WO2023124963A1 - Conjugué anticorps-médicament ayant une réaction réversible réduite, procédé de préparation s'y rapportant et application associée - Google Patents

Conjugué anticorps-médicament ayant une réaction réversible réduite, procédé de préparation s'y rapportant et application associée Download PDF

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WO2023124963A1
WO2023124963A1 PCT/CN2022/138621 CN2022138621W WO2023124963A1 WO 2023124963 A1 WO2023124963 A1 WO 2023124963A1 CN 2022138621 W CN2022138621 W CN 2022138621W WO 2023124963 A1 WO2023124963 A1 WO 2023124963A1
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cancer
antibody
stereoisomer
pharmaceutically acceptable
solvate
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PCT/CN2022/138621
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English (en)
Chinese (zh)
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柯天一
丁会
于海勇
许云雷
劳芳
刘岩
张西东
荣鹏飞
姚德惠
杜旭召
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昆山新蕴达生物科技有限公司
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    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • 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 present disclosure relates to the field of biomedicine, in particular, the present disclosure relates to an antibody-drug conjugate with reduced reversible reactions, its preparation method and application, in particular to a new type of linker structure, and a drug-drug conjugate comprising the linker structure.
  • Antibody-drug conjugates have shown unique advantages over simple antibody drugs.
  • the monoclonal antibody is linked to biologically active molecules (such as cytotoxins), thus combining the tumor recognition targeting of the antibody and the efficient killing effect of the cytotoxin, and ingeniously solving the problems caused by the low efficacy of the antibody and the lack of targeting of the toxin.
  • biologically active molecules such as cytotoxins
  • the defect of excessive toxicity This enables ADC to accurately target tumor cells while reducing the impact on normal cells compared with traditional anti-tumor drugs, greatly improving the effectiveness and safety of anti-tumor drugs.
  • ADC generally includes three parts: antibody, linker (Linker) and biologically active molecules.
  • the biologically active molecular part of ADC is a toxin small molecule that plays a killing role, and generally kills tumor cells by inhibiting DNA or protein synthesis, inhibiting cell mitosis, and other methods.
  • Toxins currently used for ADC development mainly include microtubule inhibitors maytansinoids (see EP0425235, US5208020, US5416064, US7276497) and auristatins (MMAE/MMAF, see US2016304621A).
  • cytotoxins also include calicheamicins (Calicheamicin, see US5606040), benzobipyrrole derivatives (duocarmycin, see US7129261), pyrobenzodiazepines (PBDs, see WO2005/040170) and Dendrite derivatives.
  • the camptothecin derivatives include SN-38, DXD, CPT-11, exatecan, 9-nitrocamptothecin, 10-hydroxycamptothecin and the like.
  • the toxin is coupled to the antibody through a linker; the antibody can specifically recognize the target on the surface of the tumor cell, and enrich the ADC on the surface of the tumor cell, so that the ADC enters the tumor cell through the endocytosis effect, releases the toxin, and achieves specific killing role of tumors.
  • ADC joints are divided into two types: cleavable and non-cleavable.
  • the ideal joint should meet the requirements of "good stability and high release efficiency". Unstable joints will cause ADC off-target and increase safety risks, while overly stable joints will Affect the release rate of toxins, thereby affecting the efficacy of drugs. Therefore, the design of the linker is very important, which directly affects the efficacy and safety of ADC.
  • One end of the linker is connected to the antibody, and the other end is connected to the drug.
  • lysine and cysteine are common linking sites between antibodies and linkers. The ⁇ -amino group of the former can react with the activated carboxyl group of the linker to form an amide bond.
  • the antibody has multiple amino groups, which makes the coupling site and DAR value uncertain, and the product is not uniform, which is not conducive to drug stability.
  • ADCs choose cysteine as the coupling site.
  • One of the current methods for coupling linkers to antibody thiols is Michael addition reaction between free thiols on the antibody and maleimide (MC), or a specific substrate and free thiols on the antibody through two passes.
  • the present disclosure relates to a class of linker molecules with a specific structure, and the linker molecule ADC, which is obtained by improving the coupling method of toxins and targeting moieties in ADC or SMDC drugs, and the obtained conjugates have better stability, Higher therapeutic window, better therapeutic effect in colon cancer, pancreatic cancer and other tumor animal models, anti-tumor drug effect is better than traditional ADC with MC as linker.
  • the first aspect of the present disclosure provides an antibody-drug conjugate represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the compound, its stereoisomer or a solvate of a pharmaceutically acceptable salt thereof,
  • Ab is an antibody, such as a monoclonal antibody or an antigen-binding fragment thereof;
  • L 1 is -L 12 -L 13 -L 14 -L 15 -
  • L 12 is selected from 5-6 membered heteroarylene
  • L 13 is selected from direct bonds
  • n is an integer selected from 1-10;
  • L 2 is selected from direct bonds, Preferably, L2 is , the amino terminal is connected to L 1 or L 15 , and the carbonyl terminal is connected to L 3 ;
  • p is an integer selected from 1-10;
  • L3 is an amino acid unit, preferably selected from amino acid residues or peptide residues consisting of 2-10 amino acid residues;
  • L 4 is selected from direct bonds
  • D is a drug linked to L4 through a chemical bond; if L4 is a direct bond, those skilled in the art will understand that D is linked to L3 ;
  • n is any value between 1-20.
  • antibody-drug conjugate represented by the above formula (I) refers to a composition of ADC molecules with the same or different numbers of linked drug molecules.
  • compositions comprising a plurality of ADC molecules.
  • each ADC in the compositions described herein comprises the same number of one or more drug molecules.
  • each ADC in the compositions described herein comprises a different number of one or more drug molecules.
  • each antibody can be coupled with 1, 2, 3, 4, 5, 6, 7, 8 or more drug molecules, such as 1 to 5 (e.g. 1, 2, 3, 4 or 5) drug molecules, 5 to 8 (e.g. 5, 6, 7 or 8) drug molecules or 8 to 12 (e.g. 8, 9, 10, 11 or 12) drug molecules.
  • 1 to 5 e.g. 1, 2, 3, 4 or 5
  • 5 to 8 e.g. 5, 6, 7 or 8
  • 8 to 12 e.g. 8, 9, 10, 11 or 12
  • the Drug Antibody Ratio refers to the number of drug molecules conjugated to the antibody (eg, n in Formula I).
  • the number of drug molecules contained in the ADC described herein is generally an integer, and when the number of drug molecules contained in the ADC described herein (for example, n in formula I) is a fraction, the fraction refers to the number of drug molecules contained in the ADC described herein.
  • L 12 is selected from:
  • L 12 is selected from:
  • L 12 is selected from
  • L 12 is
  • L 13 is selected from direct bonds.
  • m is an integer selected from 1-6.
  • m is selected from 1,2,3.
  • m is 3.
  • p is an integer selected from 1-6.
  • p is selected from 1, 2, 3.
  • p is 2.
  • L is a peptide residue consisting of 2 to 7 (preferably 2 to 4) amino acid residues; preferably, the amino acids are selected from the group consisting of phenylalanine, glycine, valine, lysine amino acid, citrulline, serine, glutamic acid, aspartic acid; more preferably, the amino acid is selected from glycine, phenylalanine, valine, citrulline, alanine.
  • L is selected from the group consisting of valine-citrulline (Val-Cit), alanine-alanine-asparagine (Ala-Ala-Asn), glycine-glycine-lysine ( Gly-Gly-lys), Valine-Lysine (Val-lys), Valine-Alanine (Val-Ala), Valine-Phenylalanine (Val-Phe), or Glycine-Glycine - phenylalanine-glycine (Gly-Gly-Phe-Gly); preferably selected from glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly), valine-citrulline (Val- Cit), valine-alanine (Val-Ala).
  • L is selected from
  • L3 is glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly).
  • ADCs comprising Gly-Gly-Phe-Gly exhibit increased stability, reduced off-target cell killing, increased on-target cell killing relative to ADCs comprising other amino acid units or other cleavable moieties , lower aggregation levels, and/or higher drug loading.
  • the amino terminus of L3 is attached to L2 and the carbonyl terminus is attached to L4 .
