A camptothecin-based drug and its antibody-drug conjugate

Abstract

This invention discloses a camptothecin-based drug and its antibody-drug conjugate. Based on a comprehensive understanding of ADC drugs, the inventors designed a series of antitumor icetane active derivatives. Through experiments, it was found that the newly designed antitumor molecular compounds exhibited good antitumor activity in experiments.

Description

Technical Field

[0001] This invention relates to camptothecin-based drugs used as antitumor agents and their antibody-drug conjugates. Prior Technology

[0002] Antibody-drug conjugates (ADCs), as novel targeted therapies, generally consist of three parts: an antibody or antibody-like ligand, a small molecule drug, and a linker that conjugates the ligand and drug. ADCs utilize the specific recognition of antigens by antibodies to transport drug molecules to the vicinity of target cells and effectively release the drug molecules, achieving therapeutic goals. In August 2011, the U.S. Food and Drug Administration (FDA) approved Adecteis™, a novel ADC developed by Seattle Genetics, for the treatment of Hodgkin's lymphoma and relapsed large cell lymphoma (ALCL). Clinical applications have demonstrated the safety and efficacy of this type of drug.

[0003] Camptothecin derivatives, small molecule compounds with antitumor properties, are known to exhibit antitumor activity by inhibiting DNA topoisomerase I. These include irinotecan, eciletcan, and SN38. Many camptothecin derivatives are widely used clinically, primarily for bone cancer, prostate cancer, breast cancer, and pancreatic cancer. Unlike irinotecan currently used clinically, eciletcan does not require enzyme activation. Furthermore, compared to SN38, the pharmacodynamic component of irinotecan, and topotecan, which is also used clinically, eciletcan exhibits stronger topoisomerase I inhibitory activity and stronger cell-damaging activity against various cancer cells in vitro. In particular, it shows efficacy against cancer cells resistant to SN38, which express P-glycoprotein. Ecinotecan has not yet been successfully marketed as a standalone chemotherapy drug, presumably due to its high cellular activity, resulting in a narrow therapeutic window.

[0004] Antibody-drug conjugates (ADCs) offer advantages such as increased water solubility, improved targeting, and the specific binding of antibodies to antigens, delivering the drug to the vicinity of target cells. By releasing the drug near the target cells, they effectively kill tumor cells and reduce toxic side effects. Camptothecin-based drugs show considerable promise for application in ADCs.

[0005] The technical problem this patent aims to solve is to explore and discover better anti-tumor camptothecin compounds, improve the safety and efficacy of small molecule compounds against tumors in ADC drug applications, and obtain anti-tumor drugs with excellent efficacy.

[0006] Based on a comprehensive understanding of ADC drugs, the inventors designed a series of antitumor camptothecin active derivatives. Through experiments, they found that the small molecule compounds exhibited higher antitumor activity in cell experiments. Summary of the Invention

[0007] This invention aims to provide a camptothecin derivative with superior antitumor effects and its antibody-drug conjugate, an antitumor camptothecin compound as shown in Formula I, or a pharmaceutically acceptable salt thereof: Formula I R1 and R2 are independently selected from C1-C3 alkyl or substituted alkyl, -H, -CF3, aryl or substituted aryl; or R1 and R2 together with the carbon atoms attached to them constitute cyclobutane, cyclopentane or cyclohexane; R1 and R2 are not both hydrogen.

[0008] As a preferred embodiment, R1 is hydrogen, and R2 is a C1-C3 alkyl, -CF3, aryl, heteroaryl, monofluoro-substituted aryl, or difluoro-substituted aryl; or R1 and R2 are C1-C3 alkyl, -CF3, aryl, heteroaryl, monofluoro-substituted aryl, or difluoro-substituted aryl; or R1 and R2 together with the carbon atoms they are attached to constitute cyclobutane, cyclopentane, or cyclohexane. In structural formula (a), R2 is independently -(CH2)n1-CH3, -CF3, aryl, heteroaryl, monofluoro-substituted aryl, or difluoro-substituted aryl, where n1 = 0, 1, or 2; In structural formula (b), R1 and R2 are independently -(CH2)n1-CH3, -CF3, aryl, heteroaryl, monofluorosubstituted aryl, or difluorosubstituted aryl, where n1 = 0, 1, or 2; In structural formula (c), R1 and R2, together with the carbon atoms they are attached to, constitute cyclobutane, cyclopentane, and cyclohexane, where m = 1, 2, or 3.

[0009] More preferably, R1 is hydrogen, and R2 is independently -(CH2)n1-CH3, -CF3, aryl, heteroaryl, monofluoro-substituted aryl, or difluoro-substituted aryl, wherein n1 = 0, 1, or 2. The carbon atom bonded to R2 has two configurations: R and S. In structural formula (a-1), the carbon atom bonded to R2 has an R configuration. In structural formula (a-2), the carbon bonded to R2 has an S configuration.

[0010] As a preferred example, the camptothecin compound or its pharmaceutically acceptable salt comprises the following structure: .

[0011] As a preferred example, the camptothecin compound or its pharmaceutically acceptable salt is an antitumor drug used for solid tumors and hematological malignancies such as lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, multifocal glioma, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, lung cancer, or esophageal cancer.

[0012] Another aspect of the present invention includes an antibody-drug conjugate as shown in Formula II, which exerts its therapeutic effect by releasing drug D upon reaching the target cells. Formula II Where Ab represents an antibody, antibody fragment, or protein; L is an optional connection unit; D is selected from any of the camptothecin compounds mentioned above or its pharmaceutically acceptable salt, which is linked to L through a hydroxyl group in the molecule. m is an integer selected from 1 to 20.

[0013] As a preferred example, the antibody-drug conjugate, wherein the linker unit L comprises a group selected from the group consisting of chemical bonds -O-, -N(R)n1-, -CH2-, -CH(R)n1-, acetamide, ester bond, -S-, —(PEG)n2-; n1 is selected from 1 to 3 integers, and n2 is selected from 1 to 20 integers.

