WO2022099762A1 - Antibody conjugate intermediate and preparation method therefor - Google Patents
Antibody conjugate intermediate and preparation method therefor Download PDFInfo
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- WO2022099762A1 WO2022099762A1 PCT/CN2020/130589 CN2020130589W WO2022099762A1 WO 2022099762 A1 WO2022099762 A1 WO 2022099762A1 CN 2020130589 W CN2020130589 W CN 2020130589W WO 2022099762 A1 WO2022099762 A1 WO 2022099762A1
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- Prior art keywords
- antibody
- antibody conjugate
- drug
- compound
- conjugate intermediate
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- 229940127121 immunoconjugate Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 21
- 239000000611 antibody drug conjugate Substances 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000012986 modification Methods 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
- 239000002254 cytotoxic agent Substances 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 230000002924 anti-infective effect Effects 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims 1
- 239000000562 conjugate Substances 0.000 claims 1
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- 238000009509 drug development Methods 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 4
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
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- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 2
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
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- 230000007017 scission Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
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- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- -1 antibodies Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 229940125645 monoclonal antibody drug Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
Definitions
- the invention belongs to the cross field of biological drugs and chemical drugs, and in particular relates to an intermediate of an antibody conjugate and a preparation method thereof
- Antibody-drug conjugate is a combination of the high specificity of monoclonal antibody drugs and the high activity of small molecule cytotoxic drugs to improve the targeting of tumor drugs and reduce toxic side effects. Compared with traditional fully or partially humanized antibodies or antibody fragments, ADCs are theoretically more effective because they can release highly active cytotoxins in tumor tissues. Compared with fusion proteins, it has higher tolerance or lower side effects.
- the targeting of ADC drugs comes from the antibody part, and most of the toxicity comes from the toxic part of the small molecule drug.
- the antibody moiety and the toxin moiety are linked to each other by a linker. After the antibody moiety binds to the targeted antigen on the tumor cell surface, the tumor cell will internalize the ADC. Afterwards, the ADC drug will be decomposed in the lysosome, releasing the active chemical toxin, destroying the DNA or preventing the tumor cell from dividing, and playing the role of killing the cell.
- the linker should remain stable so that it does not cause off-target toxicity and efficiently release the toxicant inside the cell.
- ADCs usually consist of a fully humanized monoclonal antibody, a cytotoxic drug, an appropriate linker, and an antigen specifically expressed on tumor cells. This structure mainly maintains the cytotoxicity, targeting, and stability of the ADC in the systemic circulation. The right combination of choices is the key to successful ADC development.
- Patent CN201380053256.2 discloses an antibody-coupled drug.
- its structural stability has not been studied.
- the stability of ADC drugs has always been a common problem in the art. technical difficulties.
- the present invention aims to provide an antibody conjugate intermediate with good stability. Specifically, the present invention provides an antibody conjugate intermediate, which is represented by the following structure: T-GGFG-L1-D;
- T is a linker that can be connected to the antibody site, L1 linker, D represents a small molecule cytotoxic drug, G in -GGFG- represents glycine, and F represents phenylalanine;
- T is selected from Where m is an integer of 0-6, n is an integer of 0-6, p is an integer of 0-12, and q is an integer of 0-6;
- the L1 structure is Wherein the amino end is connected with -GGFG-, the carbonyl end is connected with D, r is an integer of 1-6, s is 0 or 1; t is an integer of 1-6;
- R1 and R2 and R3 independently represent hydrogen, halogen, hydroxyl, amino, cyano, C2-C8 alkenyl, C2-C8 alkynyl, aldehyde group, carbamoyl, C1-C8 alkyl, C1-C8 alkoxy base;
- the T is selected from one of the.
- the T is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the L1 is selected from
- the present invention provides a kind of antibody conjugate intermediate, and its structure is as follows:
- the present invention provides a kind of antibody conjugate intermediate, and its structure is as follows:
- the present invention provides an antibody conjugate obtained by connecting the above-mentioned antibody conjugate intermediate with an antibody or an antibody modification, and the antibody or antibody modification is an intermediate with an antibody conjugate the T-phase connection.
