CN111686259B - SN 38-containing antibody drug conjugate - Google Patents
SN 38-containing antibody drug conjugate Download PDFInfo
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Abstract
The invention discloses an antibody drug conjugate containing SN38, and the inventor designs a series of ADC molecules containing SN-38 on the basis of comprehensively understanding ADC drugs, and experiments show that the designed ADC molecules show good anti-tumor activity.
Description
Technical Field
The invention relates to camptothecins medicine and its antibody medicine conjugate as antitumor medicine.
Background
Antibody Drug Conjugates (ADCs) as novel targeted drugs are generally composed of three parts: antibodies or antibody-like ligands, small molecule drugs, and linkers coupling the ligands and drugs. The antibody drug conjugate utilizes the specific recognition of the antibody to the antigen to transport the drug molecules to the vicinity of the target cells and effectively release the drug molecules, thereby achieving the therapeutic purpose. 8 2011, the U.S. Food and Drug Administration (FDA) approved new ADC drug Adectois developed by Seattle Gene company for treating Hodgkin's lymphoma and recurrent degenerative large cell lymphoma (ALCL) TM The clinical application of the drugs on the market has proved the safety and effectiveness of the drugs.
Camptothecin derivative SN-38 inhibits DNA topoisomerase I (TopoisomeraseI), inhibits DNA synthesis, and causes frequent DNA single strand breaks. The drug Sacituzumab go tecan (IMMU-132), developed by the leading biopharmaceutical company Immunomerics in the field of antibody-coupled drugs (ADC), was used for metastatic triple negative breast cancer (mTNBC) previously treated at least twice, and Sacituzumab go tecan was expected to be the first ADC class of biopharmaceuticals used for mTNBC treatment. Sacituzumab go-detect is a novel, first-in-class ADC drug consisting of anti-TROP-2 mab and cytotoxic SN-38. SN-38 is an active metabolite of Irinotecan (Irinotecan) that is 100-1000 times more active than Irinotecan. IMMU-132 is used to attach the antibody to the hydroxyl functionality of SN38 by attaching SN38 to the anti-Trop-2 antibody via a pH sensitive carbonate linkage. Due to the chemical instability of the carbonate bond, the half-life period of the ADC drug in plasma is only about 12 hours, and the drug release in a large amount in plasma can cause the problems of reduced drug effect, increased side effect and the like.
In view of the above, it is of great clinical importance to design a novel ADC molecule comprising SN38 or a derivative thereof.
Based on comprehensive understanding of ADC drugs, the inventor designs a series of ADC molecules containing SN-38, and experiments show that the designed ADC molecules show good anti-tumor activity.
Disclosure of Invention
The invention relates to an antibody-drug conjugate shown in a formula I or pharmaceutically acceptable salt thereof, which comprises an antibody unit, a ligand unit, a drug unit and a connector unit:
wherein the method comprises the steps of
D is SN-38 and derivatives thereof;
o connected with D is derived from hydroxyl connected with C10 position or 20 position of SN-38 and derivatives thereof;
L 1 an aminomethyleneoxy structural unit in a molecular structure represented by the formula:
wherein the left wavy line indicates the site of attachment to the alkyl group, and the right wavy line indicates the site of attachment to L 2 Is a ligation site of (2);
L 2 represents L 1 A linking unit with Ab;
ab is an antibody, antibody fragment or protein, m is an integer selected from 1 to 8;
R 1 r is R 2 Independently selected from C 1 -C 3 Alkyl or substituted alkyl, -H, -CF 3 Aryl, monofluoro-substituted aryl, or difluoro-substituted aryl; or R is 1 、R 2 Together with the carbon atoms to which they are attached form a cyclobutane, cyclopentane, cyclohexane, n 1 =0 or 1.
R 3 、R 4 R is R 5 Respectively is an optional substituent group, or R 3 、R 5 Together with the nitrogen and carbon atoms to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl group, and R 4 Is hydrogen;
preferably, at n 1 When=1, the structural unit in which the SN-38 hydroxyl is covalently linked has the following two structures:
in formula (a), R 1 R is R 2 Independently hydrogen, - (CH) 2 )n 3 -CH 3 、-CF 3 Aryl, heteroaryl, monofluoro-substituted aryl or bifluoride-substituted aryl, wherein n 3 =0, 1 or 2;
in the structural formula (b), R 1 、R 2 Together with the carbon atoms to which they are attached form a cyclobutane, cyclopentane or cyclohexane, n 2 =1, 2 or 3; wavy line means and L 1 Is a ligation site of (2).
