WO2018103739A1 - Conjugué anticorps-médicament, procédé de préparation, intermédiaire, composition pharmaceutique et utilisation - Google Patents

Conjugué anticorps-médicament, procédé de préparation, intermédiaire, composition pharmaceutique et utilisation Download PDF

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WO2018103739A1
WO2018103739A1 PCT/CN2017/115281 CN2017115281W WO2018103739A1 WO 2018103739 A1 WO2018103739 A1 WO 2018103739A1 CN 2017115281 W CN2017115281 W CN 2017115281W WO 2018103739 A1 WO2018103739 A1 WO 2018103739A1
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compound
group
cancer
alkyl
antibody
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Chinese (zh)
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向少云
马兴泉
杨鸿裕
谢铁刚
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凯惠科技发展(上海)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes

Definitions

  • the present invention relates to an antibody drug conjugate, a process for the preparation thereof, an intermediate, a pharmaceutical composition and use thereof.
  • a typical antibody drug conjugate comprises monoclonal antibodies (mAbs) that bind to cancer cell surface specific antigens and bind these specific antibodies to a highly toxic drug via a cleavable linker.
  • the mechanism of action of ADC is to recognize and bind to specific antigens by antibodies, trigger a series of reactions, and then enter the cytoplasm through endocytosis, and lysosomal enzymes release strong toxic drugs to kill cancer cells.
  • mAbs monoclonal antibodies
  • mAbs monoclonal antibodies
  • Monoclonal antibodies in ADCs include proteins on the surface of immune system B cells and T cells, such as CD20, CD22, and human epidermal growth factor receptor 2 (Her2) and prostate specific membrane antigen (PSMA).
  • proteins on the surface of immune system B cells and T cells such as CD20, CD22, and human epidermal growth factor receptor 2 (Her2) and prostate specific membrane antigen (PSMA).
  • anthracyclines are antibiotic compounds that exhibit cytotoxic activity, including doxorubicin, epirubicin, idarubicin, and daunorubicin. Studies have shown that anthracycline antibiotics can kill cells through a variety of different mechanisms, including: 1) embedding drug molecules in the DNA of cells to inhibit DNA-dependent nucleic acid synthesis; 2) by free radical drug production and reaction with cellular macromolecules Causes damage to cells; 3) Interaction of drug molecules with cell membranes. Due to the cytotoxic potential of anthracyclines, they have been used to treat a variety of cancers including leukemia, breast cancer, lung cancer, ovarian cancer and the like.
  • PNU-159682 has stronger in vitro and in vivo tumor model cytotoxicity than nemoxil (Beulz-Riche, et. al. Fundamental & Clinical Pharmacology, 2001, 15, 373,; Quintieri, L., Geroni, C., et. al .Clinical. Cancer. Research, 2005, 11, 1608; EP 0889898; WO 2004/082689; WO 2004/082579).
  • the use of antibody drug conjugates can target the toxin drugs capable of killing or always tumor cells to the tumor, and the general formula for seeking the maximum efficacy of the drug can significantly improve the selectivity and reduce the side effects of the antitumor drugs (Xie). Et al., Expert. Opin. Biol. Ther., 2006, 6, 281.; Kovtun et al., Cancer. Res., 2006, 66, 3214.; Law et al, Cancer. Res., 2006, 66, 2328. Wu et al, Nature. Biotech. 2005, 23, 1137.; Lamber J. et al. Current. Opin. in Pharmacol. 2005, 5, 543.; Hamann P. et al., Expert. Opin. Ther. Patents. 2005, 15, 1087.; Payne, G., Cancer. Cell. 2003, 3, 207.; Trail et al, Cancer. Immunol. Immunother., 2003, 52, 328.).
  • antibody drug conjugates In a typical antibody drug conjugate, the choice of antibody and drug will depend on the particular disease, which has a significant impact on the safety and efficacy of the antibody drug conjugate. Factors that determine the efficacy of antibody drug conjugates include the stability of the linker unit and its cleavage sensitivity, cell surface internalization, transport, and release of cytotoxin.
  • T-DM1 which is much less cytotoxic than some anthracycline antibiotics, is prone to prematurely degrade and release toxins before endocytosis of antigen-binding protein (Abu), causing side effects, and the drug/antibody obtained by coupling it with antibodies
  • Abu antigen-binding protein
  • the ratio is low and the distribution changes are relatively large, and it is difficult to accurately control the efficacy and safety (such as patent application WO2012/061590 A1 or WO201139721).
  • the technical problem to be solved by the present invention is to overcome the prior art antibody drug conjugate which lacks cytotoxin release efficiency, high cytotoxicity and good anticancer effect, and provides an antibody drug conjugate and preparation method thereof. , intermediates, pharmaceutical compositions and applications.
  • the antibody drug conjugate of the invention has high cytotoxicity, good anticancer effect and good market application prospect.
