

[0153] Immunologically specific antibodies against malignant cell antigens can be obtained by commercial routes or several common technical methods, for example, by chemical synthesis or recombinant expression techniques. Similarly, nucleotide sequences encoding immunologically specific antibodies against malignant cell antigens can be obtained from commercial routes such as the GenBank database or other similar databases, known literature, or routine cloning and sequencing.

[0154] In addition to antibodies, polypeptides or proteins can also act as binding molecules and interact with the corresponding receptors or epitopes on the target cell surface by binding, blocking, attacking, or other means. As long as these peptides or proteins can specifically bind to the epitope or its corresponding receptor, they do not necessarily belong to the immunoglobulin family. These polypeptides are also isolated by techniques similar to phage display antibodies (Sza rdenings, J Recept Signal Transduct Res. 2 003; 23(4):307-49). Peptide fragments obtained from random peptide libraries are similar to the applications of antibodies and antibody fragments. Polypeptides or protein molecules The child maintains its antigen-binding specificity by connecting to several macromolecules or media via a linker molecule. These macromolecules include, but are not limited to, albumin, polymers, liposomes, nanoparticles, or dendrimers. For the treatment of cancer, autoimmune diseases, and infectious diseases, antibodies used for drug binding by the conjugates of the present invention include, but are not limited to, for example, the following: 3F8 (anti-GD2 antibody), abagovomab (anti-CA-125 antibody), abciximab (anti-CD41 antibody (integrin α-IIb)), adalimumab (anti-TNF-α antibody), adalimumab (anti-EpCAM antibody, CD326), afelimomab (anti-TNF-α); afucosylated antibody (anti-CD

[0155] 20 antibody), alacizumab pegol (anti-VEGFR2 antibody), ALD518 (anti-IL-6 antibody), alemtuzumab (also known as Campath, MabCampath, anti-CD52 antibody), altumomab (anti-CEA antibody), anatumomab (anti-tag-72 antibody ), anrukinzumab (IMA-638, anti-IL-13 antibody), apolizumab (anti-HLA-DR antibody), arcitumomab (anti-CEA antibody), aselizumab (anti-L-selectin (CD62L) antibody), atelizumab (Atlizumab) (also known as tocilizumab, Actemra, RoActemra, anti-IL-6 receptor antibody), atorolimumab (anti-rheumatoid factor antibody), bapineuzumab (anti-β-amyloid antibody), basiliximab (Simulect , anti-CD25 (IL-2 receptor α chain) antibody), bavituximab (anti-phosphatidylserine antibody), bectumomab (also known as LymphoScan, anti-CD2 antibody), ) ​​​​​​​2 antibodies), belimumab (alias: BENLYSTA, LymphoStat-B, anti-BAFF antibody), benralizumab (Benralizumab) (anti-CD125 antibody), belchlimumab (anti-CCL11 (eotaxin-1) antibody), besilesomab (alias: Scintimun, anti-CEA-related antigen antibody), bevacizumab (alias: Avastin, anti-VEGF antibody), bivalirudin (alias: FibriScint, anti-fibrin IIβ chain antibody), bivatuzumab (anti-CD44v6 antibody), blinatumomab (alias: BiTE, anti-CD19 antibody), brentuximab (Brentuximab) (cAC10, anti-CD30 TNFRSF8 antibody), briakinumab (anti-IL-12, IL-23 antibody), canakinumab (alias: Ilaris, anti-IL-1 antibody), canzumab (alias: C242, anti-CanAg antibody), capromab, catumaxomab (alias: removab, anti-EpCAM, anti-CD3 antibody), CC49 (anti-TAG-72 antibody) , cedelizumab (anti-CD4 antibody), certolizumab pegol (alias: CIMZIA, anti-TNF-α antibody) , cetuximab (alias: Erbitux, IMC-C225 , anti-EGFR antibody), sitaxizumab (anti-EpCAM antibody), cixutumumab (anti-IGF-1 antibody), clenoliximab (anti-CD4 antibody), clivatuzumab (anti-MUC1 antibody), conatumumab (anti-TRAIL-R2 antibody ), CR6261 (anti-influenza A hemagglutinin antibody), dacetuzumab (anti-CD40 antibody), daclizumab (alias: Zenapax, anti-CD25C (IL-2 receptor Antibody of the α-chain of the body), Daratumumab (anti-CD38 (cyclic ADP rib ose hydrolase) antibody), Denosumab (alias: Prolia, anti-RANKL antibody), Detumo mab (anti-B-lymphocyte antibody), Dolrimomab, Dorlixizumab, E cromeximab (anti-GD3 ganglioside antibody), Eculizumab (alias : Soliris, anti-C5 antibody), Edobacumab (anti-endotoxin antibody), Edrecolomab ( alias: Panorex, MAb17-A1, anti-EpCAM antibody), Efalizumab (alias: Rapti va, anti-LFA-1 (CD11a) antibody), Efungumab (alias: Mycogra b, anti-Hsp90 antibody), Elotuzumab (anti-SLAMF7 antibody), Els ilimomab (anti-IL-6 antibody), Enlimomab pegol (anti-ICAM-1 ( CD54) antibody), Epitumomab (anti-epicerin antibody), Epratuzumab (anti-CD22 antibody), Erlizumab (anti-ITGB2 (CD18) antibody) , Ertumaxomab (alias: Rexomun, anti-HER2 / neu, CD3 antibody ), Etaracizumab (alias: Abegrin, anti-integrin αvβ3), Exibivirumab ( anti-hepatitis B surface antigen antibody (HBs antibody)), Fanolesomab (alias: Neu troSpec, anti-CD15 antibody), Faralimomab antibody (anti-interferon receptor antibody), Farletuzumab (anti-folate receptor 1 antibody), Felviz umab (antibody against RS virus), Fezakinumab ( Anti-IL-22 antibody), Figitumumab (anti-IGF-1 receptor antibody), Fontolizumab (anti-IFN-γ antibody), Foravirumab (anti-rabies virus glycoprotein antibody), Fresolimumab (anti-TGF -β antibody), Galiximab (anti-CD80 antibody), Gantenerumab (anti-β amyloid antibody), Gavilimomab (anti-CD147 (basigin antibody)), Gemtuzumab (anti-CD33 antibody), Girentuximab (anti carbonic anhydrase 9 antibody), Glembatumumab (alias: CR011, anti-GPNM B antibody), Golimumab (alias: Simponi, anti-TNF-α antibody), Gomiliximab (anti-CD23C (IgE receptor) antibody), Ibalizumab (anti-C D4 antibody), Ibritumomab (anti-CD20 antibody), Igovomab (alias: Indimacis-125, anti-CA-125 antibody), Imciromab (alias :Myoscint, anti-myocardial myosin antibody), Infliximab (alias: Remicade, anti-TNF-α antibody), Intetumumab (anti-CD51 antibody), Inolimomab (anti-CD25 (IL-2 receptor α chain) antibody), Inotuzumab (anti-CD 22 antibody), Ipilimumab (anti-CD152 antibody), Iratumumab (anti-CD 30 (TNFRSF8) antibody), Keliximab (anti-CD4 antibody), Labes Zumab (alias: CEA-Cide, anti-CEA antibody), lebrikizumab (anti-IL- 13 antibody), lemalesomab (anti-NCA-90 (granulocyte antigen) antibody), le rdelimumab (anti-TGFβ-2 antibody), lexatumumab (anti-TRAIL-R2 antibody), libivirumab (anti-hepatitis B surface antigen an tibody), lintuzumab (anti-CD33 antibody), lucatumumab (anti-CD40 antibody), lumiliximab (anti-CD23 (IgE receptor ) antibody), mapatumumab (anti-TRAIL-R1 antibody), maslimomab (anti T cell receptor antibody), matuzumab (anti-EGFR antibody), mepolizumab (alias : Bosatria, anti-IL-5 antibody), metelimumab (anti-TGFβ-1 antibody ), milatuzumab (anti-CD74 antibody), minretumomab (anti-TAG-72 antibody), mitumomab (alias; BEC-2, anti-gangli oside antibody-GD3), morolimumab (anti-rhesus factor antibody), mota vizumab (alias: Numax, anti-RS virus antibody), muromonab (Muromona b)-CD3 (alias: Orthoclone OKT3, anti-CD3 antibody), nacolomab (anti C242 antibody), naptumomab (anti-5T4 antibody), natalizumab (alias: Tysabri, anti-integrin α4 antibody), nebacumab (anti-endotoxin antibody ) Necitumumab (anti-EGFR antibody), Nerelimomab ( anti-TNF-α antibody), Nimotuzumab (alias: Theracim, Theraloc, anti-EGFR antibody), No fetumomab, Ofatumumab (anti-CD20 antibody), Odetuximab ( alias: Afolimomab, anti-LFA-1 (CD11a) antibody), Ofatumumab (alias: Arzer a, anti-CD20 antibody), Olaratumab (anti-PDGF-Rα antibody), Omalizu mab (alias: Xolair, anti-IgE Fc region antibody), Oportuzumab (O portuzumab) (anti-EpCAM antibody), Oregovomab (alias: OvaRex, anti-C A-125 antibody), Otelixizumab (anti-CD3 antibody), Pagibaxi mab (Pagibaximab) (anti-LTA antibody), Palivizumab (alias: Synagis, Abbosynagis, anti RS virus antibody), Panitumumab (alias: Vectibix, ABX-EGF, anti-EGFR antibody ), Panobacumab (anti-Pseudomonas aeruginosa antibody), Pascolizumab (anti-IL-4 antibody), Pemtumomab (alias: Theragyn, anti-MUC1 antibody) , Pertuzumab (alias: Omnitarg, 2C4, anti-HER2 / neu antibody), Pexelizu mab (Pexelizumab) (anti-C5 antibody), Pintumomab (anti-adenocarcinoma antigen antibody), Pr iliximab (Priliximab) (anti-CD4 antibody), Pritumumab (pritumumab) (anti-viment tin antibody), PRO140 (anti-CCR5 antibody), Racotumomab (racotumomab) (alias: 1E10, anti-(N-glycolylneuraminic acid (NeuGc, NGNA)-ganglioside (GM3) antibody), Rafivirumab (anti-rabies virus glycoprotein antibody ), Ramucirumab (anti-VEGFR2 antibody), Ranibizumab (alias: Lucen tis, anti-VEGF-A antibody), Raxibacumab (anti-anthrax toxin, protective antigen antibody), Regavirumab (anti-CMV glycoprotein B antibody), Reslizumab (anti-IL-5 antibody), rilotumumab (anti-HGF antibody), Rituximab (alias: MabThera, Rituxanmab, anti-CD20 antibody), Robatumumab (anti-IGF-1 receptor antibody), Rontalizumab (anti-IFN-α antibody), Rovelizumab (alias: LeukArrest, anti-CD11, CD18 antibody ), Ruplizumab (alias: Antova, anti-CD154 (CD40L) antibody), Satumomab (anti-TAG-72 antibody), Sevirumab (anti-CMV antibody), Sibrotuzumab (anti-FAP antibody), Sifalimumab (anti-IFN -α antibody), Siltuximab (anti-IL-6 antibody), Siprilizumab (anti-CD 2 antibody), (Smart) MI95 (anti-CD33 antibody), solanezumab ( anti-β-amyloid antibody), Sonepcizumab (anti-sphingosine-1-phosphate antibody), Sontuzumab (anti-epicardin antibody), Stamulumab (Stam ulumab) (anti - myostatin antibody), sulesomab (alias: LeukoScan, (anti - N CA - 90 (granulocyte antigen) antibody))), Tacatuzumab (anti - α - fetoprotein tein antibody), tadocizumab (anti - integrin αIIbβ3 antibody), talarizumab (anti - IgE antibody), tanezumab (anti - NGF antibody), taplitumomab (anti - CD19 antibody), Tefibazumab (alias: Aurexis, anti - clamping factor A antibody), Telimomab, Tenatumomab (anti - tenascin C antibody), Teneliximab (anti - CD40 antibody), Teplizumab (anti - CD3 antibody), TGN1412 (anti - CD28 antibody), ipilimumab (alias: Tremelimumab, anti - CTLA - 4 antibody), Tigatuzumab (anti - TRAIL - R2 antibody), TNX - 650 (anti - IL - 13 antibody), tocilizumab (alias: Atlizumab, Actemra, RoActemra, (anti - IL - 6 receptor antibody), tolarizumab (anti - CD154 (CD40L) antibody), tositumomab (anti - CD20 antibody), trastuzumab (alias: Herceptin, anti - HER2 / neu antibody), tremelimumab (anti - CTLA - 4 antibody), Tucotuzumab celmoleukin (anti - EpCAM antibody), tuvirumab (anti - hepatitis B antibody), urtoxazumab (anti - Escherichia coli antibody), ustekinumab (alias: St ​​elara, anti-IL-12, IL-23 antibody), Vapaliximab (anti-AOC3 (VAP-1) antibody), Vedolizumab, (anti-integrin α4β7 antibody ), Belzutuzumab (anti-CD20 antibody), Vepalimomab (anti-AOC3 (V AP-1)) antibody), Bisilizumab (alias: Nuvion, anti-CD3 antibody), Vitaxin (anti- angiogenic integrin avb3 antibody), Volociximab (anti-integrin α5β1), Votumumab (alias: HumaSPECT, anti-tumor antigen CTAA16.8 8 antibody), Zalutumumab (alias: HuMax-EGFr, (anti-EGFR antibody), Zanomimumab (alias : HuMax-CD4, anti-CD4 antibody), Ziralimumab (anti-CD147 (basic immunoglobulin antibody)), Zolimomab (anti-CD5 antibody), Etanercept (registered trademark 「Enbrel」), Alefacept (registered trademark「Amevive」), Abatacept (registered trademark「Orencia」), Rilonacept (Arcalyst), 14F7 anti-IRP-2 (iron regulatory protein 2) antibody], 14G2a (from Nat. Cancer Inst. for melanoma and solid tumors anti-ganglioside GD2 antibody), J591 (from Weill Cornell Medi cal School for the treatment of prostate cancer anti-PSMA antibody,), 225.28S [for melanoma anti-HMW-MAA (high molecular weight melanoma-associated antigen) antibody, Sorin Radiofarmaci S.R.L .(Milan, Italy)], COL-1 (from Nat. Cancer Inst. for colorectal and gastric cancers The anti-CEACAM3 antibody, CGM1), CYT-356 (registered trademark "Oncoltad", prostate cancer), HNK20 (from Ora Vax Inc. for RS virus), ImmuRAIT (IMMU NOMEDICS for non-Hodgkin lymphoma), Lym-1 (anti-HLA-DR10 antibody, Pe regrine Pharm for tumors), MAK-195F [from Abbott / Knoll for sepsis, toxin shock anti-TNF (tumor necrosis factor; TNFA, TNF-α; TNFSF2) antibody] , MEDI-500 [alias: T10B9, anti-CD3 antibody from MedImmune Inc for graft-versus-host disease, TRαβ (T cell receptor α / β), ], RING SCAN [from Neoprobe Corp. anti-TAG72 (tumor-associated glycoprotein 72) antibody for breast cancer, colon cancer and colorectal cancer) , Avicidin (anti-EPCAM (epithelial cell adhesion molecule) antibody), anti-TACSTD1 ( tumor-associated calcium signal transducer 1) antibody, anti-GA733-2 (gastrointestinal tumor associated protein 2) antibody, anti-EGP-2 (epithelial glycoprotein 2) antibody; anti-KSA antibody; K S1 / 4 antigen; M4S; tumor antigen 17-1A; CD326 from NeoRx Corp. for colon cancer, ovarian cancer, prostate cancer, and non-Hodgkin lymphoma; LYMPHOCIDE (IMMUNOMEDICS , NJ), Smart ID10 (Protein Design Labs), Oncolym (Techniclone Inc, C A), Allomune (BioTransplant, CA), anti-VEGF antibody (Genentech, CA); CEAcide (Immunomedics, NJ), IMC-1C11 (ImClone Systems, NJ) , and cetuximab (ImClone, NJ).

[0156] Other antibodies as cell-binding molecules / ligands include, but are not limited to, the following antigens including: aminopeptidase N (CD13), annexin A1, B7-H3 (CD276 , various cancers), CA125 (ovary), CA15-3 (carcinoma), CA19-9 (carcinoma), L 6 (carcinoma), Lewis Y (carcinoma), Lewis X (carcinoma), alpha-fetoprotein (carcinoma), C A242 (colorectal), placental alkaline phosphatase (carcinoma), prostate-specific antigen (prostate ), prostate acid phosphatase (prostate), epidermal growth factor (carcinoma), CD2 (Hodgkin's disease , NHL lymphoma, multiple myeloma), CD3ε (T-cell lymphoma, lung cancer, breast cancer, gastric cancer, ovary cancer, autoimmune disease, malignant ascites), CD19 (B-cell malignancy), CD20 (non-Hodgkin's lymphoma), CD22 (leukemia, lymphoma, multiple myeloma, systemic lupus erythematosus), CD30 (Hodgkin lymphoma), CD33 (leukemia, autoimmune disease), CD38 (multiple myeloma), CD40 (lymphoma, multiple myeloma, leukemia (CLL)), CD51 (metastatic melanoma, sarcoma), CD52 (leukemia), CD56 (small cell lung cancer, ovarian cancer, Merkel cell carcinoma and liquid tumors, multiple myeloma), CD66e (cancer), CD70 (metastatic renal cell carcinoma and non-Ho dkin lymphoma), CD74 (multiple myeloma), CD80 (lymphoma), CD98 (cancer) , mucin (carcinoma), CD221 (solid tumor), CD227 (breast cancer, ovarian cancer), CD262 (non-small cell lung cancer and other cancers), CD309 (ovarian cancer), CD326 (solid tumor), CEA CAM3 (colorectal cancer, gastric cancer), CEACAM5 (carcinoembryonic antigen; CEA, CD66e) (breast cancer, colorectal cancer and lung cancer), DLL4 (Δ-like-4), EGFR (epidermal growth fac Sub-receptors, various cancers), CTLA4 (melanoma), CXCR4 (CD184, hemangioma, solid tumors), endoglin (CD105, solid tumors), EPCAM (epithelial cell adhesion molecule, bladder , head, neck, colon cancer, NHL prostate cancer, and ovarian cancer), ERBB2 (epidermal growth factor receptor 2; lung cancer, breast cancer, prostate cancer), FCGR1 (autoimmune diseases), FOLR (folate receptor , ovarian cancer), GD2 ganglioside (cancer), G-28G (cell surface antigen glycolipid, melanoma) , GD3 idiotype (cancer), heat shock protein (cancer), HER1 (lung cancer, gastric cancer) , HER2 (breast cancer, lung cancer and ovarian cancer), HLA-DR10 (NHL), HLA-DRB( NHL, B-cell leukemia), human chorionic gonadotropin (carcinoma), IGF1R (insulin -like growth factor-1 receptor, solid tumors, blood cancers), IL-2 receptor (interleukin-2 receptor , T-cell leukemia and lymphoma), IL-6R (interleukin 6 receptor, multiple myeloma , RA, Castleman disease, IL6-dependent tumors), integrin (for various cancers αVβ3, α5β1, α6β4, αIIβ3, α5β5, αVβ5), MAGE-1 (cancer tumors), MAGE-2 (carcinoma), MAGE-3 (carcinoma), MAGE-4 (carcinoma), anti-transferrin receptor (carcinoma), p97 (melanoma), MS4A1 (membrane-spanning 4-domain family A member 1, non-Hodgkin B-cell lymphoma, leukemia), MUC1 or MUC1-KLH (breast cancer, ovarian cancer, cervical cancer, bronchus and gastrointestinal cancer), MUC16 (CA125) (ovarian cancer ), CEA (colon), gp100 (melanoma), MART1 (melanoma), MPG (melanoma) , MS4A1 (membrane-spanning 4-domain family A member 1, small cell lung cancer, NHL), nucleolin , neuro-oncogene product (carcinoma), P21 (carcinoma), anti-(N-glycolylneuraminic acid Paratope of minic acid (breast cancer, melanoma), PLAP-like testicular alkaline phosphatase (ovary cancer, testicular cancer), PSMA (prostate cancer), PSA (prostate), ROBO4, TAG72 (tumor associated glycoprotein 72, leukemia (AML), gastric cancer, colorectal cancer, ovarian cancer), membrane penetrating protein of T cells (cancer), Tie (CD202b), TNFRSF10B (tumor necrosis factor receptor superfamily member 10B, cancer), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B, multiple myeloma, NHL, other cancers, RA and SLE ), TPBG (trophoblast glycoprotein, renal cell carcinoma), TRAIL-R1 (TNF-related apoptosis ligand receptor 1, lymphoma, NHL, colorectal cancer, lung cancer), VCAM-1 (CD 106, melanoma), VEGF, VEGF-A, VEGF-2 (CD309) (various cancers) are included. Other tumor-associated antigens recognized by antibodies have already been reported (Ge rber, et al, mAbs 1:3, 247-253 (2009); Novellino et al, cancer immunol immunothe r. 54 (3), 187-207 (2005) Franke et al, cancer biother radiopharm. 2000, 15,45 9-76).

[0157] The cell-binding agent, more preferably the antibody, can be any agent capable of counteracting tumor cells, virus-infected cells, microbe-infected cells, parasite-infected cells, autoimmune cells, activated cells, bone marrow cells, activated T cells, B cells, or macrophages. More specifically, the cell-binding agent can be any drug capable of counteracting any one of the following antigens or receptors ​It can be used as an agent / molecule: CD3, CD4, CD5, CD6, CD7, CD8, CD 9, CD10, CD11a, CD11b, CD11c, CD12w, CD14, CD15 , CD16, CDw17, CD18, CD19, CD20, CD21, CD22, CD2 3, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD3 1, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD3 9, CD40, CD41, CD42, CD43, CD44, CD45, CD46, CD4 7, CD48, CD49b, CD49c, CD51, CD52, CD53, CD54, C D55, CD56, CD58, CD59, CD61, CD62E, CD62L, CD62 P, CD63, CD66, CD68, CD69, CD70, CD72, CD74, CD7 9, CD79a, CD79b, CD80, CD81, CD82, CD83, CD86, C D87, CD88, CD89, CD90, CD91, CD95, CD96, CD98, C D100, CD103, CD105, CD106, CD109, CD117, CD120 , CD125, CD126, CD127, CD133, CD134, CD135, CD1 38, CD141, CD142, CD143, CD144, CD147, CD151, C D147, CD152, CD154, CD156, CD158, CD163, CD166 , CD168, CD174, CD180, CD184, CDw186, CD194, CD 195, CD200, CD200a, CD200b, CD209, CD221, CD22 7, CD235a, CD240, CD262, CD271, CD274, CD276(B 7-H3), CD303, CD304, CD309, CD326, 4-1BB, 5AC , 5T4 (nutritional bud cell glycoprotein, TPBG, 5T4, Wnt activation inhibitor 1 or W AIF1), adenocarcinoma antigen, AGS-5, AGS-22M6, activin receptor-like kinase 1 , AFP, AKAP-4, ALK, α-integrin, αvβ6, aminopeptidase N, amyloid β, androgen receptor, angiopoietin 2, angiopoietin 3, a nexin A1, Bacillus anthracis toxin protective antigen, anti-transferrin receptor, AOC3 (VAP -1), B7-H3, Bacillus anthracis, BAFF (B-cell activation factor), B-lymphoma cells, b cr-abl, bombesin, BORIS, C5, C242 antigen, CA125 (carbohydrate antigen 125, MUC16), CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg, canine IL31, carbonic anhydrase IX, cardiac myosin, CCL11 (C-C motif chemokine 11), CCR4 (CC chemokine receptor type 4, CD194), CCR5 , CD3E (epsilon), CEA (carcinoembryonic antigen), CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD (factor D), Ch4D5, cholecystokinin 2 (CCK2R) , CLDN18 (claudin-18), clamping factor A, CRIPTO, FCSF 1R (colony-stimulating factor 1 receptor, CD115), CSF2 (colony-stimulating factor 2, granulocyte macrophage colony-stimulating factor (GM-CSF)), CTLA4 (cytotoxic T lymphocyte associated protein 4), CTAA16.88 tumor antigen, CXCR4 (CD184), C XC chemokine receptor type 4, cADP ribose hydrolase, Cyclin B1, CY P1B1, cytomegalovirus, cytomegalovirus glycoprotein B, dabigatran , DLL4 (Delta-like ligand 4), DPP4 (dipeptidyl peptidase 4), DR5 (Death receptor 5), Escherichia coli Shiga toxin type 2, ED-B, EGFL7 (protein 7 containing EGF-like domain), EGFR, EGFRII, EGFRvIII, endoglin (CD 105), endothelin B receptor, endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, epithin, ERBB2 (epidermal growth factor receptor 2), ERBB3, ERG (TMPRSS2ETS fusion gene), Escherichia coli, ETV6-AML, FAP (fibroblast activation protein α), FCGR1, α-fetoprotein, fibrin II, β chain, f ibronectin external domain B, FOLR (folate receptor), folate receptor α, folate hydrola se, Fos-related antigen 1, F protein of RSV, Frizzled receptor, fucos yl GM1, GD2 ganglioside, G-28 (cell surface glycolipid antigen), GD3 idio type, GloboH, glypican 3, N-glycolylneuraminic acid, GM3, GMCS F receptor α chain, growth differentiation factor 8, GP100, GPNMB (transmembrane protein NMB), GUCY2C (guanylate cyclase 2C, guanylate cyclase C (GC-C), intestinal gua nylate cyclase, guanylate cyclase-C receptor, heat-stable enterotoxin receptor body (hSTAR)), heat shock protein, hemagglutinin, hepatitis B surface antigen, hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2 / neu, HE R3 (ERBB-3), IgG4, HGF / SF (stem cell growth factor / cell dispersion factor), H HGFR, HIV-1, histone complex, HLA-DA (human leukocyte antigen), HLA-D R10, HLA-DRB, HMWMAA, human chorionic gonadotropin, HNGF, human cells Cell Scattering Factor Receptor Kinase, HPV E6 / E7, Hsp90, hTERT, ICAM- 1 (Intercellular Adhesion Molecule 1), Idiotype, IGF1R (IGF-1, Insulin-like Growth Factor 1 Receptor), IGHE, IFN-γ, Influenza Hemagglutinin, IgE, IgE Fc Region, IGHE, IL-1, IL-2 Receptor (Interleukin 2 Receptor), IL -4, IL-5, IL-6, IL-6R (Interleukin 6 Receptor), IL-9, IL -10, L-12, IL-13, IL-17, IL-17A, IL-20, IL-22, IL-23, IL-31RA, ILGF2 (Insulin-like Growth Factor 2), Integrin ( α4, α IIIb β3, αvβ3, α4β7, α5β1, α6β4, α7β7, αIIβ 3, α5β5, αvβ5), Interferon γ-Induced Protein, ITAGA2, ITG B2, KIR2D, LCK, Le, Legumain, Lewis-Y Antigen, LFA-1 (Lymphocyte Function-Associated Antigen 1, CD11a), LHRH, LINGO-1, Lipoteichoic Acid, LIV1A , LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE- 2, MAGE-3, MAGEA1, MAGEA3, MAGEA4, MART1, MCP- 1, MIF (Macrophage Migration Inhibitory Factor or Glycosylation Inhibitory Factor (GIF)), MS 4A1 (Transmembrane 4-Domain Subfamily A Member 1), MSLN (Mesothelin), M UC1 (Mucin 1, Cell Surface-Associated (MUC1) or Polymorphic epith elial mucin (PEM)), MUC1-KLH, MUC16 (CA125), MCP1 (Monocyte Chemotactic Protein 1), MelanA / MART1, ML-IAP, MP G, MS4A1 (membrane - spanning 4 - domain subfamily A), MYCN, myelin - associated glycoprotein, myostatin, NA17, NARP - 1, NCA - 90 (granulocyte antigen), Ne ctin - 4 (ASG - 22ME), NGF, neuronal apoptosis regulatory protease 1, NOGO - A, Notch receptor, nucleolin, Neu oncogene product, NY - BR - 1 NY - ESO - 1, OX - 40, OxLDL (oxidized low - density lipoprotein), OY - T ES1, P21, wild - type p53, P97, Page4, PAP,, paratope against (N - glycolyl neuraminic acid), PAX3, PAX5, PCSK9, PDCD1 (PD - 1, programmed cell death protein 1, CD279), PDGF - Rα, (platelet - derived growth factor receptor α), PDGFR - β, PDL - 1, PLAC1, PLAP - like testicular alkaline phosphatase, platelet - derived growth factor receptor β, sodium phosphate cotransporter, PMEL 17, polysialic acid, protease 3 (PR1), prostate cancer, PS (phosphatidylserine), prostate cancer cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI), CD240), rhesus factor (Rh esus factor), RANKL, PhoC, Ras mutant, RG55, ROBO 4, RS virus, RON, sarcoma metastasis breakpoint, SART3, sclerostin, SLAMF7 (SLAM family member 7), selectin P, SDC1 (syndecan 1), sLe(a), somatomedin C, SIP (sphingosine - 1 - phosphate), somatostatin, sperm protein 17, SSX2, STEAP1 (prostate 1 six - transmembrane epithelial antigen), STEAP2, STn, TAG - 22 (tumor - associated glycoprotein 72), saba ​ Evin, T cell receptor, T cell transmembrane protein, TEM1 (tumor endothelial marker 1), T ENB2, tenascin C (TN-C), TGF-α, TGF-β (transforming growth factor β), TGF-β1, TGF-β2 (transforming growth factor β2), T ie (CD202b), Tie2, TIM-1 (CDX-014), TN, TNF, TN F-α, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member -13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (tumor necrosis apoptosis inducing ligand receptor 1), TRAILR2 (death receptor 5 (DR5)), major related ca lcium signal transducer 2, tumor-specific glycosylation of MUC1, TWEA K receptor, TYRP1 (glycoprotein 75), TRP-2, tyrosinase, VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR- 1, VEGFR2, or cells expressing vimentin, WT1, XAGE1, or any insulin growth fac tor receptor, or any epithelial growth factor receptor.