Preferably, self-dissociating junctions wherein the hydroxyl group of the drug unit is covalently linkedBuilding block L 1 There are two structures:
in the structural formula (c), R 3 、R 4 R is R 5 Independently hydrogen, -CH 2 -CH 2 -O)n 1 、-CH 2 -CH 2 -NH)n 2 、-CH 2 -CH 2 -N(CH 3 ))n 3 、-CH 2 -CH 2 -N(CH 3 ) 2 Optionally substituted C 1 -C 6 Alkyl, or optionally substituted C-linked C 3 -C 8 Heteroaryl, wherein n 1 ，n 2 ，n 3 An integer selected from 1 to 6;
in the structural formula (d), R 3 R is R 5 Together with the nitrogen and carbon atoms to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group, and R 4 Is hydrogen; wherein m is 1 An integer selected from 1 to 6;
the wavy line indicates the attachment site to SN-38 and its derivatives.
Preferably, the O attached at D is derived from the hydroxyl group attached at the C10 or 20 position of SN-38, and has the following two structures:
in formula (e), O attached at D is derived from the hydroxyl group attached at the C10 position of SN-38, n 1 =0 or 1;
in formula (f), O attached at D is derived from the hydroxy group attached at the C20 position of SN-38, n 1 =0 or 1;
wavy line means and L 1 Is a ligation site of (2).
Preferably, the drug conjugate or a pharmaceutically acceptable salt thereof is an antitumor agent, which is used for lung cancer, kidney cancer, urinary tract cancer, colon cancer, rectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, lung cancer or esophageal cancer and other solid tumors and blood tumors.
Preferably, a method of treating a patient in need thereof, comprising administering to said patient an antibody drug conjugate of any of the preceding claims, wherein said patient has a tumor, an autoimmune disease or an infectious disease, and the antibody of said drug-ligand conjugate specifically binds to target cells of said cancer, autoimmune disease.
Drawings
Fig. 1 is a block diagram of the MTS tetrazolium salt and the formazan product.
Detailed Description
Abbreviations and definitions
The following terms and phrases as used herein are intended to have the following meanings unless otherwise indicated. When trade names are used herein, unless the context indicates otherwise, trade names include product formulas, general drugs, and active pharmaceutical ingredients of the trade name products.
The term "alkylene" refers to a divalent straight chain saturated hydrocarbon group having 1-20 carbon atoms, including groups from 1 to 10 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH 2-), ethylene (-CH 2-CH 2-), n-propylene, n-butylene, n-pentylene, and n-hexylene. Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, generally aromatic, hydroxyl group, which may be a single ring or a fused or covalently linked multiple ring (up to three rings). The term "arylheteroaryl" refers to an aryl group (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. Heteroaryl groups may be attached to the remainder of the molecule through heteroatoms. Non-limiting examples of aryl groups include: phenyl, naphthyl, and diphenyl, while non-limiting examples of heteroaryl groups include: pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl (pyrimidyl), triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl (phtalazinyl), benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisozolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, imidazopyridine, benzothiazolyl (benzofuranyl), benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. When described as "substituted", the substituents of the above aromatic and heteroaromatic ring systems are selected from the following acceptable substituents.
Unless otherwise indicated herein, substituents for hydrocarbyl groups (including those commonly referred to as alkylene, alkenyl, alkynyl, and cycloalkyl groups) may be a variety of groups selected from the group consisting of: -halogen, -OR ', -NR' R ', -SR', -SiR 'R', -OC (O) R ', -C (O) R', -CO 2 R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O) 2 R’、-NH-C(NH 2 )＝NH、-NR’C(NH 2 )＝NH、-NH-C(NH 2 )＝NR’、-S(O)R’、-S(O) 2 R’、-S(O) 2 NR’R”、-NR’S(O) 2 R', -CN and-NO 2 The number of substituents is from 0 to (2 m '+1), where m' is the total number of carbon atoms in the group. R ', R ' and R ' each independently represent hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy, or unsubstituted aryl-C 1-4 An alkyl group. When R 'and R' are attached to the same nitrogen atom, they may form together with the nitrogen atom a 3-,4-,5-, 6-or 7-membered ring. For example, -NR' R "includes 1-pyrrolidinyl and 4-morpholinyl.
As used herein, a "derivative" of a compound refers to a substance that has a chemical structure similar to the compound but that also contains at least one chemical group that is not present in the compound and/or lacks at least one chemical group that is present in the compound. The compound to which the derivatives are compared is referred to as the "parent" compound. In general, a "derivative" may be produced from a parent compound in one or more chemical reaction steps.