  • the present invention provides an antibody drug conjugate of the formula IB, which is a tautomer, an optical isomer, a hydrate, a solvate, a polymorph, an isotope compound, and a pharmaceutically acceptable thereof. Salt or its prodrug,
  • the mAb is a monoclonal antibody fragment
  • the monoclonal antibody includes, but is not limited to, Herceptin, an anti-TPBG (embryonic trophoblastic glycoprotein) antibody, an anti-CD70 antibody or an anti-EGFRVIII (epidermal growth factor receptor) antibody
  • the monoclonal antibody may be a monoclonal antibody conventional in the art as long as it can form an antibody drug conjugate with a fragment other than the mAb in the antibody drug conjugate of the formula IB.
  • 0 ⁇ k ⁇ 8 (preferably, 0 ⁇ k ⁇ 6, such as 0.3, 0.73, 3.21, 3.76, 2.65, 3.96, 3.31, 2.98, 1.80, 2.23, 2.57, 1.89, 1.63, 2.63, 3.05, 1.53, 1.68, 3.10, 1.47, 3.20, 1.56, 1, 2, 3, 4, 5 or 6);
  • R 1 is hydrogen, hydroxy, C 1-6 alkoxy (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy), C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), -NR a R b or -C(O)NR c R d ;
  • R a , R b , R c and R d are each independently hydrogen, C 1-6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) Or a C 6-10 aryl group (eg phenyl);
  • R 2 and R 3 are each independently C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl), C 1-6 alkoxy a group (eg methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy) or a C 1-6 alkylthio (eg methylthio, Ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio);
  • C 1-6 alkyl e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutylthio or tert-butylthio
  • C 1-6 alkyl e.g
  • Y is (preferably R 4a and R 4b are each independently hydrogen, C 1-4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C 3 ⁇ 6 cycloalkyl substituted C 1-4 alkyl (the C 1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • the C 3-6 cycloalkyl group such as a cyclopropyl group;
  • the C 3-6 cycloalkyl substituted C 1-4 alkyl group is preferably a cyclopropylmethyl group, a C 3 -6 cycloalkyl group (for example) a cyclopropyl), C 2-8 heteroalkyl group (the hetero atom in the C 2-8 heteroalkyl group may be one
  • Z is Or a 4-6 membered heteroarylene group
  • the hetero atom in the 4-6 membered heteroarylene group is preferably one or more of N, O and S; the number of hetero atoms is preferably 1, 2 or 3; the 4-6 membered heteroarylene group may be a 4 member, 5 or 6 membered heteroarylene; the 5-membered heteroarylene group is preferably R 5a and R 5b are each independently hydrogen or C 1-4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl);
  • R 6 is hydrogen, C 1-4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C 2-8 heteroalkyl (described
  • the hetero atom in the C 2-8 heteroalkyl group may be one or more of O, S and N, and the number of hetero atoms may be 1, 2, 3 or 4; preferably, the C 2 is -8heteroalkyl is CH 3 OCH 2 -), or -(OCH 2 CH 2 ) j2 OH; j2 is 1, 2, 3, 4, 5, 6, 7, or 8;
  • p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and when Z is When p is not 0;
  • n 0 or 1
  • R 7a and R 7b are each independently hydrogen, C 1-4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl), C 3-6 a cycloalkyl-substituted C 1-4 alkyl group (the C 1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl; a C 3-6 cycloalkyl group such as a cyclopropyl group; the C 3-6 cycloalkyl substituted C 1-4 alkyl group is preferably a cyclopropylmethyl group), a C 3 -6 cycloalkyl group (for example, a cyclopropyl group) a C 2-8 heteroalkyl group (the hetero atom in the C 2-8 heteroalkyl group may be one or
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; when there are multiple Es (ie, when n is greater than or equal to 2), E may be the same or different ( For example, it can be ),
  • u is 0 or 1
  • R 8 is hydrogen, C 1-4 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), C 3-6 cycloalkyl substituted C a 1-4 alkyl group (the C 1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl; the C 3-6 ring
  • the alkyl group is, for example, a cyclopropyl group;
  • the C 3-6 cycloalkyl-substituted C 1-4 alkyl group is preferably a cyclopropylmethyl group, a C 3-6 cycloalkyl group (e.g., a cyclopropyl group), C 2- a heteroalkyl group (the hetero atom in the C 2-8 heteroalkyl group may be one or more
  • q is 0, 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10; when a plurality of -C(R 8 )- are contained (that is, when q is greater than or equal to 2), -C(R 8 ) - can be the same or different ( For example, it can be );
  • Y is an integer from 0 to 24 (for example, 0, 1, 2, 3, 4, 5 or 6);
  • s is 0 or 1;
  • Q is t 1 , t 3 and t 4 are each independently 0, 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9, or 10.
  • k represents a molar ratio of a drug molecule to a mAb (also referred to as DAR, that is, a drug antibody coupling ratio), and is preferably understood to be: an antibody-conjugated drug obtained by coupling a single monoclonal antibody molecule to a drug.