  • L2 is a direct bond
  • the amino terminal of L3 is connected to L1 or L15 .
  • L 4 is a direct bond
  • the carbonyl end of L 3 is connected to D, for example, to the amino group of eribulin.
  • the linker in the antibody conjugates of the present disclosure comprises at least one spacer unit linking the eribulin derivative D to the cleavable moiety. In some embodiments, the linker comprises a spacer unit attached to D.
  • the spacer unit comprises p-aminobenzyloxycarbonyl (PAB)
  • the spacer unit comprises p-aminobenzoyl
  • L is selected from direct bonds
  • L4 is a direct bond
  • the linker is stable extracellularly such that the ADC remains intact when present in the extracellular environment, but is capable of cleavage when internalized in a cell, eg, a cancer cell.
  • the ADC enters a cell expressing an antigen specific for the antibody portion of the ADC
  • the biologically active molecule portion is cleaved from the antibody portion, and the cleavage releases the unmodified form of the biologically active molecule.
  • the cleavable moiety in the linker is a cleavable peptide moiety.
  • ADCs comprising a cleavable peptide moiety exhibit lower levels of aggregation, improved antibody-to-drug ratios, increased targeted killing of cancer cells, reduced non- Off-target killing of cancer cells, and/or higher drug load (n).
  • addition of a cleavable moiety increases cytotoxicity and/or potency relative to a non-cleavable linker.
  • the increased potency and/or cytotoxicity is in cancers that express moderate levels of the antigen targeted by the antibody portion of the ADC (eg, moderate FRA expression).
  • the cleavable peptide moiety is capable of being cleaved by an enzyme
  • the linker is one that is cleavable by an enzyme.
  • the enzyme is a cathepsin and the linker is a linker that the cathepsin is capable of cleaving.
  • an enzyme-cleavable linker eg, a cathepsin-cleavable linker
  • the linker comprises a cleavable disulfide moiety that is capable of being cleaved under reducing conditions.
  • the linker can be attached via the amino group of D.
  • the linker can be attached via the hydroxyl group of D.
  • D is selected from eribulin or its derivatives (such as eribulin mesylate, etc.), DNA topoisomerase inhibitors, such as topoisomerase I inhibitors (such as camptophyllin Alkaline, Hydroxycamptothecin, 9-Aminocamptothecin, SN-38, Gemitecan, Gematecan, Irinotecan, Topotecan, Exatecan, DXD, Belotecan, Leto tecan, CKD-602, karenitecin, BN-80915, or rubitecan), topoisomerase II inhibitors (eg, actinomycin D, doxorubicin, doxorubicin, duocarmycin, daunorubicin drugs that interfere with DNA synthesis, such as methotrexate, 5-fluorouracil, cytarabine, gemcitabine, mercaptopurine, pentostatin, fludarabine , cladribine or n
  • the drug is selected from eribulin or its derivatives (such as eribulin mesylate, etc.), camptothecin or its derivatives (such as hydroxycamptothecin, 9-aminocamptothecin Alkaline, SN-38, gemitecan, gemotecan, irinotecan, topotecan, exatecan, DXD, belotecan, letotecan, CKD-602, karenitecin, BN-80915 or rubitecan), Monomethyl auristatin E (MMAE), Monomethyl auristatin F (MMAF), MonoMethyl Dolastatin 10 (MMAD).
  • camptothecin or its derivatives such as hydroxycamptothecin, 9-aminocamptothecin Alkaline, SN-38, gemitecan, gemotecan, irinotecan, topotecan, exatecan, DXD, belotecan, letotecan, CKD-60
  • the drug is selected from eribulin or its derivatives (such as eribulin mesylate, etc.), MMAE, DXD, preferably eribulin or its derivatives (such as eribulin mesylate, etc. Riblin, etc.).
  • the drug moiety conjugated to the subject antibody is selected from eribulin or a derivative thereof, eg, the mesylate salt of eribulin.
  • eribulin refers to a synthetic analog of halichondrin B, a macrocyclic compound originally isolated from the sponge Halichondria okadais. Eribulin is a microtubule inhibitor that is thought to bind tubulin and cause cell cycle arrest in G2/M phase by inhibiting mitotic spindle assembly.
  • eribulin mesylate refers to the mesylate salt of eribulin, which is sold under the tradename Halaven TM .
  • the drug is eribulin or its derivatives (such as eribulin mesylate, etc.).
  • D 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-N-phenyl
  • n is any value between 1-10.
  • n is any value between 1-5.
  • n is any value between 3.5-5.0, eg, n is 3.9, 4.1 or 4.7.
  • the Ab in the antibody-drug conjugate (ADC) of the present disclosure is an antibody, such as a monoclonal antibody or an antigen-binding fragment thereof, and the antibody or an antigen-binding fragment thereof is selected from anti-Trop-2, CD37, HER2 , CD70, EGFRvIII, Mesothelin, Folate eceoptor1, Mucin 1, CD138, CD20, CD19, CD30, SLTRK6, Nectin 4, Tissue factor, Mucin16, Endothelin receptor, STEAP1, SLC39A6, Guanylylcyclase C, PSMA, CCD79b, CD22, Sodium ph osphate cotransporter2B, GPNMB, Trophoblast glycoprotein, AGS-16, EGFR, CD33, CD66e, CD74, CD56, PD-L1, TACSTD2, DR5, E16, STEAP1, 0772P, MPF, Napi3b, Sema 5b,
  • the monoclonal antibody or antigen-binding fragment thereof comprises Fab, Fab', F(ab') 2 , Fd, Fv, dAb, complementarity determining region fragments, single chain antibody (for example, scFv ), non-human antibody, humanized antibody, chimeric antibody, fully human antibody, pre-antibody (Probody), bispecific antibody or multispecific antibody.
  • the Ab is an anti-Her 2 monoclonal antibody, such as Trastuzumab, Pertuzumab, or an anti-Trop-2 monoclonal antibody, such as Sacituzumab.
  • the antibody in the antibody-drug conjugate is a known antibody, selected from but not limited to Trastuzumab (Trastuzumab), Pertuzumab (Pertuzumab), niger Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Vitin-Pinatuzumab , Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96, and Glematumamab or antigen-binding fragments thereof.
  • the targeting moiety is trastuzumab described in US5821337, pertuzumab described in US7560111 of SEQ ID No.: 16 and SEQ ID No.: 15 ( pertuzumab), the antibodies that can be used in the present disclosure can also be screened by the carrier design, construction and construction of the antibody library displaying antibodies disclosed in CN103476941A, or can be screened with the library of Sorrento Therapeutics, Inc. get.
  • the Lys at the end of the heavy chain of the targeting moiety is easily deleted without affecting the biological activity, see Dick, L.W. et al., Biotechnol. Bioeng., 100: 1132-1143.
  • the targeting moiety is an anti-Trop-2 monoclonal antibody, such as the deletion of Lys at the end of the heavy chain of Sacituzumab, for example, the targeting moiety is an anti-Her 2 monoclonal antibody, such as Trastuzumab, Paragon Deletion of Lys at the end of the heavy chain of Pertuzumab.
  • the Her-2 antibody is the trastuzumab antibody described in US5821337
  • the complementarity determining region (CDR) of the light chain variable region includes CDR1 consisting of the RASQDVNTAVA amino acid sequence; consisting of the SASFLYS amino acid sequence and CDR3 consisting of the QQHYTTPPT amino acid sequence
  • the CDRs of the heavy chain variable region thereof include CDR1 consisting of the DTYIH amino acid sequence; CDR2 consisting of the RIYPTNGYTRY amino acid sequence; and CDR3 consisting of the WGGDGFYAMDY amino acid sequence.
  • the light chain sequence and heavy chain sequence of the trastuzumab antibody are shown in SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • Antibodies that retain Her2-binding activity after conservative amino acid substitutions to the above-mentioned antibodies may also be included.
  • trastuzumab antibody Heavy chain amino acid sequence of trastuzumab antibody:
  • ErbB2 and Her2/neu are used interchangeably, both of which refer to the native sequence human Her2 protein (Genebank accession number: X03363, see e.g. Semba et al., 1985, PNAS, 82:6497-6501; and Yamamoto et al., 1986, Nature, 319:230-234) and their functional derivatives, such as amino acid sequence variants.