[0014] Another aspect of the invention includes a method of treating a patient in need, comprising administering to the patient the antibody-drug conjugate described in any of the preceding claims, wherein the patient has a tumor, an autoimmune disease, or an infectious disease, and the antibody of the drug-ligand conjugate specifically binds to the target cells of the cancer, autoimmune disease, or cancer.

[0015] Preferably, the antibody-drug conjugate or its salt is an antitumor or anticancer drug, used for solid tumors and hematological malignancies such as lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, glioma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer. Simple Explanation of the Diagram

[0016] none Implementation

[0017] Abbreviations and Definitions Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. When a trademark name is used herein, unless the context otherwise indicates, the trademark name includes the product formulation, generic medicine, and active pharmaceutical ingredient of the product for which the trademark name is used.

[0018] The term "alkylene" refers to a divalent, straight-chain saturated hydrocarbon group having 1 to 20 carbon atoms, including groups with 1 to 10 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2-CH2-), n-propylene, n-butylene, n-pentylene, and n-hexylene. Unless otherwise stated, the term "aryl" refers to a polyunsaturated, generally aromatic, hydroxyl group, which can be monocyclic or fused or covalently linked polycyclic (up to three rings). The term "aromatic heterol" refers to an aryl (or ring) containing 1 to 5 heteroatoms selected from N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaromatic groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of aryl groups include phenyl, naphthyl, and diphenyl, while non-limiting examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cyclophosphinyl, phthalaziniyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoazolyl, and isobenzofuranyl. The following are examples of substituents: isoindolyl, inazinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyridopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazoleyl, pteridinyl, imidazoyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazoyl, pyrroleyl, thiazoyl, furanyl, and thiopheneyl. When described as "substituted," the substituents in the above aromatic and heteroaromatic ring systems are selected from the following acceptable substituents.

[0019] Unless otherwise stated in the text, the substituents of alkyl groups may be selected from a variety of groups from the group consisting of: -halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R'', -NR''C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -CN, and -NO2, with the number of substituents ranging from 0 to (2m'+1), where m' is the total number of carbon atoms in the group. R', R'', and R''' each independently refer to hydrogen, an unsubstituted C1-8 alkyl group, an unsubstituted aryl group, an aryl group substituted with 1-3 halogens, an unsubstituted C1-8 alkyl group, a C1-8 alkoxy group or a C1-8 thioalkoxy group, or an unsubstituted aryl-C1-4 alkyl group. When R' and R'' are attached to the same nitrogen atom, they can form a 3-, 4-, 5-, 6-, or 7-membered ring with that nitrogen atom. For example, -NR'R'' includes 1-pyrrolidinyl and 4-morpholinyl.

[0020] In this article, the term "derivative" refers to a substance that has a similar chemical structure to the compound but also contains at least one chemical group not present in the compound and / or lacks at least one chemical group present in the compound. The compound to which the derivative is compared is called the "parent" compound. Typically, the "derivative" can be generated from the parent compound in one or more chemical reaction steps. L-ligands

[0021] A ligand unit is a targeting agent that specifically binds to a target moiety. The ligand is capable of specifically binding to cellular components or other target molecules of interest. The target moiety or target is typically located on the cell surface. In some aspects, the role of the ligand unit is to deliver a drug unit to a specific target cell population with which the ligand unit interacts. Ligands include, but are not limited to, proteins, polypeptides, and peptides, as well as non-proteins such as sugars. Suitable ligand units include, for example, antibodies, such as full-length (intact) antibodies and their antigen-binding fragments. In embodiments where the ligand unit is a non-antibody targeting agent, it may be a peptide or polypeptide, or a non-protein molecule. Examples of such targeting agents include interferons, lymphocytes, hormones, growth factors and colony-stimulating factors, vitamins, nutrient transport molecules, or any other cell-binding molecules or substances. In some embodiments, a linker is covalently linked to a sulfur atom of the ligand. In some aspects, the sulfur atom is a sulfur atom of a cysteine ​​residue that forms an interchain disulfide bond in the antibody. In another aspect, the sulfur atom is a sulfur atom of a cysteine ​​residue that has been incorporated into the ligand unit, forming an interchain disulfide bond of the antibody. In yet another aspect, the sulfur atom is a sulfur atom of a cysteine ​​residue that has been incorporated into the ligand unit (e.g., by site-directed mutagenesis or chemical reaction). In still another aspect, the sulfur atom bound to the linker is selected from cysteine ​​residues that form an interchain disulfide bond of the antibody or cysteine ​​residues that have been incorporated into the ligand unit (e.g., by site-directed mutagenesis or chemical reaction). In some embodiments, the EU indexing system is followed as in Kabat (Kabat EA et al., (1991)), Sequences of Proteins of Immunological Interest, 5th Edition, NIH Publication 91-3242.

[0022] As used herein, "antibody" or "antibody unit" within its scope includes any part of an antibody structure. This unit may bind, reactively associate, or chelate a receptor, antigen, or other receptor units present in a target cell population. An antibody can be any protein or protein-like molecule that can bind, chelate, or react with a portion of a cell population to be treated or bioengineered.

[0023] In this invention, the antibodies constituting the antibody-drug conjugate preferably retain their original wild-state antigen-binding ability. Therefore, the antibodies in this invention can, preferably specifically, bind to antigens. The antigens involved include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, cell survival regulators, cell proliferation regulators, molecules associated with tissue growth and differentiation (such as those known or anticipated to be functional), lymphocytes, cytokines, molecules involved in cell circulation regulation, molecules involved in angiogenesis, and molecules associated with angiogenesis (such as those known or anticipated to be functional). Tumor-associated factors may be cluster differentiation factors (such as CD proteins). [This is consistent with the description in this invention.]