  • the average of the molar ratio of the drug molecule to the monoclonal antibody molecule can be generally hydrophobic-interaction Chromatography (HIC), polyacrylamide-SDS gel electrophoresis (SDS-PAGE, electrophoresis), liquid chromatography mass spectrometry (liquid) Chromatograph-mass spectrometer, LC-MS) was measured.
  • k can be 0.43, 0.49, 2.56, 5.64, 2.26, 2.17 or 2.83.
  • E is
  • E e1, e2, e3, e4, e5, and e6 are each independently 0, 1, 2, 3, 4, 5, 6, 7 , or 8;
  • R 7a , R 7b , R 7c , R 7d , R 7e And R 7f and R 7h are each independently hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 2-8 heteroalkyl , -(OCH 2 CH 2 ) j3 OH or J3 is 1, 2, 3, 4, 5, 6, 7, or 8;
  • r1, r2, r3 and r4 are independently 0, 1 , 2, 3, 4 , 5 , 6, 7, 8 , 9 or 10;
  • R 6e is hydrogen, C 1-4 alkyl, C 2-8 Heteroalkyl or -(OCH 2 CH 2 ) j2a OH;
  • j2a is 1, 2, 3, 4, 5, 6, 7, or 8;
  • R 8e is hydrogen, C 1-4 alkyl, C 3-6 naphthenic a substituted C 1-4 alkyl group, a C 3-6 cycloalkyl group, a C 2-8 heteroalkyl group or a -(OCH 2 CH 2 ) j4a OH;
  • j4a is 1, 2, 3, 4, 5, 6, 7 or 8;
  • R e is a glycosyl group (eg, glucosyl) Or maltosyl), Fmoc Or -(OCH 2 CH 2 ) en OH, en is 0, 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10,
  • the -NR a R b is a methylamino group or a dimethylamino group.
  • m is preferably 1.
  • Z is preferably p is preferably 1; m is preferably 0; n is preferably 1; E is preferably u is preferably 0 or 1; q is preferably 2; y is preferably 2; s is preferably 0 or 1 (when u is 1, S is preferably 0); G is preferred Q is preferably (and when G is When Q is preferred ).
  • Z is preferably
  • R 4a , R 4b , R 5a and R 5b have the same meanings as defined above.
  • R 4a , R 4b , R 5a , R 5b and R 6 have the same meanings as defined above.
  • Drug molecule fragment of the antibody drug conjugate as shown in Formula IB of the present invention may refer to such drug molecules in the field (ie, anthracyclines such as doxorubicin, epirubicin, idarubicin, idarubicin, naimo) Conventional selection of spirulina, PNU-159682, etc., for example Optimal Most preferred
  • the antibody drug conjugate as shown in Formula IB is preferably a compound of Formula IB-1:
  • R 1 , R 2 , R 3 , X, Y, Z, R 6 , p, m, E, n, u, R 8 , q, y, G, s and Q are as defined above.
  • the antibody drug conjugate as shown in Formula IB is selected from any one of the following compounds, wherein the mAb in the following compounds is Herceptin, an anti-TPBG antibody, an anti-CD70 antibody or an anti-EGFRVIII antibody:
  • the antibody drug conjugate of formula IB is the following compound:
  • the monoclonal antibody is reacted with a thiol group or an amino group in an amino acid residue to Connected
  • a thiol group or an amino group in an amino acid residue to Connected
  • Q is Wherein the S atom is derived from a thiol group in the monoclonal antibody
  • Q is Wherein NH is derived from the amino group of the monoclonal antibody.
  • the present invention also provides a method for preparing the antibody drug conjugate according to Formula IB, which comprises the steps of: IA compound and single in an organic solvent at a pH of 6-8.
  • the cloning antibody is subjected to a coupling reaction as shown below to obtain the antibody drug conjugate as shown in Formula IB;
  • k, R 1 , R 2 , R 3 , X, Y, Z, R 6 , p, m, E, n, u, R 8 , q, y, G, s, Q and mAb are as defined above ;
  • Q 1 is The definitions of t 1 , t 3 and t 4 are as described above.
  • the present invention particularly preferably as follows:
  • the organic solvent is preferably one or more of an amide solvent, a sulfoxide solvent, and an ether solvent.
  • the amide solvent is preferably N,N dimethylformamide (DMF) and/or dimethylacetamide (DMA); and the sulfoxide solvent is preferably dimethyl sulfoxide (DMSO).
  • the ether solvent is preferably tetrahydrofuran.
  • the mass to volume ratio of the IA compound to the organic solvent is preferably from 0.1 mg/mL to 100 mg/mL.
  • the molar ratio of the IA compound to the monoclonal antibody is preferably from 1 to 10 (e.g., 6), preferably from 1 to 5.
  • the pH is preferably 7.5.