[0158] In another specific embodiment, the cell-binding ligand-drug conjugate via the linker of the present invention is used for the treatment of cancer. Such cancers include, but are not limited to, adrenocortical carcinoma, anal cancer, bladder cancer, brain tumors (adult, brainstem glioma, child, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal and pineal tumors, visual pathway and hypothalamic Endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's family tumor (PNET), extracranial malignant embryo Cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer (stomach), germ cell tumor, extragonadal, gestational trophoblastic tumor Tumor, head and neck cancer, hypopharyngeal cancer, pancreatic islet cell carcinoma, kidney cancer (renal cell carcinoma), laryngeal carcinoma, leukemia (acute Lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cell), lip and oral cavity cancer, Liver cancer, lung cancer (non-small cell, small cell, lymphoma (AIDS-related, central nervous system, cutaneous T cell, Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma, melanoma, Merkel cell carcinoma, metastatic of unknown primary Squamous cell carcinoma, multiple myeloma and other plasma cell tumors, mycosis fungoides, myelodysplastic syndrome, bone Myeloproliferative syndrome, nasopharyngeal cancer, neuroblastoma, oral cancer, pharyngeal cancer, osteosarcoma, ovarian cancer (epithelial, germ Cell tumor, low malignant potential tumor), pancreatic cancer (exocrine gland, pancreatic islet cell carcinoma), paranasal and Nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitary cancer, plasma cell tumor, prostate cancer, rhabdomyosarcoma Rectal cancer, renal cell carcinoma (renal cancer), renal pelvis and ureter (transitional cell), salivary gland cancer, Sezary syndrome Skin cancer, skin cancer (cutaneous T cell lymphoma, Kaposi's sarcoma, melanoma), small intestine cancer, soft tissue sarcoma Stomach cancer, testicular cancer, thymoma (malignant), thyroid cancer, urethral cancer, uterine cancer (sarcoma), abnormal cancer in children Cancer, vaginal cancer, vulvar cancer, Wilms tumor are included.

[0159] In another specific embodiment, the cell-binding molecule-drug conjugate via the cross-linked linker of the present invention can Be used for the treatment or prevention of autoimmune diseases by its components and methods. The autoimmune Diseases include, but are not limited to, autoimmune achlorhydria, chronic active hepatitis, acute disseminated Encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, Amyotrophic lateral sclerosis, ankylosing spondylitis, anti - GMB / TBM nephritis, antiphospholipid syndrome, antisynthetase syndrome, arthritis, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune myocarditis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral nervous system disease, autoimmune pancreatitis, multiple autoimmune endocrine disorders types I, II, III, autoimmune progesterone dermatitis , autoimmune thrombocytopenic purpura, autoimmune uveitis, Behçet's disease / Behçet's concentric sclerosis, Behçet's disease, Berger's disease, Bickerstaff encephalitis, Blau syndrome , bullous pemphigoid, Castleman's disease, Chagas disease, chronic fatigue immune dysfunction syndrome , chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, chronic Lyme disease, chronic obstructive pulmonary disease, allergic granulomatous angiitis, cicatricial pemphigoid, celiac disease, Cogan syndrome , cold agglutinin disease, complement component C2 deficiency, temporal arteritis, CREST syndrome, Crohn's disease (especially inflammatory bowel disease), Cushing's syndrome, cutaneous leukocytoclastic vasculitis, malignant atrophic papulosis, painful fat syndrome, dermatitis herpetiformis, dermatomyositis, type 1 diabetes, diffuse cutaneous scleroderma, myocardial infarction, discoid lupus erythematosus, eczema, endometriosis, adhesive capsulitis - related arthritis, eosinophilic fasciitis, acquired epidermolysis bullosa, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, progressive ossifying fibromatosis, fibromyalgia, fibromyositis, fibrosing alveolitis, gastritis, gastrointestinal pemphigoid, giant cell arteritis, glomerulonephritis, Goodpasture syndrome, Graves' disease, Guillain - Barré syndrome , Hashimoto's encephalopathy, Hashimoto's thyroiditis, hemolytic anemia, allergic purpura, herpes gestationis, suppurative hidradenitis, Hughes syndrome (antiphospholipid antibody syndrome), hypogammaglobulinemia, idiopathic inflammation Inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (autoimmune thrombocytopenic purpura), IgA nephropathy (Berger's disease), inclusion body myositis, inflammatory demyelinating polyneuropathy, interstitial cystitis, irritable bowel syndrome, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, mucocutaneous lymph node syndrome, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease (LAD), Lou Gehrig's disease (amyotrophic lateral sclerosis), lupoid hepatitis, lupus erythematosus, Blau syndrome, Meniere's disease, microscopic polyangiitis, Miller-Fisher syndrome, mixed connective tissue disease, scleroderma, Creutzfeldt-Jakob disease, McCune-Albright syndrome, multiple myeloma, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's disease), neurogenic muscle, ocular cicatricial pemphigoid, opsoclonus-myoclonus syndrome, Hashimoto's thyroiditis, relapsing rheumatism, Pandas syndrome (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, Persistent-Joubert syndrome, uveitis, pemphigus, pemphigus vulgaris, pernicious anemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen encephalitis, Raynaud's disease, relapsing polychondritis, Reiter's syndrome, restless legs syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler syndrome, episcleritis, scleroderma, Sjogren's syndrome, spondyloarthritis, adhesive capsulitis, Still's disease, including, but not limited to, those mentioned above, are all autoimmune diseases. These diseases are characterized by the body's immune system attacking its own tissues and organs, leading to various symptoms and pathological changes. Autoimmune diseases can affect multiple systems in the body, such as the nervous system, musculoskeletal system, cardiovascular system, digestive system, urinary system, and skin. The specific symptoms and manifestations vary depending on the type of autoimmune disease and the affected organs or tissues. Common symptoms may include fatigue, joint pain, muscle weakness, skin rashes, swelling, inflammation, and organ dysfunction. Diagnosis of autoimmune diseases often requires a comprehensive evaluation of the patient's medical history, physical examination, laboratory tests, and imaging studies. Treatment options for autoimmune diseases typically include medications to suppress the immune system, such as corticosteroids, immunosuppressants, and biologics, as well as symptomatic treatment to relieve symptoms and manage complications. Early diagnosis and appropriate treatment are crucial for improving the prognosis and quality of life of patients with autoimmune diseases. Research on autoimmune diseases is ongoing to better understand their causes, develop more effective Stiffman syndrome, subacute bacterial endocarditis, Suzaku syndrome, acute febrile neutrophilic dermatosis, Sydenham chorea, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis (giant cell arteritis), Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, Wegener granulomatosis, Wilson syndrome, Wiskott-Aldrich syndrome are included. Skin disease, Sydenham chorea, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis (giant cell arteritis), Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, Wegener granulomatosis, Wilson syndrome, Wiskott-Aldrich syndrome are included. Skin disease, Sydenham chorea, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis (giant cell arteritis), Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, Wegener granulomatosis, Wilson syndrome, Wiskott-Aldrich syndrome are included. Skin disease, Sydenham chorea, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis (giant cell arteritis), Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, Wegener granulomatosis, Wilson syndrome, Wiskott-Aldrich syndrome are included. Skin disease, Sydenham chorea, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis (giant cell arteritis), Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, Wegener granulomatosis, Wilson syndrome, Wiskott-Aldrich syndrome are included.

[0160] In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG; In another specific embodiment, the binding molecules used to conjugate via the cross-linked linker of the present invention for the treatment or prevention of autoimmune diseases include, but are not limited to, anti-elastin antibodies; Abys anti-epithelial cell antibodies; anti-type IV collagen protein antibodies of the basement membrane; anti-nuclear antibodies; anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anti-cardiolipin antibodies IgM, IgG;

[0161] In some preferred embodiments, the binding molecule used in the conjugate of the present invention binds to a receptor or receptor complex expressed by activated lymphocytes associated with autoimmune diseases. The receptor or receptor complex can be, for example, a member of the immunoglobulin gene superfamily (e.g., CD2, CD3, CD4, CD8, CD19, CD20, CD 22, CD28, CD30, CD33, CD37, CD38, CD56, CD70, CD 79, CD90, CD125, CD147, CD152 / CTLA-4, PD-1, or ICOS), TNF receptor superfamily (e.g., CD27, CD40, CD95 / Fas, CD134 / OX40, CD137 / 4-1BB, INF-R1, TNFR- 2, RANK, TACI, BCMA, osteoprotegerin, Apo2 / TRAIL-R 1, TRAIL-R2, TRAIL-R3, TRAIL-R4, and APO-3), integrin, cytokine receptor, chemokine receptor, major histocompatibility protein, lectin (C-type, S-type, or I-type), or complement regulatory protein. In another specific embodiment, a useful conjugate having immunological specificity for a viral antigen or bacterial antigen is a humanized or human monoclonal antibody. As used herein, the term "viral antigen" includes any viral peptide, polypeptide protein (e.g., HIV gp120, HIV nef, RSV F glycoprotein,

[0162] influenza virus neuraminidase, influenza virus hemagglutinin, HTL Vtax, herpes simplex virus glycoproteins (e.g., gB, gC, gD, and gE), that can induce an immune response. polypeptide protein (e.g., HIV gp120, HIV nef, RSV F glycoprotein, influenza virus neuraminidase, influenza virus hemagglutinin, HTL and hepatitis B surface antigen), but is not limited thereto. As used herein, the term "bacterial antigen" refers to any microbial peptide, polypeptide, protein, saccharide, polysaccharide, or lipid molecule capable of inducing an immune response (e.g., bacteria, fungi, pathogenic protozoa, yeast polypeptides (e.g., LPS and 5 / 8)), but is not limited thereto. Type I antibodies useful for the treatment of viral or bacterial infections include palivizumab (a humanized anti-respiratory syncytial virus monoclonal antibody used for the treatment of RVS infection), PRO542 (a CD4 fusion antibody used for the treatment of HIV infection), Ostavir (a human antibody used for the treatment of hepatitis B virus), PROTVIR (a humanized antibody IgG1 antibody used for the treatment of cytomegalovirus), anti-LPS antibodies, but is not limited thereto.

[0163] The cell-binding molecule-drug conjugate via the cross-linked conjugate of the present invention can be used for the treatment of infectious diseases. The infectious diseases include Acinetobacter infection, actinomycosis, African sleeping sickness ( African trypanosomiasis), AIDS (acquired immunodeficiency syndrome), amebiasis, anaplasmosis, anthrax, bacterial tuberculosis infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterial vaginitis, bacteroides infection, Balantidium infection, Baylisascaris infection, BK virus infection, black piedra, Blastocystis hominis infection, Blastomyces, Bolivian hemorrhagic fever, Borrelia infection, botulism (and infant botulism), Brazilian hemorrhagic fever, brucellosis, Burkholderia infection, Buruli ulcer, infectious calicivirus (norovirus, sapovirus), Campylobacter Listeria infections, Candida infections (candidiasis, thrush), cat scratch disease, Cellulitis, Chagas disease (American trypanosomiasis), chancroid, chickenpox, Chlamydia, Chlamydia trachomatis infection, cholera, chromoblastomycosis, clonorchiasis, Clostridium difficile infection, Coccidioides, Colorado tick fever, cold (acute viral nasopharyngitis, acute rhinitis), Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, Cryptococcus, Cryptosporidium, cutaneous larva migrans, Cyclospora infection, cysticercosis, cytomegalovirus infection, dengue fever, Dientamoeba, diphtheria, diphyllobothriasis, guinea worm disease, Ebola hemorrhagic fever, echinococcosis, ehrlichiosis, Enterobius (enterobiasis), enterococcal infection, enterovirus infection, epidemic typhus, erythema infectiosum (fifth disease), exanthema subitum, fasciolopsis buski, fascioliasis, fatal familial insomnia, filariasis, food poisoning caused by Vibrio welchii, free-living ameba infection, fusobacterium infection, gas gangrene (Clostridium myonecrosis), Geotrichum, Gerstmann-Straussler-Scheinker syndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, granuloma inguinale (Donovanosis), group A streptococcal infection, group B streptococcal infection, Haemophilus influenzae infection, hand, foot, and mouth disease (HFMD), hantavirus pulmonary syndrome, Helicobacter pylori infection, hemolytic uremic syndrome, hemorrhagic fever with renal syndrome, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworm infection, human Balkan virus infection, human ehrlichiosis evansi, human granulocytic anaplasmosis, human metapneumovirus infection, human monocytic ehrlichiosis, human papillomavirus infection, human parainfluenza virus infection, hymenolepiasis nana, influenza, isosporiasis, Kawasaki disease, mononucleosis 、 Klebsiella infection, Q fever, Lassa fever, Legionnaires' disease, Pontiac fever, Leishmaniasis, Hansen's disease, leptospirosis, listeriosis, Lyme disease (Lyme borreliosis), lymphatic filariasis (elephantiasis), lymphocytic choriomeningitis, malaria, Marburg hemorrhagic fever, measles, melioidosis (Whitmore's disease), meningitis, meningococcal disease 、 microsporidiosis, molluscum contagiosum, mumps, endemic typhus, Mycoplasma pneumonia, mycetoma, myiasis, neonatal conjunctivitis (ophthalmia neonatorum), Creutzfeldt-Jakob disease (vCJD, nvCJD), Nocardiosis, onchocerciasis (river blindness ), paracoccidioidomycosis (South American blastomycosis), paragonimiasis, Pasteurella disease, body lice, body louse disease, crab louse disease (crab louse, Crabb ice), pelvic inflammatory disease, pertussis (whooping cough), plague, pneumococcal infection, Pneumocystis pneumonia, pneumonia, polio, Prevotella infection, PAME, progressive multifocal leukoencephalopathy, psittacosis, Q fever, rabies, rat bite fever, respiratory syncytial virus infection, rhinovirus infection, rickettsial infection, rickettsia, Rift Valley fever, Rocky Mountain spotted fever, rotavirus infection, rubella, salmonellosis, SARS (severe acute respiratory syndrome ), scabies, schistosomiasis, sepsis, shigellosis (dysentery), shingles (Herpes zoster), smallpox, sporotrichosis, staphylococcal food poisoning, staphylococcal infection, nematodes, syphilis , taeniasis, tetanus (lockjaw), tinea barbae (barber's itch), tinea manuum , tinea nigra, tinea pedis, onychomycosis, vitiligo, toxocariasis (ocular larva migrans), Toxocara ​​​​​​​​​​Disease (visceral larva migrans), toxoplasmosis, Trichinella, Trichomonas, cryptobiosis (Trichuris infection), pulmonary tuberculosis, tularemia, Ureaplasma urealyticum infection, Venezuelan equine encephalomyelitis Encephalitis, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever, white piedra, Yersinia pseudotuberculosis Infections, including but not limited to Escherichia, yellow fever, zygomycosis

[0164] Cell binding molecules, preferably antibodies against the pathogenic strains described in the present application, said pathogenic strains include Acinetobacter baumannii, Actinomyces israelii, Actinomyces odontolyticus, Propionibacterium propionicum, Trypanosoma brucei, HIV (human immunodeficiency virus), Entamoeba histolytica, Anaplasma spp., Bacillus anthracis, Methicillin-resistant Staphylococcus aureus ( Arcanobacterium haemolyticum), Funin virus, Ascaris lumbricoides , Aspergillus, Astroviridae, Babesia spp., Bacillus cereus, multiple bacteria, Bacteroides spp., Balantidium coli, Baylisascaris, BK virus , Piedraia hortae, Blastocystis hominis, Blastomyces dermatitidis, Macacine herpesvirus 1, Borrelia spp., Clostridium botulinum, Sabia virus, Brucella spp., Burkholderia cepacia and other Burkholderia species, Mycobacterium ulcerans, Caliciviridae family, Campylobacter spp., Candida albicans and other Candida species, Bartonella henselae ( English: Bartonella henselae), Group A streptococci and staphylococci, Trypanosoma cruzi, Chancroid and other pathogens species, usually Burkholderia cepacia and other Burkholderia species, Mycobacterium tuberculosis ulcerans, Caliciviridae family, Campylobacter spp., usually Candida albicans and other Candida species, Bartonella henselae ( English: Bartonella henselae), Group A streptococci and staphylococci, Trypanosoma cruzi, Chancroid species, usually Burkholderia cepacia and other Burkholderia species, Mycobacterium tuberculosis Marasmius, varicella-zoster virus (VZV), Chlamydia trachomatis, Chlamydia pneumoniae Moeller, Vibrio cholerae, Fonsecaea pedrosoi, Clonorchiasis, Clostridium difficile Israeli, Coccidioides immitis, Coccidioides posadasii, Colorado tick fever virus Rhinovirus, Coronavirus, Creutzfeldt-Jakob disease prion Crimean-Congo hemorrhagic fever virus, Cryptococcus neoformans, Cryptosporidium Genus, Ancylostoma braziliense, Co-parasite, Cyclospora, Taenia solium, Cytomegalovirus, Dengue virus (DEN-1, DEN-2, DEN-3 and DEN-4) - Flavivirus Dientamoeba, Corynebacterium diphtheriae, Diphyllobothrium latum, Dracunculus medinensis Ebola virus, Echinococcus, Ehrlichia Genus, Enterobius, Enterococcus, Enterovirus, Typhus rickettsia, Parvovirus B19 Human herpesvirus 6, Human herpesvirus 7, Fasciola gigantica, Hepatic fluke and Fasciola magna, FFI prion, Filariidae, Welch bacillus, Fusobacterium Umbellatum, Welch bacillus, Other Clostridium genus, Geotrichum candidum, GSS prion On, Giardia lamblia, Burkholderia mallei Gnathostoma spinigerum, Gnathostoma hispidum, Neisseria gonorrhoeae, Granuloma inguinale, Streptococcus pyogenes, Streptococcus agalactiae Kuti, Haemophilus influenzae, Enterovirus, Most Coxsackievirus A, Enterovirus 71 Simbu virus, Helicobacter pylori, Escherichia coli O158:H7, Bunyaviridae Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, Herpes simplex virus 1, Herpes simplex virus 2 Type 2, Histoplasma capsulatum, Necator americanus, Ancylostoma duodenale, Influenza bacteria, Bocavirus, Ehrlichia ewingii , Anaplasma phagocytophilum, Human metapneumovirus, Ehrlichia chaffeensis, Human papillomavirus, Human parainfluenza virus, Trichuris trichiura , Hymenolepis nana, Epstein-Barr virus, Orthomyxoviridae, Isospora belli, Kingella kingae , Klebsiella pneumoniae, Klebsiella ozaenae, Klebsiella rhinoscleromatis , Kuru prion, Lassa fever virus, Legionella pneumophila, Legionella pneumophila, Leishmania major, Mycobacterium lepromatosis, Leptospira genus, Listeria monocytogenes, Borrelia disease and other Borrelia species, Wuchereria bancrofti and Brugia malayi, Lymphocytic choriomeningitis virus (L CMV), Plasmodium genus, Marburg virus, Measles virus, Burkholderia pseudomallei , Neisseria meningitidis, Metagonimus yokogawai, Microsporidia, Molluscum contagiosum virus (MCV), Mumps virus , Rickettsia typhi, Mycoplasma pneumoniae, various bacteria (Actinomycetoma ), and fungi (fungal mycetoma), Diptera larvae of parasitic flies, Chlamydia trachomatis and Neisseria gonorrhoeae, vCJD prion, Nocardia asteroides and other Nocardia species, Spirometra mansoni , Rickettsia typhi, Mycoplasma pneumoniae, various bacteria (Actinomycetoma ), and fungi (fungal mycetoma), Diptera larvae of parasitic flies, Chlamydia trachomatis and Neisseria gonorrhoeae, vCJD prion, Nocardia asteroides and other Nocardia species, Spirometra mansoni worms, Blastomyces brasiliensis, Paragonimus and other Paragonimus species, Pasteurella species, Atamaj Lami, Collembola, Phthirus pubis, Bordetella pertussis, Pe Streptococcus, Streptococcus pneumoniae, Pneumocystis carinii, Poliovirus, Prevotella species, Naegleria amoeba of Negleria, JC virus, Chlamydia psittaci, Coxiella burnetii, Rabies virus, Streptobacillus moniliformis and Rat-bite fever spirochete, Respiratory syncytial virus , Linospodium saberi, Rhinovirus, Rickettsia species, Rickettsia duttoni, Rift Valley fever virus, Rocky Mountain spotted fever Rickettsia, Rotavirus, Rubella virus, Monkey Monera, SARS-CoV, Sarcoptes scabiei, Schistosoma species, Shigella dysenteriae, Varicella-zoster virus , Smallpox or Variola, Sporothrix schenckii, Staphylococcus species, Staphylococcus aureus , Streptococcus pyogenes, Strongyloides stercoralis, Treponema pallidum, Taenia species, Clostridium tetani, Tinea tonsurans, Tinea, Epidermophyton floccosum, Trichophyton rubrum and Tinea barbae Trichophyton mentagrophytes, Trichophyton rubrum, Hortaea werneckii, Tinea, Malassezia species, Toxocara canis and Toxocara cati , Toxoplasma, Trichinella spiralis, Trichomonas vaginalis, Trichuris trichiura, Mycobacterium tuberculosis, Tularemia Francisella bacteria, Ureaplasma urealyticum, Venezuelan equine encephalitis virus, Vibrio cholerae, G Anaritvirus, West Nile virus, Trichosporon beigelii, Mycobacterium pseudotuberculosis, Yersinia enterocolitica, Yellow fever virus, Zygomycetes (Mucormycosis) and Entomophthorales (Entomophthoramycosis), Pseudomonas aeruginosa , Campylobacter fetus (Vibrio), Aeromonas bacteria, Edwardsiella genus. Tarda , Yersinia pestis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Salmonella typhi, Treponema pallidum pertenue, Treponema carateum, Fensemblergdolferi, Borrelia burgdor Ferry, Leptospira icterohaemorrhagiae, Pneumocystis carinii, Brucella abortus, Brucella suis, Brucella melitensis, Mycoplasma, Rickettsia typhi, Rickettsia tsutsugamushi, Kleb sia, pathogenic fungi (Aspergillus fumigatus, Candida albicans, Histoplasma capsulatum); protozoa (Entamoeba histolytica, Trichomonas vaginalis, Trichomonas hominis, Trypanosoma gambiense, Trypanosoma rhodesiense, Leishmania donovani, Leish mania tropica, Leishmania braziliensis, Pneumocystis carinii pneumonia, Plasmodium malariae protozoa, Plasmodium falciparum, Plasmodium vivax); or helminths (Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium and hookworms) are included, but not limited thereto.

[0165] Other antibodies as cell-binding ligands used in the present invention for the treatment of viral diseases include, but are not limited to, antibodies against pathogenic virus antigens, and examples of such pathogenic viruses include, but are not limited to, the Poxviridae (Poxyiridae e), Herpesviridae, Adenoviridae, Papovaviridae, Enteroviridae Picornaviridae, Parvoviridae, Reoviridae, Retroviridae, Infl uenza virus, Parainfluenza virus, Mumps, Measles, Respiratory syncytial virus, Rubella, Arbovirus, Rabies virus, Arenaviridae, Non-A / Non-B hepatitis virus, Rhinovirus, Coronavirus, Rotavirus, Tumor virus [e.g., HBV (hepatocellular carcinoma), HPV (cervical cancer, anal cancer), Kaposi's sarcoma-associated herpesvirus ( Kaposi's sarcoma), Epstein-Barr virus (nasopharyngeal carcinoma, Burkitt lymphoma, primary central nervous system lymphoma Tumors), MCPyV (Merkel cell carcinoma), SV40 (Simian virus 40), HCV (hepatocellular carcinoma), HTLV-I (adult T-cell leukemia / lymphoma)]; immune diseases caused by viruses: [e.g., human immunodeficiency virus (AIDS)], CNS viruses: hepatocellular carcinoma), HTLV-I (adult T-cell leukemia / lymphoma)]; immune diseases caused by viruses: [e.g., human immunodeficiency virus (AIDS)], CNS viruses: e.g., JCV (progressive multifocal leukoencephalopathy), MeV (subacute sclerosing panencephalitis), LCV (lymphocytic choriomeningitis), arbovirus encephalitis, Orthomyxovirus family (presumed) (encephalitis lethargica), RV (rabies), vesicular stomatitis, herpesvirus meningitis, Ramsay Hunt syndrome type II; poliovirus (acute poliomyelitis, post-polio syndrome), HTLV- I (tropical spastic paraparesis)]; cytomegalovirus (CMV retinitis, HSV (herpetic keratitis)); cardiovascular viruses [e.g., CBV (pericarditis, myocarditis)]; respiratory system / acute nasopharyngitis / viral pneumonia: [EB virus (EBV infection / infectious mononucleosis), cytomegalovirus virus, SARS coronavirus (severe acute respiratory syndrome), Orthomyxovirus family: influenza virus A / B / C (influenza / avian influenza )], paramyxovirus: human parainfluenza virus (parainfluenza), R SV (human respiratory syncytial virus), hMPV]; digestive system viruses [MuV (epidemic parotitis), cytomegalovirus (CMV esophagitis); adenovirus (adenovirus infection)]; rotavirus, norovirus, astrovirus, coronavirus, HBV (hepatitis B virus), CBV, HAV (hepatitis A virus), HCV (hepatitis C virus), HDV (hepatitis D virus), HEV (hepatitis E virus), HGV (hepatitis G virus )]; genital viruses [e.g., BK virus, MuV (epidemic parotitis)] are included are included )], paramyxovirus: human parainfluenza virus (parainfluenza), R SV (human respiratory syncytial virus), hMPV]; digestive system viruses [MuV (epidemic parotitis), cytomegalovirus (CMV esophagitis); adenovirus (adenovirus infection)]; rotavirus, norovirus, astrovirus, coronavirus, HBV (hepatitis B virus), CBV, HAV (hepatitis A virus), HCV (hepatitis C virus), HDV (hepatitis D virus), HEV (hepatitis E virus), HGV (hepatitis G virus )]; genital viruses [e.g., BK virus, MuV (epidemic parotitis)] are included HDV (hepatitis D virus), HEV (hepatitis E virus), HGV (hepatitis G virus )]; genital viruses [e.g., BK virus, MuV (epidemic parotitis)] are included )]; genital viruses [e.g., BK virus, MuV (epidemic parotitis)] are included is suppressed.