- the present invention provides a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition is an anti-tumor drug, an anti-immune disease drug or an anti-infectious disease drug, wherein the anti-tumor drug includes an anti-cancer drug.
- the synthesis of compound 6 adopts solid-phase synthesis method, the coupling reagent adopts HOBT/DIC, DMF is used as the reaction solvent, and the reaction monitoring adopts ninhydrin detection method.
- Compound 5 Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc -Gly-OH, Fmoc-Cys(Trt)-OH were connected to 2Cl-Trt resin, Fmoc was removed, DMF washing, DCM washing, methanol washing and drying, adding cleavage reagent 1% TFA/DCM, MTBE precipitation on ice, After washing, the crude product was purified by column chromatography, concentrated and dried to obtain 2.56 g of compound 6 as a white solid with a yield of 60.8%.
- the aqueous solution of the above-mentioned antibody-antibody MC derivative 11 was added to a 10 ml reaction flask, a DMSO solution containing compound 9 (4.5eq) was added at room temperature, and dialyzed after 1 hour to obtain a solution of antibody-drug conjugate a.
- the synthesis of compound 13 adopts solid phase synthesis method, the coupling reagent adopts HOBT/DIC, DMF is used as the reaction solvent, and the reaction monitoring adopts ninhydrin detection method.
- Compound 5 Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc -Gly-OH, compound 12 was connected to 2Cl-Trt resin, Fmoc was removed, washed with DMF, DCM, methanol and then dried, cleavage reagent 1% TFA/DCM was added, MTBE on ice was precipitated, washed, and the crude product was passed through the column layer It was purified by analysis, concentrated and dried to obtain 2.86 g of compound 13 as a white solid with a yield of 62.9%.
Abstract
Provided is an antibody conjugate intermediate having good stability. Not only the antibody conjugate intermediate has good stability, but also the prepared antibody conjugate has good inhibitory effects on tumor cells, and has a good prospect for drug development.
Description
本发明属于生物药和化学药交叉领域，具体涉及一种抗体偶联物中间体及其制备方法The invention belongs to the cross field of biological drugs and chemical drugs, and in particular relates to an intermediate of an antibody conjugate and a preparation method thereof
抗体偶联药物(antibody-drug conjugate，简称ADC)是将单克隆抗体药物的高特异性和小分子细胞毒药物的高活性相结合，用以提高肿瘤药物的靶向性、减少毒副作用。和传统的完全或部分人源化抗体或抗体片段相比，ADC因为能在肿瘤组织内释放高活性的细胞毒素从而理论上疗效更高。和融合蛋白相比，它具有更高的耐受性或较低的副作用。Antibody-drug conjugate (ADC) is a combination of the high specificity of monoclonal antibody drugs and the high activity of small molecule cytotoxic drugs to improve the targeting of tumor drugs and reduce toxic side effects. Compared with traditional fully or partially humanized antibodies or antibody fragments, ADCs are theoretically more effective because they can release highly active cytotoxins in tumor tissues. Compared with fusion proteins, it has higher tolerance or lower side effects.
ADC药物对靶点的准确识别性及非癌细胞不受影响性，极大地提高了药效并减少了毒副作用；由于ADC药物结构较为复杂，且不同ADC药物设计之间存在较大的差异。即使同一靶点的不同药物，由于识别位点、连接位点、连接子及所连接小分子的不同，其毒性的差异显而易见。The accurate identification of targets of ADC drugs and the unaffectedness of non-cancerous cells greatly improve drug efficacy and reduce toxic and side effects; due to the complex structure of ADC drugs, and there are large differences between different ADC drug designs. Even for different drugs of the same target, the differences in toxicity are obvious due to the differences in recognition sites, attachment sites, linkers and small molecules to which they are attached.