[0024] Antibodies used in antibody-drug conjugates include, but are not limited to, antibodies targeting cell surface receptors and tumor-associated antigens. Such tumor-associated antigens are well-known in the industry and can be prepared using well-known antibody preparation methods and information. To develop effective cellular-level targets for cancer diagnosis and treatment, researchers seek transmembrane or other tumor-associated peptides. These targets are specifically expressed on the surface of one or more cancer cells, while being expressed sparingly or not at all on the surface of one or more non-cancer cells. Typically, such tumor-associated peptides are more overexpressed on the surface of cancer cells compared to non-cancer cells. Identifying such tumor-associated factors can significantly improve the specific targeting properties of antibody-based cancer therapies.

[0025] Tumor-associated antigens include, but are not limited to, the tumor-associated antigens listed below (1)-(36). For convenience, information on antigens well-known in the industry is indicated below, including name, other names, and gene bank accession number. Nucleic acid and protein sequences corresponding to tumor-associated antigens can be found in public databases, such as GenBank. Tumor-associated antigens targeted by antibodies include all amino acid sequence variants and homologs, and have at least 70%, 80%, 85%, 90%, or 95% homology with the sequences identified in the reference documents, or have biological properties and characteristics completely consistent with the tumor-associated antigen sequences in the cited documents.

[0026] The term "inhibition" or "suppression of" refers to reducing the detectable amount or completely blocking it.

[0027] The term "cancer" refers to a physiological condition or disease characterized by disordered cell growth. "Tumor" includes cancer cells.

[0028] The term "autoimmune disease" refers to a disease or disorder that affects an individual's own tissues or proteins.

[0029] As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound (e.g., a drug, drug-connector, or ligand-connector-drug conjugate). The compound may contain at least one amino or carboxyl group and is therefore capable of forming an addition salt with the corresponding acid or base. Exemplary salts include, but are not limited to: sulfates, trifluoroacetates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbic acid salts, salicylates, formates, benzoylformates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, potassium salts, sodium salts, etc. Furthermore, pharmaceutically acceptable salts have more than one charged atom in their structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt can have multiple counterexamples. For example, pharmaceutically acceptable salts have one or more charged atoms and / or one or more counter atoms.

[0030] Based on the mechanism of drug release within cells, as used in this article, "linkers" or "linkers of antibody-drug conjugates" can be divided into two categories: unbreakable linkers and breakable linkers.

[0031] For antibody-drug conjugates containing unbreakable linkers, the drug release mechanism is as follows: after the conjugate binds to the antigen and is endocytosed by the cell, the antibody is enzymatically cleaved in lysosomes, releasing an active molecule composed of a small molecule drug, the linker, and antibody amino acid residues. This alteration in drug molecular structure does not weaken its cytotoxicity; however, because the active molecule is charged (amino acid residues), it cannot penetrate neighboring cells. Therefore, such active drugs cannot kill neighboring tumor cells that do not express the target antigen (antigen-negative cells) (bystander effect) (Ducry et al., 2010, Bioconjugate Chem. 21:5-13).

[0032] Twisterable linkers, as the name suggests, can break down within target cells and release the active drug (the small molecule drug itself). Twisterable linkers can be divided into two main categories: chemically unstable linkers and enzyme-unstable linkers.

[0033] Chemically unstable linkers can be selectively broken due to differences in plasma and cytoplasmic properties. Such properties include pH value and glutathione concentration.

[0034] pH-sensitive linkers are often called acid-splitting linkers. Such linkers are relatively stable in the neutral environment of blood (pH 7.3-7.5), but will be hydrolyzed in weakly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0). First-generation antibody-drug conjugates mostly utilize these types of linkers, such as hydrazones, carbonates, acetals, and ketals. Due to the limited plasma stability of acid-splitting linkers, antibody-drug conjugates based on these linkers typically have a short half-life (2-3 days). This short half-life limits the application of pH-sensitive linkers in next-generation antibody-drug conjugates to some extent.

[0035] For glutathione-sensitive linkers, also known as disulfide linkers, drug release is based on the difference between the high intracellular glutathione concentration (millimolar range) and the relatively low blood glutathione concentration (micromolar range). This is especially true for tumor cells, where low oxygen levels lead to increased reductase activity, resulting in even higher glutathione concentrations. Disulfide bonds are thermodynamically stable, thus exhibiting good stability in plasma.

[0036] Unstable enzyme linkers, such as peptide linkers, offer better control over drug release. Peptide linkers can be effectively cleaved by lysosomal proteases, such as cathepsin B or plasmin (which is found in increased amounts in some tumor tissues). These peptide links are considered highly stable in plasma circulation because unsuitable extracellular pH and serum protease inhibitors typically render the proteases inactive. Given their high plasma stability and good intracellular cleavage selectivity and efficiency, unstable enzyme linkers are widely used as cleavable linkers for antibody-drug conjugates. Typical unstable enzyme linkers include Val-Cit(vc) and Phe-Lys.

[0037] Suicide linkers are typically embedded between a breakable linker and the active drug, or are themselves part of a breakable linker. The mechanism of action of suicide linkers is that when the breakable linker breaks under suitable conditions, the suicide linker spontaneously rearranges its structure, thereby releasing the attached active drug. Common suicide linkers include para-aminobenzyl alcohols (PABs) and β-glucuronides.

[0038] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under general conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, proportions, ratios, or parts are by weight.