  • the pH of 6-8 can be achieved by adding a buffer solution to the reaction solution; the buffer solution is generally a low salt buffer, preferably a phosphate buffer solution (for example, potassium phosphate and potassium dihydrogen phosphate). Buffer solution) or borate buffer solution (for example, a buffer solution of boric acid and sodium borate).
  • the temperature of the coupling reaction is preferably 4 ° C to 37 ° C, more preferably 10 to 35 ° C.
  • the monoclonal antibody is preferably a monoclonal antibody after dialysis.
  • the method of dialysis can be a conventional method of dialysis of monoclonal antibodies in the art.
  • the coupling reaction is preferably carried out under gas protection; when the coupling reaction is carried out under gas protection, the gas is preferably nitrogen.
  • the method comprises the steps of: dialysis of the monoclonal antibody and the IA compound in a buffer solution having a pH of 6-8; The organic solvent is mixed and the coupling reaction is carried out.
  • the mixing order of "mixing the dialyzed monoclonal antibody with the IA compound and the organic solvent" is not particularly limited, and generally the IA compound and the organic solvent are added to the The dialysis monoclonal antibody can be used.
  • the progress of the coupling reaction can be monitored by a conventional test method (such as TLC, HPLC or NMR) in the art, generally when the IA compound disappears. The end of the reaction.
  • a conventional test method such as TLC, HPLC or NMR
  • the IA compound can be prepared by a person skilled in the art according to the disclosure of the specific embodiments of the present invention, combined with the conventional experimental techniques in the art.
  • the invention also provides an IA compound,
  • R 1 , R 2 , R 3 , X, Y, Z, R 6 , p, m, E, n, u, R 8 , q, y, G, s and Q 1 have the same meanings as defined above.
  • the IA compound is preferably a compound represented by IA-1:
  • R 1 , R 2 , R 3 , X, Y, Z, R 6 , p, m, E, n, u, R 8 , q, y, G, s and Q1 are as defined above.
  • the IA compound is selected from any of the following compounds:
  • the IA compound is the following compound:
  • the invention also provides an IC-1, IC-2 or IC-3 compound:
  • R 1 , R 2 , R 3 , X, Y, Z, R 6 , p, m, E, n, u, R 8 , q and y are as defined above, and R 9 is
  • Drug molecule fragments in the IC-1, IC-2 and IC-3 compounds The definition is the same as above.
  • the IC-1 compound is preferably an IC-1-1 compound:
  • the IC-1 compound is more preferably any of the following compounds:
  • the IC-1 compound is preferably any of the following compounds:
  • the IC-2 compound is preferably an IC-2-1 compound:
  • the IC-3 compound is preferably an IC-3-1 compound:
  • the IC-3 compound is more preferably any of the following compounds:
  • IC-1 compound, the IC-2 compound and the IC-3 compound can be prepared by those skilled in the art according to the disclosure of the specific embodiments of the present invention in combination with conventional experimental techniques in the art.
  • the present invention also provides the antibody drug conjugate, the tautomer, the optical isomer, the hydrate, the solvate, the polymorph, the isotope compound, and the pharmaceutically acceptable compound thereof, as shown in Formula IB.
  • the present invention also provides the IA compound, its tautomer, optical isomer, hydrate, solvate, polymorph, pharmaceutically acceptable salt thereof or prodrug thereof for preparation for treatment And/or the use of drugs for the prevention of cancer.
  • the present invention also provides the IC-1, IC-2 or IC-3 compound, tautomer, optical isomer, hydrate, solvate, polymorph, isotopic compound thereof, and pharmaceutically thereof thereof.
  • the cancer of the present invention may be a cancer conventional in the art, including but not limited to breast cancer, lymphoma, lung cancer, liver cancer, colon cancer, head and neck cancer, bladder cancer, kidney cancer, esophageal cancer, gallbladder cancer, ovarian cancer, Pancreatic cancer, stomach cancer, Cervical cancer, thyroid cancer, prostate cancer, skin cancer including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma , non-Hodgkin's lymphoma, hairy cell lymphoma, Burkitt's lymphoma, acute and chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, nerve Head cell tumor, glioma, schwannomas, melanoma
  • the tumor cells of the cancer include, but are not limited to, Her2 positive human BT474 breast tumor cells, Her2 low expressed human MCF-7 breast tumor cells, or human breast tumor MCF7-Her2 stable cells transduced with Her2 in MCF-7. Strain.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the antibody drug conjugate of the formula IB, which is a tautomer, an optical isomer, a hydrate, a solvate, a polymorph.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the IA compound, a tautomer, an optical isomer, a hydrate, a solvate, a polymorph, an isotope compound, which is pharmaceutically acceptable a salt or a prodrug thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the IC-1, IC-2 or IC-3 compound, tautomer, optical isomer, hydrate, solvate, polymorph thereof a compound, an isotope compound, a pharmaceutically acceptable salt thereof or a prodrug thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipient refers to a conventional pharmaceutical excipient in the pharmaceutical field, and is an antibody drug conjugate of the present invention added to solve the moldability, effectiveness, stability and safety of the preparation.