L-ligands
The ligand unit is a targeting agent that specifically binds to the target moiety. The ligand is capable of specifically binding to a cellular component or to other target molecule of interest. The target moiety or target is typically on the cell surface. In some aspects, the ligand unit functions to deliver the drug unit to a particular 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 antigen binding fragments thereof. 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, lymphokines, hormones, growth factors, colony stimulating factors, vitamins, nutrient transport molecules, or any other cell binding molecule or substance. In some embodiments, the linker is covalently linked to the 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 of an antibody. In another aspect, the sulfur atom is a sulfur atom of a cysteine residue into which a ligand unit has been introduced, which forms an interchain disulfide bond of the antibody. In another aspect, the sulfur atom is a sulfur atom of a cysteine residue into which the ligand unit has been introduced (e.g., by site-directed mutagenesis or chemical reaction). In other aspects, the sulfur atom to which the linker binds is selected from cysteine residues that form an interchain disulfide bond of an antibody or a frontal cysteine residue that has been incorporated into a ligand unit (e.g., by site-directed mutagenesis or chemical reaction). In some embodiments, the numbering system is according to the EU index in Kabat (Kabat E.A et al, (1991)) (protein sequences of immunological interest) (Sequences of proteins of Immunological Interest), fifth edition, NIH publication 91-3242).
As used herein, an "antibody" or "antibody unit" is within its scope, including any portion of an antibody structure. This unit may bind, reactively associate, or complex with a receptor, antigen, or other receptor unit that the targeted cell population has. An antibody may be any protein or proteinaceous molecule that can bind, complex, or otherwise react with a portion of a cell population to be treated or biologically engineered.
The antibodies comprising the antibody drug conjugates of the invention preferably retain their antigen binding capacity in their original wild state. Thus, the antibodies of the invention are capable of, preferably specifically, binding to an antigen. Antigens involved include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, cell survival modulators, cell proliferation modulators, molecules associated with tissue growth and differentiation (e.g., known or predicted to be functional), lymphokines, cytokines, molecules involved in the regulation of the cell cycle, molecules involved in angiogenesis, and molecules associated with angiogenesis (e.g., known or predicted to be functional). The tumor-associated factor may be a cluster differentiation factor (e.g., CD protein). As described in the present invention
Antibodies for use in antibody drug conjugates include, but are not limited to, antibodies directed against cell surface receptors and tumor-associated antigens. Such tumor-associated antigens are well known in the art and can be prepared by methods and information for antibody preparation that are well known in the art. In order to develop effective cellular level targets useful in cancer diagnosis and treatment, researchers have sought to find transmembrane or other tumor-associated polypeptides. These targets are capable of specific expression on the surface of one or more cancerous cells, while little or no expression is present on the surface of one or more non-cancerous cells. Typically, such tumor-associated polypeptides are more overexpressed on the surface of cancer cells relative to the surface of non-cancer cells. The identification of such tumor-associated factors can greatly enhance the specific targeting characteristics of antibody-based treatment of cancer.
Tumor-associated antigens include, but are not limited to, tumor-associated antigens (1) - (36) listed below. For convenience, antigen-related information, which is well known in the art, is indicated below, including names, other names, gene bank accession numbers. Nucleic acid and protein sequences corresponding to tumor associated antigens can be found in public databases, such as Genbank. Antibodies target the corresponding tumor-associated antigen include all amino acid sequence variants and homologs that are at least 70%,80%,85%,90%, or 95% homologous to the sequences identified in the references, or that have biological properties and characteristics that are entirely identical to the tumor-associated antigen sequences in the references.
The term "inhibit" or "inhibition" refers to a reduction in the amount detectable, or a complete prevention.
The term "cancer" refers to a physiological condition or disease characterized by deregulated cell growth. "tumor" includes cancer cells.
The term "autoimmune disease" is a disease or disorder derived from a tissue or protein directed against an individual itself.
The phrase "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt of a compound (e.g., a drug-linker or a ligand-linker-drug conjugate). The compounds may contain at least one amino or carboxyl group and may thus form addition salts with the corresponding acids or bases. Exemplary salts include, but are not limited to: sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, salicylate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, potassium salt, sodium salt, and the like. In addition, pharmaceutically acceptable salts have more than one dotted atom in the structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt can have multiple counter examples. For example, a pharmaceutically acceptable salt has one or more charged atoms and/or one or more counter atoms.
According to the mechanism of intracellular drug release, as used herein, the "linker" or "linker of an antibody drug conjugate" can be divided into two classes: non-cleavable linkers and cleavable linkers.
For antibody drug conjugates containing non-cleavable linkers, the mechanism of drug release is: after the conjugate is combined with antigen and endocytosed by cell, the antibody is enzymolyzed in lysosome to release active molecule comprising small molecule medicine, connector and antibody amino acid residue. The resulting change in the structure of the drug molecule does not impair its cytotoxicity, but because the active molecule is charged (amino acid residues), it cannot penetrate into neighboring cells. Thus, such active agents cannot kill tumor cells (bystander effect) adjacent to cells that do not express the targeted antigen (antigen negative cells) (Ducry et al, 2010,Bioconjugate Chem.21:5-13).
