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WO2021260582A1 - Association d'un conjugué anticorps-médicament et d'un inhibiteur d'aurora b - Google Patents

Association d'un conjugué anticorps-médicament et d'un inhibiteur d'aurora b Download PDF

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Publication number
WO2021260582A1
WO2021260582A1 PCT/IB2021/055551 IB2021055551W WO2021260582A1 WO 2021260582 A1 WO2021260582 A1 WO 2021260582A1 IB 2021055551 W IB2021055551 W IB 2021055551W WO 2021260582 A1 WO2021260582 A1 WO 2021260582A1
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cancer
amino
pharmaceutical product
antibody
alkyl
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Jerome Thomas Mettetal Ii
Stephen Thomas DURANT
Azadeh Cheraghchi Bashi ASTANEH
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AstraZeneca UK Ltd
Daiichi Sankyo Co Ltd
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AstraZeneca UK Ltd
Daiichi Sankyo Co Ltd
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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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • 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
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the present disclosure relates to a pharmaceutical product for administration of a specific antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 antibody via a linker structure, in combination with an Aurora B inhibitor, and to a therapeutic use and method wherein the specific antibody-drug conjugate and the Aurora B inhibitor are administered in combination to a subject.
  • Aurora kinases are cell cycle regulated serine-threonine protein kinases (summarised in Adams et al., 2001, Trends in Cell Biology. 11(2): 49-54). These show a peak of expression and kinase activity through G2 and mitosis and a role for human Aurora kinases in cancer has long been implicated. Aurora kinase inhibitors are disclosed, for example, in W02004/058781 .
  • ADCs Antibody-drug conjugates
  • ADCs which are composed of a cytotoxic drug conjugated to an antibody, can deliver the drug selectively to cancer cells, and are therefore expected to cause accumulation of the drug within cancer cells and to kill the cancer cells
  • trastuzumab deruxtecan which is composed of a HER2-targeting antibody and a derivative of exatecan (Ogitani Y. et al., Clinical Cancer Research (2016) 22(20), 5097-5108;
  • the antibody-drug conjugate used in the present disclosure (an anti-HER2 antibody-drug conjugate that includes a derivative of the topoisomerase I inhibitor exatecan) has been confirmed to exhibit an excellent antitumor effect in the treatment of certain cancers such as breast cancer and gastric cancer, when administered singly. Furthermore, an Aurora B inhibitor has been confirmed to exhibit an antitumor effect in the treatment of certain cancers. However, it is desired to provide a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers, such as enhanced efficacy, increased durability of therapeutic response and/or reduced dose-dependent toxicity.
  • the present disclosure provides a pharmaceutical product which can exhibit an excellent antitumor effect in the treatment of cancers, through administration of an anti-HER2 antibody-drug conjugate in combination with an Aurora B inhibitor.
  • the present disclosure also provides a therapeutic use and method wherein the anti-HER2 antibody-drug conjugate and Aurora B inhibitor are administered in combination to a subject.