[0166] According to a further object, the present invention provides a conjugate via the cross-linked conjugate of the present invention and a pharmaceutically acceptable carrier, diluent, or excipient, together with a conjugate for treating cancer, infectious diseases, or autoimmune diseases also relates to a pharmaceutical composition. Methods for treating cancer, infectious diseases, and autoimmune diseases can be performed in vitro, in vivo, or ex vivo (ex vivo). Examples of in vitro therapy include killing all cells other than the desired mutants that do not express the target antigen, or killing mutants that express an undesired antigen. Examples of ex vivo therapy include treating hematopoietic stem cells (HSCs) prior to the performance of transplantation (HSCT) and returning them to the body of the same patient to kill diseased or malignant cells . For example, prior to autologous transplantation in the treatment of cancer and autoimmune diseases, to remove cancer cells or lymphocyte cells from the bone marrow, or to prevent graft-versus-host disease, clinical ex vivo treatment to remove T cells and other lymphocytes from allogeneic bone marrow or tissue prior to transplantation can be performed as follows. After obtaining bone marrow cells from a patient or other individual, the conjugate of the present invention is added to a serum-containing medium such that the concentration range is about 1 pM to 0.1 mM, and the cells are cultured at 37°C for 30 minutes to about 48 hours . The exact concentration conditions and culture time (= dose) can be easily determined by an experienced clinician . After culturing, the bone marrow cells are washed with a serum-containing medium and returned to the human body by a known method such as intravenous injection . During the acquisition and reinfusion treatment of bone marrow cells, if the patient is receiving other treatments (e.g., ablative chemotherapy or total body irradiation), the treated bone marrow cells are administered using standard medical devices . After culturing, the bone marrow cells are washed with serum-containing medium and returned to the human body by known methods such as intravenous injection . During the acquisition and reinfusion treatment of bone marrow cells, if the patient is receiving other treatments (e.g., ablative chemotherapy or total body irradiation), the treated bone marrow cells are administered using standard medical devices It is cryopreserved with liquid nitrogen using .

[0167] In in vivo clinical applications, the conjugate via the linker of the present invention is provided in the form of a lyophilized solid that can be redissolved in sterile water for injection purposes. Examples of suitable methods of administering the conjugate are as follows. Over 8 to 20 weeks, the conjugate is administered by intravenous bolus. Dissolve the bolus dose in 50 to 500 mL of physiological saline, and human serum albumin can be added to the physiological saline (for example, 0.5 to 5 mL of concentrated human serum albumin solution at 100 mg / mL). The drug dosage is about 50 μg to 20 mg / kg body weight / week, and is by intravenous injection (the dose per injection is in the range of 10 μg to 200 mg / kg). After the 4 to 20-week treatment is completed, the patient can receive a second course of treatment. The detailed treatment method, including the route of administration, excipient, diluent, dosage, and treatment period, can be determined by an experienced surgeon. For injection purposes, it is provided in the form of a lyophilized solid that can be redissolved in sterile water. Examples of suitable methods of administering the conjugate are as follows. Over 8 to 20 weeks, the conjugate is administered by intravenous bolus. Dissolve the bolus dose in 50 to 500 mL of physiological saline, and human serum albumin can be added to the physiological saline (for example, 0.5 to 5 mL of concentrated human serum albumin solution at 100 mg / mL). The drug dosage is about 50 μg to 20 mg / kg body weight / week, and is by intravenous injection (the dose per injection is in the range of 10 μg to 200 mg / kg). After the 4 to 20-week treatment is completed, the patient can receive a second course of treatment. The detailed treatment method, including the route of administration, excipient, diluent, dosage, and treatment period, can be determined by an experienced surgeon. Over 8 to 20 weeks, the conjugate is administered by intravenous bolus. Dissolve the bolus dose in 50 to 500 mL of physiological saline, and human serum albumin can be added to the physiological saline (for example, 0.5 to 5 mL of concentrated human serum albumin solution at 100 mg / mL). The drug dosage is about 50 μg to 20 mg / kg body weight / week, and is by intravenous injection (the dose per injection is in the range of 10 μg to 200 mg / kg). After the 4 to 20-week treatment is completed, the patient can receive a second course of treatment. The detailed treatment method, including the route of administration, excipient, diluent, dosage, and treatment period, can be determined by an experienced surgeon. Examples of treating diseases by selectively killing cell populations by in vivo or ex vivo methods include any type of cancer, autoimmune diseases, transplant rejection reactions, and infectious diseases (including viruses, bacteria, or parasites). Due to multiple factors, the amount of conjugate drug required for the desired biological effect varies. These factors include the nature of the compound, the effectiveness and bioavailability of the conjugate drug, the type of disease, the patient's ethnicity, the patient's pathological condition, and the route of administration. These factors together determine the dosing schedule and route of administration.

[0168] Examples of treating diseases by selectively killing cell populations by in vivo or ex vivo methods include any type of cancer, autoimmune diseases, transplant rejection reactions, and infectious diseases (including viruses, bacteria, or parasites). Due to multiple factors, the amount of conjugate drug required for the desired biological effect varies. These factors include the nature of the compound, the effectiveness and bioavailability of the conjugate drug, the type of disease, the patient's ethnicity, the patient's pathological condition, and the route of administration. These factors together determine the dosing schedule and route of administration.

[0169] Due to multiple factors, the amount of conjugate drug required for the desired biological effect varies. These factors include the nature of the compound, the effectiveness and bioavailability of the conjugate drug, the type of disease, the patient's ethnicity, the patient's pathological condition, and the route of administration. These factors together determine the dosing schedule and route of administration. These factors include the nature of the compound, the effectiveness and bioavailability of the conjugate drug, the type of disease, the patient's ethnicity, the patient's pathological condition, and the route of administration. These factors together determine the dosing schedule and route of administration.

[0170] ​​​Generally speaking, the conjugate through the linker of the present invention may be a formulation for parenteral administration dissolved in a physiological buffer so as to contain the conjugate at a concentration of 0.1 to 10% w / v. The typical dosage range is 1 μg / kg body weight to 0.1 g / kg body weight per day, and the preferred dosage range is 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to the pediatric dosage. The preferred drug dosage appropriately depends on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time). The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules Typical dosage ranges are from 1 μg / kg body weight to 0.1 g / kg body weight per day, and preferred dosage ranges are from 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to pediatric dosages. Preferred drug dosages depend appropriately on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time). Typical dosage ranges are from 1 μg / kg body weight to 0.1 g / kg body weight per day, and preferred dosage ranges are from 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to pediatric dosages. Preferred drug dosages depend appropriately on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time). Typical dosage ranges are from 1 μg / kg body weight to 0.1 g / kg body weight per day, and preferred dosage ranges are from 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to pediatric dosages. Preferred drug dosages depend appropriately on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time). Typical dosage ranges are from 1 μg / kg body weight to 0.1 g / kg body weight per day, and preferred dosage ranges are from 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to pediatric dosages. Preferred drug dosages depend appropriately on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time). Typical dosage ranges are from 1 μg / kg body weight to 0.1 g / kg body weight per day, and preferred dosage ranges are from 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to pediatric dosages. Preferred drug dosages depend appropriately on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time). Typical dosage ranges are from 1 μg / kg body weight to 0.1 g / kg body weight per day, and preferred dosage ranges are from 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to pediatric dosages. Preferred drug dosages depend appropriately on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time). Typical dosage ranges are from 1 μg / kg body weight to 0.1 g / kg body weight per day, and preferred dosage ranges are from 0.01 mg / kg body weight to 20 mg / kg body weight per day, or equivalent to pediatric dosages. Preferred drug dosages depend appropriately on variables such as the type and degree of progression of the disease or disorder, the overall health status of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular, or others), the pharmacokinetic characteristics of the drug in the selected mode of administration, and the administration rate (single injection or continuous infusion) and administration schedule (frequency of administration within a certain time).

[0171] The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly / monthly dosage range is 0.01 to 100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, per week, per two weeks, or per month. Preferably, the unit dose is administered 1 to 4 times a week at 1 mg to 500 mg, and more preferably, 1 mg to 100 mg is administered once a week. The conjugate provided here can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. The unit dose drug can be, for oral administration, tablets, simple capsules or soft capsules The conjugate through the linker of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a patient, can be used for simple and convenient packaging, and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, the typical daily / weekly / bi-weekly as; for nasal administration, as a powder, nasal drops, or aerosol; or, for skin administration, for example, as an ointment, cream, lotion, gel, or spray or skin patch and can be administered.

[0172] Drug / cytotoxic agent

[0173] In the present invention, a drug that can be conjugated with a cell-binding molecule is a small molecule drug containing a cytotoxic agent and can be linked to a cell-binding molecule directly or after modification. Here, "small molecule drug" may have a molecular weight of, for example, 100 to 2500, more preferably 120 to 1500 and organic, inorganic, or organometallic compounds are widely used. For a better definition of small molecule drugs, WO05058367A2 and US Patent No. 4,956,303, and other documents can be referred to and these are incorporated herein by reference in their entirety. The above drugs include known drugs and those that may become drugs.

[0174] Known drugs include, but are not limited to, the following.

[0175] a) Alkylating agents: Nitrogen mustard: Chlorambucil, Chloronaphazine, Cyclophosphamide, Dacarbazine, Estramustine, Ifosfamide, Mechlorethamine , Mechlorethamine hydrochloride oxide, Mannomustine, Mitobronitol, Melphalan , Mitolactol, Pipobroman, Novembicin, Phenesterine, Prednimustine, Thiotepa, Trofosfamide, Uracil mustard; CC-1065 (including synthetic analogs of adozelesin, carzelesin, and bizelesin); Duocarmycin (synthetic analogs, and synthetic analogs of It includes KW-2189 and CBI-TMI.); Benzodiazepine dimers (pyrrolobenzodiazepines (PBD) or tomamycin, indolobenzodiazepines, imidazobenzothiadiazepines, or oxazolidinobenzodiazepines selected from dimers of); Nitrosourea compounds: (carmustine, lomustine, chlorozotocin, fotemustine , nimustine, ranimustine); Alkyl sulfonates: (busulfan, treosulfan, improsulfan, and piposulfan); Triazene (dacarbazine); Platinum containing compounds: (carboplatin, cisplatin, oxaliplatin); Aziridines, bendopar, carboquone, metsulidopa, and uredopa; Ethylenimines, and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; b) Plant alkaloids: Vinca alkaloids: (vincristine, vinblastine, vindesine, vinorelbine, navelbine); Taxoids: (paclitaxel, docetaxel ) and their analogs, maytansinoids (DM1, DM2, DM3, DM4, D M5, DM6, DM7, maytansine, ansamitocin) and their analogs, cryptophycins (selected from cryptophycin 1 and cryptophycin 8).); Epothilones, erythrobins, discodermolide, bryostatins, drostatins, auristatins, tubulysins, cephalostatins; Pancratistatin; S ulcodictine; Spongistatin, etc.; c) DNA topoisomerase inhibitors: [Epipodophyllins: (9-aminocamptothe cins, etc.); d) Other drugs: e) Other drugs: c) DNA topoisomerase inhibitors: [Epipodophyllins: (9-aminocamptothe Cis, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acid (retinols), teniposide, topotecan, 9-nitrocamptothecin (RFS 2000); mitomycin Cins: (mitomycin C))] etc.; d) Antimetabolites: {[Antifolates: Dihydrofolate reductase inhibitors: (methotrexate , trimethoprexate, denopterin, pteropterin, aminopterin (4-aminopter erioic acid), or folic acid analogs); IMP dehydrogenase inhibitors (mycophenolic acid, thiazofurin, ribavirin, EICAR); Ribonucleotide reductase inhibitors (hydroxy urea, deferoxamine)]; [Pyrimidine analogs: Uracil analogs (ancitabine , azacitidine, 6-azauridine, capecitabine (Xeloda), carmofur, cytarabine , didoxuridine, doxifluridine, enocitabine, 5-fluorouracil, floxuridine, raltitrexed (Tomudex)); Cytosine analogs: (cytarabine , cytarabine, fludarabine); Purine analogs: (azathioprine, fludarabine , mercaptopurine, thiampurine, thioguanine)]; Folic acid supplements, folinic acid} etc.; e) Hormone therapy agents: {Receptor antagonists: [Anti-estrogens: (megestrol, laro xifen, tamoxifen); LHRH agonists: (goserelin, leuprolide acetate ); Anti-androgens: (bicalutamide, flutamide, calusterone, drostanolone propionate , epithioestanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, trilostane, and other androgen inhibitors)]; Retinoids Class / Triangular Ribs: Vitamin D3 Analogs: (CB1093, EB1089, KH1060, Calcifediol, Ergocalciferol); Photodynamic Therapy Agents: (Verteporfin, Phthalocyanine, Photosensitizer Pc4, Demethoxy-Hypocrellin A); Cytokines : (Interferon α, Interferon γ, Tumor Necrosis Factor (TNF), TNF Domain -Containing Human Protein)]}, etc.; f) Kinase Inhibitors: BIBW2992 (anti-EGFR / Erb2), Imatinib, Gefitinib, Gefitinib, Pegaptanib, Sorafenib, Dasatinib, Sunitinib, Erlotinib, Nilotinib, Lapatinib, Axitinib, Pazopanib, Vandetanib, E7080 (anti-VEGFR2), Mubritinib, Ponatinib (AP24534), Bafetinib (INNO-406), Bosutinib (SKI-606), Cabozantinib, Bismodegib, Iniparib, Luxolitinib, CYT387, Axitinib, Thiothixene, Sorafenib, Bevacizumab, Cetuximab, Trastuzumab, Ranibizumab, Panitumumab, Ispinesib, etc.; g) Olaparib, Niraparib, Iniparib, Talazoparib, Veliparib, CEP9722 (Cephalon), E7016 (Eisai), BGB-290 (BeiGene), ) or a Poly(ADP-Ribose) Polymerase (PARP) Inhibitor selected from the group consisting of 3-Aminobenzamide, etc.; h) Antibiotics: Enediyne Antibiotics (Calicheamicins, Calicheamicin γ1, δ1, α1 and β1; Dynemicin A and Dynemicin Containing Deoxydynemicin; Esperamicin, Chedalasin, C-1027, Mazlopeptin, and Neocarzinostatin Chromophore and Related Pigment Protein Enediyne Antibiotic Chromophore)] selected from the group), the aclacinomycins, actinomycin, anthramycin, a zaserine, the bleomycins, cactinomycin, carabicin , calminomycin, cardinophilin; the chromomycins , dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-nor leucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxo rubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, the mitomycins, mycophenolic acid , nogalamycin, the olivomycins, peplomycin, potfiromycin, puro mycin, querramycin, rhodrubicin, streptozocin, streptonigrin, tu bersidine, ubenimex, dinostatin, zorubicin, etc.; i) polyketide (acetogenins), bratasin and bratasinone; gemcitabine, e poxomicins (including carfilzomib.), bortezomib, thalidomide, lenalid omide, pomalidomide, tosedostat, zibestat, PLX4032, STA- 9090, Stimuvax, alovectin-7, zygev, proben dine, erboy, isoprenylation inhibitors (selected from lovastatin), dopamine-acting motility neurotoxins (selected from 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors selected from (staurosporine), the aclacinomycins (selected from the group consisting of actinomycin D, d actinomycin), the bleomycins (selected from the group consisting of bleomycin A2, bleomycin B2, peplomycin), anthracycline Class (selected from the group consisting of daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, zorubicin), mitoxantrone, MDR inhibitor or verapamil, Ca ATP inhibitor or thapsigargin, histone deacetylase 2+ inhibitor (selected from the group consisting of vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat (MGCD0103), belinostat, PCI-24781, entinostat, SB939, resminostat, givinostat, AR-42, CUDC-101 , sulforaphane, trichostatin A); thapsigargin, celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A, anti-adrenal drugs (selected from the group consisting of aminoglutethimide, mitotane, trilostane ); aceglutamide; aldophosphamide glycoside; aminolevulinic acid; amsacrine; arabinoside, bestrabucil; bisantrene; edatrexate; defofamine , dexamethasone, diacron, difluoromethylornithine (DFMO), elfomycin; acetic acid elliptinium acetate, etoglucid; gallium nitrate; gasitocin; hydroxyurea; ibandronate , lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nifraerine , pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethyl hydrazide; procarbazine; PSK (registered trademark); razoxane; lysoxine; sizofiran , spirogermanium; tenuazonic acid; triacron; 2,2’,2’’-tri chloroethylamine; trichothecenes (T2 toxin, verrucarin A, roridin A, , pirarubicin, podophyllinic acid, 2-ethyl hydrazide, procarbazine, PSK (registered trademark), razoxane, lysoxine, sizofiran, spirogermanium, tenuazonic acid, triacron, 2,2’,2’’-trichloroethylamine, trichothecenes (T2 toxin, verrucarin A, roridin A, ); pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethyl hydrazide; procarbazine; PSK (registered trademark); razoxane; lysoxine; sizofiran , spirogermanium; tenuazonic acid; triacron; 2,2’,2’’-tri chloroethylamine; trichothecenes (T2 toxin, verrucarin A, roridin A, (selected from the group consisting of angiotensin); urethane, siRNA, antisense medicine drugs, and nucleolytic enzymes, etc.

[0176] (2) Anti-autoimmune disease drugs: Cyclosporine, Cyclosporine A, Aminocaproic acid, Azathioprine, Bromocriptine Chlorambucil, Chloroquine, Cyclophosphamide, Corticosteroids (Amcinonide, Betamethasone, Budesonide, Hydrocortisone, Flunisolide, Fluticasone Propionate ester, Fluocortodanazol, Dexamethasone, Triamcinolone acetonide Beclomethasone dipropionate, etc.), DHAE, Etanercept, Hydroxychloroquine Infliximab, Meloxicam, Methotrexate, Mycophenolate mofetil Prednisone, Sirolimus, Tacrolimus are included, but not limited to these.

[0177] (3) Anti-infective drugs: a) Aminoglycosides: Amikacin, Astromicin, Gentamicins (Netilmicin, Sisomicin, Isepamicin), Hygromycin B, Kanamycins (Amikacin, Albekacin, Bekanamycin, Dibekacin, Tobramycin), Neomycins (Framycetin, Paromomycin, Ribostamycin), Netilmicin, Spectinomycin, Streptomycin, Tobramycin, Verdamicin; b) Chloramphenicols: Azidamfenicol, Chloramphenicol, Florfenicol, Thiamphenicol; c) Ansamycins: Geldanamycin, Herbimycin; d) Carbapenems: Biapenem, Doripenem, Ertapenem, Imipenem / Cilastatin Chin, meropenem, panipenem; e) Cephems: carbacephems (loracarbef), cefacetrile, cefaclor, cefradine, cefadroxil, cefalonium, cefaloridine, cefalothin or c efalosporin, cephalexin, cefaloglycin, cefamandole, cefapirin , cefatrizine, cefazafur, cefazedone, cefazolin, cefbuperazone, cef capene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil , cefalosporin, ceftezole, cefuroxime, cefixime, cefdinir, cefdit ren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cef operazone, ceforanide, cefotaxime, cefothiam, cefozopran, cephalexi sin, cefpimazole, cefpiramide, cefpirome, cefpodoxime, cefprozil, c fquinome, cefsulodin, ceftazidime, cefteram, cefibutene, cefthiolen, c fthizoxime, ceftibiprole, ceftriaxone, cefuroxime, cefzonam, cef amycin (cefoxitin, cefotetan, cefmetazole), oxacephems (flo moxef, latamoxef); f) Glycopeptides: bleomycin, vancomycin (oritavancin, telavancin ), teicoplanin (dalbavancin), ramoplanin; g) Glycylcyclines: tigecycline; h) β-Lactamase inhibitors: penams (sulbactam, tazobactam), clavams (c lavulanic acid); i) Lincomamides: clindamycin, lincomycin; j) Lipopeptides: daptomycin, A54145, calcium-dependent antibiotics (C DA); k) Macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolides (telithromycin, cethromycin), midecamycin, miocamycin, oleandomycin, rifamycins (rifampicin, rifampin, rifabutin, rifapentine), rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus (FK506), troleandomycin, telithromycin; l) Monobactams: aztreonam, tigemonam; m) Oxazolidinones: linezolid; n) Penicillins: amoxicillin, ampicillins (pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, chromocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam (pivmecillinam), mezlocillin, methicillin, nafcillin, oxacillin, penamcilin, penicillin, phenethicillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin; l) Monobactams: aztreonam, tigemonam; m) Oxazolidinones: linezolid; n) Penicillins: amoxicillin, ampicillins (pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, chromocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam (pivmecillinam), mezlocillin, methicillin, nafcillin, oxacillin, penamcilin, penicillin, phenethicillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin; l) Monobactams: aztreonam, tigemonam; m) Oxazolidinones: linezolid; n) Penicillins: amoxicillin, ampicillins (pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, chromocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam (pivmecillinam), mezlocillin, methicillin, nafcillin, oxacillin, penamcilin, penicillin, phenethicillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxacin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin; l) Monobactams: aztreonam, tigemonam; m) Oxazolidinones: linezolid; Ciprofloxacin, canofloxacin, levofloxacin, lomefloxacin, marbofloxacin Ciprofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin Ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin; q) Streptogramins: pristinamycin, quinupristin / dalfopristin ; r) Sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethoxazole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim - sulfamethoxazole (cotrimoxazole); s) Steroid antibacterial agents: fusidic acid, etc.; t) Tetracyclines: doxycycline, chlortetracycline, chlormocycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, glycylcyclines (tigecycline, etc.); u) Other types of antibiotics: annonacin, arsphenamine, bacteriophage inhibitor (bacitracin), DADAL / AR inhibitor (cycloserine), dactiostatin, discodermolide, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laurimolide, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitor (fosfomycin), nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin / dalfo ​​​​​​​​Pristine, rifampin (rifampin), tazobactamtinidazole, uvaricin; These include, but are not limited to:

[0178] (4)Antiviral drugs: a) Entry / fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41(E Nfuvirtide), PRO140, CD4 (ibalizumab); b) Integrase inhibitors: Raltegravir, Elvitegravir, Globoidonan A; c) Maturation inhibitors: Bevirimat, Vivicon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleosides and nucleotides: Abacavir, Acyclovir, Adefovir, Am Doxovir, Apricitabine, Brivudine, Cidofovir, Clevudine, Dexerbucitabine Bin, didanosine (DDI), elvucitabine, emtricitabine (FTC), entecavir vir, famciclovir, fluorouracil (5-FU), 3'-fluoro substituted 2',3 '-Deoxynucleoside analogue (3'-fluoro-2',3'-dideoxythymidine ( FLT) and 3'-fluoro-2',3'-dideoxyguanosine (FLG) ), fomivirsen, ganciclovir, idoxuridine, lamivudine ( 3TC), L-nucleosides (β-L-thymidine and β-L-2'-deoxycytidine) ), penciclovir, rasvir, ribavirin, stampidine, Stavudine set (d4T), taribavirin (viramidine), telbivudine, tenofovir , trifluridine, valacyclovir, valganciclovir, zalcitabine (ddC), Dovudine (AZT); f) Non-nucleosides: amantadine, ateviridin, capravirine, diarylpyrimidin (etravirine, rilpivirine), delavirdine, docosanol, emivirine, efavirdine Virenz, foscarnet (phosphoryl formate), imiquimod, interferon alpha, Robin Lido, rhodenosine, methisazone, nevirapine, NOV-205, peginterferon alpha , podophyllotoxin, rifampicin, rimantadine, resiquimod (R-848), Romantadine; g) Protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir , fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, Tonavir, saquinavir, telaprevir (VX-950), tipranavir; h) Other antiviral drugs: Abzyme, Arbidol, Calanolide A, Seragenin, Cyanovirin-N, Diarylpyrimidine, Epigallocatechin Gallate (EGCG), Phospholipid Carnet, Griffithsin, Taribavirin (Viramidine), Hydroxyurea, KP- 1461, Miltefosine, Pleconaril, Portmanteau inhibitors, Ribavirin, Sericin Crib;

[0179] 5) Drugs used for conjugation via the bridge linkers of the present invention include radioisotopes. Examples of radioisotopes (radionuclides) include: 3 H, 11 C. 14 C. 18 F, 32 P, 35 S, 64 Cu, 68 Ga, 86 Y, 99 Tc, 111 In, 123 I, 124 I , 125I, 131 I, 133 Xe, 177 Lu, 211 At, and 213 Bi mentioned Radiolabeled antibodies are very useful in receptor-targeted imaging experiments, or For example, the invention of antibody-drug conjugates (Wu et al (2005) Nature Biotechnology 23(9):1137 -1146), cell-binding molecules that can be used directly for relative targeting therapy, e.g. The antibodies may be conjugated, chelated or otherwise complexed with the radioactive materials via the cross-linkers of the present application, as described above. This labeling technique is described in accordance with the Current Protocol. s in Immunology, Volumes 1 and 2, Coligen et al, Ed. Wiley-Interscience, New York k, NY, Pubs. (1991). Chelating agents capable of forming complex metal complexes include , DOTA, DOTP, DOTMA, DTPA, and TETA (Macrocyclics, Dallas, Tex.) are included.

[0180] 6) Pharmaceutically acceptable salts, acids, or derivatives of any of the above drugs.

[0181] In another embodiment, the drug of formula (II) and / or (IV) is a targeting agent that binds a cell. Chromophores that can be conjugated to detect, monitor, or study interactions with cells The chromophore molecules can be UV, fluorescent, IR, near IR, or visual light. Chromophores are compounds that have the ability to absorb certain types of light, such as xanthophores, red The classes or subclasses of chromatophores, iridophores, leucophores, melanophores, cerelophores, and fluorophores comprises, the phosphor being a fluorescent chemical substance that re - emits light upon illumination with light; a visible - light - transmitting molecule of the class or subclass; of the class or subclass of luminescent molecules; of the class or subclass; of the class or subclass of luciferin compounds.

[0182] Chromophore molecules include, but are not limited to, xanthene derivatives (fluorescein, rhoda mine, Oregon Green, eosin, and Texas Red); cyanine derivatives (cyanine , indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine ); squalene derivatives and ring - substituted squarylium (including Seta, SeTau, and Squa re dyes); naphthalene derivatives (dansyl and prodan derivatives); coumarin derivatives ; oxadiazole derivatives (pyridyloxazole, nitrobenzoxadiazole, and benzoxadiazole); anthracene derivatives (anthraquinones including DRAQ5, DRAQ7, and CyT RAK Orange); pyrene derivatives (such as cascade blue, etc.) ; oxazine derivatives (Nile Red, Nile Blue, cresyl violet, oxazine 170, etc.). Acridine derivatives (proflavine, acridine orange, acridine yellow - etc.). Aryl - methane derivatives (auramine, crystal violet, malachite green ). Tetrapyrrole derivatives (porphyrin, phthalocyanine, bilirubin), etc., non - protein organic phosphors can be selected from. Alternatively, the chromophore molecule can be selected from any analogs and derivatives of the following phosphor compounds

[0183] :CF dyes (Biotium), DRAQ and CyTRAK probes (Bio - Status ), etc. )、BODIPY (Invitrogen), Alexa Fluor (Invitrogen), DyLight Fluor (Thermo Scientific, Pierce), Atto and Transcy (Sigma Aldrich), FluoProbes (Interchim), Abberior Dyes (Abberior), DY and MegaStokes Dyes (Dyomics), SulfoCy Dyes (Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau and Square Dyes (SETABioMedicals), Quasar and Cal Fluor Dyes (Biosearch Technologies) ldrich), FluoProbes (Interchim), Abberior Dyes (Abberior), DY and MegaStokes Dyes (Dyomics), SulfoCy Dyes (Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau and Square Dyes (SETABioMedicals), Quasar and Cal Fluor Dyes (Biosearch Technologies) Lyte Fluor (AnaSpec), Seta, SeTau and Square Dyes (SETABioMedicals), Quasar and Cal Fluor Dyes (Biosearch Technologies) BioMedicals), Quasar and Cal Fluor Dyes (Biosearch Technologies) 、SureLight Dyes (APC, RPEPerCP, phycobilisomes) (Columbia Biosciences), APC, APCXL, RPE, BPE (Phyco - Biotech). Biosciences), APC, APCXL, RPE, BPE (Phyco - Biotech).