Cleavable linkers, as the name suggests, can cleave and release the active agent (the small molecule drug itself) within the target cell. Cleavable linkers can be divided into two main categories: chemically labile linkers and enzymatically labile linkers.
Chemically labile linkers can be selectively cleaved due to differences in plasma and cytoplasmic properties. Such properties include pH, glutathione concentration, etc.
pH sensitive linkers, also commonly referred to as acid-cleavable linkers. Such linkers are relatively stable in the neutral environment of blood (pH 7.3-7.5), but will be hydrolyzed in the weakly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0). The first generation of antibody drug conjugates mostly used such linkers, e.g. hydrazones, carbonates, acetals, ketals. Antibody drug conjugates based on such linkers typically have a short half-life (2-3 days) due to the limited plasma stability of the acid-cleavable linker. This short half-life limits to some extent the use of pH-sensitive linkers in new generation antibody drug conjugates.
For glutathione-sensitive linkers, also known as disulfide linkers. Drug release is based on the difference between the high concentration of intracellular glutathione (millimolar range) and the relatively low concentration of glutathione in the blood (micromolar range). This is especially true for tumor cells, where low oxygen content leads to an increased activity of the reductase and thus to higher glutathione concentrations. Disulfide bonds are thermodynamically stable and thus have better stability in plasma.
Enzyme labile linkers, such as peptide linkers, can better control drug release. Peptide linkers can be effectively cleaved by an in vivo protease, such as cathepsin (cathepsin b) or plasmin (an increase in such enzyme content in some tumor tissues). This peptide linkage is believed to be very stable in the plasma cycle because extracellular unfavorable pH values and serum protease inhibitors result in proteases that are generally inactive. In view of the high plasma stability and good intracellular cleavage selectivity and availability, enzyme labile linkers are widely used as cleavable linkers for antibody drug conjugates. Typical enzyme labile linkers include Val-Cit (vc), phe-Lys, and the like.
The suicide linker is typically chimeric between the cleavable linker and the active agent or is itself part of the cleavable linker. The suicide type connector has the following action mechanism: when the cleavable linker is cleaved under convenient conditions, the suicide linker is capable of spontaneously undergoing structural rearrangement, thereby releasing the active agent attached thereto. Common suicide linkers include p-aminobenzyl alcohols (PAB) and beta-glucuronides (beta-glucuronides), among others.
The invention will be further illustrated with reference to specific examples, which are to be understood as illustrative only and are not intended to limit the scope of the invention. The test methods in the following examples, in which specific conditions are not noted, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. All percentages, ratios, or parts are by weight unless otherwise specified. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
EXAMPLE 1 Synthesis of Compound 1
N-fluorenylmethoxycarbonyl-glycyl-glycine (10 g,28.2mmol,1.0 eq), lead tetraacetate (17.5 g,55.3mmol,1.4 eq), 200mL dry tetrahydrofuran and 67mL toluene were added to a 500mL single-necked flask, stirred well, nitrogen-protected, and heated to 85℃for 2.5 hours. After the reaction of the starting materials was completed by TLC, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 1 (8.7 g, 83.7%).
EXAMPLE 2 Synthesis of Compound 2
In a 25mL single flask, compound 1 (2.0 g,5.43mmol,1.0 eq), p-toluenesulfonic acid monohydrate (103.3 mg,0.54mmol,0.1 eq) and 10mL of THF were added, the mixture was stirred well, the temperature was lowered to 0℃and benzyl L-lactate (4.5 g,27.15mmol,5 eq) was slowly added and the mixture was allowed to react at room temperature. After the reaction was completed, saturated NaHCO3 solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse phase column to give compound 2 (1.72 mg, 65.4%).
EXAMPLE 3 Synthesis of Compound 3
In a 25mL single flask, compound 3 (1.7 g,3.59mmol,1.0 eq) and 10mL DMF were added, and after stirring well, the temperature was lowered to 0deg.C, DBU (0.76 g,3.95mmol,1.1 eq) was slowly added and the reaction was allowed to warm to room temperature. TLC monitoring, after the reaction, concentration, compound 3 crude (3.5 g) was obtained, directly put into the next step without purification.
EXAMPLE 4 Synthesis of Compound 4
In a 25mL single vial was added Z-Gly-Gly-Phe-OH (1.63 g,3.95mmol,1.1 eq), pyBOP (3.74 g,7.18mmol,2.0 eq) and 20mL DMF, stirred at room temperature for 5 minutes, then added crude compound 3 (3.5 g), reacted at room temperature and monitored by HPLC. After the completion of the reaction, water was added, extraction was performed with ethyl acetate, drying over anhydrous sodium sulfate, filtration and concentration were performed, and the residue was purified by reverse phase column to give compound 4 (2.0 g, 87.0%).