  • ErbB2 indicates the gene encoding human Her2, and neu indicates the gene encoding rat p185neu.
  • the compounds or conjugates of the present disclosure can inhibit or kill cells expressing ErbB2 receptors, such as breast cancer cells, ovarian cancer cells, gastric cancer cells, endometrial cancer cells, salivary gland cancer cells, lung cancer cells, Kidney, colon, thyroid, pancreatic, bladder, or liver cancer cells.
  • ErbB2 receptors such as breast cancer cells, ovarian cancer cells, gastric cancer cells, endometrial cancer cells, salivary gland cancer cells, lung cancer cells, Kidney, colon, thyroid, pancreatic, bladder, or liver cancer cells.
  • the targeting portion of the anti-Trop-2 antibody is RS7 described in US Patent No. 7,517,964; RS7 described in US Patent No. 6,653,104; and hRS7 described in US2012/0237518.
  • the full name of Trop-2 antibody is human trophoblast cell surface antigen 2 (Trop-2), which is a 40kDa transmembrane glycoprotein encoded by the TACSTD2 gene. Trop-2 was first identified in the human trophoblast choriocarcinoma cell line, and its intracellular tail plays an important role in controlling many signaling pathways that regulate cell functions, such as cell-cell adhesion, cell proliferation, and cell migration.
  • Trop-2 protein in many human tumors such as breast cancer, colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, kidney cancer, urethral cancer, glioma, melanoma, liver cancer, bladder cancer, Gastric cancer, esophageal cancer
  • Trop-2 has the functions of regulating tumor cell growth, promoting tumor cell invasion and metastasis.
  • Trop-2 antibodies that can be used in the present disclosure include, but are not limited to: m7E6, h7E6, h7E6_SVG, h7E6_SVG1, h7E6_SVG2, h7E6_SVG3, h7E6_SVG4, h7E6_SVG5, h7E6_SVG6, h7E6_SVG7, h7E6_SVG described, for example, in CN104053672A 8.
  • the anti-Trop-2 antibody that can be used in the present disclosure can also be obtained by screening the carrier design, construction and construction of an antibody library displaying antibodies disclosed in CN103476941A, and can also be obtained from the library of Sorrento Therapeutics, Inc. obtained by screening.
  • the natural sequence Trop-2 in the present disclosure can be isolated from nature, and can also be prepared by recombinant DNA technology, chemical synthesis or a combination thereof.
  • Antibodies used in the present disclosure are preferably anti-human Trop-2 antibodies.
  • the CDR1, CDR2 and/or CDR3 of the heavy chain and light chain of the anti-human Trop-2 antibody are respectively the CDR1, CDR2 and/or CDR3 of the heavy chain and light chain of the RS7 monoclonal antibody.
  • the anti-human Trop-2 antibody can be a humanized antibody or a fully human antibody.
  • the antibody is the RS7 antibody described in CN100360567C, wherein the complementarity determining region (CDR) of the light chain variable region of the humanized or chimeric RS7 antibody includes CDR1 consisting of the KASQDVSIAVA amino acid sequence; CDR2 consisting of the amino acid sequence of SASYRYT; and CDR3 consisting of the amino acid sequence of QQHYITPLT, and wherein the CDR of the heavy chain variable region of the humanized or chimeric RS7 MAb comprises CDR1 consisting of the amino acid sequence of NYGMN; CDR2 consisting of the amino acid sequence of WINTYTGEPTYTDDFKG; and CDR3 consisting of the GGFGSSYWYFDV amino acid sequence.
  • CDR complementarity determining region
  • the light chain sequence and heavy chain sequence of RS7 are respectively shown in SEQ ID NO: 1 and SEQ ID NO: 2;
  • the coding nucleotide sequences of the light chain and heavy chain of the anti-Trop-2 antibody are respectively shown in SEQ Shown in ID NO:3 and SEQ ID NO:4.
  • Antibodies that retain Trop-2 binding activity after conservative amino acid substitutions to the above antibodies may also be included.
  • the antibody drug conjugate is selected from:
  • -S- is not an additional external sulfur atom, but the sulfhydryl group contained in the Ab itself after the disulfide bond is opened. -S- formed after making a ligation.
  • the second aspect of the present disclosure provides a compound represented by formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof,
  • L 1' is L 11 -L 12 -L 13 -L 14 -L 15 -;
  • L 12 , L 13 , L 14 , L 15 are as described above;
  • L 2 , L 3 , L 4 , and D are as described above.
  • the compound represented by formula (II) can be formed by linking the compound represented by the following formula (IV) with a drug, the linking site of the drug is an amino group, and the drug is as described above, Eribulin or its derivatives (such as Eribulin mesylate, etc.) are preferred.
  • provided linkers comprise a cleavable sulfonamide moiety, which linkers are capable of cleavage under reducing conditions.
  • the compound represented by formula (II) is selected from:
  • the third aspect of the present disclosure provides the compound represented by formula (III), its pharmaceutically acceptable salt, its stereoisomer, or its solvate,
  • L 12 , L 13 , L 14 are as described above;
  • the compound represented by formula (III) 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-N-N-phenyl
  • the fourth aspect of the present disclosure provides an intermediate compound represented by formula (IV), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof,
  • L 1' is L 11 -L 12 -L 13 -L 14 -L 15 -;
  • L 12 , L 13 , L 14 , L 15 are as described above;
  • L 2 and L 3 are as described above.
  • the intermediate compound represented by formula (IV) is selected from
  • the method comprises:
  • the sixth aspect of the present disclosure provides a method for preparing the aforementioned antibody-drug conjugate represented by formula (I), its pharmaceutically acceptable salt, its stereoisomer, or its solvate, which includes:
  • the compound represented by formula (II), its pharmaceutically acceptable salt, its stereoisomer, or its solvate is prepared by the method described in the fifth aspect.
  • the seventh aspect of the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the antibody-drug conjugate of the first aspect of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof, or the antibody-drug conjugate
  • the eighth aspect of the present disclosure provides a pharmaceutical preparation, which comprises the antibody-drug conjugate of the first aspect of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof, or the antibody- Drug conjugates, solvates of their stereoisomers or pharmaceutically acceptable salts thereof, or compounds of the second aspect of the disclosure, their stereoisomers, pharmaceutically acceptable salts thereof, or solvates thereof thing.
  • the ninth aspect of the present disclosure provides the antibody-drug conjugate of the first aspect of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof, or the antibody-drug conjugate, its stereo
  • the solvate of the isomer or its pharmaceutically acceptable salt, or the compound of the second aspect of the present disclosure, its stereoisomer, its pharmaceutically acceptable salt, or its solvate, or the seventh aspect of the present disclosure The pharmaceutical composition according to the aspect or the pharmaceutical preparation according to the eighth aspect, which is used for preventing and/or treating tumor or cancer.
  • the tenth aspect of the present disclosure provides a method for preventing or treating cancer, which comprises administering an effective amount of the antibody-drug conjugate described in the first aspect of the present disclosure, its stereoisomer or Its pharmaceutically acceptable salt, or the solvate of the antibody-drug conjugate, its stereoisomer or its pharmaceutically acceptable salt, or the compound of the second aspect of the present disclosure, its stereoisomer , a pharmaceutically acceptable salt thereof, or a solvate thereof, or the pharmaceutical composition described in the seventh aspect or the pharmaceutical preparation described in the eighth aspect of the present disclosure.
  • the eleventh aspect of the present disclosure provides the antibody-drug conjugate of the first aspect of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof, or the antibody-drug conjugate, its A solvate of a stereoisomer or a pharmaceutically acceptable salt thereof, or the compound of the second aspect of the present disclosure, its stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof, or the compound of the second aspect of the present disclosure
  • the twelfth aspect of the present disclosure provides the antibody-drug conjugate described in the first aspect, its stereoisomer or a pharmaceutically acceptable salt thereof, or the antibody-drug conjugate, its stereoisomer or the solvate of the compound or its pharmaceutically acceptable salt, or the compound of the second aspect of the present disclosure, its stereoisomer, its pharmaceutically acceptable salt, or its solvate, or the compound of the seventh aspect of the present disclosure
  • the use of the above-mentioned pharmaceutical composition or the pharmaceutical preparation according to the eighth aspect for preparing a reagent for inhibiting the growth, proliferation or migration of cancer cells.