  • All other conventional pharmaceutical materials such as diluents (such as sodium carboxymethyl starch), binders (such as povidone, etc.), disintegrants (such as microcrystalline cellulose, etc.), lubricants (such as stearic acid) Magnesium, micronized silica gel, etc.), as well as other adjuvants.
  • the above-mentioned excipients may be selected as needed, and the antibody drug conjugate of the present invention is formulated into a pharmaceutical preparation according to a conventional method in the art; the pharmaceutical preparations are various conventional dosage forms in the art, such as tablets, powders, pills, capsules. Agents, granules, oral liquids, dry suspensions or pills.
  • isotopic compound refers to an antibody drug conjugate of the present invention, the IA compound, the IC-1, IC-2 or IC-3 compound, its tautomer, optical isomerism.
  • the body, hydrate, solvate, polymorph, isotope compound, pharmaceutically acceptable salt thereof or prodrug thereof contains one or more atomic isotopes of natural or non-natural abundance.
  • Non-natural abundance of atomic isotopes including, but not limited to, hydrazine ( 2 H or D), hydrazine ( 3 H or T), iodine-125 ( 125 I), phosphorus-32 ( 32 P), carbon-13 ( 13 C) Or carbon-14 ( 14 C).
  • the aforementioned isotopic compounds can also be used as therapeutic or diagnostic agents (i.e., in vivo developers), or as research tools. All isotopic variations of the compounds of the invention, whether or not they are radioactive, are included within the scope of the invention.
  • halogen means fluorine, chlorine, bromine, iodine or hydrazine.
  • cyano means -CN.
  • a heteroalkyl group (C 2-8 heteroalkyl group) generally means that one or more CH 2 structures in an alkyl group (including a branched or linear alkyl group) are heteroatoms (for example, O, S or NH). Instead, it is attached to other groups by a carbon atom, such as CH 2 OCH 2 -, CH 3 CH 2 OCH 2 - or CH 2 OCH(CH 3 )- and the like.
  • the present invention relates to a group containing two linking sites (such as G or Q, etc.), the manner of which is generally understood to be linked to the corresponding compound or structure in a left-right sequential manner according to the structure of the group, for example when G for In the case of the compound of formula IB, the linkage is as follows:
  • the room temperature referred to in the present invention refers to an ambient temperature of 10 ° C to 35 ° C.
  • the reagents and starting materials used in the present invention are commercially available.
  • the present invention uses a highly cytotoxic anthracycline antibiotic as a toxin, and designs and synthesizes a series of novel antibody drug conjugates which are stable to acid and peptidase cathepsins, preferably substituted with water-soluble glycosyl groups.
  • the use of a stable ether bond for attachment significantly improves water solubility and stability. In vitro activity tests indicate that it has higher cytotoxicity and has good market application prospects.
  • the antibody drug conjugate of the present invention exhibits higher cancer cell killing activity than an antibody drug conjugate having a traditional drug such as maytansin, Auristatin or the like as a toxin.
  • CL-081 is:
  • CL-066 is:
  • SMCC is:
  • the reaction product 2-1 (1.4 g, 8 mmol) was dissolved in 50 mL of THF.
  • propargyl bromide 1.4 mL, 16 mmol
  • 10 mL of saturated ammonium chloride solution dropwise to quench the reaction
  • extract with ethyl acetate 3 times 40 mL ⁇ 3
  • LCMS (ESI) m / z 236.7 (M + H) +.
  • reaction product of the previous step 9-1 (40 mg, 0.12 mmol) and the compound 5-1 (40 mg, 0.06 mmol) were weighed into an eggplant type bottle, and 2 mL of t-butanol and 2 mL of methanol were added thereto, followed by sodium ascorbate (Sodium Ascorbate) (6 mg). , 0.03 mmol) and copper sulfate (10 mg, 0.06 mmol), and the reaction mixture was stirred at room temperature overnight.
  • sodium ascorbate sodium Ascorbate
  • copper sulfate (10 mg, 0.06 mmol
  • reaction product 10-1 (15 mg, 0.015 mol) in the previous step was dissolved in 1 mL of acetonitrile, cooled to 0 ° C in an ice water bath, 0.5 mL of diethylamine was added, and the mixture was stirred at room temperature for 1.5 hours, and acetonitrile and diethylamine were removed under reduced pressure at room temperature. And using diethylamine with diethylamine twice, 15 mg of crude product 11-1 was obtained as a red solid, which was directly used for the next reaction.
  • LCMS (ESI) m / z 780.3 (M + H) +.
  • reaction product 5-2 (5 mg, 0.007 mmol) from the previous step was dissolved in 2 mL of acetonitrile, cooled to 0 ° C in an ice water bath, and 1 mL of diethylamine was added and stirred for 1 hour. Concentration and removal of the organic solvent gave 4 mg of crude compound 6-2 as a red solid. The crude product was used directly in the next step.