EXAMPLE 5 Synthesis of Compound 5
In a 25mL single vial was added compound 4 (200 mg,1.0eq,0.31 mmol), 5% Pd/BaSO 4 (200 mg), 8mL of DMF, hydrogenation reaction at room temperature. After the reaction was completed, water was added to the mixture and the mixture was filtered, and the filtrate was concentrated to give a crude compound 5 (130 mg) which was directly taken to the next step without purification.
EXAMPLE 6 Synthesis of Compound 6
In a 25mL single vial was added compound 5 (130 mg), SMCC (104 mg,0.31mmol,1.0 eq), DIEA (80.1 mg,0.62mmol,2.0 eq) and 3mL of LDMF, reacted at room temperature, monitored by HPLC, prepared for purification, and lyophilized to give compound 6 (85 mg, 42.9%). MS: [ M+H ]643.2.
EXAMPLE 7 Synthesis of Compound 7
Compound 6 (100 mg,1 eq), SN38-TBS (118 mg,1.5 eq), DMAP (114 mg,6 eq), CMPI (119 mg,3 eq) were added sequentially to a 25mL single-port bottle, dissolved in 5mL DMF, reacted for 4h at room temperature, monitored by hplc. After the reaction, the product was purified and lyophilized to 44mg. LC-MS:1131.4[ M+H ]] +
EXAMPLE 8 Synthesis of Compound 8
44mg of the compound was dissolved in 2.5mL of THF, 0.2mL of pyridine was added thereto, 0.2mL of HF-pyridine was added thereto under ice-water bath, and the mixture was allowed to react at room temperature for 2 hours, followed by HPLC. After the reaction, the mixture was purified and lyophilized to obtain 22mg of a product. LC-MS:1017.3[ M+H ]] +
EXAMPLE 9 Synthesis of Compound 9
To a 4mL brown bottle were added, in order, compound 6 (35 mg, 54. Mu. Mol,1.0 eq), SN-38 (25.4 mg, 64.8. Mu. Mol,1.2 eq), TBTU (24.5 mg, 64.8. Mu. Mol,1.2 eq), HOBT (8.7 mg, 64.8. Mu. Mol,1.2 eq) and DMF (1.5 mL), after stirring, DIEA (6.3 mg, 48.6. Mu. Mol,0.9 eq), nitrogen protection, reaction at room temperature for 18h, HPLC monitoring, semi-preparative purification of pure water, lyophilization gave Compound 9 (5.21 mg, 9.5%), MS: [ M+1]1017.2.
EXAMPLE 10 Synthesis of Compound 10
In a 25mL single flask, compound 1 (500 mg,1.4mmol,1.0 eq), paratoluenesulfonic acid monohydrate (26 mg,0.1mmol,0.1 eq) and 10mL of THF were added, the mixture was stirred uniformly, the temperature was lowered to 0℃and L-benzyl lactate (1.2 g,7.0mmol,5 eq) was slowly added thereto, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated NaHCO3 solution was added thereto, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse phase column to give compound 10 (400 mg, 60.3%).
EXAMPLE 11 Synthesis of Compound 11
In a 25mL single flask, compound 10 (400 mg,0.8mmol,1.0 eq) and 10mL DMF were added, and after stirring well, the temperature was lowered to 0℃and DBU (137 mg,0.9mmol,1.1 eq) was slowly added and the reaction was allowed to warm to room temperature. TLC monitoring and concentration after the reaction was completed gave crude compound 11 (550 mg), which was directly taken to the next step without purification.
EXAMPLE 12 Synthesis of Compound 12
In a 25mL single vial was added Z-Gly-Gly-Phe-OH (372 mg,0.9mmol,1.1 eq), pyBOP (850 mg,1.6mmol,2.0 eq) and 3mL DMF, stirred at room temperature for 5 minutes, and then added crude compound 11 (550 mg), reacted at room temperature and monitored by HPLC. After the completion of the reaction, water was added, extraction was performed with ethyl acetate, drying over anhydrous sodium sulfate, filtration and concentration were performed, and the residue was purified by reverse phase column to give compound 12 (326 mg, 59.2%).
EXAMPLE 13 Synthesis of Compound 13
In a 25mL single vial was added compound 12 (50 mg,1.0eq,0.08 mmol), 5% Pd/C (50 mg), 3mL DMF, room temperature hydrogenation. After the reaction was completed, water was added thereto for filtration, and the filtrate was concentrated to obtain a crude product (52 mg) of compound 13, which was directly taken into the next step without purification.