[0039] Unless otherwise defined, all technical and scientific terms used herein are to have the same meaning as commonly understood by one of skill in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only. Example 1: Synthesis of Compound 2

[0040] Compound 1 (eceticon mesylate, purchased) (40 mg, 75.3 mmol, 1.0 eq) and L-lactic acid (10 mg, 113.0 mmol, 1.5 eq) were dissolved in 5 mL of dry DMF, followed by the addition of PyBop (58.8 mg, 113.0 mmol, 1.5 eq) and DIEA (15.7 μL, 113.0 mmol, 1.5 eq). After stirring at room temperature for 3 hours, the reaction was confirmed to be complete by TLC. The reaction was quenched with water, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 2 (30.9 mg, 81.1%). LC-MS: [M+H]+: 508.2. 1H NMR (400 Mz, CDCl3 / CD3OD): 0.91-0.94 (3H, m), 1.32-1.39 (3H, m), 1.71-1.83 (2H, m), 2.31 (3H, s), 2.78-3.02 (2H, 7.58 (1H, s), 7.75 (1H, d, J=12.0 Hz). Example 2 Synthesis of Compound 4

[0041] Compound 3: N-fluorenylmethoxycarbonyl-glycine (10 g, 28.2 mmol, 1.0 eq), lead tetraacetate (17.5 g, 55.3 mmol, 1.4 eq), 200 mL of dry tetrahydrofuran, and 67 mL of toluene were added to a 500 mL single-necked flask. The mixture was stirred thoroughly, and under nitrogen protection, the mixture was heated to 85 °C for 2.5 h. The reaction was monitored by TLC. After the reactants had reacted completely, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 4 (8.7 g, 83.7%). Example 3 Synthesis of Compound 5

[0042] Compound 3 (500 mg, 1.4 mmol, 1.0 eq), p-toluenesulfonic acid monohydrate (26 mg, 0.1 mmol, 0.1 eq), and 10 mL THF were added to a 25 mL single-necked flask. After stirring thoroughly, the mixture was cooled to 0 °C, and then L-benzyl lactate (1.2 g, 7.0 mmol, 5 eq) was slowly added. After the addition was complete, the mixture was brought back to room temperature to allow the reaction to proceed. The reaction was monitored by TLC. After the reaction was complete, saturated NaHCO3 solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse-phase column chromatography to give compound 5 (400 mg, 60.3%). 1H NMR (400 Mz, CDCl3): 1.39 (3H, d, J=6.8 Hz), 3.78 (2H, t, J=4.0 Hz), 4.17-4.27 (2H, m), 4.42 (2H, d, J=4.0 Hz), 4.72-4.85 (2H, m), 5.11-5.58 (2H, m), 5.43 (1H, s), 7.06 (1H, t, J=8.0 Hz), 7.25-7.33 (6H, m), 7.38 (2H, t, J=8.0 Hz), 7.57 (2H, d, J=8.0 Hz), 7.75 (2H, d, J=8.0 Hz). Example 4 Synthesis of Compound 6

[0043] Compound 5 (400 mg, 0.8 mmol, 1.0 eq) and 10 mL of DMF were added to a 25 mL single-necked flask. After stirring thoroughly, the mixture was cooled to 0 °C, and then DBU (137 mg, 0.9 mmol, 1.1 eq) was slowly added. After the addition was complete, the mixture was brought to room temperature to allow the reaction to proceed. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated to obtain crude compound 6 (550 mg), which was directly added to the next step without purification. Example 5 Synthesis of Compound 7

[0044] Z-Gly-Gly-Phe-OH (372 mg, 0.9 mmol, 1.1 eq), PyBOP (852 mg, 1.6 mmol, 2.0 eq), and 3 mL of DMF were added to a 25 mL single-necked flask. The mixture was stirred at room temperature for 5 minutes, and then crude compound 6 (550 mg) was added. The reaction was continued at room temperature and monitored by HPLC. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse-phase column chromatography to give compound 7 (326 mg, 59.2%). Example 6 Synthesis of Compound 8

[0045] Compound 7 (50 mg, 1.0 eq, 0.08 mmol), 5% Pd / C (50 mg), and 3 mL LDM were added to a 25 mL single-necked flask and hydrogenated at room temperature. The reaction was monitored by HPLC. After the reaction was completed, water was added and the mixture was filtered. The filtrate was concentrated to obtain crude compound 8 (52 mg), which was directly added to the next step without purification. Example 7 Synthesis of Compound 9

[0046] Compound 8 (52 mg), SMCC (23 mg, 0.07 mmol, 1.0 eq), DIEA (22.2 mg, 0.24 mmol, 2.5 eq), and 3 mL LDM were added to a 25 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to obtain compound 9 (9.0 mg, 18.1%). MS: [MH] 655.1. Example 8 Synthesis of Compound 11

[0047] Compound 9 (9.0 mg, 0.014 mmol, 1.0 eq), eczema mesylate (6.6 mg, 0.014 mmol, 1.0 eq), PyBOP (14.3 mg, 0.028 mmol, 2.0 eq), DIEA (6.2 mg, 0.048 mmol, 3.5 eq), and 0.5 mL LDM were added to a 25 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to obtain compound 11 (7.0 mg, 48.3%). TOF: [M+Na]+ 1096.42. Example 9 Synthesis of compounds 12 and 13

[0048] Compound 1 (ecinetidine mesylate) (40 mg, 75.3 mmol, 1.0 eq) and trifluorolactic acid (16.3 mg, 113.0 mmol, 1.5 eq) were dissolved in 5 mL of dry DMF, followed by the addition of PyBop (58.8 mg, 113.0 mmol, 1.5 eq) and DIEA (15.7 μL, 113.0 mmol, 1.5 eq). After stirring at room temperature for 3 hours, the reaction was confirmed to be complete by TLC. The reaction was quenched with water, extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 12 (13.5 mg, 32%). LC-MS: [M+H]+: 562.2. ¹H NMR (400 Mz, CDCl3 / CD3OD): 0.91–0.95 (3H, m), 1.78–1.84 (2H, m), 2.34 (3H, s), 3.04–3.14 (2H, m), 3.27–3.32 (2H, m), 4.42–4.47 (1H, m), 5.08–5.20 (3H, m), 5.41–5.58 (2H, m), 7.23–7.25 (1H, m), 7.52–7.55 (1H, m); Compound 13 (15.5 mg, 36.7%). LC-MS: [M+H]+: 562.2. 1H NMR (400 Mz, CDCl3 / CD3OD): 0.90-1.00 (3H, m), 1.74-1.89 (2H, m), 2.34 (3H, s), 3.01-3.09 (2H, m), 3.32-3.38 (2H, m), 4.65-4.71 (1H, m), 4.89-4.96 (1H, m), 5.17-5.30 (2H, m), 5.55-5.65 (2H, m), 7.53-7.61 (2H, m). Example 10 Synthesis of Compound 14