ADC药物的靶向性来自其中抗体部分，毒性大部分来自小分子化药毒物部分。抗体部分与毒素部分通过连接物互相连接。抗体部分与肿瘤细胞表面的靶向抗原结合后，肿瘤细胞会将ADC内吞。之后ADC药物会在溶酶体中分解，释放出活性的化药毒物，破坏DNA或阻止肿瘤细胞***，起到杀死细胞的作用。理想化的连接物应该保持稳定，所以不会导致靶外毒性，并且在细胞内高效释放毒物。The targeting of ADC drugs comes from the antibody part, and most of the toxicity comes from the toxic part of the small molecule drug. The antibody moiety and the toxin moiety are linked to each other by a linker. After the antibody moiety binds to the targeted antigen on the tumor cell surface, the tumor cell will internalize the ADC. Afterwards, the ADC drug will be decomposed in the lysosome, releasing the active chemical toxin, destroying the DNA or preventing the tumor cell from dividing, and playing the role of killing the cell. Ideally, the linker should remain stable so that it does not cause off-target toxicity and efficiently release the toxicant inside the cell.
现在的ADC通常由一个完全人源化的单克隆抗体、一个细胞毒药物、一个合适的连接体和肿瘤细胞上特异性表达的抗原组成。该结构主要保持药物的细胞毒性、靶向性和ADC在体循环中的稳定性。正确的选择组合是成功研制ADC的关键。Current ADCs usually consist of a fully humanized monoclonal antibody, a cytotoxic drug, an appropriate linker, and an antigen specifically expressed on tumor cells. This structure mainly maintains the cytotoxicity, targeting, and stability of the ADC in the systemic circulation. The right combination of choices is the key to successful ADC development.
专利CN201380053256.2公开了一种抗体耦联药物，采用的连接体的典型结构为：-(琥珀酰亚胺-3-基-N)-CH2CH2CH2CH2CH2-C(＝O)-GGFG-NH-CH2-O-CH2-C(＝O)-(NH-DX)，但是该连接体还存在一定的不足，如其并未研究结构稳定性，众所周知，ADC药物的稳定性问题一直是本领域普遍需要面对的技术难题。Patent CN201380053256.2 discloses an antibody-coupled drug. The typical structure of the linker used is: -(succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2- O-CH2-C(=O)-(NH-DX), but this linker still has certain deficiencies. For example, its structural stability has not been studied. As we all know, the stability of ADC drugs has always been a common problem in the art. technical difficulties.
因此，本领域亟需一种稳定性好的可作为抗体偶联物的中间体。Therefore, there is an urgent need in the art for an intermediate with good stability that can be used as an antibody conjugate.
发明内容SUMMARY OF THE INVENTION
基于以上背景技术提到的技术问题，本发明旨在提供一种稳定性好的抗体偶联物中间体，具体地，本发明提供了一种抗体偶联物中间体，其采用如下结构表示，T-GGFG-L1-D；Based on the technical problems mentioned in the above background art, the present invention aims to provide an antibody conjugate intermediate with good stability. Specifically, the present invention provides an antibody conjugate intermediate, which is represented by the following structure: T-GGFG-L1-D;
其中，T是可和抗体部位连接的连接头，L1连接子，D表示小分子细胞毒药物，-GGFG-中G表示甘氨酸，F表示苯丙氨酸；Among them, T is a linker that can be connected to the antibody site, L1 linker, D represents a small molecule cytotoxic drug, G in -GGFG- represents glycine, and F represents phenylalanine;
T选自
其中m为0-6的整数，n为0-6的整数，p为0-12的整数，q为0-6的整数；
T is selected from Where m is an integer of 0-6, n is an integer of 0-6, p is an integer of 0-12, and q is an integer of 0-6;
L1结构为
其中氨基端和-GGFG-相连接，羰基端和D相连，r为1-6的整数，s为0或1；t为1-6的整数；
The L1 structure is Wherein the amino end is connected with -GGFG-, the carbonyl end is connected with D, r is an integer of 1-6, s is 0 or 1; t is an integer of 1-6;
所述D的结构为
The structure of the D is
其中R1和R2和R3分别独立表示氢、卤素、羟基、氨基、氰基、C2-C8烯基、C2-C8炔基、醛基、氨基甲酰基、C1-C8烷基、C1-C8烷氧基；Wherein R1 and R2 and R3 independently represent hydrogen, halogen, hydroxyl, amino, cyano, C2-C8 alkenyl, C2-C8 alkynyl, aldehyde group, carbamoyl, C1-C8 alkyl, C1-C8 alkoxy base;
上述结构中
表示连接位点。
In the above structure Indicates the attachment site.