  • the present disclosure relates to the following [1] to [59]:
  • a pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor for administration in combination, wherein the anti-HER2 antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond;
  • Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
  • X is 0, S, S(O), S(0) 2 or NR 14 ;
  • m is 0, 1, 2 or 3;
  • Z is a group selected from -NR 1 R 2 , phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C 1-4 alkyl groups;
  • R 1 is a group selected from -COR 8 , -CONR 8 R 9 and C 1-6 alkyl which C 1-6 alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 2 is a group selected from is a group selected from hydrogen, -COR 10 , -CONR 10 R 11 and Ci-6alkyl which Ci-6alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups or -S(0) p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C 2-6 alkenyl, C 2-6 alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or -NR 8 R 9 , and where the ring is optionally further substituted
  • R 3 is a group selected from hydrogen, halo, cyano, nitro, C 1-6 alkoxy, C 1-6 alkyl, -OR 12 , -CHR 12 R 13 , -0C(0)R 12 , - C (0)R 12 , -NR 12 C (0)R 13 , -C (0)NR 12 R 13 , -NR 12 S0 2 R 13 and -NR 12 R 13 ;
  • R 4 is hydrogen or a group selected from C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, aryl and arylC 1-4 alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 2 -4alkenyl, C 2 -4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, C 1-4 alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
  • R 8 is C 1-4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 9 is selected from hydrogen and C 1-4 alkyl
  • R 10 is selected from hydrogen and C 1-4 alkyl (optionally substituted by halo, C 1-4 alkoxy, S(0) q (where q is 0,1 or 2) or phosphonooxy);
  • R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, C 1-4 alkyl and heterocyclyl, or a pharmaceutically acceptable salt thereof;
  • Ring A is a group of formula (a), (b), (c), (d) or (e): where * is the point of attachment to the X group of formula (I) and ** is the point of attachment to the (CR 6 R 7 ) group of formula (I);
  • R 1 is Ci-salkyl substituted by phosphonooxy and R 2 is a group selected from hydrogen and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups, or R 2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6cycloalkylC 1-4 alkyl;
  • R 1 is 2-phosphonooxyethyl
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • nanoparticle comprises:
  • the pharmaceutical product according to any one of [1] to [22] wherein the product is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration;
  • the medicament is a composition comprising the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor, for simultaneous administration;
  • an anti-HER2 antibody-drug conjugate for use, in combination with an Aurora B inhibitor, in the treatment of cancer wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of [1] to [22];
  • the anti-HER2 antibody-drug conjugate for the use according to [48] wherein the cancer is as defined in any one of [26] to [41];
  • an Aurora B inhibitor for use, in combination with an anti-HER2 antibody-drug conjugate, in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are as defined in any one of [1] to [22];
  • [56] a method of treating cancer comprising administering an anti-HER2 antibody-drug conjugate and an Aurora B inhibitor as defined in any one of [1] to [22] in combination to a subject in need thereof; [57] the method according to [56], wherein the cancer is as defined in any one of [26] to [41]; and
  • the present disclosure provides a pharmaceutical product wherein an anti-HER2 antibody-drug conjugate, having an antitumor drug conjugated to an anti-HER2 antibody via a linker structure, and an Aurora B inhibitor are administered in combination, and a therapeutic use and method wherein the specific antibody- drug conjugate and the Aurora B inhibitor are administered in combination to a subject.
  • the present disclosure can provide a medicine and treatment which can obtain a superior antitumor effect in the treatment of cancers.
  • Figure 1 is a diagram showing the amino acid sequence of a heavy chain of an anti-HER2 antibody (SEQ ID NO: 1]
  • Figure 2 is a diagram showing the amino acid sequence of a light chain of an anti-HER2 antibody (SEQ ID NO: 2).
  • SAS light chain CDRL2
  • Figure 12 is a diagram showing combination matrices obtained with high-throughput screens combining DS-8201 with AZD2811 (AZ11792866; Aurora B inhibitor) in a breast cancer cell line and a gastric cell line with high HER2 expression.
  • SI Systeme International de Unites
  • inhibitor refers to any statistically significant decrease in biological activity, including full blocking of the activity.
  • inhibition can refer to a decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in biological activity.
  • Cellular proliferation can be assayed using art recognized techniques which measure rate of cell division, and/or the fraction of cells within a cell population undergoing cell division, and/or rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., thymidine incorporation) .
  • subject refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • subject and patient are used interchangeably herein in reference to a human subject.
  • pharmaceutical product refers to a preparation which is in such form as to permit the biological activity of the active ingredients, either as a composition containing all the active ingredients (for simultaneous administration), or as a combination of separate compositions (a combined preparation) each containing at least one but not all of the active ingredients (for administration sequentially or simultaneously), and which contains no additional components which are unacceptably toxic to a subject to which the product would be administered.
  • Such product can be sterile.
  • simultaneous administration is meant that the active ingredients are administered at the same time.
  • sequential administration is meant that the active ingredients are administered one after the other, in either order, at a time interval between the individual administrations. The time interval can be, for example, less than 24 hours, preferably less than 6 hours, more preferably less than 2 hours.
  • Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • a subject is successfully "treated” for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancers include but are not limited to, breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head- and-neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma
  • Cancers include hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
  • hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
  • cytotoxic agent as used herein is defined broadly and refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells (cell death), and/or exerts anti- neoplastic/anti-proliferative effects.