[0049] Trifluorolactic acid (3.5 g, 24.3 mmol, 1.0 eq) and K₂CO₃ (5.0 g, 36.5 mmol, 1.5 eq) were dissolved in 35 mL of dry DMF. Benzyl bromide (5.0 g, 29.2 mmol, 1.2 eq) was added dropwise under an ice-water bath under nitrogen protection. After the addition was complete, the mixture was allowed to react at room temperature for 5 hours. The reaction was monitored by TLC until complete. The reaction was quenched with water, extracted with dichloromethane (100 mL × 3), and the organic phases were combined. The mixture was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 14 (3.14 g, 55%). ¹H NMR (400 MHz, DMSO): 4.91–4.94 (¹H, m), 5.25 (²H, s), 7.17–7.19 (¹H, d), 7.39 (⁵H, s); Example 11 Synthesis of Compound 15

[0050] Compound 4 (1.45 g, 3.9 mmol, 1.0 eq), compound 14 (1.84 g, 7.8 mmol, 2.0 eq), Zn(OAc)2 (1.44 g, 7.86 mmol, 2.0 eq), and 25 mL T ol were added to a 50 mL single-necked flask. Under nitrogen protection, the mixture was stirred thoroughly and then heated to 100 °C for 5.5 h. TLC monitoring showed a clear product spot. The mixture was filtered, and the filtrate was concentrated to obtain a yellow oily substance (4.0 g). The crude product was purified by column chromatography to obtain compound 15 (0.99 g, 46%). 1H NMR (400 Mz, CDCl3): 3.68-3.83 (2H, m), 4.20-4.23 (1H,m), 4.49 (2H, d,J=8.0 Hz), 4.73-4.78 (1H, m), 4.89-5.00 (2H, m), 5.19(1H, s), 5.25 (2H, s), 7.11 (1H, s, ), 7.29-7.35 (7H, m), 7.43 (2H, t,J=8.0 Hz), 7.59 (2H, d,J=8.0 Hz), 7.79 (2H, d,J=8.0 Hz). Example 12 Synthesis of Compound 16

[0051] Compound 15 (990 mg, 1.8 mmol, 1.0 eq) and 10 mL of DMF were added to a 25 mL single-necked flask. After stirring thoroughly, the mixture was cooled to 0 °C, and then DBU (335 mg, 2.2 mmol, 1.2 eq) was slowly added under nitrogen protection. After the addition was complete, the reaction was continued at 0 °C for 30 min. The reaction was monitored by TLC. Once the starting material had reacted completely, the reaction solution was directly proceeded to the next step. Example 13 Synthesis of Compound 17

[0052] Z-Gly-Gly-Phe-OH (909 mg, 2.2 mmol, 1.2 eq), PyBOP (1.4 g, 2.7 mmol, 1.5 eq), and 10 mL of DMF were added to a 50 mL single-necked flask. DIEA was added dropwise under an ice-water bath and nitrogen protection. The reaction was continued for 10 min. The reaction solution of compound 16 was then slowly added dropwise to this reaction solution under an ice-water bath. After the addition was complete, the mixture was brought to room temperature and reacted for 1.5 h. The reaction was monitored by HPLC. After the reaction was completed, the mixture was purified and lyophilized to obtain compound 17 (0.91 g, 71%). Example 14 Synthesis of Compound 18

[0053] Compound 17 (85 mg, 1.0 eq, 0.12 mmol), 5% Pd / C (85 mg), and 6 mL LDM were added to a 25 mL single-necked flask and the mixture was hydrogenated at room temperature for 1 h. The reaction was monitored by HPLC. After the reactants had reacted completely, the reaction solution was filtered, and the filtrate was directly added to the next reaction step. Example 15 Synthesis of Compound 19

[0054] The reaction solution of compound 18 was filtered into a 25 mL single-necked flask. SMCC (80 mg, 0.24 mmol, 2.0 eq) and DIEA (62 mg, 0.48 mmol, 4.0 eq) were added sequentially under an ice-water bath. Nitrogen protection was maintained. After the addition was complete, the mixture was brought to room temperature and reacted for 1 h. The reaction was monitored by HPLC, purified, and lyophilized to obtain compound 19 (66 mg, 78%). MS: [MH] 709.2. Example 16 Synthesis of compounds 20 and 21

[0055] Compound 19 (10 mg, 14 μmol, 1.0 eq), compound 1 (9 mg, 21 μmol, 1.5 eq), and PyBop (14.6 mg, 28 mmol, 2.0 eq) were dissolved in dry DMF (0.5 mL). DIEA (5 μL, 28 μmol, 2.0 eq) was added under an ice-water bath. The mixture was kept under nitrogen protection and then allowed to react at room temperature for 1 h. The reaction was monitored by HPLC. After the reaction of the starting material compound 19 was complete, the reaction solution was directly purified by HPLC to obtain compound 20 (2.77 mg, 17.5%), LC-MS: [M+H]+: 1128.0; and compound 21 (3.92 mg, 24.8%), LC-MS: [M+H]+: 1128.0. Example 17 Synthesis of Compound 22

[0056] The reaction solution of compound 18 (0.15 mmol, 1.0 eq) was filtered into a 25 mL single-necked flask. MC (93 mg, 0.3 mmol, 2.0 eq) and DIEA (78 mg, 0.6 mmol, 4.0 eq) were added sequentially under an ice-water bath. The reaction was carried out under nitrogen protection and then allowed to proceed to room temperature for 1 h. The reaction was monitored by HPLC, purified by pure water, and lyophilized to obtain compound 22 (90 mg, 86%). MS: [MH] 683.2. Example 18 Synthesis of compounds 23 and 24