  • LCMS (ESI) m / z 754.1 (M + H) +.
  • CL-055 is:
  • reaction product 3-3 (20mg, 0.018mol) was dissolved in 2mL acetonitrile in the previous step, cooled to 0 ° C in ice water bath, 1 mL of diethylamine was added, stirred for 1.5 hours, acetonitrile and diethylamine were removed under reduced pressure at room temperature, and dichlorochloride was used. Methane was taken twice with diethylamine to give 15 mg of crude product 4-3 as a red solid which was used directly for the next reaction.
  • LCMS (ESI) m / z 888.3 (M + H) +.
  • reaction product 6-3 (30mg, 0.03mol) in the previous step was dissolved in 2mL acetonitrile, cooled to 0 ° C in ice water bath, 1 mL of diethylamine was added, stirred for 1.5 hours, acetonitrile and diethylamine were removed under reduced pressure at room temperature, and dichloroethylene was used. Methane was taken twice with diethylamine to give 22 mg of crude product 7-3 as a red solid which was used directly for the next reaction.
  • LCMS (ESI) m / z 756.3 (M + H) +.
  • reaction product 2-9 (12 g, 24.8 mmol) was dissolved in a mixed solvent of 50 mL of isopropanol and 250 mL of chloroform, and 5 g of silica gel was added thereto, and the mixture was cooled to 0 ° C in an ice water bath, and sodium borohydride (1.4 g, 37.2 mmol) was slowly added in portions. After stirring for 2 hours, the reaction solution was poured into 300 mL of ice water, and the organic phase was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and evaporated. Solid, yield 83%.
  • LCMS (ESI) m / z 508.0 (M + Na) +.
  • reaction product 5-9 (374 mg, 0.5 mmol) and PNP-CO-PNP (bis(p-nitrophenyl) carbonate, 304 mg, 1 mmol) were dissolved in 10 mL of N,N-dimethylformamide and added to DIPEA. (170 ⁇ L, 1 mmol), stirred at room temperature overnight.
  • Example 42 The procedure for coupling a linker toxin to an antibody is as follows:
  • Antibody proteins eg Herceptin, anti-TPBG antibodies, anti-CD70 antibodies or anti-EGFRVIII antibodies
  • dialysis buffer 25 mM Sodium Borate, sodium borate
  • 25 mM NaCl 25 mM NaCl
  • 1 mM DTPA final pH 7.4.
  • the volume of the dialysis buffer is more than 500 times the volume of the antibody protein.
  • the concentration was measured using A280 (i.e., A280 (nm) ultraviolet absorption method for measuring protein concentration).
  • TCEP tris(2-carboxyethyl)phosphine hydrochloride
  • the freshly prepared TCEP (tris(2-carboxyethyl)phosphine hydrochloride) solution is added to the antibody in a set ratio to reduce it by 2 to 5 times the amount of the antibody substance.
  • the antibody was switched to a coupling buffer (20 mM succinate 150 mM NaCl, 2 mM EDTA, using a desalting column). About 75mM Tris.).
  • the compound to be coupled was dissolved to a concentration of 10 mM using DMSO.
  • the final concentration of 10-30% DMSO was slowly added, and immediately mixed; the dissolved compound was added to the antibody solution in a certain ratio.
  • the antibody substance After reacting at 25 ° C for 2 hours, dialysis was carried out using a dialysis membrane having a pore size of 10 kDa and exchanged once, and dialyzed overnight at 4 °C.
  • the volume of the dialysis buffer needs to be more than 500 times the volume of the antibody-compound.
  • the antibody-compound was taken out, filtered through a 0.22 ⁇ m green membrane, and the concentration was measured.
  • Her2-positive human BT474 breast tumor cells (abbreviated as BT474), Her2 low-expression human MCF-7 breast tumor cells (abbreviated as MCF-7), and MCF-7-expressing Her2 human breast tumor MCF7-Her2 stable cells Strain (MCF-7-Her2 for short)
  • MCF-7 Her2-positive human BT474 breast tumor cells
  • MCF-7 Her2 low-expression human MCF-7 breast tumor cells
  • MCF-7-Her2 Her2-positive human BT474 breast tumor cells
  • MCF-7 Her2 low-expression human MCF-7 breast tumor cells
  • MCF-7-expressing Her2 human breast tumor MCF7-Her2 stable cells Strain (MCF-7-Her2 for short)
  • BT474, MCF7-Her2 and MCF-7 were digested with 0.25% (vol/vol) trypsin to detach the cells, then suspended in 100 ⁇ L of complete medium, and 2,000 cells were seeded in 96-well plates for culture. Incubate at 37 ° C overnight, then add 100 ⁇ L of antibody drug conjugate containing different concentration gradients and complete medium. Add 50 ⁇ L after 120 hours Fluorescent cell activity assay reagent Luminescent, Promega) performs relative cell proliferation assays. The activity data is shown in Table 1.