[0184] Examples of widely used phosphor compounds that can react or conjugate with the conjugate of the present invention include 、allophycocyanin (APC), aminocoumarin, APC - Cy7 conjugate, BODIPY - FL, Y - FL, cascade blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5 .5, Cy7, fluorescein, FluorX, hydroxycoumarin, rhodamine B, lucifer yellow, methoxycoumarin, NBD, Pacific Blue, P acific Orange, PE - Cy5 conjugate, PE - Cy7 conjugate, PerCP, R - phycoerythrin (PE), Red613, Seta - 555 - azide, Seta - 555 - DBCO, Seta - 555 - NHS, Seta - 580 - NHS, Seta - 555 - DBCO, Seta - 555 - NHS, Seta - 580 - NHS, Seta - 680 - NHS, Seta - 780 - NHS, Seta - APC - 780, Seta - P erCP-680, Seta-R-PE-670, SeTau380-NHS, SeTa u405-maleimide, SeTau405-NHS, SeTau425-NHS, SeT au647-NHS, Texas Red, TRITC, TruRed, X-rhodamine are listed as follows.

[0185] For the study of nucleic acids or proteins, the fluorophores that can be linked to the conjugates of the present invention are selected from the following compounds or their derivatives: 7-AAD (7-amino actinomycin D, CG selectivity), acridine orange, chromomycin A3, CyTR AK orange (Biostatus, red excitation dark), DAPI, DRAQ5, DRAQ7, ethidium bromide, Hoechst 33258, Hoechst 33342, LDS751, mithramycin , propidium iodide (PI), SYTOX blue, SYTOX green, SYTO X orange, thiazole orange, TO-PRO: cyanine monomer, TOTO-1, TO -PRO-1, TOTO-3, TO-PRO-3, YOseta-1, YOYO-1. The fluorescent dyes that can be linked to the conjugates of the present invention for cell research are selected from the following compounds or their derivatives: DCFH (2’7’ dichlorodihydro-fluorescein, acidified form), DHR (dihydrorhodamine 123, oxidized form, light catalyzes oxidation), Fluo -3 (AM ester, pH>6), Fluo-4 (AM ester, pH 7.2), Ind o-1 (AM ester, low / high calcium (Ca )), and SNARF (pH 6 / 9 ). Preferred fluorescent dyes that can be linked to the conjugates of the present invention for protein / antibody research are selected from the following compounds or their derivatives: allophycocyanin (APC 2+ ), ​ )、AmCyan1 (tetramer, Clontech), AsRed2 (tetramer, Clontech), Aza mi Green (monomer, MBL), Azurite, B - phycocyanin (BPE), Cellu an, CyPet, DsRed monomer (Clontech), DsRed2 ("RFP", Clonte ch), EBFP, EBFP2, ECFP, EGFP (weak dimer, Clontech), Emerald (weak dimer, Invitrogen), EYFP (weak dimer, Clontech), GFP (S65A variant ), GFP (S65C variant), GFP (S65L variant), GFP (S65T variant) 、GFP (Y66F variant), GFP (Y66H variant), GFP (Y66W variant), GFP uv 、HcRed1, J - Red, Cachusha, Kusabira Orange e (monomer, MBL), mCFP, mCherry, mCitrine, Midriish i Cyan (dimer, MBL), mKate (TagFP635, monomer, Evrogen), m Keima - Red (monomer, MBL), mKO, mOrange, mPlum, mRas pberry, mRFP1 (monomer, Tsien Lab), mStrawberry, mTFP1, mTurquoise2, P3 (phycobilisome complex), Peridi nin Chlorophyll (PerCP), R - phycocyanin (RPE), T - Sapphire, TagCFP (dimer, Evrogen), TagGFP (dimer, Evrog en), TagRFP (dimer, Evrogen), TagYFP (dimer, Evrogen), tdTo mato (tandem dimer), Topaz, TurboFP602 (dimer, Evrogen), TurboFP635 (dimer, Evrogen), TurboGFP (dimer, Evrogen), T urboRFP (dimer, Evrogen), TurboYFP635 (dimer, Evrogen), bi rnas, native GFP, YPet, Zs Green 1 (tetramer, Clontech), Zs Yellow 1 (tetramer, Clontech).

[0186] As an example of the structure of a conjugate of an antibody-chromophore molecule via a cross-linking linker, the following Ac01, Ac02, Ac03, Ac04, Ac05, Ac06, Ac07, Ac08, and Ac0 9 are listed:

Chemical formula

[0187] Wherein,

Chemical formula

[0188] In another embodiment, the drugs of formulas (II) and (III) may also be polyalkylene glycols used to extend the half-life of a cell-binding molecule when administered to a mammal. Poly alkylene glycols include, but are not limited to, poly(ethylene glycol) (PEG), poly(propylene glycol), and copolymers of ethylene oxide and propylene oxide. Particularly preferred is PEG, and even more particularly preferred is... are mentioned, but not limited thereto. Particularly preferred is PEG, and even more particularly preferred The ino is a monofunctional activated hydroxy PEG (e.g., of hydroxy PEG-monocarboxylic acid reactive esters, hydroxy PEG-monoaldehyde, hydroxy PEG-monoamine, hydroxy PEG-monohydrazide, hydroxy PEG-monocarbazate, hydroxy PEG-monoiodoacetamide, hydroxy PEG-maleimide, hydroxy PE G-monoorthopyridyl disulfide, hydroxy PEG-monoorthopyridyl disulf ide, hydroxy PEG-monooxime, hydroxy PEG-monophenyl carbonate hydroxyl PEG-monophenyl glyoxal, hydroxyl PEG-monothiazo lysine-2-thione, hydroxyl PEG-monothioester, hydroxyl PEG-mo notiol, hydroxyl PEG-monotriazine, and hydroxyl PEG-monoviny l sulfone, hydroxy PEGs activated at a single terminus).

[0189] In such embodiments, the polyalkylene glycol has a molecular weight of about 10 Daltons to about 20 0 kDa, preferably about 88 Da to about 40 kDa; the two branches each have a molecular weight of from about 88 Da to about 40 kDa; and more preferably, the two branches each are from about 88 Da to about 20 kDa. In a particular embodiment, the polyalkylene glycol is poly(ethylene) glycol and has a molecular weight of about 10 kDa; about 20 kDa, or about 40 kDa . In certain embodiments, the PEG is PEG10kDa (linear or branched), PEG20kDa (linear or branched), or PEG40kDa (linear or branched). Many U.S. patents, such as U.S. Patent Nos. 5,428,128; 5,621,039; 5,622,986; 5,643,575; 5,728,56 0; 5,730,990; 5,738,846; 5,811,076; 5,824,701; 5,840,900; 5,880,131; 5,900,402; 5,902,588; 5,919,455; 5,951,974; 5,965,119; 5,965,566; 5,969,040; 5,981,709; 6,0 11,042; 6,042,822; 6,113,906; 6,127,355; 6,132,713; 6,177,087, and 6,180,095 disclose the preparation of linear or branched "non-antigenic" PEG polymers and their derivatives or conjugates. The structure of the conjugate of an antibody and a polyalkylene glycol via a cross-linker is as follows: Pg01, Pg02, Pg03, Pg04, Pg05, Pg06, and Pg07 are listed below:

[0190] [Chemical formula] TIFF2025093934000072.tif84157

[0191] wherein mAb is an antibody; R' is H or CH3; m3 is an integer from 1 to 5000; R3 is OH, H, or R1; [Chemical formula] represents a single bond or a double bond; m1, m2, n, L1, L2, X1, X2, R1, R2, and R3 have the same definitions as in formulas (I) and (II); further, R1 and R3 may each independently be H, OH, OCH3, or OC2H5; p is from 1 to 2000; Drug1 has the same definition as in formula (III).

[0192] In yet another embodiment, it is preferred to conjugate a cell-binding molecule via the cross-linker of the present application​​ Preferred cytotoxic agents include tubulysins, maytansinoids, taxanoids (taxanes), CC-1065 analogs, daunorubicin and doxorubicin compounds, benzodiazepine dimers (e.g., pyrrolobenzodiazepine (PBD), tomamycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepine, or oxazolidinobenzodiazepine dimers), calicheamicins and enediyne antibiotics, actinomycin, azaserines, bleomycins, epirubicin, tamoxifen, idarubicin, drastatins, auristatins (e.g., monomethyl auristatin E, MMAE, MMAF, auristatin PYE, auristatin TP, auristatin 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP)), duocarmycins, geldanamycins, methotrexates, thiotepa, vindesines, vincristines, hemiasterlins, nazumamides, microginins, radiothumins, alterobactins, microsclerodermins, theonellamides, esperamicins, PNU- 159682, and their analogs and derivatives. Tubulysins, which are preferred compounds for the conjugates of the present invention, are well known in the art and can be extracted from natural products based on known methods or synthesized by known methods.

[0193] For example: Balasubramanian, R.; et al. J. Med. Chem., 2009, 52, 238-240. Wipf, P.; et al. Org. Lett., 2004, 6, 4057-4060. Pando, O.; et al. J. Am. Chem. Soc., 201 1, 133, 7692-7695. Reddy, J. A.; et al. Mol. Pharmaceutics, 2009, 6, 1518-1525. Raghavan, B.; et al. J. Med. Chem., 2008, 51, 1530-1533. Patterson, A. W.; et al . J. Org. Chem., 2008, 73, 4362-4369. Pando, O.; et al. Org. Lett., 2009, 11 (2 4), pp 5567-5569. Wipf, P.; et al. Org. Lett., 2007, 9 (8), 1605-1607. Fries tad, G. K.; Org. Lett., 2004, 6, pp 3249-3252. Hillary M. Peltier, H. M.; et al. J. Am. Chem. Soc., 2006, 128, 16018-16019. Chandrasekhar, S.; et al. J. Org. Ch em., 2009, 74, 9531-9534. Liu, Y.; et al. Mol. Pharmaceutics, 2012, 9, 168-175. Friestad, G. K.; et al. Org. Lett., 2009, 11, 1095-1098. Kubicek, K.; et al., An gew Chem Int Ed Engl, 2010. 49: p. 4809-12. Chai, Y.; et al., Chem Biol, 2010, 1 7: 296 - 309. Ullrich, A.; et al., Angew Chem Int Ed Engl, 2009, 48, 4422 - 5. Sani, M.; et al. Angew Chem Int Ed Engl, 2007, 46, 3526 - 9. Domling, A.; et al., Ang ew Chem Int Ed Engl, 2006. 45, 7235 - 9. Patent applications: Zanda, M. ; et al, C an. Pat. Appl. CA 2710693 (2011). Chai, Y.; et al. Eur. Pat. Appl. 2174947 (2 010), WO 2010034724. Leamon, C.; et al, WO 2010033733, WO 2009002993. Ellman, J .; et al, WO 2009134279; WO 2009012958, US appl. 20110263650, 20110021568, Mats chiner, G.; et al, WO 2009095447.Vlahov, I.; et al, WO 2009055562, WO 2008112873 . Low, P.; et al, WO 2009026177. Richter, W., WO 2008138561. Kjems, J.; et al, W O 2008125116. Davis, M.; et al, WO 2008076333. Diener, J.; et al, U.S. Pat. Appl . 20070041901, WO 2006096754. Matschiner, G.; et al, WO 2006056464. Vaghefi, F.; et al, WO 2006033913. Doemling, A., Ger. Offen. DE 102004030227; WO 200400532 7; WO 2004005326; WO2004005269. Stanton, M.; et al, U.S. Pat. Appl. Publ. 200402 49130. Hoefle, G.; et al, Ger. Offen. DE 10254439 ; DE 10241152; DE 10008089. Le ung, D.; et al, WO 2002077036. Reichenbach, H.; et al, Ger. Offen. DE 19638870; Wolfgang, R.; US 20120129779, Chen, H.,US appl. 20110027274.)。For co - acting with cell - binding molecules, the preferred structures of tubulysins are described in PCT / IB2012 / 053554 For co - acting with cell - binding molecules, the preferred structures of tubulysins are described in PCT / IB2012 / 053554 are described in PCT / IB2012 / 053554

[0194] As an example of the structure of the conjugate of an antibody - tubulysin analog via the linker of this patent, the following T01, T02, T03, T04, T05, T06, T07, T08, T09, T1 0, and T11 are listed: 0, and T11 are listed:

[0195]

Chemical formula

[0196] wherein, mAb is an antibody or a cell - binding molecule; n, m1, m2, Drug1, X1, X 2, L1, L2, L3, R1, R2, R3, R4, and R5 are as defined in formulas (I) and (II) and are the same definition; R1, R2, R3, and R4 are preferably each independently H, C 1-C8 linear or branched alkyl, aryl, heteroaryl, heteroalkyl, a lkylcycloalkyl, ester, ether, amide, amine, heterocycloalkyl, or acyloxyamine; or a peptide containing 1 to 8 amino acids, or the structural formula (O CH2CH2) p or (OCH2CH(CH3)) p (p; an integer from 0 to about 2000) are polyethyleneoxy units of; furthermore, two of R: R1R2, R2R3, R1R3, or R3R4 can form a 3- to 8-membered ring of an alkyl, aryl, heteroaryl, heteroalkyl, or alkylcyclo alkyl group; X3 is H, CH3, or X 1’ R1 ’ wherein X 1’ is NH, N(CH3), NHNH, O, or S, and R 1’ is , H or C1-C8 linear or branched alkyl, aryl, heteroaryl, heteroalkyl , alkylcycloalkyl, acyloxyamine; Z3 is H, OP(O) (OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, R1 , or an O-glycoside (glucoside, galactoside, mannoside, glucuronoside / glucurono nide, alloside, fructoside, etc.), NH-glycoside, S-glycoside or CH2-glycoside ; [Chemical formula] represents a single bond or a double bond; M1 and M2 are each independently H, Na, K, Ca, Mg, NH4, NR1R2R3; furthermore, R 1’ is described throughout this patent It may also be a cytotoxic agent.

[0197] Preferred calicheamicins and related enediyne antibiotics in the cell-binding molecule-drug conjugate of the present application are described in the following documents. Nicolaou, K. C. et al, Science 1992, 256, 1172-1178; Proc. Natl. Acad. Sci USA. 1993, 90, 5881-5888), U.S. Pa tent Nos. 4,970,198; 5,053,394; 5,108,912; 5,264,586; 5,384,412; 5,606,040; 5,71 2,374; 5,714,586; 5,739,116; 5,770,701; 5,770,710; 5,773,001; 5,877,296; 6,015,5 62; 6,124,310; 8,153,768. As an example of the structure of the conjugate of an antibody-calicheamicin analog via this cross-linking linker, the following C01 and C02 are mentioned.

[0198]

Chemical formula

[0199] In the formula, mAb is an antibody or a cell-binding molecule;

Chemical formula

[0200] ​ Maytansinol and its analogs, which are preferably used in the present invention, including maytans noids, are described in the following US patent documents. US Patent 4,256,746, 4,361,650, 4 ,307,016, 4,294,757, 4,294,757, 4,371,533, 4,424,219, 4,331,598, 4,450,254, 4,36 4,866, 4,313,946, 4,315,929 4,362,663, 4,322,348, 4,371,533, 4,424,219, 5,208,02 0, 5,416,064, 5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821, 7,276,497, 7,301,019, 7,303,749, 7,368,565, 7,411,063, 7,851,432, and 8,163,888. As an example of the structure of the conjugate of antibody-maytansinoids through the conjugate of this patent, the following My01, My02, and My03 are mentioned. My02, and My03 are mentioned.

[0201]

Chemical formula

[0202] wherein mAb is an antibody or a cell-binding molecule;

Chemical formula

[0203] Paclitaxel (Taxol), which is preferable for conjugation via the cross-linked conjugate of this patent Taxanes, which are cytotoxic natural products containing it, and docetaxel (Taxotere), which is a semi-synthetic derivative ), and their analogs are described in the following literature. K C. Nicolaou et al ., J. Am. Chem. Soc. 117, 2409-2420, (1995); Ojima et al, J. Med. Chem. 39:3889 -3896 (1996); 40:267-278 (1997); 45, 5620-5623 (2002); Ojima et al., Proc. Natl. Acad. Sci., 96:4256-4261 (1999; Kim et al., Bull. Korean Chem. Soc., 20, 1389-1 390 (1999); Miller, et al. J. Med. Chem., 47, 4802-4805(2004); U.S. Patent Nos. 5,47 5,011 5,728,849, 5,811,452; 6,340,701; 6,372,738; 6,391,913, 6.436,931; 6,589,97 9; 6,596,757; 6,706,708; 7,008,942; 7,186,851; 7,217,819; 7,276,499; 7,598,290; and 7,667,054.

[0204] As an example of the structure of the antibody-taxane conjugate via the conjugate of this patent, the following Tx0 1, Tx02, and Tx03 are mentioned.

[0205]

Chemical formula

[0206] In the formula, mAb is an antibody or a cell-binding molecule; [Chemical formula] represents a single bond or a double bond; n, m1, X1, L1, L2, and R1 have the same definitions as in formula (I) and (II); R 1’ and R 3’ are each independently H or a C1-C6 linear or branched alkyl; p is from 0 to 2000; furthermore, R 1’ may be a cytotoxic agent, Drug1, as described throughout this patent. CC-1065 analogs and duocarmycin analogs are also

[0207] preferred for use in the conjugation by the crosslinking conjugate of the present invention. Examples of CC-1065 analogs and duocarmycin analogs, and their syntheses, are described in the following references: For example, Warpehoski, et al, J. Med. Chem. 31:590-603 (1988), D. Boger et al., J. Org Chem; 66; 6654-6661, 2001; U.S. Patent Nos.: 4169888, 4391904, 4671958, 4816567, 4912227, 4923990, 4952394, 4975278, 4978757, 4994578, 5037993, 5070092, 5084468, 5101038, 5117006, 5137877, 5138059, 5147786, 5187186, 5223409, 5225539, 528851 0, 5290843, 5304653, 5304654, 5310867, 5331192, 5336734, 5349137, 5359046, 5369134, 4, 5324483, 5332740, 5332837, 5334528, 5403484, 5427908, 5475092, 5495009, 55301 01, 5545806, 5547667, 5569825, 5571698, 5573922, 5580717, 5585089, 5585499, 5587 161, 5595499, 5606017, 5622929, 5625126, 5629430, 5633425, 5641780, 5660829, 566 1016, 5686237, 5693762, 5703080, 5712374, 5714586, 5739116, 5739350, 5770429, 57 73001, 5773435, 5786377 5786486, 5789650, 5814318, 5846545, 5874299, 5877296, 58 77397, 5885793, 5939598, 5962216, 5969108, 5985908, 6060608, 6066742, 6075181, 6 103236, 6114598, 6130237, 6132722, 6143901, 6150584, 6162963, 6172197, 6180370, 6194612, 6214345, 6262271, 6281354, 6310209, 6329497, 6342480, 6486326, 651210 1, 6521404, 6534660, 6544731, 6548530, 6555313, 6555693, 6566336, 6,586,618, 65 93081, 6630579, 6,756,397, 6759509, 6762179, 6884869, 6897034, 6946455, 7,049,31 6, 7087600, 7091186, 7115573, 7129261, 7214663, 7223837, 7304032, 7329507, 7,329 , 760, 7,388,026, 7,655,660, 7,655,661, 7,906,545, and 8,012,978. An example of the structure of the conjugate of an antibody-CC-1065 analog through the cross-linked linker of this patent is as follows: CC01, CC02, and CC03 are listed below. CC02, and CC03 are listed below.

[0208]

Chemical formula

[0209] In the formula, mAb is an antibody; Z3 is H, PO(O)(OM1)(OM2), SO3M1 , CH2PO(OM1)(OM2), CH3N(CH2CH2)2NC(O)-, O(C H2CH2)2NC(O)-, R1, or a glycoside; X3 is O, NH, NHC(O) , OC(O), -C(O)O, or R1, or does not exist;

Chemical formula

Chemical formula

[0210] Daunorubicin / doxorubicin analogs are also preferred for conjugation via the cross-linked conjugates of this patent. Their preferred structures and synthetic methods are exemplified below: Hurwitz, E., et al ., Cancer Res. 35, 1175-1181 (1975). Yang, H. M., and Reisfeld, R. A., Proc. Nat l. Acad. Sci. 85, 1189-1193 (1988); Pietersz, C. A., E., et al., E., et al.," C ancer Res. 48, 926-9311 (1988); Trouet, et al., 79, 626-629 (1982); Z. Brich et al., J. Controlled Release, 19, 245-258 (1992); Chen et al., Syn. Comm., 33, 23 77-2390, 2003; King et al., Bioconj. Chem., 10, 279-288, 1999; King et al., J. M ed. Chem., 45, 4336-4343, 2002; Kratz et al., J Med Chem. 45, 5523-33. 2002; Kra tz et al., Biol Pharm Bull. Jan. 21, 56-61, 1998; Lau et al., Bioorg. Med. Chem . 3, 1305-1312, 1995; Scott et al., Bioorg. Med.l Chem. Lett. 6, 1491-1496; 199 6; Watanabe et al., Tokai J. Experimental Clin. Med. 15, 327-334, 1990; Zhou et et al., J. Am. Chem. Soc. 126, 15656-7, 2004; WO 01 / 38318; U.S. Patent No. 5,106,951; 5 ,122,368; 5,146,064; 5,177,016; 5,208,323; 5,824,805; 6,146,658; 6,214,345; 7569 358; 7,803,903; 8,084,586; 8,053,205. An example of the structure of the conjugate of the antibody-CC-10 65 analogs is shown below as Da01, Da02, Da03, and D a04.

[0211]

Chemical formula

[0212] In the formula, mAb is an antibody or a cell-binding molecule;

Chemical formula

[0213] Auristatins and dolastatins ins are preferred for conjugation via the linker conjugate of the present invention. Auristatins (e.g., auristatin E (AE), auristatin EB (AEB), auristatin EFP (A EFP), monomethyl auristatin E (MMAE), monomethyl auristatin (MM AF), auristatin F phenylenediamine (AFP), and phenylalanine mutants of MMAE are synthetic analogs of dolastatins and are described in the following literature: In t. J. Oncol. 15:367-72 (1999); Molecular Cancer Therapeutics, vol. 3, No. 8, pp. 921-932 (2004); US Patent Application 11134826, 20060074008, 2006022925. US Patent No. 4414 205, 4753894, 4764368, 4816444, 4879278, 4943628, 4978744, 5122368, 5165923, 516 9774,5286637, 5410024, 5521284, 5530097, 5554725, 5585089, 5599902, 5629197, 563 5483, 5654399, 5663149, 5665860, 5708146, 5714586, 5741892, 5767236, 5767237, 57 80588, 5821337, 5840699, 5965537, 6004934, 6033876, 6034065, 6048720, 6054297, 6 054561, 6124431, 6143721, 6162930, 6214345, 6239104, 6323315, 6342219, 6342221, 6407213, 6569834, 6620911, 6639055, 6884869, 6913748, 7090843, 7091186, 7097840, 7098305, 7098308, 7498298, 7375078, 7462352, 7553816, 7659241, 7662387, 7745394 , 7754681, 7829531, 7837980, 7837995, 7902338, 7964566, 7964567, 7851437, 799413 5. As an example of the structure of the conjugate of an antibody - auristatins via the cross - linked linker of this patent, the following Au01, Au02, Au03, Au04, Au05, Au06, Au07, Au 08, Au09, Au10, Au11, Au12, and Au13 are exemplified.

[0214]

Chemical formula

[0215] In the formula,

Chemical formula

[0216] Preferred benzodiazepine dimers as the cytotoxic agents of the present invention (e.g., pyrrolobenzodiazepine (PBD) or (tomaymycin), indolinobenzodiazepines, imid azobenzodiazepines, or oxazolidinobenzodiazepine dimers) are exemplified in the prior art : U.S. Patent Nos. 8,163,736; 8,153,627; 8,034,808; 7,834,005; 7,741 ,319; 7,704,924; 7,691,848; 7,678,787; 7,612,062; 7,608,615; 7,557,099; 7,528,12 8; 7,528,126; 7,511,032; 7,429,658; 7,407,951; 7,326,700; 7,312,210; 7,265,105; 7,202,239; 7,189,710; 7,173,026; 7,109,193; 7,067,511; 7,064,120; 7,056,913; 7,0 67,511; 7,064,120; 7,056,913; 7,0 49,311; 7,022,699; 7,015,215; 6,979,684; 6,951,853; 6,884,799; 6,800,622; 6,747, 144; 6,660,856; 6,608,192; 6,562,806; 6,977,254; 6,951,853; 6,909,006; 6,344,451 ; 5,880,122; 4,935,362; 4,764,616; 4,761,412; 4,723,007; 4,723,003; 4,683,230; 4 ,663,453; 4,508,647; 4,464,467; 4,427,587; 4,000,304; U.S. Patent Application 20100203007, 2 0100316656, 20030195196. Conjugates of Antibody-Benzodiazepine Dimers via a Bridging Linker An example of the structure of the conjugate is shown in PB01, PB02, PB03, PB04, PB05, PB0 6, PB07, PB08, PB09, PB10, and PB11 below.

[0217] [Chemical formula] TIFF2025093934000097.tif215160TIFF2025093934000098.tif79161

[0218] wherein mAb is an antibody; X3 is CH2, O, NH, NHC(O), NHC(O)N H, C(O), OC(O), OC(O)(NR3), R1, NHR1, NR1, or C(O)R1, or is absent; X4 is CH2, C(O), C(O)NH, C( O)N(R1), R1, NHR1, NR1, C(O)R1, or C(O)O; M1 and M2 are each independently H, Na, K, Ca, Mg, NH4, NR1R2R3 ; [Chemistry] represents a single bond or a double bond; n, m1, m2, X1, X2, L1, L2, R1, R2, and R3 have the same definitions as in formulas (I) and (II); R 1’ and R 3’ are each independently H or a straight-chain or branched alkyl having 1-6 carbon atoms; p is from 0 to 2000; Furthermore, R 1’ may also be a cytotoxic agent, Drug1, described throughout this patent.