EXAMPLE 14 Synthesis of Compound 14
In a 25mL single vial was added compound 13 (52 mg), SMCC (23 mg,0.07mmol,1.0 eq), DIEA (22.2 mg,0.24mmol,2.5 eq) and 3mL of LDMF, reacted at room temperature, monitored by HPLC, prepared and purified, and lyophilized to give compound 14 (9.0 mg, 18.1%). MS: [ M-H ]655.1.
EXAMPLE 15 Synthesis of Compound 15
In a 25mL single vial was added compound 14 (9.0 mg,0.014mmol,1.0 eq), SN38 (5.3 mg,0.014mmol,1.0 eq), TBTU (9.0 mg,0.028mmol,2.0 eq), DIEA (1.63 mg,0.0126mmol,0.9 eq) and 0.5mL of LDMF, reacted at room temperature, monitored by HPLC, semi-prepared and purified, lyophilized to afford compound 15 (3.4 mg, 24.3%). LCMS: [ M+H ]1031.0.
EXAMPLE 16 Synthesis of Compound 16
SN-101 (30 mg,0.059 mmol), SN-38-TBS (44 mg,0.119 mmol), anhydrous zinc acetate (11 mg,0.06 mmol) and 5ml toluene were added to a 25ml single-port flask, then the reaction was refluxed at 115℃for 4h (15 batches were repeated), the reaction was stopped, cooled to room temperature, the 15 batches of reaction solutions were combined, concentrated under reduced pressure at 50℃and the residue was dissolved in 30ml DCM, washed with water and saturated brine in this order, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated, stirred with silica gel, and purified by column chromatography (DCM: meOH=80:1-30:1) to give 135mg of pale yellow solid.
EXAMPLE 17 Synthesis of Compound 17
In a 25ml single flask, compound 16 (30 mg,0.037 mmol) and 2ml THF were added, stirred and dissolved, cooled to 5℃in an ice-water bath, pyridine (0.2 ml, 2.480 mmol) and pyridinium hydrofluoric acid (0.1 ml) were added in sequence, and after the addition, the reaction was completed under nitrogen protection at the same temperature for 20min, and TLC monitored the completion of the reaction of the starting materials. 10ml of DCM was added for dilution, the organic layer was separated by washing with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was dissolved in a small amount of THF solution to prepare a silica gel plate for purification to give 22mg of pale yellow solid.
EXAMPLE 18 Synthesis of Compound 18
In a 25mL single flask, compound 17 (13 mg, 18.6. Mu. Mol,1.0 eq) and THF (1 mL) were added, after stirring well, the temperature was lowered to 0℃and DBU (6 mg, 37.2. Mu. Mol,2.0 eq) was slowly added under nitrogen protection, after the addition was completed, the reaction was continued at 0℃for 30min, monitored by TLC, the starting material was reacted, and the reaction solution was reacted directly to the next step.
EXAMPLE 19 Synthesis of Compound 19
PyBOP (19.4 mg, 37.2. Mu. Mol,2.0 eq) and SMCC-tripeptide (18.5 mg, 37.2. Mu. Mol,2.0 eq) were added successively to a reaction solution of compound 18 (18.6. Mu. Mol,1.0 eq) in an ice-water bath under nitrogen protection, and the mixture was allowed to react at room temperature for 1h after the addition, monitored by HPLC, purified by semi-preparation of pure water, and lyophilized to give compound 19 (8.46 mg, 47.5%), MS: [ M+H ]959.0.
EXAMPLE 20 Synthesis of Compound 20
PyBOP (10.4 mg,20umol,2.0 eq) and MC-tripeptide (9.5 mg,20umol,2.0 eq) were added to the reaction mixture of the compound (10 um18ol,1.0 eq) in sequence in an ice-water bath under nitrogen protection, and the mixture was warmed to room temperature after the addition for 1h, monitored by HPLC, purified by semi-preparative pure water, and lyophilized to give compound 20 (6.16 mg, 66%), MS: [ M+H ]933.3.
EXAMPLE 21 Synthesis of Compound 21
Glycinamide hydrochloride (10 g,1 eq) was dissolved in 100mL of water/acetone (1/1), the pH was adjusted to about 8 by adding saturated sodium carbonate solution, the mixture was cooled in an ice-water bath, cbz-Cl (14.2 mL,1.1 eq) was added dropwise, and the mixture was reacted at room temperature for 2 hours. After the reaction is finished, filtering, washing a filter cake with water for three times, and drying at 50 ℃ to obtain 12g of product. LC-MS:209.2[ M+H ]] + .