[0057] Compound 22 (15 mg, 21.9 μmol, 1.0 eq), compound 1 (14.3 mg, 32.8 μmol, 1.5 eq), and PyBop (22.8 mg, 43.8 mmol, 2.0 eq) were dissolved in dry DMF (0.8 mL). DIEA (7.3 μL, 43.8 μmol, 2.0 eq) was added under an ice-water bath. The mixture was kept under nitrogen protection and then allowed to react at room temperature for 1 h. The reaction was monitored by HPLC. After the reaction of starting material compound 22 was complete, the reaction solution was directly purified by HPLC to obtain compound 23 (6.01 mg, 25%), LC-MS: [M+H]+: 1102.0; and compound 24 (5.57 mg, 23.2%), LC-MS: [M+H]+: 1102.0. Example 18 Synthesis of Compound 25

[0058] Mandelic acid (42 mg, 0.09 mmol, 1.1 eq), eczema (35 mg, 0.08 mmol, 1.0 eq), PyBOP (84 mg, 0.16 mmol, 2.0 eq), DIEA (36.4 mg, 0.28 mmol, 3.5 eq), and 1 mL LDMF were added to a 5 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to give compound 25 (15.0 mg, 32.6%). ¹H NMR (CDCl₃, 400 MHz) was then performed. []δ7.70(d,1H,J=8.0Hz),7.64(s,1H),5.64-5.75(m,2H),5.48-5.38(m,1H),5.29-5.21(m,1H),5.19-5.11(m,1H),3.37-3.11(m,2H LC-MS: [M+H] 548.4. Example 19 Synthesis of Compound 26

[0059] D-lactic acid (11.2 mg, 0.08 mmol, 1.1 eq), eczema (30.0 mg, 0.07 mmol, 1.0 eq), PyBOP (119.5 mg, 0.14 mmol, 2.0 eq), DIEA (31.2 mg, 0.25 mmol, 3.5 eq), and 1 mL LDMF were added to a 5 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to give compound 26 (7.2 mg, 20.6%). ¹H NMR (CDCl₃, 400 MHz) was then performed. []δ7.75(d,1H,J=10.4Hz),7.70(s,1H),5.75-5.63(m,2H),5.46-5.38(m,1H),5.30-5.16(m,2H),4.50-4.40(m,1H),3.34-3.13(m,2H LC-MS: [M+H] 508.3. Example 20 Synthesis of Compound 27

[0060] 2-Methyllactic acid (10.5 mg, 0.10 mmol, 1.1 eq), eczema (40 mg, 0.09 mmol, 1.0 eq), PyBOP (95.6 mg, 0.18 mmol, 2.0 eq), DIEA (41.4 mg, 0.32 mmol, 3.5 eq), and 1 mL LDMF were added to a 5 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to give compound 27 (10.0 mg, 20.8%). ¹H NMR (CDCl₃, 400 MHz) was then performed. []δ7.68(d,1H,J=24Hz),7.63(s,1H),5.77-5.59(m,2H),5.48-5.39(m,1H),5.30-5.22(m,1H),5.19-5.11(m,1H),3.33 -3.10(m,2H),2.24(s,3H),1.71-1.63(m,2H),1.58-1.52(m,2H),1.40-1.20(m,6H),1.05(t,3H,J=7.2Hz);LC-MS:[M+H] 522.2. Example 4 Synthesis of Compound 28

[0061] R)-(-)-mandelic acid (15.2 mg, 0.10 mmol, 1.1 eq), eczema (40 mg, 0.09 mmol, 1.0 eq), PyBOP (95.6 mg, 0.18 mmol, 2.0 eq), DIEA (41.4 mg, 0.32 mmol, 3.5 eq), and 1 mL LDMF were added to a 5 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to give compound 28 (12.2 mg, 23.3%). ¹H NMR (CDCl₃, 400 MHz) []δ7.76(d,1H,J=8.0Hz),7.69(s,1H),7.53-7.35(m,5H),5.77-5.70(m,1H),5.65-5.55(m,1H),5.34-5.20(m,4H),3.32-3 .31(m,2H),2.47-2.40(m,3H),2.30-2.27(m,1H),2.05-2.02(s,1H),1.93-1.89(m,3H),1.07(t,3H,J=8.0Hz);LC-MS:[M+H] 570.2. Example 21 Synthesis of Compound 29

[0062] 3,5-Difluoromandelic acid (23.7 mg, 0.13 mmol, 1.1 eq), eczema (50 mg, 0.11 mmol, 1.0 eq), PyBOP (119.5 mg, 0.23 mmol, 2.0 eq), DIEA (37.1 mg, 0.29 mmol, 2.5 eq), and 1 mL LDMF were added to a 5 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to give compound 29 (13.5 mg, 19.4%). ¹H NMR (DMSO, 400 MHz) was then performed. []δ8.76(d,1H,J=8.4Hz),7.81(d,1H,J=10.8Hz),7.31(s,1H),7.27-7.07(m,4H),5.54-5.47(m,1H),5.43(s,2H),5.20-5. 03(m,4H),3.20-3.09(m,2H),2.43-2.38(m,3H),2.17-2.09(m,1H),1.96-1.79(m,3H),0.88(t,3H,J=7.2Hz);LC-MS:[M+H] 606.2. Example 22 Synthesis of Compound 30

[0063] 3,5-Difluoromandelic acid (22.5 mg, 0.13 mmol, 1.1 eq), eczema (50 mg, 0.11 mmol, 1.0 eq), PyBOP (119.5 mg, 0.23 mmol, 2.0 eq), DIEA (37.1 mg, 0.29 mmol, 2.5 eq), and 1 mL LDMF were added to a 5 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and purified by lyophilization to give compound 30 (8.2 mg, 11.7%). ¹H NMR (DMSO, 400 MHz) was then performed. δ8.60(d,1H,J=8.4Hz),7.79(d,1H,J=11.2Hz),7.31(s,1H),7.02-6.90(m,2 H),6.90-6.72(m,1H),6.05-5.93(m,2H),5.52-5.40(m,2H),5.19-5.09(m,1 H),5.09-4.92(m,2H),2.98-2.85(m,2H),2.22-2.14(m,3H),1.94-1.83(m,1 H),1.75-1.59(m,1H),1.53-1.45(m,2H),0.66(t,3H,J=7.2Hz);LC-MS:[M+H] 614.2. Example 23 Synthesis of Compound 31