[0219] Some poisonous mushrooms, most notably Amanita phalloides and at least 10 toxic compounds found in some other mushroom species, amatoxins, which are also preferred for conjugation via the crosslinking conjugates of this application. α-Amanitin, β-amanitin, γ-amanitin, ε-amanitin, amanullin , amanullinic acid, amaninamid, amanine, and 10 amatoxins named proamanullin are hard bicyclic peptides, synthesized as 35-amino acid preproteins from which the last 8 amino acids are cleaved by prollyl oligopeptidase (Litten, W. 1975 Scientific American 232 (3): 90-101; H. E. Hallen, et al 2007 Proc. Natl. Acad. Sci. USA 104, 19097-101;. K. Baumann, et al, 1993 Biochemistry 32 (15) : 4043-50; Karlson-Stiber C, Persson H. 2003, Toxicon 42 (4): 339-49; Horgen, P. A. et al. 1978 Arch. Microbio. 118 (3): 317-9). The amatoxins are potent and selective inhibitors of RNA polymerase II (Pol II) and kill cells by stopping gene transcription and protein synthesis (Brodner, O. G. and Wieland, T. 1976 Biochemistry,15(16): 3480-4; Fiume, L., Curr Probl Clin Biochem, 1977, 7: 23-8; Karlson-Stiber C, Persson H. 2003, Toxicon 42(4): 339-49; Chafin, D. R., Guo, H. & Price, D. H. 1995 J. Biol. Chem. 270 (32): 19114-19; Wieland (1983) Int. J. Pept. Protein Res. 22(3): 257-76.). The amatoxins are obtained from collected Amanita phalloides mushrooms (Yocum, R. R. 1978 Bioc hemistry 17(18): 3786-9; Zhang, P. et al, 2005, FEMS Microbiol. Lett. 252(2), 22 3-8), or from fermentation using basidiomycetes (Muraoka, S. and Shinozawa T., 2000 J. Biosci. Bioeng. 89(1): 73-6), or from fermentation using A. fissa (Guo, X. W., et al, 2 006 Wei Sheng Wu Xue Bao 46(3): 373-8), or from the culture of Galerina fascicul ata or Galerina helvoliceps (WO / 1990 / 009799 ​​​, can be manufactured (JP11137291). However, the yields from these isolations and fermentations were very low (less than 5 mg / L in the culture broth). In the past 30 years, semi-chemical or synthetic production of several amatoxins and their analogs has been reported (W. E. Savige, A. Fonta na, Chem. Commun. 1976, 600-1; Zanotti, G., et al, Int J Pept Protein Res, 1981. 18(2): 162-8; Wieland, T., et al, Eur. J. Biochem. 1981, 117, 161-4; P. A. Bart lett, et al, Tetrahedron Lett. 1982, 23, 619-22; Zanotti, G., et al., Biochim B iophys Acta, 1986. 870(3): 454-62; Zanotti, G., et al., Int. J. Peptide Protein Res. 1987, 30, 323-9; Zanotti, G., et al., Int. J. Peptide Protein Res. 1987, 30, 450-9; Zanotti, G., et al., Int J Pept Protein Res, 1988. 32(1): 9-20; G. Z anotti, T. et al, Int. J. Peptide Protein Res. 1989, 34, 222-8; Zanotti, G., et al., Int J Pept Protein Res, 1990. 35(3): 263-70; Mullersman, J. E. and J. F. Pr eston, 3rd, Int J Pept Protein Res, 1991. 37(6): 544-51; Mullersman, J.E., et al , Int J Pept Protein Res, 1991. 38(5): 409-16; Zanotti, G., et al, Int J Pept Pr otein Res, 1992. 40(6): 551-8; Schmitt, W. et al, J. Am. Chem. Soc. 1996, 118, 4380-7; Anderson, M.O., et al, J. Org. Chem., 2005, 70(12): 4578-84; J. P. May, et al, J. Org. Chem. 2005, 70, 8424-30; F. Brueckner, P. Cramer, Nat. Struct. Mol. Biol. 2008, 15, 811-8; J. P. May, D. M. Perrin, Chem. Eur. J. 2008, 14, 340 4-9; J. P. May, et al, Chem. Eur. J. 2008, 14, 3410-17; Q. Wang, et al, Eur. J. Org. Chem. 2002, 834-9; May, J. P. and D. M. Perrin, Biopolymers, 2007. 88(5): 7 14-24; May, J. P., et al., Chemistry, 2008. 14(11): 3410-7; S. De Lamo Marin, et al, Eur. J. Org. Chem. 2010, 3985-9; Pousse, G., et al., Org Lett, 2010. 12(16) : 3582-5; Luo, H., et al., Chem Biol, 2014. 21(12): 1610-7; Zhao, L., et al., Ch embiochem, 2015. 16(10): 1420-5), most of these preparations are by partial synthesis Due to their extremely potent and unique cytotoxic mechanisms, amatoxins have been used as the payload of conjugates (Fiume, L., Lancet, 1969. 2 (7625): 853-4 ; Barbanti-Brodano, G. and L. Fiume, Nat New Biol, 1973. 243(130): 281-3; Bonett i, E., M. et al, Arch Toxicol, 1976. 35(1): p. 69-73; Davis, M. T., Preston, J. F. Science 1981, 213, 1385-1388; Preston, J.F., et al, Arch Biochem Biophys, 19 81. 209(1): 63-71; H. Faulstich, et al, Biochemistry 1981, 20, 6498-504; Barak, L.S., et al., Proc Natl Acad Sci U S A, 1981. 78(5): 3034-8; Faulstich, H. and L . Fiume, Methods Enzymol, 1985. 112: 225-37; Zhelev, Z., A. et al, Toxicon, 1987 . 25(9): 981-7; Khalacheva, K., et al, Eksp Med Morfol, 1990. 29(3): 26-30; U. B ermbach, H. Faulstich, Biochemistry 1990, 29, 6839-45; Mullersman, J. E. and J. F. Preston, Int. J. Peptide Protein Res. 1991, 37, 544-51; Mullersman, J.E. and J.F. Preston, Biochem Cell Biol, 1991. 69(7): 418-27; J. Anderl, H. Echner, H. Faulstich, Beilstein J. Org. Chem. 2012, 8, 2072-84; Moldenhauer, G., et al, J. Natl. Cancer Inst. 2012, 104, 622-34; A. Moshnikova, et al; Biochemistry 2013, 5 2, 1171-8; Zhao, L., et al., Chembiochem, 2015. 16(10): 1420-5; Zhou, B., et al. , Biosens Bioelectron, 2015. 68: 189-96; WO2014 / 043403, US20150218220, EP 166158 4). We have been working on amatoxin conjugates for some time. Through the linker An example of the structure of an antibody - amatoxin conjugate is preferably the following Am01, Am02, Am03, and Am04.

[0220]

Chemical formula

[0221] wherein, mAb is an antibody; X3 is CH2, O, NH, NHC(O), NHC(O)N H, C(O), OC(O), OC(O)(NR3), R1, NHR1, NR1, or C(O)R1, or does not exist; R7, R8, R9, R 10 , and R 11 are each independently H, OH, OR1, NH2, NHR1, or C1 - C6 alkyl ​either present or absent; Y1 is O, O2, S, or NH, or is absent;

Chemical formula

[0222] In yet another embodiment, it is preferred that two or more different cytotoxic agents are conjugated with the cell-binding molecule via the cross-linking conjugate of the present invention. The two or more different cytotoxic agents are tubulysins, maytansinoids, taxanoids (taxanes), CC-1065 analogs, daunorubicin and doxorubicin compounds, benzodiazepine dimers (e.g., pyrrolobenzodiazepine (PBD), tomamycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines, or oxazolidinobenzodiazepines dimers), calicheamicins and enediyne antibiotics, actinomycin, amanitin analogs, azaserines, bleomycins, epirubicin, tamoxifen, idarubicin, dolastatin analogs, auristatin analogs (e.g., monomethyl auristatin E, MMAE, MMAF, auristatin PYE, auristatin TP, auristatin 2-AQ, 6- AQ, EB (AEB), and EFP (AEFP)), duocarmycins, thiotepa, vincristine analogs, hemiasterlins, nazumamides, miku Microginins, radiosumins, Alterobactins, microsclerodermicins (m icrosclerodermins, theonellamides s), esperamicins, PNU-159682, and The bridge linker may be selected from any combination of analogs and derivatives thereof. An example of the structure of a conjugate containing two or more different cytotoxic agents via the aryloxy group is shown below: Z03, Z04, Z05, Z06, Z07, Z08, Z09, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, and Z18.

[0223] [ka] TIFF2025093934000104.tif201166TIFF2025093934000105.tif237163TIFF2025093934000106.tif216161TIFF2025093934000107.tif229163

[0224] wherein mAb is an antibody; X3 and X'3 are each independently CH2, O, NH, NHC(O), NHC(O)NH, C(O), OC(O), OC(O)(NR3), R1 , NHR1, NR1, or C(O)R1, or absent; X4 and X'4 are each independently H, CH2, OH, O, C(O), C(O)NH, C(O)N(R 1), R1, NHR1, NR1, C(O)R1, or C(O)O; M1 and M2 are are independently H, Na, K, Ca, Mg, NH4, NR1R2R3; n, m1, m2, [ka] X1, X2, R1, R2, and R3 have the same definitions as in formulas (I) and (II); further, R1 and / or R2 may each independently not be present.

[0225] In yet another embodiment, the immunotoxin can be conjugated to a cell-binding molecule via the linker of the present application. The immunotoxins herein are typically high molecular weight drugs that are cytotoxic proteins derived from bacterial or plant proteins such as diphtheria toxin (DT), cholera toxin (CT), trichosanthin (TCS), dianthin, Pseudomonas exotoxin A (ET A’), hemolysin, diphtheria toxin, AB toxin, type III exotoxin, etc. It can also be a very toxic bacterial pore-forming protoxin that requires proteolytic processing for activation. Examples of this protoxin include proaerolysin and its genetically modified forms, as well as topsalysin. Topsalysin is a modified recombinant protein designed to be selectively activated by a prostate enzyme and causes local cell death and tissue destruction without damaging adjacent tissue and nerves.

[0226] In yet another embodiment, the cell-binding ligand or cell receptor agonist can be conjugated to a cell-binding molecule via the linker of the present application. These conjugated cell-binding ligands or receptors, particularly antibody-receptor conjugates, not only act as targeting conductors / directors for delivering the conjugate to malignant cells, but can also be used to regulate or costimulate the desired immune response, or to alter signaling pathways.

[0227] ​​​​​In immunotherapy, the cell-binding ligand or receptor agonist is preferably conjugated to an antibody of a TCR (T cell receptor ) T cell, or a CAR (chimeric antigen receptor) T cell, or a B cell receptor (BCR), a natural killer (NK) cell, or a cytotoxic cell. Such antibodies are preferably anti-CD3, CD4, CD8, CD16 (FcγRIII), CD27, CD40, CD40L, CD45RA, CD45RO, CD56, CD57, CD57 CD57 bright , TNFβ, Fas ligand, MHC class I molecules (HAL-A, B, C), or NKR-P1. The cell-binding ligand or receptor is not limited, but includes folic acid derivatives (binding to folate receptors, proteins overexpressed in ovarian cancer and other malignancies (Low, P. S. et al 2008, Acc. Chem. Res. 41, 120-129)); glutamate derivatives (binding to prostate-specific membrane antigen, a surface marker of prostate cancer cells) (Hillier, S. M.et al, 2009, Cancer Res. 69, 6932-6940); somatostatin (growth hormone-inhibiting hormone (GHIH), somatotropin release-inhibiting factor (SRIF), or somatotropin release inhibiting hormone, also known as) and their derivatives, such as octreotide (sandostatin) and lanreotide (somatuline) (especially for neuroendocrine tumors, GH-producing pituitary adenomas, paragangliomas, non-functional pituitary adenomas, pheochromocytomas) (Ginj, M., et al, 2006, Pro c. Natl. Acad. Sci. U.S.A. 103, 16436-16441); generally, somatostatin and its receptors subtypes (sst1, sst2, sst3, sst4, and sst5) are within the nervous system (Ginj, M., et al, 2006, Proc. Natl. Acad. Sci. U.S.A. 103, 16436-16441); generally, somatostatin and its receptors subtypes (sst1, sst2, sst3, sst4, and sst5) are within the nervous Many types of tumors, such as secretory tumors, especially GH-secreting pituitary adenomas (Reubi J. C., Landolt, A. M. 1984 J. Clin. Endocrinol Metab 59: 1148-51; Reubi J. C., Landolt A. M. 1987 J Clin Endocrinol Metab 65: 65-73; Moyse E, et al, J Clin Endocrinol Metab 61: 98-103) and gastrointestinal pancreatic tumors (Reubi J. C., et al, 1987 J Clin Endocrinol Metab 65: 11 27-34; Reubi, J. C, et al, 1990 Cancer Res 50: 5969-77), pheochromocytomas (Epel-baum J, et al 1995 J Clin Endocrinol Metab 80:1837-44; Reubi J. C., et al, 1992 J Cl in Endocrinol Metab 74: 1082-9), neuroblastomas (Prevost G, 1996 Neuroendocrinolo gy 63:188-197; Moertel, C. L, et al 1994 Am J Clin Path 102:752-756), medullary thyroid carcinomas (Reubi, J. C, et al 1991 Lab Invest 64:567-573), small cell lung carcinomas (Sagman U, et al, 1990 Cancer 66:2129-2133), and non-neuroendocrine tumors including brain tumors such as meningiomas, medulloblastomas, gliomas, etc. (Reubi J. C., et al 1986 J Clin Endocrinol Metab 63: 433-8; Reubi J . C., et al 1987 Cancer Res 47: 5758-64; Fruhwald, M. C, et al 1999 Pediatr Res . C., et al 1987 Cancer Res 47: 5758-64; Fruhwald, M. C, et al 1999 Pediatr Res 45: 697-708), breast cancer (Reubi J. C., et al 1990 Int J Cancer 46: 416-20; Srkalov ic G, et al 1990 J Clin Endocrinol Metab 70: 661-669), lymphoma (Reubi J. C., e t al 1992, Int J Cancer50: 895-900), renal cell carcinoma (Reubi J. C., et al 1992, Cance r Res 52: 6074-6078), mesenchymal tumors (Reubi J. C., et al 1996 Cancer Res 56: 1922-3 1), prostate (Reubi J. C., et al 1995, J. Clin. Endocrinol Metab 80: 2806-14; et al 1989, Prostate 14:191-208; Halmos G, et al J. Clin. Endocrinol Metab 85: 2564 -71), ovary (Halmos, G, et al, 2000 J Clin Endocrinol Metab 85: 3509-12; Reubi J. C., et al 1991 Am J Pathol 138:1267-72), stomach (Reubi J. C., et al 1999, Int J Cancer 81: 376-86; Miller, G. V, 1992 Br J Cancer 66: 391-95), hepatocellular (Kourou malis E, et al 1998 Gut 42: 442-7; Reubi J. C., et al 1999 Gut 45: 66-774), and pharyngeal cancer (Loh K. S, et al, 2002 Virchows Arch 441: 444-8); specific aromatic sulfonamides specific for carbonic anhydrase IX (a marker for hypoxia and renal cell carcinoma) ​Neri, D., et al, Nat. Rev. Drug Discov. 2011, 10, 767-777); pheochromocytoma and paraganglioma Pituitary adenylate cyclase-activating peptide (PACAP) for pheochromocytoma and paraganglioma (PAC 1); Vasoactive intestinal peptide (VIP) and its receptor subtypes (VPAC1, VCA P2) for lung, stomach, colon, rectum, breast, prostate, pancreatic duct, liver, bladder, and epithelial cancers; α-Melanocyte-stimulating hormone (α-MSH) receptor for various tumors; Cholecystokinin (CCK) / gastrin receptor and its receptor subtypes (CCK1 (formerly CCK -A) and CCK2) for small cell lung cancer, medullary thyroid cancer, astrocytoma, insulinoma, and ovarian cancer; Bombesin (Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) / gastrin-releasing peptide (GRP) and its receptor subtypes (BB1, GRP receptor subtype (BB2), BB3, and BB4) for renal cell carcinoma, breast cancer, lung cancer, gastric cancer, and prostate cancer, and neuroblastoma ( and neuroblastoma (neuroblastoma)); Neurotensin (NTR1, NTR2, NTR3) for small cell lung cancer, neuroblastoma, pancreatic cancer, and colon cancer; Substance P and its receptor subtypes for glioma (NK1 receptor for glioma, etc., ., 2009, Cur. Opin. Endocri. Diab. Obesity 16(1): 66-71, Gonzalez N, et al, 2008 , Cur. Opin. Endocri. Diab. Obesity 15(1), 58-64); ​​ Hennig I. M., et al 1995 Int. J. Cancer 61, 786-792); Neuropeptide Y and its receptor subtypes (Y1-Y6) for breast cancer; RGD (Arg-Gly-Asp), NGR (Asn -Gly-Arg), dimeric and multimeric cyclic RG D peptides that recognize receptors (integrins) on the tumor surface (e.g., cRGDfV) (Laakkonen P, Vuorinen K. 2010, Integr Biol ( Camb). 2(7-8): 326-337; Chen K, Chen X. 2011, Theranostics. 1:189-200; Garanger E, et al, Anti-Cancer Agents Med Chem. 7 (5): 552-558; Kerr, J. S. et al, Antica ncer Research, 19(2A), 959-968; Thumshirn, G, et al, 2003 Chem. Eur. J. 9, 2717- 2725), as well as TAASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteoglycan NG2 receptor) and F3 peptide (a 31-amino acid peptide that binds to cell surface-expressed nucleolin receptor) (Zitzmann, S., 2002 Cancer Res., 62, 18, pp. 5139 -5143, Temminga, K., 2005, Drug Resistance Updates, 8, 381-402; P. Laakkonen an d K. Vuorinen, 2010 Integrative Biol, 2(7-8), 326-337; M. A. Burg, 1999 Cancer R es., 59(12), 3076-3080; S. Zitzmann, 2002 Cancer Res., 62(18), 5139-5143; K. Temminga, 2005 Drug Resistance Updates, 8(6), 381-402; P. Laakkonen and K. Vuorinen, 2010 Integrative Biol, 2(7-8), 326-337; M. A. Burg, 1999 Cancer R e.g., 59(12), 2869 - 2874; K. Porkka, et al 2002, Proc. Nat. Acad. Sci. USA 99(11) , a homing peptide containing 7444 - 9); a cell - penetrating peptide (CPP) (Nakase I, et al l, 2012, J. Control Release. 159(2),181 - 188); a peptide hormone, e.g., test osterone production, as well as follicle - stimulating hormone (FSH) and luteinizing hormone (LH) targets Luteinizing hormone - releasing hormone (LHRH) agonists and antagonists that act by targeting luteinizing hormone production, as well as gonadotropin - releasing hormone (GnRH) agonists, e.g., buserelin (Pyr - His - Trp - Ser - Tyr - D - Ser(OtBu)-Leu - Arg - Pro - NHEt), gonadorelin (Pyr - His - Trp - Ser - Tyr - Gly - Leu - Arg - Pro - Gly - NH2), goserelin (Pyr - His - Trp - Ser - Tyr - D - Ser(OtB u)-Leu - Arg - Pro - AzGly - NH2), histrelin (Pyr - His - Trp - Ser - Tyr - D - His(N - benzyl)- Leu - Arg - Pro - NHEt), leuprolide (Pyr - His - Trp - Ser - Tyr - D - Leu - Leu - Arg - Pro - NHEt), nafarelin (Pyr - His - Trp - Ser - Tyr - 2Nal - Leu - Arg - Pro - Gly - NH2), tryptorelin (Py r - His - Trp - Ser - Tyr - D - Trp - Leu - Arg - Pro - Gly - NH2), nafarelin, deslorelin, abarelix (Ac - D - 2Nal - D - 4 - chloroPhe - D - 3-(3 - pyridyl)Ala - Ser-(N - Me)Tyr - D - Asn - Leu - ​​isopropylLys-Pro-DAla-NH2), cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-py ridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2), degarelix (Ac-D-2Nal-D-4- chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(car bamoyl)-Leu-isopropylLys-Pro-D-Ala-NH2), and ganirelix (Ac-D-2Nal-D-4-ch loroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-(N9, N10-diethyl)-homoArg-Leu-(N9, N10-di ethyl)-homoArg-Pro-D-Ala-NH2)(Thundimadathil, J., J. Amino Acids, 2012, 96734 7, doi:10.1155 / 2012 / 967347; Boccon-Gibod, L.; et al, 2011, Therapeutic Advances in Urology 3 (3): 127-140; Debruyne, F., 2006, Future Oncology, 2(6), 677-696; Schally A. V; Nagy, A. 1999 Eur J Endocrinol 141:1-14; Koppan M, et al 1999 Pros tate 38:151-158); and for example, small molecules (imiquimod, guanidine and adenosine analogues), from lipopolysaccharide (LPS), nucleic acids (CpG DNA, polyI:C) and lipope ptide (Pam3CSK4)(Kasturi, S. P., et al, 2011, Nature 470, 543-547; Lan e, T., 2001, J. R. Soc. Med. 94, 316; Hotz, C., and Bourquin, C., 2012, Oncoimmu nology 1, 227-228; Dudek, A. Z., et al, 2007, Clin. Cancer Res. 13, 7119-7125) Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), C -type lectins, and Nod-like receptors (NLRs) (Fukata, M., et al, 2009, Semin. Immu nol. 21, 242-253; Maisonneuve, C., et al, 2014, Proc. Natl. Acad. Sci. U. S. A. 111, 1-6; Botos, I., et al, 2011, Structure 19, 447-459; Means, T. K., et al, 2 000, Life Sci. 68, 241-258), which recognize up to large and complex biomacromolecules. Calcitonin receptor, a 32-amino acid neuropeptide that is widely involved in the regulation of calcium levels due to its effects on osteoclasts and the kidney (Zaidi M, et al, 1990 Crit Rev Clin Lab Sci 28, 109-174 ; Gorn, A. H., et al 1995 J Clin Invest 95:2680-91); integrin receptors and their receptor subtypes (e.g., αVβ1, αVβ3, αV β5, αVβ6, α6β4, α7β1, αLβ2, αIIbβ3) that are expressed on the surface of various cells, especially osteoclasts, endothelial cells, and tumor cells and generally play an important role in angiogenesis (Ruoslahti, E. et a l). l, 1994 Cell 77, 477-8; Albelda, S. M. et al, 1990 Cancer Res., 50, 6757-64). Short peptides and GRGDSPK that showed high binding affinity for integrin receptors, and Cyclic RGD pentapeptides such as cyclo(RGDfV)(L1) and their derivatives [cyclo( -N(Me)R-GDfV), cyclo(R-Sar-DfV), cyclo-(RG-N(M e)D-fV), cyclo(RGD-N(Me)f-V), cyclo(RGDf-N(Me) V-)(Cilengitide)] (Dechantsreiter, M. A. et al, 1999 J. Med. Ch em. 42, 3033-40, Goodman, S. L., et al, 2002 J. Med. Chem. 45, 1045-51).

[0228] Cell-binding ligands or cell receptor agonists can be Ig-based and non-Ig-based tan Protein scaffold molecules. Ig-based scaffolds include, but are not limited to, Nanobodies (derivatives of VHH (camelid Ig)) (Muyldermans S., 20 13 Annu Rev Biochem. 82, 775-797); Domain antibodies (dAb, derivatives of VH or VL domains )(Holt, L. J, et al, 2003, Trends Biotechnol. 21, 484-490); Bispecific T cell engagers (BiTE, bispecific dimers) (Baeuerle, P. A, et al, 2009, Curr. Opin. M ol. Ther. 11, 22-30); Dual-affinity retargeting (DART, bispecific dimers) (Moore P . A. P, et al. 2011, Blood 117(17), 4542-4551); tetravalent tandem antibody (TandAb , bispecific dimer) (Cochlovius, B, et al. 2000, Cancer Res. 60(16):...

Claims

1. Linker compounds of formula (I) and (II): 【Chemistry 1】 During the ceremony, 【Chemistry 2】 represents a single bond, and when bonded to a single bond or a double bond, 【Chemistry 3】 may be an enantiomeric or stereoisomeric bond; 【Chemistry 4】 represents either a single bond, a double bond, or a triple bond; 【Chemistry 5】 When represents a single bond, Lv １ and Lv ２ are not both H; 【Chemistry 6】 When represents a double bond, Lv １ and Lv ２ Either of these can be H, but at the same time It will not become H; 【Chemistry 7】 When represents a triple bond, Lv １ does not exist, Lv ２ is optionally H; Lv １ and Lv ２ represents the same or different leaving groups that can be displaced by a thiol, Halides (selected from fluoride, chloride, bromide, and iodide), methanesulfur toluenesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethylsulfonyl (tosyl) Fluoromethylsulfonate, trifluoromethylsulfonate, nitrophenoxyl, N-succinimide Midyloxyl (NHS), phenoxyl; dinitrophenoxyl; pentafluorophenoxyl Noxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluorophenoxyl xyl, monofluorophenoxyl, pentachlorophenoxyl, 1H-imidazole- 1-yl, chlorophenoxyl, dichlorophenoxyl, trichlorophenoxyl, tetrachlorophenoxyl Lachlorophenoxyl, N-(benzotriazolyl)oxyl, 2-ethyl-5- Phenylisoxazolium-3'-sulfonyl, Phenyloxadiazole-sulfonyl (-sulfone-ODA), 2-ethyl-5-phenylisoxazolium-yl, phenyl Oxadiazol-yl (ODA), oxadiazol-yl, or EDC (N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide), DCC (dicyclohexyl -carbodiimide), N,N'-diisopropylcarbodiimide (DIC), N-cyclo Hexyl-N'-(2-morpholinoethyl)carbodiimide meso-p-toluenesulfonate CMC, or CME-CDI, 1,1'-carbonyldiimidazole (CDI) , TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl fluorouronium tetrafluoroborate), N,N,N',N'-tetramethyl-O-(1 H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) ), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium Benzotriazol-1-yloxy)triptyline (BOP), Lolidinophosphonium hexafluorophosphate (PyBOP), diethylcyanophos Formamide (DEPC), chloro-N,N,N',N'-tetramethylformamidinium Hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2 ,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate HATU, 1-[(dimethylamino)(morpholino)methylene]-1H-[1,2 ,3]triazolo[4,5-b]pyridin-1-ium-3-oxide hexafluorophore Sulfate (HDMA), 2-chloro-1,3-dimethylimidazolidinium hexafluoride Orophosphate (CIP), Chlorotripyrrolidinophosphonium hexafluorophosphate Phosphate (PyCloP), fluoro-N,N,N',N'-bis(tetramethylene)phosphate Muamidinium hexafluorophosphate (BTFFH), N,N,N',N'-tetrafluoroethylene Trimethyl-S-(1-oxido-2-pyridyl)thiuronium hexafluorophosphate O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethylthio Tetrafluoroborate (TPTU), S-(1-oxido-2-pyridyl)- N,N,N',N'-Tetramethylthiuronium tetrafluoroborate, O-[(ethoxy) [N,N,N',N'-tetramethyluronium] Hexafluorophosphate (HOTU), (1-cyano-2-ethoxy-2-oxo ethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophore Sulfate (COMU), O-(benzotriazol-1-yl)-N,N,N',N' -Bis(tetramethylene)uronium hexafluorophosphate (HBPyU), N- benzyl-N'-cyclohexylcarbodiimide (with or without polymer linkage); Dipyrrolidino(N-succinimidyloxy)-carbenium hexafluorophosphate hexafluorophosphate (Py CIU), 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (C IB), (benzotriazol-1-yloxy)dipiperidinocarbenium hexafluoro Orophosphate (HBPipU), O-(6-chlorobenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), Bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP) , propylphosphonic anhydride (PPACA, T3P (registered trademark)), 2-morpholinoethyl N,N,N',N'-tetramethyl-O-(N-succinimide) 2-Bromo-1-ethyl -pyridinium tetrafluoroborate (BEP), O-[(ethoxycarbonyl)sia 3,4-Dimethylamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate TOTU, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)- 4-Methylmorpholinium chloride (MMTM, DMTMM), N,N,N',N'-tetramethylmorpholinium chloride Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TST U), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl )-N,N,N',N'-tetramethyluronium tetrafluoroborate (TDBTU ), 1,1'-(azodicarbonyl)dipiperidine (ADD), di-(4-chlorobenzene di-tert-butyl azodicarboxylate (DCAD), diisopropyl azodicarboxylate (DBAD), diisopropyl azodicarboxylate (DIAD), or diisopropyl azodicarboxylate (DIAD) Select from intermediates produced by condensation reagent of ethyl azodicarboxylate (DEAD) And; Y reacts with a drug or cytotoxic agent to form a disulfide, ether, ester, thioether, or esters, thioesters, peptides, hydrazones, carbamates, carbonates, amines (secondary , tertiary, or quaternary), imines, cycloheteroalkanes, heteroaromatics, alkyloximes or a functional group capable of forming an amide bond, and Y is selected from the following structures: ： 【Chemistry 8】 【change】 During the ceremony, X １’ is F, Cl, Br, I, or Lv ３ and X ２’ is O, NH, N(R １ ),also is CH ２ and R ３ and R ５ are each independently H, R １ , aromatic, heteroaromatic, or one or more H atoms are -R １ , -halogen, -OR １ , -SR １ , -NR １ R ２ , -NO ２ , -S(O)R １ , -S(O) ２ R １ , or -COOR １ Aromatic substituted with group; Lv ３ Nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol ;Difluorophenol;Monofluorophenol;Pentachlorophenol;Trifluorophenol Imidazole; Dichlorophenol; Tetrachlorophenol; 1-Hydroxybenzyl Tosylate; Mesylate; 2-Ethyl-5-phenylisoxazolidinium an acid anhydride selected from the group consisting of 3'-sulfonate, acetic anhydride, and formic anhydride; or for peptide coupling reactions, or a leaving group selected from intermediates generated by condensation reagents for the reaction; R １ does not exist or C １ -C ８ Alkyl; C ２ -C ８ Heteroalkyl, alkyl C cycloalkyl, heterocycloalkyl; ３ -C ８ Aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, Heteroaryl; or C ２ -C ８ (C2-8) esters, ethers, amides, and amino acids amines, imines, polyamines, hydrazines, hydrazones, ureas, semicarbazides, carbazines Alkoxyamines, alkoxylamine, urethane, amino acid, acyloxyamine , glycoside, or hydroxamic acid; or a peptide containing 1 to 8 amino acids, or The structural formula (OCH ２ CH ２ ) ｐ Or (OCH ２ CH (CH ３ )) ｐ (p; 0 to about 1 000), or a combination thereof; TはCH ２ 、NH、NH、N(R ３ )、N(R ３ )N(R ３’ )、O、S、C ２ - C ８ Heteroalkyl, alkylcycloalkyl, heterocycloalkyl of C ３ -C ８ of Aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloa alkyl, alkylcarbonyl, heteroaryl; peptides containing 1 to 4 amino acid units D; or one of the following structures: 【Chemistry 9】 【change】 【change】 During the ceremony, 【Chemistry 10】 is the linking site; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X １’ , X ２’ , and X ３’ are independent of each other. ,NH;NHNH;N(R ３ );N(R ３ ) N (R ３’ );O;S;C １ -C ６ Alki Ru;C ２ -C ６ heteroalkyl, alkylcycloalkyl, heterocycloalkyl of the formula; C ３ -C ８ Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkyl or 1 to 8 amino acids. ; In the formula, R ３ and R ３’ are each independently H; １ -C ８ Alkyl; C ２ -C ８ The Hete cycloalkyl, alkylcycloalkyl, heterocycloalkyl; ３ -C ８ Aryl of Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, a alkylcarbonyl, heteroaryl; １ -C ８ an ester, ether or amide of Or the structural formula (OCH ２ CH ２ ) ｐ Or (OCH ２ CH (CH ３ )) ｐ (p; 0 to about 1 000), or a combination thereof; m,m １ , m ２ , m ３ , m ４ , and m ５ are each independently 1 to 10, preferably is an integer from 1 to 4; L １ and L ２ are each independently the same or different, O, NH, S, NHNH, N( R ３ ), N(R ３ ) N (R ３’ ), formula (OCH ２ CH ２ ) ｐ OR ３ , or (OCH ２ CH (CH ３ )) ｐ OR ３ , or NH(CH ２ CH ２ O) ｐ R ３ , or NH(C H ２ CH (CH ３ ) O) ｐ R ３ , or N[(CH ２ CH ２ O) ｐ R ３ ][(CH ２ C H ２ O) ｐ’ R ３’ ], or (OCH ２ CH ２ ) ｐ C(=O)X １ R ３ , or C H ２ CH ２ (O.C.H. ２ CH ２ ) ｐ C(=O)X １ R ３ Polyethyleneoxy units, p and p' are independently an integer from 1 to about 1000, or a combination thereof; １ -C ８ Alkyl; C ２ -C ８ Heteroalkyl, alkylcycloalkyl, and heterocyclo Alkyl; C ３ -C ８ Ar-aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, Heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; １ , R ３ , and R ３’ is as defined above; L １ Or L ２ The peptide unit may be a self-immolative or non-self-immolative component, a peptide unit (1-8 natural or non-natural amino acid units). amino acid), hydrazone bond, disulfide bond, ester bond, oxime bond, amide bond or a thioether bond, and the self-immolative unit may be a para-aminobenzyl group. dicarbamoyl (PAB) group, 2-aminoimidazole-5-methanol derivative, hetero From the group of ring PAB analogs, β-glucuronides, and o- or p-aminobenzyl acetals The aromatic compound is selected from the group consisting of: The self-immolative unit has one of the following structures: 【Chemistry 11】 In the formula, ( ＊ ) are atoms labeled with additional spacers or releasable linker units, cells X is a binding site for a damaging agent and / or a cell adhesion molecule (CBA); １ , Y １ , Z ２ , and Z ３ is independently NH, O or S; Z １ are independently H, NHR １ , OR １ , S.R. １ , COX １ R １ wherein X １ and R １ is defined as above; v is 0 or 1. Ru;U １ are independently H, OH, and C １ -C ６ Alkyl, (OCH ２ CH ２ ) ｎ , F, Cl, Br、I、OR ５ 、SR ５ 、NR ５ R ５ ’、N=NR ５ 、N=R ５ 、NR ５ R ５ ’、NO ２ 、SOR ５ R ５ '、SO ２ R ５ 、SO ３ R ５ 、OSO ３ R ５ 、PR ５ R ５ '、POR ５ R ５ ’, PO ２ R ５ R ５ ’, OPO (OR ５ )(OR ５ ’), or OCH ２ PO (OR ５ ) (OR ５ '), wherein R ５ and R ５ ' are each independently H, C １ -C ８ Al kill; C ２ -C ８ alkenyl, alkynyl, heteroalkyl, or aminocaine of the formula: C ３ -C ８ aryl groups, heterocycles, carbocycles, cycloalkyls, heterocycloalkyls, a tert-butyl group, an alkyl group, an alkylcarbonyl group, or a glycoside group; or a medicinal cationic salt; Selected; The non-self-immolative linker moiety is selected from one of the following structures: 【Chemistry 12】 【change】 【change】 In the formula, ( ＊ ) are atoms labeled with additional spacers or releasable linker units, cells X is a binding site for a damaging agent and / or a cell adhesion molecule (CBA); １ , Y １ , U １ , R ５ , and R ５ ' is as defined above; r is 0 to 100; m and n are each independently Standing is 0 to 6; Or, L １ , L ２ , X １ , X ２ , X ３ , X １’ , X ２’ , and X ３’ Each is unique It does not have to exist in isolation.