EXAMPLE 22 Synthesis of Compound 22
Compound 21 (2 g,1 eq) was dissolved in 25mL of aqueous formaldehyde, and potassium carbonate (146 mg,0.1 eq) was added and reacted at 40℃for 2 hours. Ethyl acetate is added for extraction, the organic layers are combined, washed three times by saturated sodium chloride solution, dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude products. Purification of the crude product by column chromatography (DCM: meoh=50:1) afforded 0.9g of product. LC-MS:207.2[ M-CH2OH ]. HNMR (400 MHz, D6-DMSO): 8.55 (s, 1H), 7.33-7.39 (m, 5H), 5.04-5.14 (m, 2H), 4.71 (s, 1H), 4.51-4.54 (m, 2H).
EXAMPLE 23 Synthesis of Compound 23
In a 50mL three-necked flask, compound 22 (100 mg,1 eq), SN-38 (82 mg,0.5 eq), triphenylphosphine (216 mg,2 eq) and DMF8mL were added, nitrogen was purged, diisopropyl azodicarboxylate (164 uL,2 eq) was added dropwise to an ice-water bath, and the mixture was allowed to react at room temperature, followed by HPLC. After the reaction, the product is prepared and purified, and freeze-dried to obtain 30mg of the product. LC-MS:613.2[ M+H ]] + .
EXAMPLE 24 Synthesis of Compound 24
Compound 23 (30 mg,1 eq) was dissolved in 5mL of LDMF, 30mg of 5% Pd/C was added and the mixture was hydrogenated for 3h. The filtrate was filtered, and compound 24 (49 mg,2 eq), pyBop (50 mg,2 eq) and DIEA (32 ul,4 eq) were added to the filtrate and reacted at room temperature for 2h, monitored by hplc. Purification was prepared and lyophilized to give 2415mg of compound. LC-MS:959.2[ M+H ]] + 。
Example 25 coupled preparation of ADC Universal method
Antibody molecule C with a monomer ratio of more than 95% after preliminary purification was changed to phosphate buffer solution at a concentration of 10mg/ml using an ultrafiltration centrifuge tube. TCEP was added in an amount of 20 times the number of moles of the antibody and reacted at room temperature for 4 hours to open disulfide bonds between the antibody chains. The reaction was carried out at room temperature for 2 hours by adding 20 times the number of moles of the antibody. After the reaction was completed, the solution was removed from the reaction mixture in PBS using an ultrafiltration centrifuge tube having a molecular weight cut-off of 30kDa, and uncoupled payload was removed. The liquid-exchanged ADC samples were filtered using a 0.22 micron sterile filter for use. The coupling compounds 8, 9, 15, 19, 20, 24 were coupled to the antibody molecule C by the coupling method described in example 25.
| Numbering of compounds | Coupling the resulting ADC numbering |
| 8 | C-8 |
| 9 | C-9 |
| 15 | C-15 |
| 19 | C-19 |
| 20 | C-20 |
| 24 | C-24 |
Example 26 ADC anti-tumor cell Activity assay
The cytotoxic activity of the drug-antibody conjugate obtained in example 25 was determined by the following experimental procedure: the drug-antibody conjugates were added to human tumor cell culture media expressed by A431, fadu, bxpc-3 (EGFR positive expressing cells), SW620 (negative control cells), respectively, and cell viability was determined after cell culture for 72 hours. Cell-based in vitro experiments were used to determine cell viability, cytotoxicity, and apoptosis induced by the camptothecin drug of the invention.
The in vitro potency of the drug-antibody conjugates was determined by a cell proliferation assay. CellTiterAqueousOne Solution Cell Proliferation Assay is commercially available (Promega corp., madison, WI). CellTiterAQueous One Solution Cell Proliferation Assay (a) is a detection reagent for colorimetrically detecting the number of living cells in cell proliferation and cytotoxicity assays. The reagent contains a novel tetrazole compound [3- (4, 5-dimethylazol-2-yl) -5- (3-carboximethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium, inner salt; MTS (magnetic resonance System)]And an electronic coupling agent (phenazine ethosulfate; PES). PES has enhanced chemical stability, which allows it to be mixed with MTS to form a stable solution. This convenient "single solution" mode is in the first generation CellTiter +.>Improvement on the basis of AQUEUS Assay, cellTiter->The electron coupling agent PMS used in the Aquality Assay is provided separately from the MTS solution. MTS (Owen's reagent) was biologically reduced by cells to a colored formazan product that was directly dissolved in the medium (FIG. 1). This conversion is most likely accomplished under the action of NADPH or NADH produced by dehydrogenases in metabolically active cells. In the detection, only a small amount of CellTiter +.>AQueous One Solution Reagent direct addition cultureIn the culture medium of the culture plate hole, incubating for 1-4 hours, and then reading the absorbance value at 490nm by an enzyme-labeled instrument.