  • a cytotoxic agent prevents directly or indirectly the development, maturation, or spread of neoplastic tumor cells.
  • the term includes also such agents that cause a cytostatic effect only and not a mere cytotoxic effect.
  • chemotherapeutic agents as specified below, as well as other HER2 antagonists, anti-angiogenic agents, tyrosine kinase inhibitors, protein kinase A inhibitors, members of the cytokine family, radioactive isotopes, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin.
  • chemotherapeutic agent is a subset of the term “cytotoxic agent” comprising natural or synthetic chemical compounds.
  • compounds of the present disclosure may be administered to a patient to promote a positive therapeutic response with respect to cancer.
  • positive therapeutic response with respect to cancer treatment refers to an improvement in the symptoms associated with the disease.
  • an improvement in the disease can be characterized as a complete response.
  • complete response refers to an absence of clinically detectable disease with normalization of any previous test results.
  • an improvement in the disease can be categorized as being a partial response.
  • a "positive therapeutic response” encompasses a reduction or inhibition of the progression and/or duration of cancer, the reduction or amelioration of the severity of cancer, and/or the amelioration of one or more symptoms thereof resulting from the administration of compounds of the present disclosure.
  • such terms refer to one, two or three or more results following the administration of compounds of the instant disclosure:
  • the size of the cancer is maintained and does not increase or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%, and
  • Clinical response can be assessed using screening techniques such as PET, magnetic resonance imaging (MRI) scan, x-radiographic imaging, computed tomographic (CT) scan, flow cytometry or fluorescence-activated cell sorter (FACS) analysis, histology, gross pathology, and blood chemistry, including but not limited to changes detectable by ELISA, RIA, chromatography, and the like.
  • MRI magnetic resonance imaging
  • CT computed tomographic
  • FACS fluorescence-activated cell sorter
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “tert-butyl” are specific for the branched chain version only. An analogous convention applies to other generic terms, for example “alkenyl” and “alkynyl”.
  • Cycloalkyl is a monocyclic, saturated alkyl ring and "aryl” is a monocyclic or bicyclic aromatic ring.
  • heteroaryl is a monocyclic or bicyclic aromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogen or sulphur may be oxidised.
  • Heterocyclyl is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring containing 4 to 12 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen, which ring may be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-; wherein a ring nitrogen or sulphur atom is optionally oxidised to form the N-oxide or S-oxide(s); wherein a ring —NH is optionally substituted by acetyl, formyl, methyl or mesyl; and wherein a ring is optionally substituted by one or more halo.
  • Phosphonooxy is in one aspect a group of formula -P(0)(OH)2.
  • phosphonooxy also includes salts of this group such as those formed with alkali metal ions such as sodium or potassium ions or alkaline earth metal ions, for example calcium or magnesium ions.
  • substituents are chosen from “1 or 2", from “1, 2, or 3” or from “1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substitutents being the sameor the substituents being chosen from two or more of the specified groups i.e. the substituents not being the same.
  • Suitable values for any R group (R 1 to R 14 in formula (I)) or any part or substituent for such groups include: for C 1-4 alkyl: methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl and tert-butyl; for C 1-6 alkyl: C 1-4 alkyl, pentyl, 2,2-dimethylpropyl,
  • alkyl cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; for aryl: phenyl and naphthyl; for arylC 1-4 alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl; for halo: fluoro, chloro, bromo and iodo; for C 1-4 alkoxy: methoxy, ethoxy, propoxy and isopropoxy; for Ci-6alkoxy: C 1-4 alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; for heteroaryl:pyridyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl, ox
  • N-formylpiperazinyl N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5- dioximidazolidinyl, 2,2-dimethyl-l,3-dioxolanyl and 3,4- dimethylenedioxybenzyl .
  • the phrase "effective amount” means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical product will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient (s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • an effective amount of a compound of formula (I) for use in the treatment of cancer in combination with the antibody-drug conjugate is an amount such that the combination is sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer, to slow the progression of cancer, or to reduce in patients with symptoms of cancer the risk of getting worse.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compounds of formula (I) may encompass compounds with one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • 0 may be in any isotopic form, including 16 O and 18 O; and the like.