  • mAb indicates the monoclonal antibody Herceptin
  • the antibody conjugate of the present invention has a good inhibitory activity against MCF-Her2 cells, and its inhibitory activity is substantially higher than that of the control drug T-DM1.
  • the small molecule toxin PNU-159682 has comparable activity to BT474, negative MCF-7 cells, and positive MCF-7-Her2 cells, and is essentially non-selective.
  • the antibody drug conjugate of the present invention greatly reduced the activity of the negative MCF-7 cells, and the activity of MCF-7-Her2 positive cells was substantially equal or slightly decreased, and the selectivity thereof was significantly improved, which was against MCF-
  • the selectivity of 7 and MCF-Her2 is almost similar to that of T-DM1, reducing potential cytotoxicity.
  • TPBG-positive human MBA-MB-468 breast cancer cells (abbreviated as MBA-MB-468) and TPBG-low expressed human NCI-H1975 non-small cell lung cancer cells (abbreviated as NCI-H1975) were used.
  • the growth inhibition of tumor cells by the antibody drug conjugate of the present invention was evaluated.
  • MBA-MB-468 and NCI-H1975 were digested with 0.25% (v/v) trypsin, the cells were exfoliated, and then suspended in 100 ⁇ L of complete medium, and 2,000 cells were seeded in 96-well plates for culture. Incubate at 37 ° C overnight, then add 100 ⁇ L of antibody drug conjugate containing different concentration gradients and complete medium. Add 50 ⁇ L after 120 hours Fluorescent cell activity assay reagent Luminescent, Promega) performs relative cell proliferation assays. The activity data is shown in Table 2.
  • mAb represents the monoclonal antibody TPBG
  • the antibody drug conjugate of the present invention is TPBG-positive human MBA-MB-468 breast cancer cell (abbreviated as MBA-MB-468) compared to the antibody drug conjugate using DM1 and MMAF as a toxin.
  • Human H1568 non-small cell lung cancer cells with high expression of TPBG have higher inhibitory activity.
  • NCI-H1975 non-small cell lung cancer cells (NCI-H1975) with low expression of TPBG the cell cytotoxic activity of the antibody drug conjugate of the present invention is much higher than the corresponding control with DM1 and MMAF as toxin.
  • the growth inhibition of tumor cells by the antibody drug conjugate of the present invention was evaluated using the CD70 recombinant cell line CHOK-hCD70 (prepared in accordance with MCF7-Her2) (abbreviated as CHOK-hCD70) and the negative cell CHOk1 not expressing CD70.
  • CD70-positive human renal cancer cell line 786-O (abbreviation 786-O)
  • CD70 low-expression human kidney cancer cell Caki-1 abbreviated as Caki-1)
  • Caki-2 abbreviated as Caki-2
  • CHOK-hCD70, CHOK1, 786-O, Caki-1 and Caki-2 were digested with 0.25% (vol/vol) trypsin to detach the cells, then suspended in 100 ⁇ L of complete medium, and 2,000 cells were seeded in 96-well plates. Cultivate. Incubate at 37 ° C overnight, then add 100 ⁇ L of antibody drug conjugate containing different concentration gradients and complete medium. Add 50 ⁇ L after 120 hours Fluorescent cell activity assay reagent Luminescent, Promega) performs relative cell proliferation assays. The activity data is shown in Table 3.
  • mAb represents the monoclonal antibody CD70.
  • the antibody drug conjugate of the present invention is equivalent to the CD70-positive recombinant cell line CHOK-hCD70 (referred to as CHOK-hCD70, the preparation method is consistent with MCF7-Her2) compared with the antibody drug conjugate using DM1 as a toxin.
  • human kidney cancer cell line 786-O (abbreviation 786-O) has near or higher inhibitory activity.
  • Caki-1 Caki-1
  • Caki-2 Caki-2
  • the antibody drug conjugate of the present invention has a near or higher cell killing power.
  • the recombinant cell line CHOK1-EGFR (CHOK1-EGFR) expressing human EGFR protein
  • CHOK1-EGFRvIII (referred to as CHOK1-EGFRvIII) expressing human GFRvIII protein
  • the negative cell CHOk1 not expressing EGFR were evaluated.
  • the antibody drug conjugate of the present invention inhibits the growth of tumor cells.
  • CHOK1-EGFR, CHOK1-EGFRvIII, and CHOk1 were digested with 0.25% (v/v) trypsin, and the cells were detached, and then suspended in 100 ⁇ L of complete medium, and 2,000 cells were seeded in a 96-well plate for culture.
  • mAb represents the monoclonal antibody EGFRVIII.
  • the antibody drug conjugate of the present invention is EGFR-positive recombinant cell line CHOK1-EGFR (referred to as CHOK1-EGFR, and the preparation method is consistent with MCF7-Her2) compared with the antibody drug conjugate using MMAF as a toxin.