  • the thirteenth aspect of the present disclosure provides the antibody-drug conjugate described in the first aspect, its stereoisomer or a pharmaceutically acceptable salt thereof, or the antibody-drug conjugate, its stereoisomer or the solvate of the compound or its pharmaceutically acceptable salt, or the compound of the second aspect of the present disclosure, its stereoisomer, its pharmaceutically acceptable salt, or its solvate, or the compound of the seventh aspect of the present disclosure
  • the pharmaceutical composition described above or the pharmaceutical preparation described in the eighth aspect which is used for inhibiting the growth, proliferation or migration of cancer cells.
  • the fourteenth aspect of the present disclosure provides a method for inhibiting the growth, proliferation or migration of cancer cells, which comprises administering to cancer cells an effective amount of the antibody-drug conjugate described in the first aspect of the present disclosure, its stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate of the antibody-drug conjugate, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the compound of the second aspect of the present disclosure, its stereoisomer Construct, its pharmaceutically acceptable salt, or its solvate, or the pharmaceutical composition described in the seventh aspect or the pharmaceutical preparation described in the eighth aspect of the present disclosure.
  • the methods are used for non-therapeutic purposes, such as for scientific research.
  • the fifteenth aspect of the present disclosure provides a kit for inhibiting the growth, proliferation or migration of cancer cells, which includes the antibody-drug conjugate described in the first aspect of the present disclosure, its stereoisomer or its pharmaceutically acceptable Accepted salts, or solvates of the antibody-drug conjugates, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or compounds of the second aspect of the present disclosure, stereoisomers thereof, pharmaceutically acceptable salts thereof, An acceptable salt, or a solvate thereof, or the pharmaceutical composition described in the seventh aspect or the pharmaceutical preparation described in the eighth aspect of the present disclosure.
  • Antibody-drug conjugates of the present disclosure may preferably be administered to mammals, more preferably humans.
  • Substances used in pharmaceutical compositions containing the antibody-drug conjugate of the present disclosure may be appropriately selected from formulation additives or other substances commonly used in this field in consideration of the dosage and concentration to be administered.
  • the antibody-drug conjugate of the present disclosure can be administered in the form of a pharmaceutical composition or pharmaceutical preparation containing one or more pharmaceutically compatible ingredients.
  • the above-mentioned pharmaceutical composition or pharmaceutical preparation may typically contain more than one pharmaceutically acceptable carrier (such as sterile liquid (such as water and oil (including petroleum, animal, vegetable, or synthetic sources) Oil (such as peanut oil, soybean oil, mineral oil, sesame oil, etc.))).
  • sterile liquid such as water and oil (including petroleum, animal, vegetable, or synthetic sources) Oil (such as peanut oil, soybean oil, mineral oil, sesame oil, etc.)
  • Oil such as peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • water is a more representative carrier.
  • saline solution, and aqueous glucose and glycerol solutions are also Can be used as a liquid carrier, especially for injection solutions.
  • Suitable pharmaceutical excipients are known in this field. According to needs, the above-mentioned composition can also contain a small amount of wetting agent or emulsifying agent, or pH buffering Examples of suitable pharmaceutical carriers are described in "Examples of W. Martin Carriers Armaceutical Sciences” by E.W. Martin. The formulation thereof corresponds to the mode of administration.
  • Various delivery systems are known and can be used for administering the antibody-drug conjugates of the present disclosure.
  • the introduction method include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous routes. Administration may be by infusion or bolus injection, for example.
  • the above-mentioned antibody-drug conjugate is administered by infusion. Parenteral administration is the preferred route of administration.
  • the above-mentioned pharmaceutical composition is formulated into a pharmaceutical composition for intravenous administration to humans, and a prescription is prepared according to conventional procedures.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the above-mentioned pharmaceutical composition may also contain a solubilizer and a local anesthetic (such as lidocaine) for relieving pain at the injection site.
  • the above-mentioned ingredients can be supplied by either: as a dry freeze-dried powder or as an anhydrous concentrate in a sealed container, such as an ampoule or sachet, etc., which seals the amount of active agent, respectively.
  • the above-mentioned drug may be supplied mixed together in a unit dosage form.
  • the above-mentioned drug can be put into an infusion bottle containing sterile pharmaceutical-grade water or saline.
  • an ampoule of sterilized water for injection or saline can be provided so that, for example, the above-mentioned components are mixed before administration.
  • the pharmaceutical composition or pharmaceutical preparation of the present disclosure may be a pharmaceutical composition or pharmaceutical preparation containing only the antibody-drug conjugate of the present disclosure, or may contain an antibody-drug conjugate and at least one other cancer therapeutic agent. pharmaceutical composition.
  • the antibody-drug conjugate of the present disclosure can also be administered together with other cancer therapeutic agents, thereby enhancing the anticancer effect.
  • Other anticancer agents used for this purpose may be administered to the individual simultaneously, separately or sequentially with the antibody-drug conjugate, or may be administered with varying intervals of administration.
  • cancer therapeutic agents include nab-paclitaxel, carboplatin, cisplatin, gemcitabine, irinotecan (CPT-11), paclitaxel, pemetrexed, sorafenib, vinblastine, and international patents.
  • Drugs described in pamphlet WO2003/038043, and LH-RH analogs (leuprolide, goserelin, etc.), estramustine phosphate, estrogen antagonists (tamoxifen, ryloxetin, etc.) oxifen, etc.), aromatase inhibitors (anastrozole, letrozole, exemestane), etc., but are not limited as long as they have antitumor activity.
  • Such a pharmaceutical composition can be formulated as a preparation having a selected composition and necessary purity, in the form of a freeze-dried preparation or a liquid preparation.
  • a freeze-dried preparation it may contain appropriate formulation additives available in the art.
  • the preparations can be formed as liquid preparations containing various preparation additives that can be used in this field.
  • composition and concentration of the pharmaceutical composition vary depending on the method of administration, but the affinity of the antibody-drug conjugate contained in the pharmaceutical composition of the present disclosure to the antigen of the antibody-drug conjugate, that is, the affinity for the antigen Considering the dissociation constant (Kd value), the higher the affinity (the lower the Kd value), the more effective the drug can be exhibited even with a small dose. Therefore, when determining the dosage of the antibody-drug conjugate, the dosage can also be set based on the condition of the affinity of the antibody-drug conjugate to the antigen.
  • the antibody-drug conjugate of the present disclosure is administered to humans, for example, it can be administered once at about 0.001 to 100 mg/kg, or administered multiple times at intervals of once every 1 to 180 days.
  • the antibody-drug conjugates, pharmaceutical compositions, and pharmaceutical preparations of the present disclosure can be used to prevent and/or treat tumors or cancers.
  • the tumor or cancer to be prevented and/or treated may be any cancer cell expressing a protein recognizable by the antibody in the antibody-drug conjugate.
  • the tumor or cancer is selected from breast cancer, colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, renal cancer, urethral cancer, glioma, melanoma tumor, liver cancer, bladder cancer, gastric cancer, esophageal cancer; preferably, the cancer is carcinoma in situ or metastatic carcinoma.
  • a prophylactically or therapeutically effective amount of the disclosed antibody-drug conjugate, pharmaceutical composition, or pharmaceutical preparation is administered to a subject in need for inhibiting the growth, proliferation, or migrate.
  • kits for inhibiting growth, proliferation or migration of cancer cells which includes the antibody-drug conjugate, pharmaceutical composition or pharmaceutical preparation of the present disclosure.
  • biologically active molecule refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction.
  • the biologically active substance or bioactive molecule in the conjugate is an anti-tumor active molecule.