The amount of formazan product detected at 490nm is proportional to the number of living cells in culture. CellTiter because the formazan product of MTS is soluble in tissue culture mediumAQueous One Solution Assay has fewer operating steps than the MTT or INT methods.
In the invention, A431, fadu, bxpc-3 (antigen positive expression cells) and SW620 (antigen negative control cells) are adopted as research systems for in vitro drug effect detection. In 96-well plates, plating was performed using appropriate cell densities, and 24 hours later, ADC drug dosing was performed. After 24 hours, the ADC drugs are diluted by a detection medium (1 uM is started, 5 times of dilution is performed, 9 concentrations are obtained, the detection medium is added in the tenth column to serve as a blank control), the diluted ADC drugs are added into corresponding cell holes, and then the diluted ADC drugs are vibrated by a microplate vibrator (model: MX 100-4A) for 3min, the vibration speed is 550rpm/min, and the diluted ADC drugs are placed into a carbon dioxide incubator for 3 days after the vibration. After 3 days, 20ul MTS (Promega, G3581) was added to each well and reacted for 2 hours, and a 490nM reading was made with a microplate reader (Molecular Device, model: spectraMAX 190). The proliferation inhibition of ADC drugs on cells was evaluated by detecting the activity of dehydrogenase in the pellet.
Through the ADC cell activity test, the ADC drug provided by the invention has good anti-tumor activity in a plurality of antigen positive tumor cell lines, and has great clinical application value.
EXAMPLE 27 in vivo efficacy testing of ADCs
In the invention, an A431 tumor-bearing mouse model is established to evaluate the in vivo efficacy of toxin ADC coupled drugs. I.e. 3X 10 6 A431 cells were injected subcutaneously to the right side of BALB/c nude mice of 4-6 weeks old, and 5 mice from each group were randomly grouped until the average size of the mice tumors grew to 140-150 mm3, each at day 0,7,14,21A blank (buffer blank) and antibody drug conjugate C-8 were administered intravenously at a dose of 10 mg/kg. Tumor volume measurement data are shown as mean tumor volume ± SE at the time of measurement, while changes in mouse body weight are recorded for observation of initial toxicity of ADC drugs in vivo.
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Through the in vivo drug effect experiments of the ADC mice, the SN38 antibody conjugate provided by the invention shows definite anti-tumor activity in tumor-bearing mice, and the average tumor body is obviously lower than that of blank control. The weight of mice does not change obviously in the administration period, no mice die in the group, and the camptothecin medicament has good safety.
Claims (5)
1. An antibody-drug conjugate of formula I or a pharmaceutically acceptable salt thereof:
wherein the method comprises the steps of
D is SN-38;
the oxygen atom attached to D is derived from the hydroxyl group attached to the C10 or 20 position of SN-38;
L 1 an aminomethyleneoxy structural unit in a molecular structure represented by the formula:
wherein the left wavy line indicates the connection site of the oxygen atom and the alkyl group in the structure, and the right wavy line indicates the nitrogen atom and L in the structure 2 Is a ligation site of (2);
L 2 represents L 1 A linking unit selected from the group consisting of Mc-glycine-phenylalanine-glycine, SMCC-glycine-phenylalanine-glycine with Ab;
ab is an antibody, antibody fragment or protein, m is an integer selected from 1 to 8;
R 1 r is R 2 Are independently selected from hydrogen, C 1 -C 3 Alkyl, n 1 =0 or 1;
R 3 、R 4 r is R 5 Is hydrogen.
2. The antibody-drug conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is n 1 When=1, the structure of the structural unit covalently linked to the SN-38 hydroxyl is:
in formula (a), R 1 R is R 2 Independently hydrogen, - (CH) 2 )n 2 -CH 3 Wherein n is 2 =0, 1 or 2.
3. The antibody-drug conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein: o linked to D is derived from the hydroxyl group linked to the C10 or 20 position of SN-38, and has the following two structures:
in formula (e), the O attached to D is derived from the hydroxyl group attached to the C10 position of SN-38, n 1 =0 or 1;
in the structural formula (f), O linked to D is derived from the hydroxyl group linked to the C20 position of SN-38, n 1 =0 or 1;
wavy line means and L 1 Is a ligation site of (2).
4. The antibody-drug conjugate or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein: the antibody of the drug-ligand conjugate specifically binds to target cells of cancer, autoimmune diseases.
5. An antitumor agent comprising the antibody-drug conjugate of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: can be used for treating lung cancer, renal cancer, urethra cancer, colon cancer, rectal cancer, prostatic cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer or esophageal cancer, or hematological tumor.
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