优选地，所述的抗体偶联物中间体中，所述T选自
中的一种。
Preferably, in the antibody conjugate intermediate, the T is selected from one of the.
优选地，所述的抗体偶联物中间体中，所述的T为
Preferably, in the antibody conjugate intermediate, the T is
优选地，所述的抗体偶联物中间体中，所述的L1选自
Preferably, in the antibody conjugate intermediate, the L1 is selected from
优选地，所述的抗体偶联物中间体中，所述的D为
Preferably, in the antibody conjugate intermediate, the D is
进一步，本发明提供一种抗体偶联物中间体，其结构如下：Further, the present invention provides a kind of antibody conjugate intermediate, and its structure is as follows:
进一步，本发明提供一种抗体偶联物中间体，其结构如下：Further, the present invention provides a kind of antibody conjugate intermediate, and its structure is as follows:
另一方面，本发明提供一种抗体偶联物，其由上述的抗体偶联物中间体与抗体或抗体修饰物相连接得到，所述的抗体或抗体修饰物是和抗体偶联物中间体的T相连接。On the other hand, the present invention provides an antibody conjugate obtained by connecting the above-mentioned antibody conjugate intermediate with an antibody or an antibody modification, and the antibody or antibody modification is an intermediate with an antibody conjugate the T-phase connection.
另一方面，本发明提供一种包括上述的抗体药物偶联物或其药学上可接受的盐的药物组合物。In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate or a pharmaceutically acceptable salt thereof.
进一步，所述药物组合物为抗肿瘤药物、抗免疫疾病药物或抗感染性疾病药物，其中，抗肿瘤药物中包括抗癌药物。Further, the pharmaceutical composition is an anti-tumor drug, an anti-immune disease drug or an anti-infectious disease drug, wherein the anti-tumor drug includes an anti-cancer drug.
另一方面，作为本发明的典型化合物的结构如下：On the other hand, the structures as typical compounds of the present invention are as follows:
上述化合物中DX结构为
The structure of DX in the above compound is
本发明所述的所有实验用试剂、抗体、反应溶剂、合成原料、催化剂等均来自商业化购买。All experimental reagents, antibodies, reaction solvents, synthetic raw materials, catalysts, etc. described in the present invention are commercially purchased.
实施例1：化合物5的合成Example 1: Synthesis of Compound 5
化合物2的合成Synthesis of Compound 2
向500mL三口瓶中加入10.00g化合物1(1.0eq)，300ml四氢呋喃，100ml甲苯，2.68g吡啶(1.2eq)，15.01g四乙酸铅(1.2eq)，加热回流，TLC监控反应完毕后，降至室温，过滤除去不溶物，浓缩后加入乙酸乙酯，稀盐酸洗涤，碳酸氢钠洗涤后浓缩，柱层析得类白色固体化合物2 7.30g，收率70.2％。10.00g compound 1 (1.0eq), 300ml tetrahydrofuran, 100ml toluene, 2.68g pyridine (1.2eq), 15.01g lead tetraacetate (1.2eq) were added to a 500mL three-necked flask, heated to reflux, and after the reaction was monitored by TLC, it was reduced to At room temperature, the insolubles were removed by filtration, concentrated and then added with ethyl acetate, washed with dilute hydrochloric acid, washed with sodium bicarbonate, and concentrated. Column chromatography gave 7.30 g of off-white solid compound 2, with a yield of 70.2%.