  • radioactive isotopes such as those of At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and Lu; metal complexes such as metal platinum complexes , metal gold complexes, oxaliplatin, etc.; glycopeptide antibiotics, such as bleomycin, pingyangmycin; DNA topoisomerase inhibitors, such as topoisomerase I inhibitors, camptothecin, hydroxyhippin Tricine, 9-aminocamptothecin, DXD, SN-38, irinotecan, topotecan, belotecan, rubitecan, topoisomerase II inhibitors, actinomycin D, doxorubicin , doxorubicin, docarmycin, daunorubicin, mitoxantrone, podophyllotoxin, etoposide, etc.; drugs
  • toxin refers to a substance capable of having deleterious effects on the growth or proliferation of cells.
  • the biologically active molecule is denoted as D, and immunomodulators, especially TLR8 agonists, can also be selected.
  • linker refers to a chemical structural fragment or bond that is connected to a ligand at one end and a drug at the other end, and can also be connected after other linkers. Then connect with the drug.
  • a joint may comprise one or more joint components.
  • exemplary linker building blocks include 4-(5-methanesulfonyl[1,3,4]-oxadiazole)butanoic acid of the present disclosure, and 6-maleimidocaproyl (MC) of the prior art, Maleimidopropionyl (MP), valine-citrulline (Val-Cit or vc), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), and Those derived from coupling with linker reagents: N-succinimidyl 4-(2-pyridylthio)pentanoate (SPP), N-succinimidyl 4-(N-maleimido Methyl)cyclohexane-1 carboxylate (SMCC, also referred to herein as MCC) and N-succinimidyl (4-iodo-acetyl)aminobenzoate (SIA
  • Linkers can include Stretch units, Spacer units, Amino Acid units and Stretcher units. Can be synthesized by methods known in the art, such as described in US2005-0238649A1.
  • the linker can be a "cleavable linker" that facilitates release of the drug in the cell.
  • acid-labile e.g., hydrazone
  • protease-sensitive e.g., peptidase-sensitive
  • photolabile, dimethyl, or disulfide-containing linkers can be used (Chari et al., Cancer Research 52:127-131 (1992); US Patent No. 5,208,020).
  • stretch unit refers to a chemical structural fragment that is covalently linked to the antibody through a carbon atom at one end and to an amino acid unit, disulfide moiety, sulfonamide moiety, or non-peptidic chemical moiety at the other end.
  • spacer unit is a bifunctional compound structural fragment that can be used to couple amino acid units and cytotoxic drugs to form antibody-drug conjugates. This coupling method can selectively link cytotoxic drugs to amino acid units superior.
  • amino acid refers to an organic compound containing an amino group and a carboxyl group in the molecular structure, and both the amino group and the carboxyl group are directly connected to the -CH- structure.
  • the general formula is H 2 NCHRCOOH, R is H, substituted or unsubstituted alkyl, etc. According to the position of the amino group connected to the carbon atom in the carboxylic acid, it can be divided into ⁇ , ⁇ , ⁇ , ⁇ , ⁇ ...-amino acids.
  • amino acids that make up natural proteins have their specific structural characteristics, that is, their amino groups are directly connected to the ⁇ -carbon atom, that is, ⁇ -amino acids, including glycine (Glycine), alanine (Alanine), valine (Valine), Leucine, Isoleucine, Phenylalanine, Tryptophan, Tyrosine, Aspartic acid, Histidine, Asparagine, Glutamic acid, Lysine, Glutamine, Methionine, Arginine , Serine, Threonine, Cysteine, Proline, etc. Unnatural amino acids such as citrulline.
  • the spacer unit in the present disclosure is PAB, which has a structure such as a p-aminobenzyloxycarbonyl fragment, and is connected to D.
  • adapter components of the present disclosure include, but are not limited to:
  • SM 4-(5-methylsulfonyl[1,3,4]-oxadiazole)butanoic acid
  • MC 6-maleimidocaproyl
  • Val-Cit or "vc” valine-citrulline (an exemplary dipeptide in a protease cleavable linker);
  • Citrulline 2-amino-5-ureidopentanoic acid
  • Me-Val-Cit N-methyl-valine-citrulline (wherein the linker peptide bond has been modified to prevent its cleavage by cathepsin B);
  • MC(PEG) 6 -OH maleimidocaproyl-polyethylene glycol (can be attached to antibody cysteine);
  • SPP N-succinimidyl 4-(2-pyridylthio)pentanoate
  • SPDP N-succinimidyl 3-(2-pyridyldithio)propionate
  • SMCC succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate
  • PBS Phosphate Buffered Saline.
  • antibody-drug conjugate means that a ligand is linked to a biologically active drug through a stable linker unit.
  • antibody drug conjugate refers to linking a monoclonal antibody or antibody fragment with a toxic drug with biological activity through a stable linker unit.
  • drug loading can be expressed as the ratio of the amount of drug to the amount of antibody.
  • the range of drug loading can be 1-20, preferably 1-10 cytotoxic drugs (D) linked to each antibody (Ab).
  • the drug loading is expressed as n, which can be exemplarily 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or the mean of any two values in between.
  • the average amount of drug per ADC molecule after conjugation can be identified using routine methods such as UV/Vis spectroscopy, mass spectrometry, ELISA assay, monoclonal antibody size variant assay (CE-SDS) and HPLC characterization.
  • the loading of antibody-drug conjugates can be controlled by the following non-limiting methods, including:
  • antibody refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds.
  • the amino acid composition and sequence of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five classes, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, and their corresponding heavy chains are ⁇ , ⁇ , and ⁇ chains, respectively. , ⁇ chain, and ⁇ chain.
  • IgG can be divided into different subclasses according to the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified as either kappa chains or lambda chains by difference in the constant region.
  • Each of the five Ig classes can have either a kappa chain or a lambda chain.
  • Antibodies of the present disclosure are preferably specific antibodies against cell surface antigens on target cells, non-limiting examples are the following antibodies: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met Antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 Antibody, Anti-CEA Antibody, Anti-A33 Antibody, Anti-Cripto Antibody, Anti-EphA2 Antibody, Anti-G250 Antibody, Anti-MUCl Antibody, Anti-Lewis Y Antibody, Anti-VEGFR Antibody, Anti-GPNMB Antibody, Anti-Integrin Antibody, Anti-PSMA Antibody, Anti-Tenascin- C antibody, anti-SLC44A4 antibody, anti-
  • the antibody is selected from Trastuzumab (Trastuzumab, trade name Herceptin), Pertuzumab (Pertuzumab, also known as 2C4, trade name Perjeta), Nimotuzumab (Nimotuzumab, trade name Mingtai Xinsheng), Embolituzumab (Enoblituzumab), Emibetuzumab (Emibetuzumab), Inotuzumab (Inotuzumab), Vitin-Pinatuzumab (Pinatuzumab) Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96, and Glematumamab.
  • Trastuzumab Trastuzumab, trade name Herceptin
  • Pertuzumab Pertuzumab, also known as 2C4, trade name Perjeta
  • Nimotuzumab Nemotuzum
  • variable region The sequence of about 110 amino acids near the N-terminal of the antibody heavy chain and light chain varies greatly, which is the variable region (Fv region); the rest of the amino acid sequence near the C-terminal is relatively stable, which is the constant region.
  • the variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conserved sequences. Three hypervariable regions determine the specificity of antibodies, also known as complementarity determining regions (CDR).
  • CDR complementarity determining regions
  • Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of 3 CDR regions and 4 FR regions, and the sequence from the amino terminal to the carboxyl terminal is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • Antibodies of the present disclosure include murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, preferably humanized antibodies and fully human antibodies.
  • murine antibody in this disclosure refers to an antibody prepared using a mouse according to the knowledge and skill in the art. In preparation, test subjects are injected with the specified antigen, and hybridomas expressing antibodies having the desired sequence or functional properties are isolated.
  • chimeric antibody is an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can reduce the immune response induced by the murine antibody.
  • To establish a chimeric antibody it is necessary to first establish a hybridoma that secretes a mouse-derived specific monoclonal antibody, then clone the variable region gene from the mouse hybridoma cell, and then clone the constant region gene of the human antibody as required, and then clone the mouse variable region gene It is connected with the human constant region gene to form a chimeric gene and inserted into an expression vector, and finally expresses the chimeric antibody molecule in a eukaryotic system or a prokaryotic system.