2. Formula (III), (IV), (V), (VI), (VII), (VIII), or (IX ) cell-binding agent-drug conjugate compound: 【Chemistry 13】 【change】 During the ceremony, n is 1 to 20; T has the same definition as in formula (I) above; Cb, Cb', Cb''Cb'' are the same or different and may be cell binding agents / molecules or immunoglobulins. represents an immunotherapeutic protein, preferably an antibody or an antibody fragment; Drug, Drug', and Drug'' are the same or different cytotoxic agents or treatments. Drugs, or immunotherapeutic proteins, antibodies or antibody fragments, or siRNA, miRNA, Promotes the binding or stabilization of mRNA, piRNA, or DNA, or cell-binding agents C represents a functional molecule for binding to a cell surface receptor or a cell surface receptor binding ligand; １ -C ８ of alkanes; C ２ -C ８ Alkylene, alkenylene, alkynylene, aromatic ring, ether, polyoxy Alkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide , urea, semicarbazide, carbazide, alkoxyamine, urethane, amino acid, peptide amides, acyloxyamines, hydroxamic acids, disulfides, thioethers, thioesters , carbamate, carbonate, heterocycle, heteroalkyl, heteroaromatic ring, or aryl coxime, or a combination thereof １ , R １’ , and R １’’ By linked to the cell binding agent via a linker; 【Chemistry 14】 represents a single bond or a double bond; m １ 、m １’ 、m １’’ 、m ２ 、m ２’ 、m ２’’ 、m ３ 、m ４ 、m ５ 、m ４’ 、m ５ ’ ,m ４’’ ,m ５’’ ,m ４’’’ ,m ５’’’ ,m ４’’’’ 、---- ５’’’’ 、 are each independently an integer from 1 to 10; X １ , X １’ , X １’’ , X １’’’ , and X ２’’’’ are each independently NH; NHNH;N(R ３ );N(R ３ ) N (R ３’ );O;S;C １ -C ６ Alkyl; C ２ - C ６ Heteroalkyl, alkylcycloalkyl, heterocycloalkyl of C ３ -C ８ of Aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloa alkyl, alkylcarbonyl, heteroaryl; 1 to 8 amino acids; ３ Reach BiR ３’ are each independently H; １ -C ８ Alkyl; C ２ -C ８ Heteroalkyl, A alkylcycloalkyl, heterocycloalkyl; ３ -C ８ Aryl, Ar-alkyl , heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl C, heteroaryl; １ -C ８ or an ester, ether or amide of the structural formula (O CH ２ CH ２ ) ｐ Or (OCH ２ CH (CH ３ )) ｐ (p is an integer from 0 to about 1000) or a combination thereof, and further comprising: X １ , X １’ , X １ ’’ , X １’’’ , and X ２’’’’ may each independently be absent; R １ , R ２ , R １’ , and R １’’ are the same or different, and C １ -C ８ Alkyl; C ２ -C ８ Heteroalkyl, alkylcycloalkyl, heterocycloalkyl of C ３ -C ８ Aryl, Ar-alkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcyclo alkyl, alkylcarbonyl, heteroaryl; ２ -C ８ Esters, ethers or or amide; or a compound represented by the structural formula (OCH ２ CH ２ ) ｐ Or (OCH ２ CH (CH ３ )) ｐ (p is an integer from 0 to about 1000), or a combination thereof. R; L １ , L １’ , L １’’ , L １’’’ , L ２ , L ２’ , L ２’’ , and L ２’’’ ,teeth The same or different and L of claim 1 １ and L ２ The same definition as １ , L １’ , L １ ’’ , L １’’’ , L ２ , L ２’ , L ２’’ , and L ２’’’ , is 6-maleimidocaprylamide methylproline (MC), maleimidopropanoyl (MP), valine-citrulline (val-ci t or vc), alanine-phenylalanine (ala-phe or af), p-aminobenzyl benzyloxycarbonyl (PAB), 4-thio-pentanoic acid ester (SPP), 4-( N-maleimidomethyl)cyclohexane-1-carboxylate (MCC), (4-a Cetyl)aminobenzoic acid (SIAB), 4-thio-butyric acid ester (SPDB), 4-thio -2-hydroxysulfonyl-butyric acid ester (2-sulfo-SPDB), one or more repeats Ethyleneoxy-CH as repeat unit ２ CH ２ O-(EO or PEO) The linker may be composed of one or more linker moieties.

3. Formula (X), (XI), (XII), (XIII), (XIV), (XV), or (XV Compound I: 【Chemistry 15】 【change】 During the ceremony, R １ 、R １’ 、R １’’ 、R ２ 、X １ 、X １’ 、X １’’ 、L １ 、L １’ 、L １’’ 、 L ２ 、L ２’ 、L ２’’ 、 【Chemistry 16】 Cb、m １ 、m １’ 、m １’’ 、m ２ 、m ２’ 、m ２’’ 、m ３ 、m ４ 、m ５ 、m ４’ 、 m ５’ , m ４’’ , and m ５’’ has the same definition as in claim 2; Y, Y', and Y'' are defined as Y in claim 1, and Y, Y', and Y'' are each independently a disulfide substituent, a maleimide, a haloacetyl, an alkoxyamine , azides, ketones, aldehydes, hydrazines, alkynes, N-hydroxysuccinimide esters, or carboxyl esters formed with phenol; dinitrophenol; Pentafluorophenol; Tetrafluorophenol; Difluorophenol; Monofluorophenol Pentachlorophenol; Triflate; Imidazole; Dichlorophenol phenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; silate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate may also be used. Y, Y', and Y'' are each independently a disulfide, a thioether, or a hydrazone; , amide, alkoxy, carbamate, ester, ether bond, or heteroaromatic ring and can react independently with cytotoxic agents.

4. Compounds of formula (XVII) or (XVIII): 【Chemistry 17】 【change】 During the ceremony, 【Chemistry 18】 L １ , L ２ , R １ , T, m １ , m ２ , m ３ , m ４ , m ５ , X １ , Lv １ , and Lv ２ teeth, The same definitions as in claim 1; and Drug １ has the same definition as in claim 2.

5. The conjugate compound of formula (III), (IV), (V) or (VI) of claim 2 is 190 with the aid of UV light having a wavelength in the range of 390 nm, II) is prepared by condensation of the compound with a pair of thiols in the cell-binding molecule.

6. The conjugate compound of formula (X), (XI), (XII), or (XIII) of claim 3 is with the aid of UV light having a wavelength in the range of 90 to 390 nm, It is prepared by condensation of a compound with a pair of thiols in the cell-binding molecule.

7. The pair of thiols of the cell-binding agent / molecule that is linked to the linker is dithiothreitol. Dithioerythritol (DTT), dithioerythritol (DTE), dithiolbutylamine (DTB A), L-glutathione (GSH), tris(2-carboxyethyl)phosphine (TC 2-mercaptoethylamine (β-MEA), or / and β-mercaptoethanol The cell-binding agent / molecule reduced by a reducing agent selected from the group consisting of β-ME and 2-ME.

4. The compound of claim 2 or 3, wherein the alkyl group is an intrachain disulfide atom.

8. The Drug, Drug', or Drug'' is independently selected from the following: The conjugate compound according to claim 2 or 4. (1) A chemotherapeutic agent selected from the group consisting of: a) an alkylating agent selected from the group consisting of: nitrogen mustard; chlorambucil; chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosulfan Famide, mechlorethamine, mechlorethamine oxide hydrochloride, mannommustine, mitobromide Nititol, Melphalan, Mitolactol, Pipobroman, Novenbitine, Fenesteryl , prednimustine, thiotepa, trofosfamide, uracil mustard; CC-10 65 (including synthetic analogues of adozelesin, carzelesin and bizelesin); Duocal mycin (including synthetic analogs, KW-2189 and CBI-TMI); benzodiazepines pyrrolobenzodiazepine (PBD) or tomaymycin, indolinobenzodimer Azepines, imidazobenzothiadiazepines, or oxazolidinobenzodiazepines ), nitrosoureas: (carmustine, lomustine, clomustine, Rozotocin, Fotemustine, Nimustine, Ranimustine); Alkyl sulfonates: ( busulfan, treosulfan, improsulfan and piposulfan); triazepam Platinum-containing compounds: (Carboplatin, Cisplatin, Oxaliplatin) tin); aziridines, benzodopa, carboquone, metholedopa and uredopa; ethylene Imines, as well as altretamine, triethylenemelamine, and triethylenephosphoramide , triethylenethiophosphoramine, and methylmelamines including trimethylolmelamine ； b) Plant alkaloids selected from the group consisting of: Vinca alkaloids: (Vincris vinblastine, vindesine, vinorelbine, navelbine); Taxoids: (pa Clitaxel, docetaxel) and their analogues, maytansinoids (DM1, DM 2, DM3, DM4, DM5, DM6, DM7, maytansine, ansamitocin) and These analogues, cryptophycins (cryptophycin 1 and cryptophycin 8 to Selected: epothilones, erytherobins, discodermolide, bryostaphylococcus aureus, statins, dolostatins, auristatins, tubulysins, cephalostatins; Pancratistatin; Sarcodictiin; Spongestatin; c) A DNA topoisomerase inhibitor selected from the group consisting of epipodophyllins: (9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etho poside, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoid retinols, teniposide, topotecan, 9-nitrocamptothecin (RFS 2000); Mitomycins: (Mitomycin C)); d) Antimetabolites selected from the group consisting of: {[antifolate: dihydrofolate reductase inhibitors Agents: (Methotrexate, Trimetrexate, Denopterin, Pteropterin, Amino Pterin (4-aminopteroic acid, or folic acid analogue); IMP dehydrogenase inhibitor agents (mycophenolic acid, tiazofurin, ribavirin, EICAR); Enzyme inhibitors (hydroxyurea, deferoxamine)]; [pyrimidine analogues: uracil ancitabine, azacitidine, 6-azauridine, capecitabine (Xeloda) , Carmofur, Cytarabine, Dideoxyuridine, Doxifluridine, Enocitabine, 5-fluorouracil, floxuridine, raltitrexed (Tomudex); Tosine analogues: (cytarabine, cytosine arabinoside, fludarabine); Purine analogues: (Azathioprine, Fludarabine, Mercaptopurine, Thiamiprine, Thioguanine)] ; folic acid supplement, floric acid}; e) A hormone therapy agent selected from the following group: {receptor antagonists: [anti-estrogen: ( Megestrol, raloxifene, tamoxifen); LHRH agonists: (Gossereli antiandrogens: (bicalutamide, flutamide, calcineurin, leuprolide acetate); , dromostanolone propionate, epithiostanol, goserelin, leuprolide , mepitiostane, nilutamide, testolactone, trilostane, and other androgens inhibitors)]; Retinoids / deltoid: [Vitamin D3 analogs: (CB1093, EB10 89, KH1060, cholecalciferol, ergocalciferol); photodynamic therapy Agents: (verteporfin, phthalocyanine, photosensitizer Pc4, demethoxy-hypocreli Cytokines: (interferon α, interferon γ, tumor necrosis factor ( TNF), TNF domain-containing human protein)]}; f) a kinase inhibitor selected from the group consisting of: BIBW2992 (anti-EGFR / Erb 2) Imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib , E7080 (anti-VEGFR2), mubritinib, ponatinib (AP24534), buff Etinib (INNO-406), bosutinib (SKI-606), cabozantinib, bis Modegib, Iniparib, Ruxolitinib, CYT387, Axitinib, Tivozanib, So Rafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab Bu, ispinesib; g) Olaparib, Niraparib, Iniparib, Talazoparib, Veliparib, CEP972 2 (Cephalon), E7016 (Eisai), BGB-290 (BeiGene ), or 3-aminobenzamide. lysine kinase (PARP) inhibitors; h) Antibiotics selected from the following group: enediyne antibiotics (calicheamicins, calicheamicin gamma 1, delta 1, alpha 1 and beta 1; dynemicin A and deoxydynemicin dynemicins including esperamicin, kedarcidin, C-1027, maduropeptin, and neocarzinostatin chromophore and related chromoprotein enediyne antibiotics chromophores), aclacinomycins, actinomycin , anthramycin, azaserine, bleomycins, cactinomycin omycin, carabicin, carminomycin, carzinophycin Phosphorus; chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazotidine 5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, Anomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxol Bicine, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin Mycophenolic acid, nogalamycin, olivomycins, peplomycin, pothofu thromycin, puromycin, queramycin, rodrubicin, streptonigrin , streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; i) Polyketides (acetogenins), bullatacin and bullatacinone; gemcitabine, Poxomicins (including carfilzomib), bortezomib, thalidomide, lenalid mide, pomalidomide, tosedostat, zybrestat, PLX4032, STA- 9090, Stimuvax, Allovectin-7, Zygeba, Probe , ervoy, isoprenylation inhibitors (selected from lovastatin), dopamine action Neurotoxicity (selected from 1-methyl-4-phenylpyridine ion), cell cycle inhibition Actinomycins (actinomycin D, daurosporine) cutinomycin), bleomycins (bleomycin A2, bleomycin B2, peplomycin), anthracyclines Daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin , pirarubicin, zorubicin), mitoxantrone, MDR Inhibitor or Verapamil, Ca ２＋ ATP inhibitors or thapsigargin, histone deacetylases Metabolic enzyme inhibitors (vorinostat, romidepsin, panobinostat, valproic acid, mocetin Nostat (MGCD0103), Belinostat, PCI-24781, Entinostat SB939, resminostat, gibinostat, AR-42, CUDC-101 , sulforaphane, trichostatin A); thapsigargin, Celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinospo Lamid A, anti-adrenal drugs (selected from the group consisting of aminoglutethimide, mitotane, and trilostane) (Aceglatone; Aldophosphamide glycoside; Aminolevulinic acid; Amsac Phosphorus; Arabinoside, Bestravcil; Bisantrene; Edatrexate; Defofami , demecolcine, diaziquone, elfornitine (DFMO), elfomycin; acetic acid Elliptinium, etocurside; gallium nitrate; gathiocyanate; hydroxyurea; iband lonate, lentinan; lonidamine; mitoguazone; mitoxatrone; mopidamol; Traerin; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethyl Ruhydrazide; Procarbazine; PSK (registered trademark); Razoxane; Rhizoxin; Schizophrenia irane; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-triazicon Chlorotriethylamine; Trichothecenes (T2 toxin, verrucarin A, roridin A, and anguidine); urethane, siRNA, antisense medicine; (2) Anti-autoimmune disease drugs: Cyclosporine, Cyclosporine A, Aminocaproic acid, Azathioprine, Bromocriptine acetaminophen, chlorambucil, chloroquine, cyclophosphamide, corticosteroids (ambutanol, Cinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone Propionate ester, fluorocortodanazol, dexamethasone, triamcinolone cetonide, beclomethasone dipropionate), DHAE, ethoxyquin, Tanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate acetaminophen, mycophenolate mofetil, prednisone, sirolimus, tacrolimus; (3) Anti-infective drugs: a) Aminoglycosides: amikacin, astromicin, gentamicins (nechima) Isomicin, Sisomycin, Isepamicin), Hygromycin B, Kanamycins (Amimycin Kashin, Arbekacin, Bekanamycin, Dibekacin, Tobramycin), Neomycin (framycetin, paromomycin, ribostamycin), netilmicin, specti nomycin, streptomycin, tobramycin, verdamycin; b) Amphenicols: azidamphenicol, chloramphenicol, florphenicol Nicole, thiamphenicol; c) Ansamycins: geldanamycin, herbimycin; d) Carbapenems: biapenem, doripenem, ertapenem, imipenem / cilastatin Chin, meropenem, panipenem; e) Cephalosporins: Carbacephems (loracarbef), cefacetrile, cefaclor, Cephradine, cefadroxil, cephalonium, cephaloridine, cephalothin or cephalothin Phalosporin, cephalexin, cephaloglycin, cefamandole, cephapirin , cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cef Capen, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil , cephalosporin, ceftezol, cefuroxime, cefixime, cefdinir, cefdito Len, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cef Operazon, Ceforanide, Cefotaxime, Cefotiam, Cefozopran, Cephalexin Cefpiramide, cefpirome, cefpodoxime, cefprozil, Fukinome, cefsulodin, ceftazidime, cefteram, ceftibuten, cefthiolene, Ceftizoxime, Ceftobiprole, Ceftriaxone, Cefuroxime, Cefuzonam, Cef Cefoxitin, cefotetan, cefmetazole, oxacephems (flo moxef, latamoxef); f) Glycopeptides: bleomycin, vancomycin (oritavancin, telavancin ), teicoplanin (dalbavancin), ramoplanin; g) Glycylcyclines: Tigecycline; h) β-lactamase inhibitors: penams (sulbactam, tazobactam), clavams (clavams), Lavranic acid); i) Lincosamides: clindamycin, lincomycin; j) Lipopeptides: Daptomycin, A54145, a calcium-dependent antibiotic (C D A); k) Macrolides: azithromycin, cethromycin, clarithromycin, zirconium Thromycin, erythromycin, flurithromycin, josamycin, ketolide ( Telithromycin, Cethromycin), Midecamycin, Miocamycin, Oleochromocycin Rifamycins (rifampicin, rifampin, rifabutin, rifapentin, rokitamycin, roxithromycin, spectinomycin, spiramycin , tacrolimus (FK506), troleandomycin, telithromycin; l) Monobactams: aztreonam, tigemonam; m) Oxazolidinones: Linezolid; n) Penicillins: amoxicillin, ampicillins (pivanpicillin, hetacillin, Bacampicillin, Methampicillin, Talampicillin), Azidocillin, Azlocillin, Be benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin clometidin, procaine benzylpenicillin, carbenicillin (calindacillin cloxacillin, dicloxacillin, epicillin, flucloxacillin, mesilin pivmecillinam, mezlocillin, methicillin, nafcillin, oxacillin, penam Penicillin, pheneticillin, phenoxymethylpenicillin, piperacillin, procillin lopicillin, sulbenicillin, temocillin, ticarcillin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, Linafloxacin, Danofloxacin, Difloxacin, Enoxacin, Enrofloxacin Shin, Floxacin, Garenoxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin Floxacin, canotrobafloxacin, levofloxacin, lomefloxacin, marbofloxacin Floxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, Tafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovaf Loxacin; q) Streptogramins: Pristinamycin, Quinupristin / Dalfopristin ； r) Sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethin zole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim , trimethoprim-sulfamethoxazole (cotrimoxazole); s) steroidal antibacterial agents: selected from fusidic acid; t) Tetracyclines: doxycycline, chlortetracycline, chromocycline Lymecycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline Cycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline tracycline, glycylcyclines (selected from tigecycline); u) Other types of antibiotics: annonacin, arsphenamine, bactoprenol inhibitors agents (bacitracin), DADAL / AR inhibitors (cycloserine), dictyostatin, Discodermolide, Eleutherobin, Epothilone, Ethambutol, Etoposide, Fu Alopenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole ru, mupirocin, mycolactone, NAM synthesis inhibitor (fosfomycin), nitrofuran Toin, paclitaxel, platensimycin, pyrazinamide, quinupristin / dalphos Pristine, rifampin (rifampin), tazobactamtinidazole, uvaricin; (4) Antiviral drugs: a) Entry / fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41(E Nfuvirtide), PRO140, CD4 (Ibalizumab); b) Integrase inhibitors: raltegravir, elvitegravir, globoidnan A; c) Maturation inhibitors: Bevirimat, Vivicon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleosides and nucleotides: abacavir, acyclovir, adefovir, amphotericin Doxovir, Apricitabine, Brivudine, Cidofovir, Clevudine, Dexerbucitabine Bin, didanosine (DDI), elvucitabine, emtricitabine (FTC), entecavir vir, famciclovir, fluorouracil (5-FU), 3'-fluoro substituted 2',3 '-Deoxynucleoside analogues (3'-fluoro-2',3'-dideoxythymidine ( FLT) and 3'-fluoro-2',3'-dideoxyguanosine (FLG) ), fomivirsen, ganciclovir, idoxuridine, lamivudine ( 3TC), L-nucleosides (β-L-thymidine and β-L-2'-deoxycytidine) ), penciclovir, rasvir, ribavirin, stampidine, Stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir , trifluridine, valacyclovir, valganciclovir, zalcitabine (ddC), Dovzin (AZT); f) Non-nucleosides: amantadine, ateviridin, capravirine, diarylpyrimidin (etravirine, rilpivirine), delavirdine, docosanol, emivirine, efavirdine Virenz, foscarnet (phosphoryl formate), imiquimod, interferon alpha, Robin Lido, rhodenosine, methisazone, nevirapine, NOV-205, peginterferon alpha , podophyllotoxin, rifampicin, rimantadine, resiquimod (R-848), Romantadine; g) Protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir , fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, Tonavir, Saquinavir, Telaprevir (VX-950), Tipranavir; h) Other antiviral drugs: abzyme, arbidol, calanolide A, seragenin, Cyanovirin-N, Diarylpyrimidine, Epigallocatechin Gallate (EGCG), Phospholipid Carnet, Griffithsin, Taribavirin (Viramidine), Hydroxyurea, KP- 1461, Miltefosine, Pleconaril, Portmanteau inhibitor, Ribavirin, Sericin Crib; (5) ３ H、 １１ C、 １４ C、 １８ F、 ３２ P, ３５ S、 ６４ Cu, ６８ Ga, ８６ Y 、 ９９ Tc、 １１１ In、 １２３ I、 １２４ I、 １２５ I、 １３１ I、 １３３ Xe、 １７ ７ Lu, ２１１ At, or ２１３ A radioisotope (radioactive nuclide); (6) Ability to absorb certain types of light, such as UV light, fluorescent light, IR light, near-IR light, and visual light. Chromophore molecules having the formula: xanthophores, erythrophores, iridophores, leucophores, melanophores, cereophores, and a class or subclass of phosphors, said phosphors being fluorescent substances that re-emit light with light. Chemicals, visual light-sensitive molecules, light-emitting molecules, luminescent molecules, luciferin compounds Class or subclass, visible light transmitting molecules, light emitting molecules, luminescent molecules, luciferins Compounds; for example, the following non-proteinaceous organic fluorophores: xanthene derivatives (fluorescein, rhodamine, Oregon green, eosin, and Texas red); cyanine derivatives (cyanine anine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocarbocyanine cyanines); squalene derivatives and ring-substituted squaraines (Seta, SeTau, and S quare dyes); naphthalene derivatives (dansyl and prodan derivatives); coumarin Derivatives: Oxadiazole derivatives (pyridyloxazole, nitrobenzoxadiazole , and benzoxadiazoles); anthracene derivatives (DRAQ5, DRAQ7, and Anthraquinones including CyTRAK Orange); pyrene derivatives (cascade bull -); oxazine derivatives (Nile red, Nile blue, cresyl violet, oxazine Acridine derivatives (proflavine, acridine orange, acridine yellow) Law et al.). Arylmethine derivatives (auramine, crystal violet, malachite Lean). Tetrapyrrole derivatives (porphine, phthalocyanine, bilirubin); Any analogues and derivatives of fluorophore compounds: CF dyes (Biotium), DRAQ and CyTR AK probe (Bio-Status), BODIPY (Invitrogen), Alexa Fluor ( Invitrogen), DyLight Fluor (Thermo Scientific, Pierce), Atto and Transy (Sigma Aldrich), FluoProbes (Interchim), Abber ior dyes (Abberior), DY and MegaStokes dyes (Dyomics), Sulfo Cy dye (Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau and and Square dyes (SETA BioMedicals), Quasar and Cal Flour dyes ( Biosearch Technologies), SureLight dyes (APC, RPEPerCP, Phosphatase Cobilisome) (Columbia Biosciences), APC, APCXL, RPE, BPE (Phyc o-Biotech), allophycocyanin (APC), aminocoumarin, APC-Cy7 conjugate , BODIPY-FL, Cascade Blue, Cy2, Cy3, Cy3.5, Cy3B, C y5, Cy5.5, Cy7, Fluorescein, FluorX, Hydroxycoumarin, Lisa Minrhodamine B, Lucifer Yellow, Methoxycoumarin, NBD, Pacific Blue, Pacific Orange, PE-Cy5 conjugate, PE-Cy7 conjugate, PerCP, R-phycoerythrin (PE), Red613, Seta-555-azide , Seta-555-DBCO, Seta-555-NHS, Seta-580-NHS , Seta-680-NHS, Seta-780-NHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-670, SeTau380-NH S, SeTau405-maleimide, SeTau405-NHS, SeTau425-N HS, SeTau647-NHS, Texas Red, TRITC, TruRed, X-Ro -damine, 7-AAD (7-aminoactinomycin D, CG selective), acridine oleate , chromomycin A3, CyTRAK Orange (Biostatus, red excitation dark), DAP I, DRAQ5, DRAQ7, ethidium bromide, Hoechst 33258, Hoechst 3 3342, LDS751, Mithramycin, Propidium Iodide (PI), SYTOX B Lu, SYTOX Green, SYTOX Orange, Thiazole Orange, TO-PRO: Cyanine monomer, TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOseta-1, YOYO-1. Can be linked to the conjugates of the present invention for cell research. The fluorescent dye that can be used is selected from the following compounds or their derivatives: DCFH (2'7'difluoromethyl) chlorodihydro-fluorescein, oxidized), DHR (dihydrorhodamine 123, oxidized type, light catalyzed oxidation), Fluo-3 (AM ester, pH>6), Fluo-4 ( AM ester, pH 7.2), Indo-1 (AM ester, low / high calcium (Ca ２ ＋ )), SNARF (pH 6 / 9), allophycocyanin (APC), AmCyan1 ( tetramer, Clontech), AsRed2 (tetramer, Clontech), Azami Green (monomer , MBL), Azurite, B-Phycoerythrin (BPE), Cerulean, CyPet, D sRed monomer (Clontech), DsRed2 ("RFP", Clontech), EBFP, EB FP2, ECFP, EGFP (weak dimer, Clontech), Emerald (weak dimer, Invitrogen) en), EYFP (weak dimer, Clontech), GFP (S65A mutant), GFP (S65C mutant), GFP (S65L mutant), GFP (S65T mutant), GFP (Y66F mutant) variant), GFP (Y66H mutant), GFP (Y66W mutant), GFP ｕｖ , HcRe d1, J-Red, Katyusha, Kusabira Orange (monomer, MBL), mCFP, mCherry, mCitrine, Midriishi Cyan (dimer , MBL), mKate (TagFP635, monomer, Evrogen), mKeima-Red ( Monomer, MBL), mKO, mOrange, mPlum, mRaspberry, mRF P1 (monomer, Tsien Lab), mStrawberry, mTFP1, mTur quoise2, P3 (phycobilisome complex), Peridinin Chloro phyll (PerCP), R-phycoerythrin (RPE), T-Sapphire, TagCFP (dimer, Evrogen), TagGFP (dimer, Evrogen), TagRFP ( dimer, Evrogen), TagYFP (dimer, Evrogen), tdTomato (tandem dimer (dimer), Topaz, TurboFP602 (dimer, Evrogen), TurboFP635 (dimer, Evrogen), TurboGFP (dimer, Evrogen), TurboRFP (dimer (dimer, Evrogen), TurboYFP635 (dimer, Evrogen), Venus, native GFP , YPet, Zs Green 1 (tetramer, Clontech), Zs Yellow 1 (tetramer, Clontech ）。 (7) A cell-binding ligand or receptor agonist that can be selected from the following: folic acid-induced Conductors; Glutamic acid urea derivatives; Somatostatin and its analogues (Octreotide (Sa lanreotide (Somatrin); Sulfonamide; Pituitary adenylate cyclase activating peptide (PACAP) (PAC1) ; Vasoactive intestinal peptide (VIP / PACAP) (VPAC1, VPAC2); Melanoma Myocyte-stimulating hormone (α-MSH); cholecystokinin (CCK) / gastrin receptor agonist (GAA) agonist; bombesin (Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 (selected from the group consisting of) / gastrin releasing peptide (GRP); neurotensin Receptor ligand (NTR1, NTR2, NTR3); Substance P (NK1 receptor) ligand Gand; Neuropeptide Y (Y1-Y6); RGD (Arg-Gly-Asp), NGR (Asn-Gly -Arg), dimeric and multimeric cyclic RGD peptides (selected from cRGDfVc), TA ASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteoglycan NG 2 receptor ligand) and homing peptides including F3 peptide; cell penetrating peptides ( CPPs); Luteinizing hormone releasing hormone (LHRH) agonists and antagonists and gonadotropin releasing hormone (GnRH) agonists. It also stimulates the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), as well as testosterone production. LH) by targeting the luteinizing hormone (LH). Bu)-Leu-Arg-Pro-NHEt, gonadorelin (Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 ), goserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2), Leurin (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), leuprolide ( Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt, nafrelin (Pyr-His-Trp-Ser-Tyr-2N al-Leu-Arg-Pro-Gly-NH 2 ), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro- Gly-NH 2 ), nafarelin, deslorelin, abarelix (Ac-D-2Nal-D-4-chloroPhe-D- 3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropyl-Pro-DAla-NH 2 ), Cetroleri (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D- Ala-NH 2 ), Degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-amino Phe(L-hydroorotyl)-D-4-amioPhe(carbamoyl)-Leu-isopropylLys-Pro-D-Ala-NH 2 ), and ganirelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-(N 9,N10-diethyl)-homoArg-Leu-(N9,N10-diethyl)-homoArg-Pro-D-Ala-NH 2 ) Peptide hormones selected from the group consisting of Toll-like receptor (TLR) ligands, C-type lectins and Nod-like receptor (NLR) ligands. Receptors (PRRs); calcitonin receptor agonists; integrin receptors and their receptors Container subtype (α Ｖ β １ 、α Ｖ β ３ 、α Ｖ β ５ 、α Ｖ β ６ 、α ６ β ４ 、α ７ β １ 、α Ｌ β ２ , α ＩＩｂ β ３ ) agonists (GRGDSPK, cyclo (RGDfV) (L1) and its derivatives [cyclo(-N(Me)R-GDfV), cyclo (R-Sar-DfV), cyclo(RG-N(Me)D-fV), cyclo(RGD-N( Me)f-V), cyclo(RGDf-N(Me)V-) (ciliate)]; nanobody (VH H (camel Ig) derivatives); domain antibodies (dAbs, VH or VL domain derivatives) , bispecific T cell induction (Bite, bispecific antibody); biaffinity retargeting ( DART, bispecific antibody); tetravalent tandem antibody (TandAb, dimerized bispecific antibody); avimer; EGF receptor and VEGF receptor agonists; (8) Pharmaceutically acceptable salts, acids, or derivatives of any of the above drugs.