[0064] S-2-hydroxybutyric acid (16.3 mg, 0.16 mmol, 1.1 eq), eczema (68.0 mg, 0.16 mmol, 1.0 eq), HATU (59.4 mg, 0.16 mmol, 1.0 eq), DIEA (50.5 mg, 0.39 mmol, 2.5 eq) and 1 mL LDMF were added to a 5 mL single-necked flask. The reaction was carried out at room temperature, monitored by HPLC, and the mixture was prepared, purified, and lyophilized to obtain compound 31 (16.3 mg, 20.1%). 1H NMR(DMSO,400Mz) δ8.36(d,1H,J=8.8Hz),7.79(d,1H,J=11.2Hz),7.31(s,1H),6.53(s,1H),5.60-5.52(m,1H),5.46-5.40(m,3H),5.24-5.17(m,2H),3.23-3 .09(m,2H),2.45-2.38(m,3H),2.28-2.08(m,2H),1.94-1.80(m,2H),1.79-1.66(m,1H),1.66-1.55(m,1H),1.05-0.84(m,6H);LC-MS:[M+H] 522.3. Example 24: Cell activity test of camptothecin

[0065] The cytotoxic activity of camptothecin was determined using the following experimental procedure: Camptothecin was added to the culture medium of human tumor cells expressing A431, Fadu, Bxpc-3 (EGFR-positive cells) and U87-MG, SW620 (negative control cells), respectively. Cell viability was measured after 72 hours of cell culture. In vitro cell-based experiments were used to determine cell viability, cytotoxicity, and programmed cell death induced by the camptothecin drug of this invention.

[0066] The in vitro efficacy of camptothecin was determined using a cell proliferation assay. The CellTiter 96® Aqueous One Solution Cell Proliferation Assay was commercially available (Promega Corp., Madison, WI). The CellTiter 96® AQueous One Solution Cell Proliferation Assay(a) is a colorimetric assay for determining the number of viable cells in cell proliferation and cytotoxicity assays. This assay contains a novel tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling agent (phenazine ethosulfate; PES). PES provides enhanced chemical stability, allowing it to be mixed with MTS to form a stable solution. This convenient "single solution" mode is an improvement on the first-generation CellTiter 96® AQueous Assay. The electron coupling agent PMS used in CellTiter 96® AQueous Assay is provided separately from the MTS solution. MTS (Owen's reagent) is biologically reduced by cells to a colored formazan product, which is directly soluble in the culture medium (the structures of MTS tetrazolium salt and its formazan product are shown below). This transformation is likely accomplished by NADPH or NADH produced by dehydrogenases in metabolically active cells. For detection, simply add a small amount of CellTiter 96® AQueous One Solution Reagent directly to the culture medium in the wells of the culture plate, incubate for 1–4 hours, and then read the absorbance value at 490 nm using a microplate reader.

[0067] The amount of formazan product detected at 490 nm is directly proportional to the number of viable cells in culture. Because the formazan product of MTS is soluble in tissue culture medium, the CellTiter 96® AQueous One Solution Assay requires fewer steps compared to the MTT or INT methods.

[0068] This invention uses A431, Fadu, Bxpc-3 (EGFR-positive cells) and U87-MG, SW620 (negative control cells) as the in vitro efficacy assay system. In 96-well plates, cells were seeded at an appropriate density, and camptothecin was added 24 hours later. 24 hours later, the camptothecin was diluted with assay medium (1 μM starting, 5-fold dilution, 9 concentrations; assay medium was added to the 10th column as a blank control). The diluted camptothecin was added to the corresponding wells, and the plates were shaken for 3 minutes at 550 rpm / min using a microplate shaker (MX100-4A). After shaking, the plates were incubated in a CO2 incubator for 3 days. After 3 days, 20 μL of MTS (Promega, G3581) was added to each well, and the reaction was carried out for 2 hours. The reading was 490 nM using a microplate reader (Molecular Device, SpectraMAX190). The inhibitory effect of camptothecin on cell proliferation was evaluated by detecting the activity of mitochondrial dehydrogenases. [Compound Number] Cell activity() [nm] [)] [Fadu] [BXPC-3] [A431] [U87-MG] [SW620] SN38 42.14 119.85 13.62 15.65 3.28 2 11.09 38.82 40.93 7.4 10.43 12 0.002 1.6 15.47 0.06 0.06 13 0.06 40.02 6.37 0.32-1.6 1.06 25 41.03 15.79 11.67 10.41 1.50 28 14.25 80.98 5.12 18.34 11.90 29 41.29 90.10 19.55 23.61 2.15 30 19.23 34.21 19.88 29.90 2.25 31 17.52 55.41 14.78 10.80 17.53

[0069] SN38 is a classic, highly active camptothecin drug, and its efficacy has been clinically demonstrated in IMMU-132 ADC. Through cell activity experiments, the inventors have demonstrated that the camptothecin derivatives described in this invention exhibited comparable or higher cell activity than SN38 in representative tumor cell lines such as Fadu, BXPC-3, A431, U87-MG, and SW620. Example 25: General Method for Coupling Fabrication of ADC