  • the present disclosure may use compounds of formula (I) as herein defined as well as salts thereof. Salts for use in pharmaceutical products will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the disclosure may, for example, include acid addition salts of compounds of formula (I) as herein defined which are sufficiently basic to form such salts.
  • acid addition salts include but are not limited to fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid.
  • salts are base salts and examples include but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • an alkali metal salt for example sodium or potassium
  • an alkaline earth metal salt for example calcium or magnesium
  • organic amine salt for example triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine or amino acids such as lysine.
  • the compounds of formula (I) may also be provided as in vivo hydrolysable esters.
  • An in vivo hydrolysable ester of a compound of formula (I) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol.
  • esters can be identified by administering, for example, intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluid.
  • esters for carboxy include C 1-6 alkoxymethyl esters for example methoxymethyl, C 1-6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3-8 cycloalkcarbonyloxyC 1-6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl,
  • esters for example (5-methyl-l,3-dioxolen-2-one )ylmethyl, and C 1-6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this disclosure.
  • Suitable pharmaceutically acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and a- acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy groups.
  • Examples of a- acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy .
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include Ci- l oalkanoyl, for example acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; Ci-ioalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-C 1-4 alkylcarbamoyl and N-(di-C 1-4 alkylaminoethyl)-N-C 1-4 alkylcarbamoyl (to give carbamates); di-C 1-4 alkylaminoacetyl and carboxyacetyl.
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, C 1-4 alkylaminomethyl and di- (Ci-4alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
  • esters include, for example, R A C(0)0C 1-6 alkyl-C0-, wherein R A is for example, benzyloxy-Ci-4alkyl, or phenyl.
  • Suitable substituents on a phenyl group in such esters include, for example, 4-C 1-4 alkylpiperazino-C 1-4 alkyl, piperazino- Ci-4alkyl and morpholino-Ci-4alkyl.
  • the antibody-drug conjugate used in the present disclosure is an antibody-drug conjugate in which a drug- linker represented by the following formula:
  • A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond.
  • the partial structure consisting of a linker and a drug in the antibody-drug conjugate is referred to as a "drug-linker".
  • the drug- linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.
  • the drug-linker of the present disclosure includes exatecan (IUPAC name: (IS,9S)-l-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H, 13H- benzo [de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin- 10,13-dione, (also expressed as chemical name: (1S,9S)-1- amino-9-ethyl-5-fluoro-2,3-dihydro- 9-hydroxy-4-methy1- 1H,12H-benzo [de]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-10,13 (9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component.
  • Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula:
  • anti-HER2 antibody-drug conjugate used in the present disclosure can be also represented by the following formula:
  • the drug-linker is conjugated to an anti-HER2 antibody ('Antibody-') via a thioether bond.
  • n is the same as that of what is called the average number of conjugated drug molecules (DAR; Drug-to- Antibody Ratio), and indicates the average number of units of the drug-linker conjugated per antibody molecule.
  • DAR Drug-to- Antibody Ratio
  • the anti-HER2 antibody-drug conjugate used in the present disclosure is cleaved at the linker portion to release a compound represented by the following formula:
  • This compound is inferred to be the original source of the antitumor activity of the antibody-drug conjugate used in the present disclosure, and has been confirmed to have a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15;22(20):5097- 5108, Epub 2016 Mar 29).
  • the anti-HER2 antibody-drug conjugate used in the present disclosure is known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039- 1046).
  • the bystander effect is exerted through a process whereby the antibody-drug conjugate used in the present disclosure is internalized in cancer cells expressing the target and the compound released then exerts an antitumor effect also on cancer cells which are present therearound and not expressing the target.
  • This bystander effect is exerted as an excellent antitumor effect even when the anti-HER2 antibody-drug conjugate is used in combination with an Aurora B inhibitor according to the present disclosure.
  • the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure may be derived from any species, and is preferably an anti-HER2 antibody derived from a human, a rat, a mouse, or a rabbit. In cases when the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well known technique.
  • the anti-HER2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody.