LC/MS(m/z):C20H20N2O5 368.14；369[M+H]+,367[M-H]-.LC/MS(m/z): C20H20N2O5 368.14; 369[M+H]+, 367[M-H]-.
化合物4的合成Synthesis of compound 4
向250mL三口瓶中加入7.00g化合物2(1.0eq)，9.47g化合物3(3.0eq)，100ml四氢呋喃，4.26g叔丁醇钾(2.0eq)，室温搅拌0.5小时后向反应液中加入水、二氯甲烷，萃取分液，收集有机相，有机相浓缩后加入100ml水、3.19g碳酸氢钠(2.0eq)，加入7.05g Fmoc-OSU(1.1eq)溶于100ml乙二醇二甲醚的溶液，再加入50ml四氢呋喃，室温搅拌，TLC监控反应完毕后，浓缩后加入乙酸乙酯萃取，稀盐酸洗涤，碳酸氢钠洗涤后浓缩，柱层析得类白色固体化合物4 5.12g，收率56.8％。To a 250mL three-necked flask, add 7.00g compound 2 (1.0eq), 9.47g compound 3 (3.0eq), 100ml tetrahydrofuran, 4.26g potassium tert-butoxide (2.0eq), stir at room temperature for 0.5 hours, add water, Dichloromethane, extracted and separated, collected the organic phase, concentrated the organic phase, added 100ml of water, 3.19g of sodium bicarbonate (2.0eq), added 7.05g of Fmoc-OSU (1.1eq) dissolved in 100ml of ethylene glycol dimethyl ether The solution was then added with 50ml of tetrahydrofuran, stirred at room temperature, and after the completion of the TLC monitoring reaction, concentrated, added ethyl acetate for extraction, washed with dilute hydrochloric acid, washed with sodium bicarbonate and concentrated, and column chromatography gave off-white solid compound 4 5.12g, yield 56.8 %.
LC/MS(m/z):r C27H26N2O6 474.18；475[M+H]+.LC/MS(m/z):r C27H26N2O6 474.18; 475[M+H]+.
化合物5的合成Synthesis of compound 5
在250mL氢化釜中加入4.00g化合物4(1.0eq)，50ml甲醇，0.4g钯碳，氮气置换后通入氢气，保持4个大气压，室温反应过夜，TLC监控反应完毕后，过滤，浓缩得类白色固体化合物5 3.01g，收率92.8％。4.00g of compound 4 (1.0eq), 50ml of methanol, 0.4g of palladium on carbon were added to a 250mL hydrogenation kettle. After nitrogen replacement, hydrogen was introduced, and the pressure was maintained at 4 atmospheres. The reaction was performed at room temperature overnight. White solid compound 5 3.01 g, yield 92.8%.
LC/MS(m/z):C20H20N2O6 384.13；[M+H]+,383[M-H]-.LC/MS(m/z): C20H20N2O6 384.13; [M+H]+, 383[M-H]-.
实施例2：化合物9的合成Example 2: Synthesis of Compound 9
化合物6的合成Synthesis of compound 6
化合物6的合成采用固相合成法，偶联试剂采用HOBT/DIC，DMF为反应溶剂，反应监控采用茚三酮检测法，依次将化合物5、Fmoc-Phe-OH、Fmoc-Gly-OH、Fmoc-Gly-OH、Fmoc-Cys(Trt)-OH连接到2Cl-Trt树脂上，脱除Fmoc，DMF洗涤、DCM洗涤、甲醇洗涤后干燥，加入裂解试剂1％TFA/DCM，冰的MTBE沉淀、洗涤，粗品经柱层析纯化、浓缩干燥，得白色固体化合物6 2.56g，收率60.8％。The synthesis of compound 6 adopts solid-phase synthesis method, the coupling reagent adopts HOBT/DIC, DMF is used as the reaction solvent, and the reaction monitoring adopts ninhydrin detection method. Compound 5, Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc -Gly-OH, Fmoc-Cys(Trt)-OH were connected to 2Cl-Trt resin, Fmoc was removed, DMF washing, DCM washing, methanol washing and drying, adding cleavage reagent 1% TFA/DCM, MTBE precipitation on ice, After washing, the crude product was purified by column chromatography, concentrated and dried to obtain 2.56 g of compound 6 as a white solid with a yield of 60.8%.