[0070] Antibody molecule C, after preliminary purification with a monomer content greater than 95%, was transferred to phosphate buffer (10 mg / ml) using an ultrafiltration centrifuge tube. TCEP (20 times the molar number of antibody molecules) was added, and the reaction was carried out at room temperature for 4 hours to open the interchain disulfide bonds. Then, payload (20 times the molar number of antibody molecules) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction, the sample was transferred to PBS using an ultrafiltration centrifuge tube with a molecular weight cutoff of 30 kDa, and any unconjugated payload was removed. The ADC sample after the buffer exchange was filtered using a 0.22-micron sterile sieve for later use. Conjugation compounds 11, 20, 21, 23, and 24 were conjugated to antibody molecule C using the conjugation method described in Example 25. [Compound Number] [Results from a chance encounter] [ADC] [serial number] 11 C-11 20 C-20 twenty one C-21 twenty three C-23 twenty four C-24 Example 26: Assay of ADC Antitumor Cell Activity

[0071] Similar to the method for testing the cell activity of camptothecin, this invention uses A431, Fadu, Bxpc-3 (antigen-positive cells), and SW620 (antigen-negative control cells) as the in vitro efficacy assay system. Cells were seeded at appropriate density in 96-well plates, and ADC drugs were added after 24 hours. ADC drugs were diluted with assay medium after 24 hours (1 μM starting, 5-fold dilution, 9 concentrations, with assay medium added in the 10th column as a blank control). The diluted ADC drugs were added to the corresponding wells, and the plates were shaken for 3 minutes at 550 rpm / min using a microplate shaker (MX100-4A). After shaking, the plates were incubated in a CO2 incubator for 3 days. After 3 days, 20 μL of MTS (Promega, G3581) was added to each well, and the reaction was carried out for 2 hours. The reading was 490 nM using a microplate reader (Molecular Device, SpectraMAX190). The inhibitory effect of ADC drugs on cell proliferation was evaluated by detecting the activity of mitochondrial dehydrogenases. [Compound Number] Cell activity() [nm] [)] [Fadu] [BXPC-3] [A431] [SW620] C-11 12.44 242.09 27.86 221.24 C-20 3.98 186.98 30.74 85.16 C-21 2.49 86.97 8.15 48.17 C-23 4.74 25.18 11.16 154.40 C-24 4.09 15.79 11.67 1.50

[0072] Based on the above ADC cell activity tests, the camptothecin drug of the present invention, after being conjugated with an antibody via the linker unit L, exhibited good antitumor activity in multiple antigen-positive tumor cell lines, and has great clinical application value. Example 27: In vivo efficacy test of ADC

[0073] In this invention, an A431 tumor-bearing mouse model was established to evaluate the in vivo efficacy of the toxin-ADC conjugate drug. Specifically, 3 × 10⁶ A431 cells were subcutaneously injected into the right side of 4-6 week old BALB / c nude mice. When the average tumor size reached 140-150 mm³, the mice were randomly sealed, with 5 mice per group. On days 0, 7, 14, and 21, mice were administered a blank control (buffered buffer solution blank) and the antibody-drug conjugate C-11 intravenously at a dose of 10 mg / kg, respectively. Tumor volume measurements are shown as mean tumor volume ± SE at the time of measurement. Mouse weight changes were also recorded to observe the preliminary in vivo toxicity of the ADC drug. [category] [Mouse weight] [D0] [D3] [D7] [D10] [D13] [D16] [D20] Blank control 16.4±0.31 17.4±0.32 18.3±0.47 18.5±0.42 18.9±0.45 18.9±0.35 19.5±0.33 C-11 17.6±0.16 18.2±0.14 18.8±0.31 19.2±0.29 19.6±0.30 19.9±0.28 20.1±0.39 [category] [Mean tumor volume ()] [mm3] [)] [D0] [D3] [D7] [D10] [D13] [D16] [D20] Blank control 152.0±16.22 296.0±38.14 621.6±87.52 823.6±71.51 1,028.0±94.51 1,227.5±98.30 1,526.5±97.14 C-11 147.4±8.04 168.8±6.76 256.5±26.69 316.8±35.44 352.8±39.31 333.0±79.16 347.2±107.67

[0074] The above in vivo pharmacodynamic experiments in mice using the ADC assay demonstrated that the camptothecin drug of this invention, after being conjugated to an antibody via the linker unit L, exhibited clear antitumor activity in tumor-bearing mice, with the average tumor size significantly lower than that in the blank control. Mouse body weight did not change significantly during administration, and no mice died in the group, indicating that the camptothecin drug of this invention has good safety.

[0075] none.

[0076] Domestic storage information (please note in order of storage institution, date, and number) none

[0077] Overseas storage information (please note in the order of storage country, institution, date, and number) none

Claims

1. A camptothecin compound selected from the following structures or a pharmaceutically acceptable salt thereof: , , , , , or.

2. An antitumor drug comprising camptothecin compounds or pharmaceutically acceptable salts thereof as described in claim 1, characterized in that it is used for solid tumors or hematologic malignancies such as lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, multifocal glioma, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, lung cancer, or esophageal cancer.

3. An antibody-drug conjugate as shown in Formula II, which exerts its therapeutic effect upon reaching a target cell by releasing drug D: Formula II Wherein Ab is an antibody, antibody fragment, or protein; L is a linker unit, one end of which is connected to Ab and the other end of which is connected to drug D, wherein L is selected from the group consisting of chemical bonds -O-, -N(R)n1-, -CH2-, -CH(R)n1-, -S-, and —(PEG)n2-; n1 is selected from an integer from 1 to 3, and n2 is selected from an integer from 1 to 20; D is selected from camptothecin compounds as described in claim 1 or pharmaceutically acceptable salts thereof, which are linked to L by a hydroxyl group in the molecule; m is selected from an integer from 1 to 20.

4. The antibody-drug conjugate as claimed in claim 3, characterized in that: the antibody of the drug-ligand conjugate specifically binds to target cells of cancer or autoimmune diseases.

5. A drug comprising an antibody-drug conjugate as described in claim 3 or 4, characterized in that it is used for solid tumors or hematologic malignancies such as lung cancer, kidney cancer, urethral cancer, colon cancer, rectal cancer, prostate cancer, glioma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.

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