9. The Drug, Drug', or Drug'' is a chromophore molecule and is a phase of a cell-binding molecule. Detecting, monitoring, or studying the interaction and / or function or interaction of the conjugate with a target cell The conjugate compound according to claim 2, which is used for

10. One, two or all of the Drug, Drug', or Drug'' are each independently and poly(ethylene glycol) (P) having a molecular weight of about 44 Da to about 300 kDa. EGs), poly(propylene glycol), ethylene oxide or propylene oxide or their analogs, which polymers, when administered to a mammal, The conjugate compound of claim 2, which is used to extend the half-life of a cell-binding molecule.

11. One, two or all of the Drug, Drug', or Drug'' are each independently and a cell-binding ligand or a cell receptor agonist, or a cell receptor-binding molecule. for delivering the conjugate to malignant cells or for modulating or co-stimulating a desired immune response. as targeted conductors / directors to stimulate or alter signaling pathways The conjugate compound of claim 2, which can act as a

12. The Drug, Drug', or Drug'' is selected from the group consisting of tubulysins, calicheamicins, and the like. amines, auristatins, maytansinoids, CC-1065 analogs, daunorubicin and doxorubicin compounds, taxanoids (taxanes), cryptophycins, epo Tirons, benzodiazepine dimers (pyrrolobenzodiazepines (PBD), tomayasi anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines or a dimer of oxazolidinobenzodiazepines. Caremicins and enediyne antibiotics, actinomycins, amanitins, azaceryl antimycins, bleomycins, epirubicin, tamoxifen, idarubicin, dolastatin Auristatins (e.g., monomethylauristatin E, MMAE, MMAF, Auristatin PYE, Auristatin TP, Auristatin 2-AQ, 6-AQ, EB ( AEB), and EFP (AEFP). ), duocarmycin , geldanamycins, methotrexate, thiotepa , vindesines, vincristines, hemiasterines, nasturtium Nazumamides, microginins, la Radiosumins, Alterobactins ins), microsclerodermicins, Theonellamids, esperamicins cins), siRNA, miRNA, piRNA, nuclease, and / or the above. The compound may be selected from the group consisting of pharma- ceutically acceptable salts, acids, and / or analogs and derivatives thereof. The conjugate compound according to claims 2 and 4,

13. The cell binding agent / molecule may be an antibody, a protein, a vitamin (e.g., folic acid), a peptide, , polymer micelles, liposomes, lipoprotein-based drug carriers, nanoparticle drug carriers, dendrites and a molecule coated with a cell-binding ligand, or a combination thereof.

4. The conjugate compound according to claims 2 and 3.

14. The cell binding molecule / agent, Cb, Cb', or Cb'' is independently an antibody, an antibody-like protein, Proteins, full length antibodies (polyclonal antibodies, monoclonal antibodies, dimers, multimers, multispecific antibodies) a specific antibody (selected from a bispecific antibody or a trispecific antibody); a single chain antibody, Binding antibody fragments, monoclonal antibodies, single-chain monoclonal antibodies, and target cell binding Monoclonal antibody fragments, chimeric antibodies, chimeric antibody fragments that bind to target cells, domain antibodies a domain antibody fragment that binds to a target cell; a resurfaced antibody; a single-chain resurfaced antibody; Reconstituted antibody fragments, probodies, and humanized antibodies that bind to target cells , surface-reconstituted humanized antibodies, single-chain humanized antibodies, humanized antibody fragments that bind to target cells, anti-Ig Diotypic (anti-Id) antibodies, CDR, dimers, trimers, tetramers, miniantibodies, probodies (probody), small immune protein (SIP), lymphokine, hormone, vitamin amines, growth factors, colony stimulating factors, nutrient transport molecules, large molecular weight proteins, and antibodies or Nanoparticles or polymers modified with large molecular weight proteins, Item 12. The conjugate compound according to item 2, 3, or 11.

15. The cell binding agent / molecule, Cb, Cb', or Cb'' is selected from the group consisting of tumor cells, virus-infected cells, and the like. , microbial-infected cells, parasite-infected cells, autoimmune disease cells, activated tumor cells, bone marrow cells, activated Activated T cells, affected B cells, or melanocytes, or the following antigens or receptors: A molecule or agent capable of targeting cells expressing one or more of the receptors. 2, 3, or 13, the conjugate compound: CD3, CD4, CD5, CD6, CD7, C D8, CD9, CD10, CD11a, CD11b, CD11c, CD12w, CD14 , CD15, CD16, CDw17, CD18, CD19, CD20, CD21, CD2 2, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD3 0, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD3 8, CD39, CD40, CD41, CD42, CD43, CD44, CD45, CD4 6, CD47, CD48, CD49b, CD49c, CD51, CD52, CD53, C D54, CD55, CD56, CD58, CD59, CD61, CD62E, CD62L , CD62P, CD63, CD66, CD68, CD69, CD70, CD72, CD7 4, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, C D86, CD87, CD88, CD89, CD90, CD91, CD95, CD96, C D98, CD100, CD103, CD105, CD106, CD109, CD117, CD120, CD123, CD125, CD126, CD127, CD133, CD13 4, CD135, CD137, CD138, CD141, CD142, CD143, CD 144, CD147, CD151, CD147, CD152, CD154, CD156, CD158, CD163, CD166, CD168, CD174, CD180, CD18 4, CDw186, CD194, CD195, CD200, CD200a, CD200b , CD209, CD221, CD227, CD235a, CD240, CD262, CD 271, CD274, CD276 (B7-H3), CD303, CD304, CD309 , CD326, 4-1BB, 5AC, 5T4 (trophoblast glycoprotein, TPBG, 5T 4, Wnt activation inhibitory factor 1 or WAIF1), adenocarcinoma antigen, AGS-5, AGS-22M 6. Activin receptor-like kinase 1, AFP, AKAP-4, ALK, α integrin, αvβ6, aminopeptidase N, amyloid β, androgen receptor, angiopoietin angiopoietin 2, angiopoietin 3, annexin A1, anthrax toxin protective antigen, anti-trans ferrin receptor, AOC3 (VAP-1), B7-H3, anthrax, BAFF (B-cell activity activating factor), BCMA, B-lymphoma cells, bcr-abl, bombesin, BORIS, C5, C242 antigen, CA125 (carbohydrate antigen 125, MUC16), CA-IX (also CAIX, carbonic anhydrase 9), CALLA, CanAg, canine IL31, carbonic anhydrase IX, cardiac myosin, CCL11 (C-C motif chemokine 11), CCR4 (CC motif chemokine 11), CCR5, CD3E (epsilon), CEA (cancer antigen receptor type 4, CD194) CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD (factor D), C h4D5, cholecystokinin 2 (CCK2R), CLDN18 (claudin-18), Clumping factor A, cMet, CRIPTO, FCSF1R (colony stimulating factor 1 receptor CD115), CSF2 (colony stimulating factor 2, granulocyte-macrophage colony stimulating factor GM-CSF), CSP4, CTLA4 (cytotoxic T-lymphocyte-associated protein 4), CTAA16.88 tumor antigen, CXCR4 (CD184), CXC chemokine receptor Type 4, cADP ribose hydrolase, Cyclin B1, CYP1B1, cytome Gallovirus, cytomegalovirus glycoprotein B, dabigatran, DLL3 (delta DLL4 (Delta-like ligand 4), DPP4 (Dipeptidyl peptide kinase 4) 4), DR5 (death receptor 5), E. coli Shiga toxin type 1, E. coli Shiga toxin type 2, ED -B, EGFL7 (EGF-like domain containing protein 7), EGFR, EGFRII, E GFRvIII, endoglin (CD105), endothelin B receptor, endotoxin , EpCAM (epithelial cell adhesion molecule), EphA2, episialin, ERBB2 (epithelial growth factor receptor 2), ERBB3, ERG (TMPRSS2ETS fusion gene), E. coli, E TV6-AML, FAP (fibroblast activation protein α), FCGR1, α-fetoprotein protein, fibrin II, β chain, fibronectin ectodomain B, FOLR (folate receptor receptor α, folate hydrolase, respiratory syncytial virus Fos-related antigen 1F protein Protein, Frizzled receptor, Fucosyl GM1, GD2 ganglioside, G-28 (cell surface glycolipid antigen), GD3 idiotype, GloboH, glypican 3, N-glycol neuraminic acid, GM3, GMCSF receptor α chain, growth differentiation factor 8, GP100, GPN MB (transmembrane protein NMB), GUCY2C (guanylate cyclase 2C, guanylate Guanylate cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase-C receptor enterotoxin receptor (hSTAR), heat shock protein, hemoglobin agglutinin, hepatitis B surface antigen, hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2 / neu, HER3 (ERBB-3), IgG4, HGF / SF (stem Cell growth factor / scatter factor), HHGFR, HIV-1, histone complex, HLA-D R (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, human chorionic Gonadotropin, HNGF, human cell scatter factor receptor kinase, HPV E6 / E7, H sp90, hTERT, ICAM-1 (intercellular adhesion molecule 1), idiotype, IGF1 R (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN-γ, influenza IgE, IgE Fc region, IGHE, IL-1, IL-2 receptor ( Interleukin 2 receptor), IL-4, IL-5, IL-6, IL-6R (Interleukin IL-9, IL-10, L-12, IL-13, IL-17, IL- 17A, IL-20, IL-22, IL-23, IL-31RA, ILGF2 (insulin α-like growth factor 2), integrin (α4, α ＩＩＩｂ β ３ , αvβ3, α ４ β ７ , α5β 1. α6β4, α7β7, αIIβ3, α5β5, αvβ5), interferon gamma induction Protein, ITAGA2, ITGB2, KIR2D, Kappa Ig, LCK, Le , legumain, Lewis-Y antigen, LFA-1 (lymphocyte function-associated antigen 1, CD11a), LHRH, LINGO-1, lipoteichoic acid, LIV1A, LMP2, LTA, MAD-C T-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGEA1 , MAGEA3, MAGEA4, MART1, MCP-1, MIF (macrophage migration blocking factor or glycosylation inhibitor (GIF), MS4A1 (transmembrane 4 domain subfamily Family A member 1), MSLN (mesothelin), MUC1 (mucin 1, cell surface associated (MUC1) or Polymorphic epithelial mucin (PEM ), MUC1-KLH, MUC16 (CA125), MCP1 (monocyte chemotactic protein 1), MelanA / MART1, ML-IAP, MPG, MS4A1 (transmembrane 4 domain insubfamily A), MYCN, myelin-associated glycoprotein, myostatin, NA1 7, NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME ), NGF, neuroapoptosis-regulating proteinase 1, NOGO-A, Notch receptor , nucleolin, Neu oncogene product, NY-BR-1, NY-ESO-1, OX-40 , OxLDL (oxidized low-density lipoprotein), OY-TES1, P21, non-mutant p53 , P97, Page 4, PAP, , Anti-(N-glycolylneuraminic acid) paratope, P AX3, PAX5, PCSK9, PDCD1 (PD-1, programmed cell death protein protein 1, CD279), PDGF-Rα, (platelet-derived growth factor receptor α), PDGFR -β, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, platelet-derived Long factor receptor β, sodium phosphate cotransporter, PMEL17, polysialic acid, protein PR1, prostate cancer, PS (phosphatidylserine), prostate cancer cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glycoprotein, RHD (Rh polypeptide) 1 (RhPI), CD240), Rhesus factor, RA NKL, PhoC, Ras mutant, RG55, ROBO4, RS virus, RON, RO R1, sarcoma metastasis breakpoint, SART3, sclerostin, SLAMF7 (SLA M family member 7), selectin P, SDC1 (syndecan 1), sLe(a), Somatomedin C, SIP (sphingosine-1-phosphate), somatostatin, sperm Protein 17, SSX2, STEAP1 (six-transmembrane epithelial antigen of the prostate 1), STEA P2, STn, TAG-22 (tumor-associated glycoprotein 72), survivin, T cell receptor , T cell transmembrane protein, TEM1 (tumor epithelial marker 1), TENB2, tenascin C (TN-C), TGF-α, TGF-β (transforming growth factor β), TGF -β1, TGF-β2 (transforming growth factor β2), Tie (CD202b) , Tie2, TIM-1 (CDX-014), TN, TNF, TNF-α, TNFRSF 8. TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), T NFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (tumor necrosis-inducing ligand receptor 1), TRAILR2 (Death Receptor 5 (DR5)), Tumor-associated calcium signaling tra inducer 2, tumor-specific glycosylation of MUC1, TWEAK receptor, TYRP1 (glycoprotein 75), TRP-2, tyrosinase, VCAM-1 (CD106), VE GF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2, or The present invention relates to cells expressing vimentin, WT1, XAGE1, or any insulin growth factor receptor. or any epidermal growth factor receptor.

16. The tumor cell according to claim 13 is selected from the group consisting of lymphoma cells, myeloma cells, renal cells, breast cancer cells, prostate cancer cells, and the like. Adenocarcinoma cells, ovarian cancer cells, colon cancer cells, gastric cancer cells, squamous cell carcinoma cells, small cell lung cancer cells, non-small Cells Lung cancer cells, testicular cancer cells, or cells that grow and divide uncontrollably, promoting the pace that leads to cancer The cell is selected from any cell that

17. Preface: Connector components, L １ , L １’ , L １’’ , L １’’’ , L ２ , L ２’ , L ２’’ ,and Bi L １’’’ may independently be one or more repeats or combinations of the following structural components:

5. The conjugated compound of claim 1, 2, 3, or 4, selected from the group consisting of: 【Chemistry 19】 【change】 During the ceremony, 【Chemistry 20】 is the linking (or connecting) site.

18. The linker component L １ , L １’ , L １’’ , L １’’’ , L ２ , L ２’ , L ２’’ , and L ２’’’ is one or more, or repeats, selected from the group consisting of the following structural components: The linker compound according to claim 1, 2, 3, or 4, -(CR ５ R ６ ) ｍ (A) ｒ (CR) ７ R ８ ) ｎ (OCH) ２ CH ２ ) ｔ 、-(CR ５ R ６ ) ｍ (CR) ７ R ８ ) ｎ (A) ｒ (OCH) ２ CH ２ ) ｔ 、-(Aa) ｒ (CR) ５ R ６ ) ｍ (CR) ７ R ８ ) ｎ (OCH) ２ CH ２ ) ｔ 、-(CR ５ R ６ ) ｍ (CR) ７ R ８ ) ｎ (OCH) ２ CH ２ ) ｒ (Aa) ｔ 、-(CR ５ R ６ ) ｍ (CR ７ =R ８ )(CR ９ R １０ ) ｎ (Aa) ｔ (O CH ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (NR １１ CO)(Aa) ｔ (CR ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (A) ｔ (NR) １１ CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (O) (A) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (OCNR) ７ )(Aa) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (C) (A) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (NR) １１ CON ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (O) (A) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (OCNR) ７ )(Aa) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ 、-(CR ５ R ６ ) ｍ (C) (A) ｔ (CR) ９ R １０ ) ｎ (O.C.H. ２ CH ２ ) ｒ , -(CR ５ R ６ ) ｍ -phenyl-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -(CR ５ R ６ ) ｍ -furyl-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -(CR ５ R ６ ) ｍ -oxazolyl-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -(CR ５ R ６ ) ｍ -Thiazolyl-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -(CR ５ R ６ ) ｔ -Thienyl- (CO) (CR ７ R ８ ) ｎ , -(CR ５ R ６ ) ｔ -imidazolyl-(CO)(CR ７ R ８ ) ｎ , -(CR ５ R ６ ) ｔ -Morpholino-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -(C R ５ R ６ ) ｔ -piperazino-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -(CR ５ R ６ ) ｔ -N-methylpiperazine-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -(CR ５ R) ｍ - ( Aa) ｔ Phenyl-, -(CR ５ R ６ ) ｍ -(Aa) ｔ Frill-,-(CR ５ R ６ ) ｍ - Oxazolyl (Aa) ｔ -, - (CR ５ R ６ ) ｍ -Thiazolyl (Aa) ｔ -, - (CR ５ R ６ ) ｍ -Thienyl (Aa) ｔ -, - (CR ５ R ６ ) ｍ -Imidazolyl (Aa) ｔ --, -- (CR ５ R ６ ) ｍ -Morpholino-(Aa) ｔ , -(CR ５ R ６ ) ｍ -piperazino-(Aa ) ｔ , -(CR ５ R ６ ) ｍ -N-methylpiperazino- (Aa) ｔ , -K(CR ５ R ６ ) ｍ (A) ｒ (CR) ７ R ８ ) ｎ (OCH) ２ CH ２ ) ｔ ,-K(CR ５ R ６ ) ｍ (CR) ７ R ８ ) ｎ (A) ｒ (OCH) ２ CH ２ ) ｔ ,-K(A]) ｒ (CR) ５ R ６ ) ｍ (CR) ７ R ８ ) ｎ (OCH) ２ CH ２ ) ｔ ,-K(CR ５ R ６ ) ｍ (CR) ７ R ８ ) ｎ (OCH) ２ CH ２ ) ｒ (Aa) ｔ 、-K(CR ５ R ６ ) ｍ (CR ７ =R ８ )(CR ９ R １０ ) ｎ (Aa) ｔ (O CH ２ CH ２ ) ｒ 、-K(CR ５ R ６ ) ｍ (NR １１ CO)(Aa) ｔ (CR ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (A) ｔ (NR) １１ CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (O) (A) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (OCNR) ７ )(Aa) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (C) (A) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (NR) １１ CON ｔ ( CR ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (O) (A) ｔ ( CR ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (OCNR) ７ )(Aa) ｔ (CR) ９ R １０ ) ｎ (OCH) ２ CH ２ ) ｒ ,-K(CR ５ R ６ ) ｍ (C) (A) ｔ (CR ９ R １０ ) ｎ (O.C.H. ２ CH ２ ) ｒ , -K(CR ５ R ６ ) ｍ -phenyl-(CO) (Aa) ｔ (CR ７ R ８ ) ｎ , -K(CR ５ R ６ ) ｍ -furyl-(CO)(Aa) ｔ (C R ７ R ８ ) ｎ , -K(CR ５ R ６ ) ｍ -oxazolyl-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -K(CR ５ R ６ ) ｍ -Thiazolyl-(CO)(Aa) ｔ (CR ７ R ８ ) ｎ , -K (CR ５ R ６ ) ｔ -Thienyl-(CO)(CR ７ R ８ ) ｎ , -K(CR ５ R ６ ) ｔ -Imi Dazolyl-(CO)(CR ７ R ８ ) ｎ , -K(CR ５ R ６ ) ｔ -morpholino-(CO) ( Aa) ｔ (CR ７ R ８ ) ｎ , -K(CR ５ R ６ ) ｔ -piperazino-(CO)(Aa) ｔ ( CR ７ R ８ ) ｎ , -K(CR ５ R ６ ) ｔ -N-methylpiperazine-(CO)(Aa) ｔ ( CR ７ R ８ ) ｎ , -K(CR ５ R) ｍ -(Aa) ｔ Phenyl-, -K(CR ５ R ６ ) ｍ - (Aa) ｔ Frill-, -K (CR ５ R ６ ) ｍ -Oxazolyl (Aa) ｔ -, -K(CR ５ R ６ ) ｍ -Thiazolyl (Aa) ｔ -, -K(CR ５ R ６ ) ｍ -Thienyl (Aa) ｔ --, -- K (CR ５ R ６ ) ｍ -Imidazolyl (Aa) ｔ -, -K(CR ５ R ６ ) ｍ -Morpholino- (Aa) ｔ , -K(CR ５ R ６ ) ｍ -Piperazino- (Aa) ｔ , -K(CR ５ R ６ ) ｍ - N-Methylpiperazino-(Aa) ｔ . (In the formula, m, Aa, m, n, R ３ , R ４ , and R ５ The definitions of are the same as in formula (I). t and r are integers from 0 to 100; R ６ , R ７ , and R ８ are each independently H , halogen, C １ -C ８ Alkyl group, aryl group, alkenyl group, alkynyl group, ether group aryl, ester, amine or amide (which may contain one or more halogens, CN, NR) １ R ２ , C.F. ３ , OR １ , aryl group, heterocycle, S(O)R １ , S.O. ２ R １ , -CO ２ H, -SO ３ H , -OR １ , -CO ２ R １ , -CONR １ , -PO ２ R １ R ２ , -PO ３ H, or P(O ) R １ R ２ R ３ and K is selected from NR １ , -SS- , -C(=O)-, -C(=O)NH-, -C(=O)O-, -C=NH-O-, -C= N-NH-, -C(=O)NH-NH-, O, S, Se, B, C ３ -C ８ Heterocycle or Hetero A heteroaromatic ring or a peptide containing 1 to 20 amino acids.