  • CHOK1-EGFR EGFR-positive recombinant cell line
  • CHOK1-EGFRvIII EGFRvIII-positive recombinant cell line CHOK1-EGFRvIII, which is produced in accordance with MCF7-Her2
  • CHOK1-EGFRvIII which is produced in accordance with MCF7-Her2

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Abstract

L'invention concerne un conjugué anticorps-médicament, un procédé de préparation, un intermédiaire, une composition pharmaceutique et l'utilisation de celui-ci. Le conjugué anticorps-médicament a une cytotoxicité élevée et de bons effets anticancéreux, et a une perspective d'application de marché.
PCT/CN2017/115281 2016-12-09 2017-12-08 Conjugué anticorps-médicament, procédé de préparation, intermédiaire, composition pharmaceutique et utilisation WO2018103739A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020074724A1 (fr) * 2018-10-11 2020-04-16 Nbe-Therapeutics Ag Conjugués protéine de liaison-toxine comprenant des anthracyclines, et leur utilisation dans des applications immuno-oncologiques
WO2020254640A1 (fr) * 2019-06-20 2020-12-24 Almac Discovery Limited Dérivés d'anthracycline
EP4180061A1 (fr) * 2021-11-10 2023-05-17 Nerviano Medical Sciences S.r.l. Réactifs de liaison dérivés d'anthracycline, conjugués anticorps-médicament et procédés
WO2024006272A1 (fr) * 2022-06-27 2024-01-04 Sutro Biopharma, Inc. CHARGES UTILES DE LIEUR β-GLUCURONIDE, LEURS CONJUGUÉS PROTÉIQUES ET MÉTHODES ASSOCIÉES

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053827A (zh) * 2018-08-06 2018-12-21 延边大学 双靶向肝肿瘤药物、合成方法及其应用
CN111138435A (zh) * 2020-01-08 2020-05-12 宜昌博仁凯润药业有限公司 一种修饰过的甲氨蝶呤及其制备方法和应用
CN115043895A (zh) * 2022-07-15 2022-09-13 戊言医药科技（上海）有限公司 一种pnu-159682及其中间体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099741A1 (fr) * 2008-02-01 2009-08-13 Genentech, Inc. Métabolite de némorubicine et réactifs analogues, conjugués anticorps-médicament et procédés
CN102159248A (zh) * 2008-07-15 2011-08-17 健泰科生物技术公司 蒽环类衍生物缀合物、它们的制备方法以及它们作为抗肿瘤化合物的用途
CN104411721A (zh) * 2012-03-30 2015-03-11 基因泰克公司 抗lgr5抗体和免疫缀合物
CN105873614A (zh) * 2013-12-16 2016-08-17 基因泰克公司 肽模拟化合物及其抗体-药物缀合物
CN106163558A (zh) * 2014-04-25 2016-11-23 豪夫迈·罗氏有限公司 用曲妥珠单抗‑mcc‑dm1和帕妥珠单抗治疗早期乳腺癌的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014106826A2 (fr) * 2013-01-07 2014-07-10 Piramal Enterprises Limited Analogue d'anthracycline et utilisations associées

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099741A1 (fr) * 2008-02-01 2009-08-13 Genentech, Inc. Métabolite de némorubicine et réactifs analogues, conjugués anticorps-médicament et procédés
CN102159248A (zh) * 2008-07-15 2011-08-17 健泰科生物技术公司 蒽环类衍生物缀合物、它们的制备方法以及它们作为抗肿瘤化合物的用途
CN104411721A (zh) * 2012-03-30 2015-03-11 基因泰克公司 抗lgr5抗体和免疫缀合物
CN105873614A (zh) * 2013-12-16 2016-08-17 基因泰克公司 肽模拟化合物及其抗体-药物缀合物
CN106163558A (zh) * 2014-04-25 2016-11-23 豪夫迈·罗氏有限公司 用曲妥珠单抗‑mcc‑dm1和帕妥珠单抗治疗早期乳腺癌的方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020074724A1 (fr) * 2018-10-11 2020-04-16 Nbe-Therapeutics Ag Conjugués protéine de liaison-toxine comprenant des anthracyclines, et leur utilisation dans des applications immuno-oncologiques
WO2020254640A1 (fr) * 2019-06-20 2020-12-24 Almac Discovery Limited Dérivés d'anthracycline
EP4180061A1 (fr) * 2021-11-10 2023-05-17 Nerviano Medical Sciences S.r.l. Réactifs de liaison dérivés d'anthracycline, conjugués anticorps-médicament et procédés
WO2023083716A1 (fr) * 2021-11-10 2023-05-19 Nerviano Medical Sciences S.R.L. Réactifs de liaison de dérivé d'anthracycline, conjugués anticorps-médicament et méthodes
WO2024006272A1 (fr) * 2022-06-27 2024-01-04 Sutro Biopharma, Inc. CHARGES UTILES DE LIEUR β-GLUCURONIDE, LEURS CONJUGUÉS PROTÉIQUES ET MÉTHODES ASSOCIÉES

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