  • humanized antibody also known as CDR-grafted antibody (CDR-grafted antibody) refers to the antibody variable region framework grafted with mouse CDR sequences to humans, that is, different types of human germline antibodies Antibodies generated in the framework sequences. It can overcome the heterologous reaction induced by chimeric antibodies due to carrying a large amount of mouse protein components.
  • framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of the human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), as well as in Kabat, E.A. et al.
  • the humanized antibody of the present disclosure also includes the humanized antibody after affinity maturation of CDR by phage display. Further descriptions of methods involving the use of mouse antibodies in humanization include, for example, Queen et al., Proc., Natl. 321, 522 (1986), Riechmann, et al., Nature, 332, 323-327 (1988), Verhoeyen, et al., Science, 239, 1534 (1988)].
  • the development of monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies.
  • the present disclosure is a fully human monoclonal antibody.
  • the relevant technologies for the preparation of fully human antibodies mainly include: human hybridoma technology, EBV transformed B lymphocyte technology, phage display technology (phage display), transgenic mouse antibody preparation technology (transgenic mouse) and single B cell antibody preparation technology, etc.
  • antigen-binding fragment refers to one or more fragments of an antibody that retain the ability to specifically bind an antigen. It has been shown that fragments of full-length antibodies can be utilized to perform the antigen-binding function of the antibody.
  • binding fragments included in "antigen-binding fragments" include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL and CH1 domains; (ii) F(ab') 2 fragments, comprising (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv fragment consisting of VH and VL domains of a single arm of an antibody; (v ) a single domain or dAb fragment (Ward et al., (1989) Nature 341:544-546) consisting of a VH domain; and (vi) isolated complementarity determining regions (CDRs) or (vii) optionally via A combination of two or more isolated CDRs joined by a synthetic linker.
  • CDRs complementarity
  • the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be linked by a synthetic linker using recombinant methods, thus making it possible to produce a single protein in which the VL and VH regions pair to form a monovalent molecule. chain (referred to as single-chain Fv (scFv); see, eg, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879-5883).
  • single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody.
  • Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.
  • Antibodies can be of different isotypes, eg, IgG (eg, IgGl, IgG2, IgG3, or IgG4 subtype), IgAl, IgA2, IgD, IgE, or IgM antibodies.
  • Fab is an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity among fragments obtained by treating an IgG antibody molecule with the protease papain (cleaving the amino acid residue at position 224 of the H chain), in which About half and the entire L chain is held together by disulfide bonds.
  • F(ab')2 is an antibody having a molecular weight of about 100,000 and having antigen-binding activity and comprising two Fab regions connected at the hinge position obtained by digesting the lower portion of the two disulfide bonds in the IgG hinge region with the enzyme pepsin fragment.
  • Fab' is an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity obtained by cleaving the disulfide bond in the hinge region of the above-mentioned F(ab')2.
  • the Fab' fragment can be produced by inserting DNA encoding a Fab' fragment of an antibody into a prokaryote expression vector or a eukaryote expression vector and introducing the vector into a prokaryote or eukaryote to express the Fab'.
  • single-chain antibody single-chain Fv or “scFv” is meant to comprise an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker molecules.
  • Such scFv molecules may have the general structure: NH2 -VL-linker-VH-COOH or NH2 -VH-linker-VL-COOH.
  • Suitable prior art linkers consist of the repeated GGGGS amino acid sequence or variants thereof, for example using 1-4 repeat variants (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448) .
  • linkers useful in the present disclosure are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur.J. Immuno 1.31:94-106, Hu et al. (1996) , Cancer Res. 56:3055-3061, described by Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56 and Roovers et al. (2001 ), Cancer Immunol.
  • CDR refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contribute to antigen binding.
  • One of the most commonly used definitions of the six CDRs is provided by Kabat E.A. et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242).
  • the Kabat definition of CDRs applies only to CDR1, CDR2, and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of the light chain variable domain, and to CDR1, CDR L2, and L3 of the heavy chain variable domain.
  • CDR2 and CDR3 CDR H2, CDR H3 or H2, H3).
  • CDR1, HCDR2, HCDR3 there are three CDRs (HCDR1, HCDR2, HCDR3) in each heavy chain variable region and three CDRs (LCDR1, LCDR2, LCDR3) in each light chain variable region.
  • Amino acid sequence boundaries for CDRs can be determined using any of a variety of well-known schemes, including the "Kabat” numbering convention (see Kabat et al.
  • the CDR amino acid residues in the heavy chain variable domain are numbered 31-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3);
  • the CDR amino acid residues in the chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3).
  • the CDR amino acid numbers in VH are 26-32 (HCDR1), 52-56 (HCDR2) and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50- 52 (LCDR2) and 91-96 (LCDR3).
  • the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) in human VH and amino acid residues 24- 34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3).
  • the numbering of CDR amino acid residues in VH is approximately 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3)
  • the numbering of CDR amino acid residues in VL is approximately 27-32 (CDR1 ), 50-52 (CDR2) and 89-97 (CDR3).
  • the CDR regions of antibodies can be determined using the program IMGT/DomainGap Align.
  • antibody framework refers to the portion of a variable domain VL or VH that serves as a scaffold for the antigen-binding loops (CDRs) of the variable domain. Essentially, it is a variable domain without CDRs.
  • epitope refers to the site on an antigen to which an immunoglobulin or antibody specifically binds.
  • An epitope typically comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous or non-contiguous amino acids in a unique spatial conformation (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Volume 66, G.E. Morris, Ed. (1996)).
  • antibodies bind with an affinity (KD) of less than about 10 "7M , eg, about less than 10 "8M , 10 "9M or 10 " 10M or less.
  • KD affinity
  • nucleic acid molecule refers to DNA molecules and RNA molecules. Nucleic acid molecules can be single-stranded or double-stranded, but are preferably double-stranded DNA. A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if the promoter or enhancer affects the transcription of the coding sequence.
  • Antigen-binding fragments can also be prepared by conventional methods.
  • the antibody or antigen-binding fragment of the invention uses genetic engineering methods to add one or more human FR regions to the non-human CDR region.
  • the human FR germline sequence can be obtained from the website http://imgt.cines.fr of ImMunoGeneTics (IMGT) by comparing the IMGT human antibody variable region germline gene database and MOE software, or from Immunoglobulin Journal, 2001ISBN012441351 get.
  • host cell refers to a cell into which an expression vector has been introduced.
  • Host cells can include bacterial, microbial, plant or animal cells.
  • Bacteria that are readily transformed include members of the enterobacteriaceae such as strains of Escherichia coli or Salmonella; the Bacillaceae such as Bacillus subtilis; Pneumococcus; Streptococcus and Haemophilus influenzae.
  • Suitable microorganisms include Saccharomyces cerevisiae and Pichia pastoris.
  • Suitable animal host cell lines include CHO (Chinese Hamster Ovary cell line) and NSO cells.
  • Antibodies or antigen-binding fragments engineered in the present disclosure can be prepared and purified using conventional methods.
  • cDNA sequences encoding heavy and light chains can be cloned and recombined into GS expression vectors.
  • the recombinant immunoglobulin expression vector can stably transfect CHO cells.
  • mammalian expression systems lead to glycosylation of antibodies, especially at the highly conserved N-terminal site of the Fc region. Positive clones are expanded in serum-free medium in bioreactors for antibody production.
  • the culture fluid from which the antibody has been secreted can be purified by conventional techniques. For example, purify with an A or G Sepharose FF column with adjusted buffer.
  • Antibodies can be concentrated by filtration using conventional methods. Soluble mixtures and aggregates can also be removed by conventional methods such as molecular sieves and ion exchange. The obtained product needs to be immediately frozen, such as -70°C, or freeze-dried.
  • 5-6 membered heteroarylene refers to an aromatic 5-membered or 6-membered monocyclic divalent group having at least one heteroatom (O, N or S).
  • Non-limiting examples of the “5-6 membered heteroarylene” are preferred
  • L 1' is L 11 -L 12 -L 13 -L 14 -L 15 -, if L 13 is a direct bond, then L 1' is L 11 -L 12 -L 14 -L 15 -.