19. Drug, Drug', or Drug'' is a chromophore molecule, and the conjugate of formula (II) The body compounds are the following Ac01, Ac02, Ac03, Ac04, Ac05, Ac06, The co-polymer of claim 2, wherein the co-polymer is selected from the group consisting of structures Ac07, Ac08, and Ac09. Role compound: 【Chemistry 21】 【change】 During the ceremony: mAb is an antibody, monoclonal antibody, or cell binding molecule; 【Chemical 22】 n, m １ , m ２ , X １ , X ２ , X ３ , L, L １ , L ２ , R １ , R ２ , and R ３ , is a claim This is the same definition as in item 1.

20. Drug, Drug', or Drug'' is a tubulysin The conjugate compound of formula (II) is the following T01, T02, T03, T04 , T05, T06, T07, T08, T09, T10, T11, T12, T13, T14 3. The conjugate of claim 2, wherein the conjugate is selected from the structures T15, T16, T17, and T18. Compound: 【Chemistry 23】 【change】 【change】 【change】 During the ceremony, 【Chemistry 24】 n, m １ , m ２ , X １ , X ２ , L １ , L ２ , L ３ , R １ , R ２ , R ３ , R ４ , and R ５ teeth has the same definition as in claim 1; mAb is an antibody or cell binding molecule; Z ３ は、H、OP(O)(OM １ )(OM ２ ),OOCCH ３ ,OCH ２ OP(O) O.M. １ ) (O.M. ２ ), OSO ３ M １ , R １ , or O-glycosides (glucosides, galactosides , mannosides, glucuronosides / glucuronides, alosides, fructosides), NH -glycoside, S-glycoside or CH ２ - is a glycoside; In addition, two R:R １ R ２ , R ２ R ３ , R １ R ３ , or R ３ R ４ is alkyl, aryl , heteroaryl, heteroalkyl, or alkylcycloalkyl group forming a 3- to 8-membered ring Can be; X ３ is H, CH ３ , or X １’ R １’ wherein X １’ is NH, N(CH ３ ), N HNH, O, or S; R １’ is H or C １ -C ８ A linear or branched alkyl group of Aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxya Min; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; M １ and M. ２ are each independently H, Na, K, Ca, Mg, or NH ４ , N.R. １ R ２ R ３ and Drug １ and a different tubulysin analogue or cytotoxic agent selected from claim 8. can be; Furthermore, R １’ may be a cytotoxic agent or drug as defined in claim 8.

21. Drug, Drug', or Drug'' is calicheamicin cin) analogues, and the conjugate compound of formula (II) has the following structures C01 and C02: The conjugated compound of claim 2, selected from: 【Chemistry 25】 During the ceremony: mAb is an antibody or cell binding molecule; 【Chemistry 26】 n, m １ , X １ , L １ , L ２ , and R １ has the same definition as in claim 1; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent or drug as defined in claim 8.

22. The Drug, Drug', or Drug'' is a maytansinoid. id) an analogue, wherein the conjugate compound of formula (II) is selected from the following structures of M01: The conjugated compound of claim 2, 【Chemistry 27】 During the ceremony: mAb is an antibody or cell binding molecule; 【Chemistry 28】 n, m １ , X １ , L １ , L ２ , and R １ has the same definition as in claim 1; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent or drug as defined in claim 8.

23. Drug, Drug', or Drug'' is a taxane analog; The conjugate compound of formula (II) is preferably the following Tx01, Tx02, and Tx03: The conjugated compound of claim 2, selected from the structures: 【Chemical 29】 【change】 During the ceremony: mAb is an antibody or cell binding molecule; 【Chemistry 30】 n, m １ , X １ , L １ , L ２ , and R １ has the same definition as in claim 1; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent or drug as defined in claim 8.

24. Drug, Drug', or Drug'' is a CC-1065 analog and / or Duoca The conjugate compound is a duocarmycin analogue, and the conjugate compound is represented by the following CC 3. The conjugated compound of claim 2, selected from the structures of: CC01, CC02, and CC03: 【Chemistry 31】 【change】 During the ceremony: mAb is an antibody or cell binding molecule; Z ４ and Z ４’ are each independently H, PO(O)(OM １ ) (O.M. ２ ), S.O. ３ M １ CH ２ P. １ ) ２ )、CH ３ N(CH ２ CH ２ ) ２ HNC(O)-,O( CH ２ CH ２ ) ２ N-C(O)-, R １ or a glycoside; X ３ is O, NH, NHC(O), OC(O), -C(O)O, or R １ or or does not exist; 【Chemistry 32】 n, m １ , X １ , L １ , L ２ , and R １ has the same definition as in claim 1; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent or drug as defined in claim 8.

25. Drug, Drug', or Drug'' is a daunorubicin or doxorubicin analogue and the conjugated compound has the following structures Da01, Da02, Da03, and Da04. The conjugated compound of claim 2, which has the structure: 【Chemical 33】 【change】 During the ceremony: mAb is an antibody or cell binding molecule; X ３ is O, NH, NHC(O), NHC(O)NH, C(O), R １ , or O.C. O) or absent; 【Chemical 34】 n, m １ , X １ , L １ , L ２ , and R １ has the same definition as in claim 1; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent or drug as defined in claim 8.

26. Drug, Drug', or Drug'' is auristatin and dolastatin (dol astatin analogues, and the conjugate compounds are the following Au01, Au02, Au 03, Au04, Au05, Au06, Au07, Au08, Au09, Au10, Au The conjugated compound according to claim 2, wherein the conjugated compound is selected from the structures of Au11, Au12, and Au13: 【Chemistry 35】 【change】 【change】 During the ceremony, 【Chemical 36】 n, m １ , m ２ , X １ , X ２ , R １ , R ２ , R ３ , R ４ , and R ５ Claim 1 or 2 and The same definition; mAb is an antibody or cell binding molecule; L １ , L ２ , L ３ , L ４ , and L ５ Each independently represents L of claim 1. １ With the same definition as can be; Z ３’ は、H、OPO(O)(OM １ )(OM ２ ),OOCCH ３ 、OCH ２ O (O) ) (O.M. １ ) (O.M. ２ ), OSO ３ M １ , R １ , or O-glycosides (glucosides, galactosides (including glycerides, mannosides, glucuronosides / glucuronides, alosides, and fructosides) NH-glycoside, S-glycoside or CH ２ - is a glycoside; In addition, two R:R １ R ２ , R ２ R ３ , R １ R ３ , or R ３ R ４ is alkyl, aryl , heteroaryl, heteroalkyl, or alkylcycloalkyl forming a 3- to 8-membered ring. Can be; X ３ is H, CH ３ , or X １’ R １’ wherein X １’ is NH, N(CH ３ ), N HNH, O, or S; R １’ is H or C １ -C ８ A linear or branched alkyl group of Aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxya Min; R ３’ is H or C １ -C ６ is a straight chain or branched alkyl group; p is 0 to 2000; M １ and M. ２ are each independently H, Na, K, Ca, Mg, or NH ４ , N.R. １ R ２ R ３ and Furthermore, R １’ , Drug １ , and Drug ２ is a cytotoxic agent as defined in claim 8. That's fine too.

27. Drug, Drug', or Drug'' is a dimer of a benzodiazepine analog; The conjugate compound is selected from the group consisting of PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08, PB09, PB10, PB11, PB12, PB13, PB14, PB15, PB16, PB17, PB18, PB19, PB20, PB21, PB22, PB23, 06, PB07, PB08, PB09, PB10, and PB11; The conjugate compound of claim 2: 【Chemical 37】 【change】 During the ceremony, 【Chemical 38】 n, m １ , m ２ , X １ , X ２ , L １ , L ２ , R １ , R ２ , R ３ , and R ４ Claim 1 or has the same definition as in 2; mAb is an antibody or cell binding molecule; X ３ はCH ２ 、O、NH、NHC(O)、NHC(O)、C(O)、 O.C. (O) (NR ３ ), R １ , N.H.R. １ , N.R. １ , or C(O)R １ or Not present; X ４ はCH ２ 、C(O)、C(O)NH、C(O)N(R １ ),R １ 、NHR １ 、NR １ , C(O)R １ or C(O)O; M １ and M. ２ are each independently H, Na, K, Ca, Mg, or NH ４ , N.R. １ R ２ R ３ and R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent as defined in claim 8.

28. Drug, Drug', or Drug'' is an amanitin analog, and the conjugate compound The product is selected from the following structures Am01, Am02, Am03, and Am04. Item 3. The conjugate compound according to item 2: 【Chemical 39】 During the ceremony, 【Chemistry 40】 n, m １ , m ２ , X １ , X ２ , L １ , L ２ , R １ , R ２ , R ３ , and R ４ Claim 1 or has the same definition as in 2; mAb is an antibody or cell binding molecule; X ３ はCH ２ 、O、NH、NHC(O)、NHC(O)、C(O)、 O.C. (O) (NR ３ ), R １ , N.H.R. １ , N.R. １ , or C(O)R １ or Not present; X ４ はCH ２ 、C(O)、C(O)NH、C(O)N(R １ ),R １ 、NHR １ 、NR １ , C(O)R １ or C(O)O; M １ and M. ２ are each independently H, Na, K, Ca, Mg, or NH ４ , N.R. １ R ２ R ３ and R ７ , R ８ , R ９ , R １０ , and R １１ are each independently H, OH, OR １ , N.H. ２ , N.H.R. １ , or C １ -C ６ is alkyl or absent; Y １ Yes, O ２ , S, or NH, or absent; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent as defined in claim 8.

29. Drug, Drug', or Drug'' is a polyalkylene glycol analog; The conjugate compound is selected from the group consisting of Pg01, Pg02, Pg03, Pg04, Pg05, and Pg 3. The conjugated compound of claim 2, wherein the conjugated compound is selected from the structures of Pg06, Pg07, and Pg08: 【Chemistry 41】 【change】 During the ceremony, 【Chemistry 42】 n, m １ , m ２ , X １ , X ２ , L １ , L ２ , R １ , R ２ , and R ３ Claim 1 or 2 and The same definition; mAb is an antibody or cell binding molecule; p is 0 to 2000; Drug １ is a cytotoxic agent as defined in claim 8.

30. Drug, Drug', or Drug'' is a cell-binding ligand or a cell receptor agonist. and its analogs, wherein the conjugate compound is LB01 (folic acid conjugate) represented by the following structure: LB02 (PMSA ligand conjugate), LB03 (PMSA ligand conjugate), LB04 (somatostatin conjugate), LB05 (octreotide, somatostatin analogue conjugate), LB06 (lanreotide, somatostatin analogue conjugate), LB07 (vapre Otide (Sanvar), somatostatin analogue conjugate), LB08 (CAIX ligand conjugate), LB09 (CAIX ligand conjugate), LB10 (gastrin releasing peptide receptor receptor (GRPr), MBA conjugate), LB11 (luteinizing hormone releasing hormone (LH- RH ligand and GnRH conjugate), LB12 (luteinizing hormone releasing hormone (LH -RH) and GnRH ligand conjugate), LB13 (GnRH antagonist, Abareri LB14 (cobalamin, VB12 analogue conjugate), LB15 (cobalamin, VB12 analogue conjugate), , VB12 analogue conjugate), LB16 (α ｖ β ３ Integrin receptor, cyclic RGD pen tapeptide conjugate), LB17 (hetero-bivalent peptide ligand conjugate for VEGF receptors) LB18 (neuromedin B conjugate), LB19 (G protein-coupled receptor conjugate) Bombesin conjugate for Toll-like receptors), and LB20 (TLR ２ Conjugates), LB21 (for androgen receptor), LB22 (α V For integrin receptors Cilengitide / cyclo(-RGDfV)-) conjugate), LB23 (fludrocortisone conjugate), LB24 (dexamethasone conjugate), LB25 (fluticasone propionate conjugate) LB26 (beclomethasone dipropionate), LB27 (triamcinolone acetate) LB28 (prednisone conjugate), LB29 (prednisolone conjugate) , LB30 (methylprednisolone conjugate), LB31 (betamethasone conjugate), LB3 2 (irinotecan analogue), LB33 (crizotinib analogue), LB34 (bortezomib LB35 (carfilzomib analog), LB36 (carfilzomib analog) , LB37 (leuprolide analogue), LB38 (triptorelin analogue), LB39 (liprolide analogue), LB40 (raglutide analogue), LB40 (semaglutide analogue), and LB41 (lixisenatide analogue) The conjugate compound of claim 2, wherein the conjugate compound is selected from the group consisting of: 【Chemistry 43】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 During the ceremony, 【Chemistry 44】 n, m １ , m ２ , X １ , X ２ , R １ , R ２ , R ３ , and R ４ has the same definition as claim 1 or 2 Righteous; mAb is an antibody or cell binding molecule; L １ , L ２ , L ３ , L ４ , and L ５ Each independently represents L of claim 1. １ With the same definition as can be; X ３ はCH ２ 、O、NH、NHC(O)、NHC(O)、C(O)、 O.C. (O) (NR ３ ), R １ , N.H.R. １ , N.R. １ , or C(O)R １ or Not present; X ４ はH、CH ２ 、OH、O、C(O),C(O)(NH、C(O)N(R). １ ),R １ 、 NHR １ , N.R. １ , C(O)R １ or C(O)O; M １ and M. ２ are each independently H, Na, K, Ca, Mg, or NH ４ , N.R. １ R ２ R ３ and R6=5′-deoxyadenosyl, Me, OH, or CN; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; Furthermore, R １’ may be a cytotoxic agent as defined in claim 8; Furthermore, R １ may be absent, and R ２ may be hydrogen.

31. Drug, Drug', or Drug'' is a DNA, RNA, mRNA, small interfering molecule, RNA (siRNA), microRNA (miRNA), or PIWI-interacting RNA ( piRNA), and the conjugate compound is the following SI-1, SI-2, SI-3, SI The conjugate compound of claim 2, wherein the conjugate compound is selected from the structures SI-4, SI-5, or SI-6: 【Chemistry 45】 【change】 During the ceremony, mAb is an antibody or cell binding molecule; 【Chemistry 46】 n, m １ , m ２ , m ３ , m ４ , X １ , X ２ , X ３ , X ４ , X ５ , and R １ Claim 1 and The same definition; R １’ and R ３’ are each independently H or C １ -C ６ Linear or branched alkyl and p is 0 to 2000; 【Chemistry 47】 is a single or double stranded DNA, RNA, or mRNA; Y and Y′ are each independently O, S, NH, CH ２ , N-R １ and L １ , L ２ , L ３ , L ４ , L １’ , and L ２’ Each independently represents L of claim 1. １ and The same definition; Furthermore, R １’ may be a cytotoxic agent or drug as defined in claim 8.

32. The two or more different functional molecules according to claim 6 are represented by the formula (I) or ( II) or via the formula (XVII) or (XVIII) according to claim 4 The conjugate of claim 2 , capable of being conjugated to a cell-binding molecule.

33. The following Z01, Z02, Z03, Z04, Z05, Z06, Z07, Z08, Z09, Structures of Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, and Z18 The conjugate of claim 32, which can be selected from one of: 【Chemistry 48】 【change】 【change】 【change】 【change】 During the ceremony, 【Chemistry 49】 n, m １ , m ２ , X １ , X ２ , L １ , L ２ , R １ , R ２ , R ３ , and R ４ Claim 1 or has the same definition as in 2; mAb is an antibody or cell binding molecule; X ３ and X' ３ are each independently CH ２ , O, NH, NHC(O), NHC(O) NH, C(O), OC(O), OC(O)(NR ３ ), R １ , N.H.R. １ , N.R. １ , young is C(O)R １ or not present; X ４ and X' ４ are each independently H, CH ２ ,OH,O,C(O),C(O)NH , C(O)N(R １ ), R １ , N.H.R. １ , N.R. １ , C(O)R １ or C(O)O ； M １ and M. ２ are independently H, Na, K, Ca, Mg, and NH ４ , N.R. １ R ２ R ３ and Furthermore, R １ and / or R ２ may not be present independently.

34. Claims 2, 3, 13, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26 34. The conjugate according to claim 27, 28, 29, 30, 31, 32 or 33, The combination molecule / agent is selected from an IgG antibody, a monoclonal antibody, or an IgG antibody-like protein. and the conjugate comprises one, two or more of the same or different functional molecules or cytotoxic agents, and the following structures: ST1, ST2, ST3, ST4, ST5, ST6, S Shown in T7, ST8, ST9, ST10, ST11, ST12, ST13, or ST14 Thus, the disulfide bond between the light chain and the heavy chain of the cell-binding molecule / agent and between the two heavy chains on the upper side The reduction of the disulfide bond on the lower side between the two heavy chains results in a pair of thiols and a specific Heterogeneously conjugated conjugates: 【Chemistry 50】 【change】 During the ceremony, X １ 、X １’ 、X ２ 、X ２’ 、X ３ 、X ３’ 、X ４ 、X ４’ 、T、L １ 、L １’ 、L ２ , L ２’ , L ３ , L ３’ , L ４ , L ４’ , and 【Chemistry 51】 has the same definition as in claim 1; 【Chemistry 52】 is the moiety for linking a functional molecule or a cytotoxic agent; Furthermore, X １ , X １’ , X ２ , X ２’ , X ３ , X ３’ , X ４ , or X ４’ are independent It is not necessary for the criterion to exist.

35. The cytotoxic agent is a tubulysin, a maytansinoid, a taxanoid (taxan benzodiazepines), CC-1065 analogues, daunorubicin and doxorubicin compounds, Zepine dimers (pyrrolobenzodiazepines (PBD), tomaymycin, anthramycin , indolinobenzodiazepines, imidazobenzothiadiazepines, or oxazolidinium ), calicheamicins and enediynes. Antibiotics, actinomycin, azaserine, bleomycin, epirubicin, tamoxifen Xifene, idarubicin, dolastatins, auristatins (monomethyl auristatins Auristatin E, MMAE, MMAF, Auristatin PYE, Auristatin TP, Auristatin The quinone is selected from 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP). , duocarmycins, thiotepa, vincristines, hemiasterlins, nasmamide nazumamides, microginins, radios radiosumins, alterobactins ), microsclerodermicins, Theonella Theonellamides, esperamicins s), PNU-159682, and analogs and derivatives thereof.

35. The conjugate compound according to claim 34.

36. The linker compound of claim 1 having the following structure: 【Chemistry 53】 【change】 【change】

37. The following formulas 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, and 2-9 、２－１０、２－１１、２－１２、２－１３、２－１４、２－１５、２－１６、２－１７ 、２－１８、２－１９、２－２０、２－２１、２－２２、２－２３、２－２４、２－２５ 、２－２６、２－２７、２－２８、２－２９、２－３０、２－３１、２－３２、２－３３ , 2-34, 2-35, F2-1, F2-2, F2-3, F2-4, F2-5, F2-6 , F2-7, F2-8, F2-9, F2-10, F2-11, F2-12, F2-13, F2-14, F2-15, F2-16, F2-17, F2-18, F2-19, F2-2 0, F2-21, F2-22, F2-23, F2-24, F2-25, F2-26, F2 -27, F2-28, F2-29, F2-30, F2-31, F2-32, F2-33, F2-34, F2-35, F2-36, F2-37, F2-38, F2-39, F2-4 0, F2-41, F2-42, F2-43, 28, 32, 53, 55, 64, 69, 70 、７８、８６、９５、９７、１０３、１１１、１１６、１１７、１２４、１２７、１４１ 、１４４、１４７、１５５、１６７、１７３、２２０、２３２、２３４、２３５、２３８ 、２３９、２６１、２６８、２７３、２８１、２８９、２９３、２９６、３０７、３０８ 、３１３、３１８、３２６、３２７、３３９、３４４、３４５、３５４、３５５、３６０ 、３６１、３７１、３７７、３７９、３８１、３９１、３９３、３９５、４０４、４１１ 、４１８、４２０、４２８、４３０、４３２、４３４、４３９、４４３、４５２、４５８ 、４６３、４６７、４７０、４７３、４７６、４７８、４８１、４８３、４９４、４９６ 498, 500, 506, and 508. 【Chemical 54】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 During the ceremony, R' is C １ -C ４ Alkyl; 【Chemistry 55】 m １ 、m ２ 、p、drug、Z ３ 、drug １ 、drug ２ 、drug ３ 、drug ４ , drug ５ , drug ６ , drug ７ , drug8, drug １’ , m, and n are The same definitions as in claims 1 and 2; L １ , L ２ , L ３ , L ４ , L ５ , L ６ , L ７ , and L ８ and independently represent L of claim 1. １ and It is the same definition.

38. The following formulas 4-1, 4-2, 4-3, 4-4, 4-5, 4-6, 4-7, 4-8, and 4-9 、４－１０、４－１１、４－１２、４－１３、４－１４、４－１５、４－１６、４－１７ 、１７、２７、３１、４４、５２、５４、６３、６８、７７、８０、８２、８５、８７、 ９２、９４、９６、１００、１０２、１１０、１１５、１２３、１２６、１４０、１４３ 、１４５、１５３、１６６、１７２、２１９、２３１、２３３、２３７、２６０、２６７ 、２７２、２８０、２８８、２９２、２９５、３０６、３１２、３１４、３２５、３３８ 、３４３、３５３、３５９、３７０、３７６、３７８、３８０、３９０、３９２、３９４ 、４０３、４１０、４１７、４１９、４２７、４２９、４３１、４３３、４３８、４４２ 、４５１、４５７、４６２、４６６、４６９、４７２、４７５、４７７、４８０、４８２ , 493, 495, 497, 499, 505, and 507. Compound: 【Chemistry 56】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 During the ceremony, 【Chemistry 57】 m １ , m ２ ,m,p,drug,Z ３ , Lv １ , and Lv ２ is the same definition as in claims 1 and 2. Righteous; L, L １ , L ２ , L ３ , L ４ , L ５ , L ６ , L ７ , and L ８ The same or different claims L in Item 1 １ is the same definition as Drug、Drug １ 、Drug ２ 、Drug ３ 、Drug ４ 、Drug ５ 、Drug ６ , Drug ７ and Drug 8 is the same or different, and has the same definition as Drug in claim 2. be.

39. A therapeutically effective amount of claims 2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 9, 30, 31, 32, 33, 34, 35, or 37, and a pharma- ceutically acceptable and a salt, carrier, diluent, or excipient, or a combination thereof, A pharmaceutical composition for treating or preventing an immune disease or an infectious disease.

40. In vitro, in vivo, or ex vivo x vivo) have a cell killing activity. 5, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, or 39 The conjugate described herein.

41. Preface: Connector components, R １ , R ２ ,L,L １ , L １’ , L １’’ , L １’’’ , L ２ , L ２ ’ , L ２’’ , L ３ , L ４ , and L ５ are independently cleavable by a protease; Claims 1, 2, 3, 4, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 , 27, 28, 29, 30, 31, 33, 34, 36, 37, or 38.

42. A therapeutically effective amount of claims 2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 9, 30, 31, 32, 33, 34, 35, 37, or 39, In combination with a therapeutic agent, radiotherapy, immunotherapy, autoimmune disease agent, anti-infective agent, or other conjugate and synergistically administering the same to a subject in need of treatment or prevention of cancer, an autoimmune disease, or an infectious disease. A pharmaceutical composition for use in treating

43. The synergist of claim 42 is selected from one or more of the following drugs: abatacept abiraterone acetate (Zytiga®), acetaminophen / hydramine Locodon, aducanumab, adalimumab, ADXS31-142 (Advaxis'), ADX S-HER2 (Advaxis'), afatinib dimaleate (Gilotrif®), Alemtuzumab (Campath®), alitretionin (Panretin®) , ado-trastuzumab em (Kadcyla®), amphetamine mixed salts (amphetamine adderall XR), anastrozole (Arimidex ( Registered trademark), aripiprazole, atazanavir, atezolizumab (MPDL3280A), Rubastatin, axitinib (Inlyta®), avelumab, belinostat ( Beleodaq™), bevacizumab (Avastin®), cabazitaxel (Jevtan a®), cabozatinib (Cometriq™), bexarotene (Targretin® (Blincyto™), blinatumomab (Blincyto™), bortezomib (Velcade® ), bosutinib (Bosulif®), brentuximab vedotin (Adcetris®), (trademark), budesonide, budesonide / formoterol, buprenorphine, capecitabine , carfilzomib (Kyprolis®), celecoxib, ceritinib (LDK378 / Zyk adia), cetuximab (Erbitux®), cyclosporine, cinacalcet, Rizotinib (Xalkori®), Cosentyx, CTL0 19. Dabigatran, Dabrafenib (Tafinlar®), Daratumab (Darzalex®) ), darbepoetin alfa, darunavir, imatinib mesylate (Gleevec®), Satinib (Sprycel®), denileukin diftitox (Ontak®) ), denosumab (Xgeva®), Depakote, dexlansoprazole le, dexmethylphenidate, dexamethasone, Dignitana Dignica p Cooling System, dinutuximab (Unituxin™), doxycycline Clin, duloxetine, duvelisib, elotuzumab, emtricitabine / rilpivir emtricitabine / tenofovir / efavirenz , enoxaparin, enzalutamide (Xtandi®), epoetin alfa, erlotinib Nib (Tarceva®), esomeprazole, eszopiclone, etanercept, Everolimus (Afinitor®), exemestane (Aromasin®), Verolimus (Afinitor®), ezetimibe, ezetimibe / simvastatin, phenytoin Nofibrate, filgrastim, fingolimod, fluticasone propionate, flu Ticazone / salmeterol, Fulvestrant (Faslodex®), Gadiva (Ga zyva), gefitinib (Iressa®), glatiramer, goserelin acetate (Zo ladex), icotinib, imatinib (Gleevec), ibritumomab tiuxetan (Zevali ibrutinib (Imbruvica™), idelalisib (Zydeligin®), (trademark), infliximab, iniparib, insulin aspart, insulin deteimi insulin glargine, insulin lispro, interferon beta-1a, interferon β1b, lapatinib (Tykerb®), ipilimumab (Yervoy®) ), ipratropium bromide / salbutamol, Ixazomi (Ninlaro®), Kanuma, lanreotide acetate (Somatuline® depot), Lenalid Revlimid (registered trademark), lenalimid (Lenvima (trademark)), (trademark), letrozole (Femara®), levothyroxine, lidocaine, Cain, linezolid, liraglutide, lisdexamfetamine, LN-144 (Lion Bio tech), MEDI4736 (AstraZeneca, Celgene), memantine, methylphenidate , metoprolol, mekinist, modafinil, mometasone, nilotinib (Tasigna (Registered Trademark), niraparib, nivolumab (Opdivo®), ofatumumab (Arzer®), a®), obinutuzumab (Gazyva™), olaparib (Lynparza™) ), olmesartan, olmesartan / hydrochlorothiazide, omalizumab, omega-3 fat Acid Ethyl Ester, Oseltamivir, Oxycodone, Palbociclib (Ibrance®) (registered trademark), palivizumab, panitumumab (Vectibix®), panobinostat (Fa rydak®), pazopanib (Votrient®), pembrolizumab (Keytr uda®), pemetrexed (Alimta), pertuzumab (Perjeta™), pulmonary Streptococcus pneumoniae conjugate vaccine, pomalidomide (Pomalyst®), pregabalin, Pros caVax, propranolol, quetiapine, rabeprazole, radium 223 chloride (Xofigo®), raloxifene, raltegravir, ramucirumab (Cyramza®), Registered Trademark), ranibizumab, regorafenib (Stivarga®), rituximab (Rituxan®), rivaroxaban, romidepsin (Istodax®), Savastatin, Ruxolitinib phosphate (Jakafi™), Salbutamol, Sevelamer , sildenafil, siltuximab (Sylvant™), sitagliptin, sitagliptin metformin, solifenacin, solanezumab, sorafenib (Nexavar (registered trademark) (trademark), sunitinib (Sutent®), tadalafil, tamoxifen, tafin Tafinlar, Talazoparib, Telaprevir, Temsirolimus (Torisel (Registered Trademark), Tenofovir / Emtricitabine, Testosterone Gel, Thalidomide (Im munoprin, Talidex), tiotropium bromide, toremifene (Fareston®), Trametinib (Mekinist®), trastuzumab, tretinoin (Vesanoid ( (Registered Trademark)), ustekinumab, valsartan, veliparib, vandetanib (Caprelsa ( Registered trademark), vemurafenib (Zelboraf®), venetoclax, vorinos (Zolinza®), divaflibercept (Zaltrap®), and Starbucks, as well as their analogs, derivatives, and pharma- ceutically acceptable salts, A carrier, diluent or excipient, or a combination thereof.

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