  • the antibody in the antibody-drug conjugate used in the present disclosure is an anti-HER2 antibody preferably having a characteristic of being capable of targeting cancer cells, and is preferably an antibody possessing, for example, a property of recognizing a cancer cell, a property of binding to a cancer cell, a property of internalizing in a cancer cell, and/or cytocidal activity against cancer cells.
  • the binding activity of the anti-HER2 antibody against cancer cells can be confirmed using flow cytometry.
  • the internalization of the antibody into cancer cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751- 761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol.
  • a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28: 162-165, January 2000).
  • the immunotoxin a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used.
  • the antitumor activity of the anti-HER2 antibody can be confirmed in vitro by determining inhibitory activity against cell growth.
  • a cancer cell line overexpressing HER2 as a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, and spheroid growth.
  • the antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining change in the cancer cell.
  • the anti-HER2 antibody-drug conjugate exerts an antitumor effect
  • the anti-HER2 antibody should have the property of internalizing to migrate into cancer cells.
  • the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure can be obtained by a procedure known in the art.
  • the antibody of the present disclosure can be obtained using a method usually carried out in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo.
  • the origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a non-human animal such as a mouse, a rat and the like.
  • the cross-reactivity of antibodies binding to the obtained heterologous antigen with human antigens can be tested to screen for an antibody applicable to a human disease.
  • antibody-producing cells which produce antibodies against the antigen are fused with myeloma cells according to a method known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495- 497; and Kennet, R. ed., Monoclonal Antibodies, p. 365- 367, Plenum Press, N.Y. (1980)) to establish hybridomas, from which monoclonal antibodies can in turn be obtained.
  • a method known in the art e.g., Kohler and Milstein, Nature (1975) 256, p. 495- 497; and Kennet, R. ed., Monoclonal Antibodies, p. 365- 367, Plenum Press, N.Y. (1980)
  • the antigen can be obtained by genetically engineering host cells to produce a gene encoding the antigenic protein. Specifically, vectors that permit expression of the antigen gene are prepared and transferred to host cells so that the gene is expressed. The antigen thus expressed can be purified.
  • the antibody can also be obtained by a method of immunizing animals with the above-described genetically engineered antigen expressing cells or a cell line expressing the antigen.
  • the anti-HER2 antibody in the antibody-drug conjugate used the present disclosure is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is preferably an antibody having only the gene sequence of an antibody derived from a human, that is, a human antibody.
  • These antibodies can be produced using a known method.
  • chimeric antibody an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human-derived antibody constant region can be exemplified (Proc. Natl. Acad. Sci. USA, 81, 6851-
  • an antibody obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), and an antibody obtained by grafting a part of the amino acid residues of the framework of a heterologous antibody as well as the CDR sequence of the heterologous antibody to a human antibody by a CDR-grafting method (WO 90/07861), and an antibody humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337) can be exemplified .
  • CDR complementarity determining region
  • human antibody an antibody generated by using a human antibody-producing mouse having a human chromosome fragment including genes of a heavy chain and light chain of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et. al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. al., Animal Cell Technology:Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et.
  • an antibody obtained by phage display the antibody being selected from a human antibody library (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science.
  • modified variants of the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure are also included.
  • the modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification.
  • Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or 0-linked carbohydrate chain, etc.
  • the biologically modified variant examples include variants obtained by post-translational modification (such as N-linked or 0-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell.
  • an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant.
  • Such a modified variant of the antibody according to the present disclosure is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.
  • deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain variants obtained by amidation of deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included.
  • the type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-HER2 antibody according to the present disclosure is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved.
  • the two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full- length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom.
  • the ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the anti-HER2 antibody according to the present disclosure and the culture conditions; however, an antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody according to the present disclosure can be exemplified as preferred.
  • IgG IgGl, IgG2, IgG3, IgG4
  • IgGl or IgG2 can be exemplified as preferred.
  • anti-HER2 antibody refers to an antibody which specifically binds to HER2 (Human Epidermal Growth Factor Receptor Type 2; ErbB-2), and preferably has an activity of internalizing in HER2-expressing cells by binding to HER2.
  • HER2 Human Epidermal Growth Factor Receptor Type 2
  • Examples of the anti-HER2 antibody include trastuzumab (U.S. Patent No. 5821337) and pertuzumab (W001/00245), and trastuzumab can be exemplified as preferred.