  • the compound shown in formula I is Ab-(L 1 -L 2 -L 3 -L 4 -D) n , if L 4 is a direct bond, the compound shown in formula I is Ab-(L 1 - L 2 -L 3 -D) n .
  • Other similar definitions can be understood with reference to the foregoing.
  • pharmaceutically acceptable salt refers to a relatively non-toxic acid addition salt or base addition salt of the compound or conjugate of the present invention.
  • the acid addition salt is a salt formed between the compound or conjugate of the present invention and a suitable inorganic acid or organic acid, and these salts can be prepared by making the compound or conjugate of the present invention and a suitable organic acid or inorganic acid prepared by reacting in a solvent.
  • Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate Salt, Luurosilicate, Borate, Benzoate, Lactate, Nitrate, Phosphate, Phosphate, Carbonate, Bicarbonate, Toluate, Citrate, Maleic Acid Salt, fumarate, succinate, malate, ascorbate, tannate, pamoate, alginate, naphthalenesulfonate, tartrate, benzoate, methanesulfonate, p-toluene Sulfonate, Gluconate, Lactobionate and Lauryl Sulfonate etc.
  • the base addition salt is a salt formed between the compound or conjugate of the present invention and a suitable inorganic base or organic base, and these salts can be obtained by making the compound or conjugate of the present invention and a suitable inorganic base or organic base prepared by reacting in a solvent.
  • Representative base addition salts include, for example, salts with alkali metal, alkaline earth metal, quaternary ammonium cations, such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium Salts, etc.; amine salts, including salts formed with ammonia (NH 3 ), primary amines, secondary amines or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.
  • quaternary ammonium cations such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium Salts, etc.
  • amine salts including salts formed with ammonia (NH 3 ), primary amines, secondary amines or tertiary amines, such as methylamine
  • the compounds or conjugates of the present invention can exist in specific geometric or stereoisomer forms.
  • the chiral center can exist in the drug, in the linker structure, or in the Antibodies and their derivatives.
  • all such compounds including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are included in the present invention within the range.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound or conjugate of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • solvates such as hydrates of the compounds, conjugates, pharmaceutically acceptable salts, and stereoisomers of the present invention are also within the scope of the present invention.
  • suitable solvates specifically, solvates formed between compounds or conjugates of the present invention and acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether, etc. . Hydrates or ethanolates are also mentioned.
  • treating means that the individual's symptoms are partially or completely relieved, or remain unchanged after treatment.
  • treatment includes prophylaxis, treatment and/or cure.
  • prevention means preventing an underlying disease and/or preventing worsening of symptoms or development of a disease. Treatment or prevention also includes any pharmaceutical use of the provided ADCs and the pharmaceutical compositions, pharmaceutical formulations provided herein.
  • the term “effective dose” refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
  • the term “effective amount” refers to the amount of a compound which, when administered, inhibits the growth, proliferation or migration of cancer cells to some extent.
  • therapeutic effect means the effect resulting from the treatment of an individual, which alters, usually ameliorates or improves the symptoms of a disease or condition, or cures the disease or condition.
  • “individual” includes human or non-human animal.
  • exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).
  • the antibody-drug conjugate of the present disclosure has rapid and efficient tumor cell killing activity, and also has good biocompatibility, low immunogenicity, biosafety and stability.
  • a new type of joint structure (such as SM) is designed
  • the present disclosure analyzes the structural characteristics of the toxin molecule eribulin.
  • the ADC molecule in the representative example of the present disclosure saves the commonly used self-breaking structure such as PAB, and directly combines the GGFG unit with Eribulin amino condensation improves the hydrophilicity of ADC, simplifies the complexity of chemical synthesis, reduces the cost of synthesis, and shows excellent efficacy.
  • the ADC prepared by the linker with the novel structure of the present disclosure has better anti-tumor efficacy.
  • Fig. 1 is the SEC-HPLC detection pattern of ADC-1 of the embodiment of the present invention.
  • Fig. 2 is the SEC-HPLC detection pattern of ADC-2 of the embodiment of the present invention.
  • Fig. 3 is the SEC-HPLC detection pattern of ADC-3 of the embodiment of the present invention.
  • Fig. 4 is the SEC-HPLC detection spectrum of the control conjugate 2 (ie ADC-6) of the present invention.
  • Fig. 5 is a graph showing the results of detecting the hydrophilicity and hydrophobicity of each ADC of the present invention by using a protein hydrophobic interaction chromatographic column (HIC).
  • HIC protein hydrophobic interaction chromatographic column
  • Fig. 6 is a graph showing the results of affinity detection between ADCs and TROP proteins of the present invention.
  • Fig. 7 is a statistical graph of the anti-tumor activity of each ADC of the present invention.
  • Fig. 8 is a graph showing body weight changes of experimental animals after treatment with various ADCs of the present invention.
  • Fig. 9 is a photograph taken of tumors taken from experimental animals after each ADC treatment of the present invention.
  • hRS7 antibody was produced in CHO cells.
  • the expression vectors containing the hRS7 antibody gene were constructed by conventional molecular biology methods.
  • the amino acid sequences of the hRS7 antibody light chain and heavy chain are shown in SEQ ID NO: 1 and SEQ ID NO: 2 respectively, and the corresponding nucleotide sequences Shown in SEQ ID NO:3 and SEQ ID NO:4 respectively.
  • Insert the above two sequences into the same expression vector extract a large number of transfection plasmids, and transfect them into CHO-K1 cells (ATCC CCL-61).
  • the specific transfection and antibody preparation processes are as follows:
  • Cell culture CHO-K1 cells were grown in suspension in ActiPro (GE HyClone) medium, and cultured at 37°C, 7% CO 2 , 140 rpm, and 90% relative humidity;
  • the highly expressed cell fluid cultured in shake flasks was collected and purified by protein A affinity purification (GE, Mab Select SuRe) and ion exchange purification (GE, Capto S).
  • SDS-PAGE and SEC-HPLC were used to analyze the molecular weight and purity of the purified antibody.
  • the results of SDS-PAGE showed that the molecular weight of the prepared hRS7 was as expected, and the purity of the antibody measured by SEC-HPLC was 99.1%.
  • Embodiment 2 preparation SM
  • LCMS: [M+1]+ 259.2.
  • Embodiment 3 Preparation of conjugate ADC-1
  • Example 1 The antibody prepared in Example 1 was placed in a 10 mg/mL pH 7.4 PBS solution, using a 25°C water bath, while stirring and mixing, an equal volume of TCEP solution 2.4 times the amount of the substance was added, and the solution was placed in a 25°C water bath for 1.5 Hour. Use a 25°C water bath for the sample, then add 8 times the amount of compound A in DMSO solution (DMSO final concentration 10%) to the antibody solution while stirring and mixing, shake the reaction at 25°C for 90 minutes, and finally stir and mix the sample At the same time, 8 times the amount of cysteine was added, and placed in a 25° C. water bath for 10 minutes to react to obtain the coupling product ADC-1.
  • DMSO solution DMSO final concentration 10%
  • Embodiment 4 Preparation of conjugate ADC-2
  • Example 1 The antibody prepared in Example 1 was placed in a 10 mg/mL pH 7.4 PBS solution, using a 25°C water bath, while stirring and mixing, an equal volume of TCEP solution 2.4 times the amount of the substance was added, and the solution was placed in a 25°C water bath for 1.5 Hour.
  • Use a 25°C water bath for the sample then add 8 times the amount of compound B in DMSO solution (DMSO final concentration 10%) to the antibody solution while stirring and mixing, shake the reaction at 25°C for 90 minutes, and finally stir and mix the sample
  • 8 times the amount of cysteine was added, and placed in a water bath at 25° C. for 10 minutes to react to obtain the coupling product ADC-2.