LC/MS(m/z):c C45H52N6O10S 868.35；869[M+H]+,867[M-H]-.LC/MS(m/z): c C45H52N6O10S 868.35; 869[M+H]+,867[M-H]-.
化合物8的合成Synthesis of Compound 8
向50mL三口瓶中加入2.40g化合物6(1.0eq)，1.54g化合物7(1.05eq)25mL DMF，降温至10℃以下，加入0.93g TBTU(1.05eq)，1.07g DIEA(3.0eq)，升至室温反应4h，TLC监控反应完毕后，将反应液倒入水中，乙酸乙酯萃取2次，合并有机相，稀盐酸洗涤、碳酸氢钠水溶液洗涤，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得淡黄色固体化合物8 3.04g，收率85.6％。Add 2.40g compound 6 (1.0eq), 1.54g compound 7 (1.05eq), 25mL DMF to a 50mL three-necked flask, cool down to below 10°C, add 0.93g TBTU (1.05eq), 1.07g DIEA (3.0eq), liter The reaction was carried out at room temperature for 4 h. After the completion of the TLC monitoring, the reaction solution was poured into water, extracted twice with ethyl acetate, and the organic phases were combined, washed with dilute hydrochloric acid, washed with aqueous sodium bicarbonate, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated to obtain 3.04 g of compound 8 as a pale yellow solid with a yield of 85.6%.
LC/MS(m/z):C69H72FN9O13S 1285.50；1286[M+H]+.LC/MS(m/z): C69H72FN9O13S 1285.50; 1286[M+H]+.
化合物9的合成Synthesis of Compound 9
向50mL圆底烧瓶中加入2.90g化合物8，15mL的90％TFA/5％H2O/5％TIS，室温反应2h，倒入预冷的TBME中，沉淀、离心，干燥得淡黄色固体化合物9的粗品，粗品经HPLC制备纯化、冻干得纯品1.33g，收率62.5％。2.90g of compound 8 and 15mL of 90%TFA/5%H2O/5%TIS were added to a 50mL round-bottomed flask, reacted at room temperature for 2h, poured into pre-cooled TBME, precipitated, centrifuged, and dried to obtain pale yellow solid compound 9. The crude product was prepared and purified by HPLC and lyophilized to obtain 1.33 g of pure product with a yield of 62.5%.
LC/MS(m/z):C45H50FN9O11S 943.33；944[M+H]+,473[M+2H]2+.LC/MS(m/z): C45H50FN9O11S 943.33; 944[M+H]+, 473[M+2H]2+.
实施例3：抗体药物偶联物aExample 3: Antibody Drug Conjugate a
抗体的MC衍生化物11MC derivatives of antibodies 11
向5mL圆底烧瓶中加入含有抗体M30-H1-L4P的PBS溶液(pH＝7.2)1ml，含抗体约20mg，搅拌下加入含有化合物10(5.1eq)的DMSO溶液0.05ml，室温反应2h，透析后得抗体MC衍生化物11的水溶液。To a 5mL round-bottom flask, add 1ml of PBS solution (pH=7.2) containing antibody M30-H1-L4P, containing about 20mg of antibody, add 0.05ml of DMSO solution containing compound 10 (5.1eq) under stirring, react at room temperature for 2h, and dialyze An aqueous solution of the antibody MC derivative 11 was obtained.
抗体药物偶联物aAntibody Drug Conjugate a
将上述抗体抗体MC衍生化物11的水溶液加入至10ml反应瓶中，室温下加入含有化合物9(4.5eq)的DMSO溶液，1小时后透析，得抗体药物偶联物a的溶液。The aqueous solution of the above-mentioned antibody-antibody MC derivative 11 was added to a 10 ml reaction flask, a DMSO solution containing compound 9 (4.5eq) was added at room temperature, and dialyzed after 1 hour to obtain a solution of antibody-drug conjugate a.