  • a drug-linker intermediate for use in production of the anti-HER2 antibody-drug conjugate according to the present disclosure is represented by the following formula:
  • the drug-linker intermediate can be expressed as the chemical name N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexanoyl]glycylglycyl-L-phenylalanyl-N- [(2- ⁇ [(IS,9S)- 9-ethyl-5-fluoro-9-hydroxy-4-methyl-1 0,13-dioxo- 2,3,9,10,13,15-hexahydro-lH,12H- benzo [de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1- yl]amino ⁇ -2-oxoethoxy)methyl]glycinamide, and can be produced with reference to descriptions in WO2014/057687, WO2015/098099, W02015/115091, WO2015/155998,
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be produced by reacting the above- described drug-linker intermediate and an anti-HER2 antibody having a thiol group (also referred to as a sulfhydryl group).
  • the anti-HER2 antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA), an anti-HER2 antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained.
  • a reducing agent such as tris(2- carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody
  • TCEP tris(2- carboxyethyl)phosphine hydro
  • an anti-HER2 antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.
  • the average number of conjugated drug molecules per anti-HER2 antibody molecule of the antibody-drug conjugate produced can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).
  • UV method UV absorbance for the antibody-drug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm
  • HPLC method a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent
  • anti-HER2 antibody-drug conjugate refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the present disclosure is an anti- HER2 antibody.
  • the anti-HER2 antibody is preferably an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1 and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2 and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2, and more preferably an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO:
  • a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2, and even more preferably an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2.
  • the average number of units of the drug-linker conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be produced with reference to descriptions in W02015/115091 and so on.
  • the anti-HER2 antibody- drug conjugate is trastuzumab deruxtecan (DS-8201).
  • Aurora B inhibitor refers to an agent that inhibits the cell cycle regulated protein kinase Aurora B.
  • the Aurora B inhibitor in the present disclosure may selectively inhibit the kinase Aurora B, or may non-selectively inhibit Aurora B and inhibit also kinase(s) other than Aurora B.
  • the Aurora B inhibitor in the present disclosure is not particularly limited as long as it is an agent that has the described characteristics, and preferred examples thereof can include those disclosed in W02004/058781 and W02015/036792.
  • the Aurora B inhibitor in the present disclosure inhibits Aurora B selectively.
  • the Aurora B inhibitor is a compound represented by the following formula (I): wherein Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
  • Z is a group selected from -NR 1 R 2 , phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C 1-4 alkyl groups;
  • R 1 is a group selected from -COR 8 , -CONR 8 R 9 and C 1-6 alkyl which C 1-6 alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 2 is a group selected from is a group selected from hydrogen, -COR 10 , -CONR 10 R 11 and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups or -S(0) p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C 2-6 alkenyl, C 2-6 alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or -NR 8 R 9 , and where the ring is optionally further
  • R 3 is a group selected from hydrogen, halo, cyano, nitro, C 1-6 alkoxy, C 1-6 alkyl, -OR 12 , -CHR 12 R 13 , -0C(0)R 12 , - C (0)R 12 , -NR 12 C (0)R 13 , -C (0)NR 12 R 13 , -NR 12 S0 2 R 13 and -NR 12 R 13 ;
  • R 4 is hydrogen or a group selected from C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, aryl and arylC 1-4 alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 2 -4alkenyl, C 2 -4alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, C 1-4 alkyl, C3-6cycloalkyl, hydroxy and alkoxy;
  • R 8 is C 1-4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 9 is selected from hydrogen and C 1-4 alkyl
  • R 10 is selected from hydrogen and C 1-4 alkyl (optionally substituted by halo, C 1-4 alkoxy, S(0) q (where q is 0,1 or 2) or phosphonooxy);
  • R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, C 1-4 alkyl and heterocyclyl; or a pharmaceutically acceptable salt thereof.
  • Additional embodiments of the Aurora B inhibitor are compounds of formula (I), and pharmaceutically acceptable salts thereof, in which A, X, m, Z, R 3 , R 4 , R 5 , R 6 and R 7 are defined as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined herein.