  • Embodiment 5 Preparation of conjugate ADC-3
  • Example 1 The antibody prepared in Example 1 was placed in a 10 mg/mL pH 7.4 PBS solution, using a 25°C water bath, while stirring and mixing, an equal volume of TCEP solution 2.4 times the amount of the substance was added, and the solution was placed in a 25°C water bath for 1.5 Hour. Use a 25°C water bath for the sample, then add 8 times the amount of compound C in DMSO solution (DMSO final concentration 10%) to the antibody solution while stirring and mixing, shake the reaction at 25°C for 90 minutes, and finally stir and mix the sample At the same time, 8 times the amount of cysteine was added, and placed in a water bath at 25° C. for 10 minutes to react to obtain the coupling product ADC-3.
  • DMSO solution DMSO final concentration 10%
  • Embodiment 6 prepares conjugate ADC-4
  • the coupling with the antibody, the detection of the coupling product, the purification and the determination of the DAR value are the same as in Example 5, and the obtained ADC-4 has a DAR value of 4.7.
  • Example 1 The antibody prepared in Example 1 was placed in an ice-water bath in a 10 mg/mL pH 7.4 PBS solution.
  • an equal volume of TCEP solution 3.5 times the amount of the substance was added while stirring and mixing, and the solution was placed at 25 °C water bath for 1 hour.
  • the temperature drops to 25°C then add 7 times the amount of compound E in 40% DMSO solution to the antibody solution while stirring and mixing, and shake the reaction at 25°C for 90 minutes.
  • cysteine was added in an amount 8 times that of the substance, and placed in a water bath at 25° C. for 10 min to react to obtain the coupling product ADC-5.
  • the detection, purification and DAR value determination methods of the coupling product are the same as in Example 5, and the obtained ADC-5 has a DAR value of 3.8.
  • Example 1 The antibody prepared in Example 1 was placed in a 5 mg/mL pH 7.4 PBS solution, while stirring and mixing, TCEP solution of 7 times the amount of the substance was added, and the solution was placed in a 37°C water bath for 1.5 hours to react. Use a 25°C water bath for the reaction solution. When the temperature drops to 25°C, then add 16 times the amount of compound F in 40% DMSO solution to the antibody solution while stirring and mixing, and shake the reaction at 25°C for 90 minutes. Finally, while the reaction solution was stirred and mixed, cysteine was added in an amount 16 times that of the substance, and placed in a water bath at 25° C. for 10 minutes to react to obtain the coupling product ADC-6.
  • DTT dithiothreitol
  • Embodiment 7 detects the hydrophilicity of each ADC
  • Coating Trop2 protein Dilute Trop2 protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) with coating solution (0.15M Na 2 CO 3 and 0.35M NaHCO 3 ) to 0.5 ⁇ g/mL, mix well and add to the microtiter plate medium, 100 ⁇ L/well, cover the plate with sealing film, and put it in a refrigerator at 4°C overnight.
  • Washing plate Take out the microplate plate Washing plate: Wash 3 times with 1*PBST.
  • Blocking Take the blocking solution (1% BSA), add 200 ⁇ L/well of the blocking solution, cover the plate with a sealing film, mix at 250 rpm and incubate at 25° C. for 1 h.
  • Plate washing wash 3 times with 1*PBST.
  • Antibody incubation After diluting the ADC prepared in Example 3 and Comparative Example 2 with 1% BSA, and the TROP-2 antibody prepared in Example 1 to 2000 ng/mL, three-fold serial dilutions were made to 12 concentrations, and 100 ⁇ L/well was added to the enzyme Mark the plate, cover the plate with sealing film, mix at 250rpm and incubate at 25°C for 1h.
  • Plate washing Wash the microplate plate 3 times with 1*PBST.
  • Plate washing Wash the microplate plate 3 times with 1*PBST.
  • Color development add TMB (Huzhou Yingchuang) color development substrate: add 100ul per well to the microtiter plate, mix at 250rpm and place at 25°C for 15 minutes.
  • Stop reading add stop solution: add 1M H 2 SO 4 100ul to each well, and read at OD450nm on a microplate reader.
  • BxPC-3 cells human orthotopic pancreatic cancer cells, ATCC CRL-1687
  • the culture conditions were 10% heat-inactivated fetal calf serum and agar in 1640 medium, at 37°C, containing 5% CO 2 in an air incubator. Digested with 0.25% trypsin twice a week for passage. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.
  • the P10 generation tumor tissue was used to evaluate the antitumor activity of the test product.
  • the P9 generation tumor grows to 500-800mm 3
  • the tumor-bearing mice are anesthetized with CO 2 and sacrificed, the tumor mass is removed, the surrounding necrotic tissue is removed, and the tumor mass in good condition is cut into small tumors of 20-30mm 3
  • Blocks were inoculated to the right shoulder blade of formal experimental mice, and a total of 65 mice were inoculated.
  • the mice with too small or too large tumor volume were excluded, and the remaining 25 mice were randomly grouped according to tumor volume and started to be administered. See the table below for the dosing regimen.
  • tumor volume (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ) (where a represents the long diameter and b represents the short diameter).
  • the relative tumor proliferation rate, T/C% is the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group at a certain time point.
  • tumors were taken from all mice, weighed and photographed.
  • Figures 7-9 The experimental results are shown in Figures 7-9, Figure 7 is the statistical curve of anti-tumor activity, Figure 8 is the curve of body weight change, and Figure 9 is the photograph taken of the tumor.
  • ADC-1 has the best anti-tumor effect, and it can completely regress the tumor with only one administration, and it is safe.
  • the antitumor effects of ADC-2 and ADC-5 were comparable.

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Abstract

Conjugué anticorps-médicament ayant une réaction réversible réduite, procédé de préparation s'y rapportant et application associée. L'invention concerne spécifiquement un conjugué anticorps-médicament représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci, un stéréoisomère de celui-ci ou un solvate de celui-ci. Le conjugué anticorps-médicament a une activité de destruction cellulaire tumorale rapide et efficace et a également une bonne biocompatibilité, une faible immunogénicité, une sécurité et une stabilité biologiques.
PCT/CN2022/138621 2021-12-27 2022-12-13 Conjugué anticorps-médicament ayant une réaction réversible réduite, procédé de préparation s'y rapportant et application associée WO2023124963A1 (fr)

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Citations (5)

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US20170035892A1 (en) * 2014-02-03 2017-02-09 Philochem Ag Small Molecule Drug Conjugates
WO2017151979A1 (fr) * 2016-03-02 2017-09-08 Eisai Inc. Conjugués anticorps-médicament à base d'éribuline et leurs procédés d'utilisation
CN109232464A (zh) * 2017-07-10 2019-01-18 上海新理念生物医药科技有限公司 噁二唑型连接子及其应用
WO2021132166A1 (fr) * 2019-12-23 2021-07-01 エーザイ・アール・アンド・ディー・マネジメント株式会社 Procédé de production d'un conjugué anticorps-médicament à base d'éribuline
WO2021148003A1 (fr) * 2020-01-22 2021-07-29 上海森辉医药有限公司 Conjugué de médicament à base de dérivé d'éribuline, son procédé de préparation et son application en médecine

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US20170035892A1 (en) * 2014-02-03 2017-02-09 Philochem Ag Small Molecule Drug Conjugates
WO2017151979A1 (fr) * 2016-03-02 2017-09-08 Eisai Inc. Conjugués anticorps-médicament à base d'éribuline et leurs procédés d'utilisation
CN109232464A (zh) * 2017-07-10 2019-01-18 上海新理念生物医药科技有限公司 噁二唑型连接子及其应用
WO2021132166A1 (fr) * 2019-12-23 2021-07-01 エーザイ・アール・アンド・ディー・マネジメント株式会社 Procédé de production d'un conjugué anticorps-médicament à base d'éribuline
WO2021148003A1 (fr) * 2020-01-22 2021-07-29 上海森辉医药有限公司 Conjugué de médicament à base de dérivé d'éribuline, son procédé de préparation et son application en médecine

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CHENG XIN, LI JING, TANAKA KEIGO, MAJUMDER UTPAL, MILINICHIK ANDREW Z., VERDI ARIELLE C., MADDAGE CHRISTOPHER J., RYBINSKI KATHERI: "MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRa Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity", MOLECULAR CANCER THERAPEUTICS, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 17, no. 12, 1 December 2018 (2018-12-01), US , pages 2665 - 2675, XP055831595, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-17-1215 *

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