实施例4：化合物14的合成Example 4: Synthesis of Compound 14
化合物13的合成Synthesis of Compound 13
化合物13的合成采用固相合成法，偶联试剂采用HOBT/DIC，DMF为反应溶剂，反应监控采用茚三酮检测法，依次将化合物5、Fmoc-Phe-OH、Fmoc-Gly-OH、Fmoc-Gly-OH、化合物12连接到2Cl-Trt树脂上，脱除Fmoc，DMF洗涤、DCM洗涤、甲醇洗涤后干燥，加入裂解试剂1％TFA/DCM，冰的MTBE沉淀、洗涤，粗品经柱层析纯化、浓缩干燥，得白色固体化合物13 2.86g，收率62.9％。The synthesis of compound 13 adopts solid phase synthesis method, the coupling reagent adopts HOBT/DIC, DMF is used as the reaction solvent, and the reaction monitoring adopts ninhydrin detection method. Compound 5, Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc -Gly-OH, compound 12 was connected to 2Cl-Trt resin, Fmoc was removed, washed with DMF, DCM, methanol and then dried, cleavage reagent 1% TFA/DCM was added, MTBE on ice was precipitated, washed, and the crude product was passed through the column layer It was purified by analysis, concentrated and dried to obtain 2.86 g of compound 13 as a white solid with a yield of 62.9%.
LC/MS(m/z):C28H34Br2N6O10 772.07；773[M+H]+.LC/MS(m/z): C28H34Br2N6O10 772.07; 773[M+H]+.
化合物14的合成Synthesis of compound 14
向50mL三口瓶中加入2.60g化合物13(1.0eq)，1.87g化合物7(1.05eq)26mL DMF，降温至10℃以下，加入1.13g TBTU(1.05eq)，1.37g DIEA(3.0eq)，升至室温反应4h，TLC监控反应完毕后，将反应液倒入水中，乙酸乙酯萃取2次，合并有机相，稀盐酸洗涤、碳酸氢钠水溶液洗涤，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得淡黄色固体化合物14 3.37g，收率84.2％。Add 2.60g compound 13 (1.0eq), 1.87g compound 7 (1.05eq), 26mL DMF to a 50mL three-necked flask, cool down to below 10°C, add 1.13g TBTU (1.05eq), 1.37g DIEA (3.0eq), liter The reaction was carried out at room temperature for 4 h. After the completion of the TLC monitoring, the reaction solution was poured into water, extracted twice with ethyl acetate, and the organic phases were combined, washed with dilute hydrochloric acid, washed with aqueous sodium bicarbonate, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrated to obtain 3.37 g of compound 14 as a pale yellow solid with a yield of 84.2%.
LC/MS(m/z):C52H54Br2FN9O13 1189.22；1190[M+H]+,1188[M-H]-.LC/MS(m/z): C52H54Br2FN9O13 1189.22; 1190[M+H]+, 1188[M-H]-.
实施例5：抗体药物偶联物bExample 5: Antibody Drug Conjugate b
抗体药物偶联物aAntibody Drug Conjugate a
向5mL圆底烧瓶中加入含有抗体M30-H1-L4P的PBS溶液(pH＝6.9)1ml，含抗体约20mg，搅拌下加入含有化合物14(4.5eq)的DMSO溶液0.05ml，室温反应1h，透析后得抗体药物偶联物b的溶液。To a 5mL round-bottomed flask, add 1ml of PBS solution (pH=6.9) containing antibody M30-H1-L4P, containing about 20mg of antibody, add 0.05ml of DMSO solution containing compound 14 (4.5eq) under stirring, react at room temperature for 1h, and dialyze Afterwards, a solution of antibody drug conjugate b was obtained.