  • Ring A in formula (I) is pyrrolyl, pyrazolyl, imidazolyl or triazolyl. In another embodiment, Ring A is a group of formula (a), (b), (c),
  • Ring A is pyrazolyl. In a more preferred embodiment, Ring A is a group of formula (a) as defined above.
  • X is NR 14 , 0 or S. In another embodiment, X is NR 14 . In yet another embodiment, X is NH. In one embodiment, m is 1, 2 or 3. In one embodiment, m is 1 or 2. In another embodiment, m is 0, 2 or 3. In another embodiment, m is 0, 1 or 2. In yet another embodiment, m is 1. In a further embodiment, m is
  • Z is —NR 1 R 2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy.
  • Z is —NR 1 -R 2 .
  • R 1 is Ci-salkyl substituted by phosphonooxy. In another embodiment, R 1 is Ci-salkyl substituted by phosphonooxy and further substituted by 1 or 2 halo. In a further embodiment, R 1 is 2- phosphonooxyethyl, 2-phosphonooxy-l,1-dimethylethyl, 2- phosphonooxy-2-methylethyl, 3-phosphonooxy-1,1- dimethylpropyl, 3-phosphonooxypropyl and 4- phosphonooxybutyl .
  • R 1 is 2- phosphonooxyethyl, 2-phosphonooxy-l,1-dimethylethyl, 3- phosphonooxy-1,1-dimethylpropyl or 3-phosphonooxypropyl. In yet another embodiment, R 1 is 2-phosphonooxyethyl. In yet another embodiment, R 1 is hydroxyethyl.
  • R 2 is selected from hydrogen and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6 alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3-6cycloalkylCi- 4alkyl.
  • R 2 is hydrogen, allyl, 2- propynyl, methyl, ethyl, propyl, isopropyl, 2- methylpropyl, butyl, 2,2-dimethylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, 3,3,3-trifluoropropyl or 2-methoxyethyl .
  • R 2 is ethyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and Ci4alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups.
  • R 1 and R 2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2-phosphonooxyethyl, N-ethyl-N-(2- phosphonooxyethyl)aminomethyl and N-(2- phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl.
  • R 1 and R 2 together with the nitrogen to which they are attached form 4- (phosphonooxymethyl)piperidinyl, 2- (phosphonooxymethyl)pyrrolidinyl, 4-(2- phosphonooxyethyl)piperazinyl, 3-
  • R 1 and R 2 together with the nitrogen to which they are attached form 2- (phosphonooxymethyl)pyrrolidinyl .
  • R 3 is C 1-4 alkoxy, halo or hydrogen. In a further embodiment, R 3 is C 1-4 alkoxy or hydrogen. In another embodiment, R 3 is methoxy. In another embodiment, R 3 is hydrogen. In yet a further embodiment, R 3 is fluoro.
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro.
  • R 4 is 3-fluorophenyl, 3-chlorophenyl, 3,5- difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 2,3- difluorophenyl, 2,4-difluorophenyl and 2,5- difluorophenyl .
  • R 4 is 3- fluorophenyl, 3,5-difluorophenyl and 2,3-difluorophenyl.
  • R 4 is 3-fluorophenyl.
  • R 4 is 3,5-difluorophenyl.
  • R 4 is 2,3-difluorophenyl.
  • R 5 is hydrogen or methyl. In another embodiment, R 5 is hydrogen.
  • R 6 is hydrogen, fluoro, chloro or methyl. In another embodiment, R 6 is hydrogen.
  • R 7 is hydrogen, fluoro, chloro or methyl. In another embodiment, R 7 is hydrogen.
  • R 8 is 2-phosphonooxyethyl.
  • R 9 is hydrogen, methyl or ethyl.
  • R 10 is hydrogen, methyl or ethyl.
  • R 11 is hydrogen, methyl or ethyl.
  • R 12 is hydrogen or methyl.
  • R 13 is hydrogen or methyl.
  • R 14 is hydrogen or methyl.