对本领域的技术人员来说，可根据以上描述的技术方案以及构思，做出其它各种相应的改变以及形变，而所有的这些改变以及形变都应该属于本发明权利要求的保护范围之内。For those skilled in the art, various other corresponding changes and deformations can be made according to the technical solutions and concepts described above, and all these changes and deformations should fall within the protection scope of the claims of the present invention.
Claims (10)
- 一种抗体偶联物中间体，其特征在于采用如下结构表示，T-GGFG-L1-D；An antibody conjugate intermediate, characterized in that it is represented by the following structure, T-GGFG-L1-D;其中，T是可和抗体部位连接的连接头，L1是连接子，D表示小分子细胞毒药物，-GGFG-中G表示甘氨酸，F表示苯丙氨酸；Among them, T is a linker that can be connected to the antibody site, L1 is a linker, D is a small molecule cytotoxic drug, G in -GGFG- is glycine, and F is phenylalanine;T选自其中m为0-6的整数，n为0-6的整数，p为0-12的整数，q为0-6的整数； T is selected from
Where m is an integer of 0-6, n is an integer of 0-6, p is an integer of 0-12, and q is an integer of 0-6;L1结构为其中氨基端和-GGFG-相连接，羰基端和D相连，r为1-6的整数，s为0或1；t为1-6的整数； The L1 structure is
Wherein the amino end is connected with -GGFG-, the carbonyl end is connected with D, r is an integer of 1-6, s is 0 or 1; t is an integer of 1-6;所述D的结构为The structure of the D is
其中R1和R2和R3分别独立表示氢、卤素、羟基、氨基、氰基、C2-C8烯基、C2-C8炔基、醛基、氨基甲酰基、C1-C8烷基、C1-C8烷氧基；Wherein R1 and R2 and R3 independently represent hydrogen, halogen, hydroxyl, amino, cyano, C2-C8 alkenyl, C2-C8 alkynyl, aldehyde group, carbamoyl, C1-C8 alkyl, C1-C8 alkoxy base;上述结构中表示连接位点。 in the above structure
Indicates the attachment site. - 如权利要求1所述的抗体偶联物中间体，其特征在于，所述T选自
中的一种。 The antibody conjugate intermediate of claim 1, wherein the T is selected from
one of the. - 如权利要求2所述的抗体偶联物中间体，其特征在于，所述的T为
The antibody conjugate intermediate of claim 2, wherein the T is
- 如权利要求1所述的抗体偶联物中间体，所述的L1选自
The antibody conjugate intermediate of claim 1, wherein the L1 is selected from the group consisting of
- 如权利要求1所述的抗体偶联物中间体，其特征在于，所述的D为The antibody conjugate intermediate of claim 1, wherein the D is
- 如权利要求1所述的抗体偶联物中间体，其结构如下：The antibody conjugate intermediate as claimed in claim 1, its structure is as follows:
- 如权利要求1所述的抗体偶联物中间体，其化合物的结构如下,The antibody conjugate intermediate as claimed in claim 1, the structure of its compound is as follows,
上述化合物中DX结构为The structure of DX in the above compound is
- 一种抗癌偶联物，其由权利要求1-7所述的抗体偶联物中间体与抗体或抗体修饰物相连接得到，所述的抗体或抗体修饰物是和抗体偶联物中间体的T相连接。An anti-cancer conjugate obtained by connecting the antibody conjugate intermediate of claims 1-7 with an antibody or an antibody modification, and the antibody or antibody modification is an antibody conjugate intermediate the T-phase connection.
- 一种包括权利要求8所述的抗体药物偶联物或其药学上可接受的盐的药物组合物。A pharmaceutical composition comprising the antibody-drug conjugate of claim 8 or a pharmaceutically acceptable salt thereof.
- 根据权利要求9所述的药物组合物，特征在于，所述药物组合物为抗肿瘤药物、抗免疫疾病药物或抗感染性疾病药物，其中，抗肿瘤药物中包括抗癌药物。The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is an anti-tumor drug, an anti-immune disease drug or an anti-infectious disease drug, wherein the anti-tumor drug includes an anti-cancer drug.
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