  • a preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a), (b), (c), (d) or
  • Z is —NR 1 R 2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring is substituted on carbon or nitrogen by phosphonooxy or Ci_4alkyl substituted by phosphonooxy;
  • R 1 is Ci-salkyl substituted by phosphonooxy;
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups or R 2 is selected from C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6 cycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 Ci_ 4 alkyl groups;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl
  • R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a), (b), (c), (d) or
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and Ci-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C 2- 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl
  • R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl; or a pharmaceutically acceptable salt thereof.
  • Another preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and Ci-6alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C 2- 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl; R 3 is C 1-4 alkoxy, halo or hydrogen;
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl;
  • R 3 is C 1-4 alkoxy
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl and C3- 6cycloalkylC 1-4 alkyl;
  • R 3 is hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2 ;
  • R 1 is Ci-salkyl substituted by phosphonooxy
  • R 2 is selected from hydrogen and C 1-6 alkyl which Ci- 6alkyl is optionally substituted by 1, 2 or 3 halo or C 1-4 alkoxy groups, or R 2 is selected from C2- 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3- 6cycloalkylC 1-4 alkyl;
  • R 3 is fluoro
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen; and R 6 and R 7 are each hydrogen; or a pharmaceutically acceptable salt thereof.
  • Another preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a), (b), (c), (d) or
  • Z is —NR 1 R 2
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom which ring is substituted by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted by 1 or 2 Ci- 4alkyl groups;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl; and R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl;
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • X is NH
  • 5 m is 0, 1 or 2;
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups;
  • R 3 is C 1-4 alkoxy, halo or hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen or methyl
  • R 6 and R 7 are independently hydrogen, fluoro, chloro or methyl
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula (I) wherein:
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups;
  • R 3 is C 1-4 alkoxy
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen
  • R 6 and R 7 are each hydrogen
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • a further preferred class of compounds is of formula
  • Ring A is a group of formula (a) as defined above;
  • Z is —NR 1 R 2
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated 5- to 6-membered ring optionally containing a further nitrogen atom wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or —NR 8 R 9 , and where the ring is optionally further substituted on carbon or nitrogen by 1 or 2 C 1-4 alkyl groups;
  • R 3 is hydrogen
  • R 4 is phenyl optionally substituted by 1 or 2 of fluoro or chloro;
  • R 5 is hydrogen
  • R 6 and R 7 are each hydrogen
  • R 8 is 2-phosphonooxyethyl
  • R 9 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • Another preferred compound of formula (I) is any compound selected from:
  • a more preferred compound of formula (I) is a compound selected from:
  • a further preferred compound of formula (I) is:
  • a more preferred compound is any compound selected from: ⁇ 1— [3—( ⁇ 4—[(5— ⁇ 2—[(3-fluorophenyl)amino]-2-oxoethyl ⁇ -1H- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl ⁇ oxy)propyl]piperidin-4-yl ⁇ methyl dihydrogen phosphate;
  • a further preferred compound is any compound selected from:
  • Another preferred compound is any compound selected from: 2- [[3— ⁇ 4—[ ⁇ 5— ⁇ 2—[(3-fluorophenyl)amino]-2-oxoethyl ⁇ -1- pyrazol-3-yl)amino]-6-methoxyquinazolin-7- yl ⁇ oxy)propyl] (isobutyl)amino]ethyl dihydrogen phosphate; 2- ⁇ (2,2-dimethylpropyl)[3— ⁇ 4—[ ⁇ 5— ⁇ 2— [(3- fluorophenyl)amino]-2-oxoethyl ⁇ -lH-pyrazol-3-yl)amino]-6- methoxyquinazolin-7-yl ⁇ oxy)propyl]amino ⁇ ethyl dihydrogen phosphate;
  • a particularly preferred compound is any compound selected from:
  • An especially preferred compound of formula (I) is any compound selected from:
  • a further preferred compound is any compound selected from :
  • a further preferred compound is any compound selected from:
  • Another more preferred compound is any compound selected from :
  • a particularly preferred compound is any compound selected from:
  • Yet another preferred compound is any compound selected from:
  • Another preferred compound is any compound selected from: 2- ⁇ 4- [( ⁇ 4- [(5— ⁇ 2— [(2,3-difluorophenyl)amino]-2-oxoethyl ⁇ - lH-pyrazol-3-yl)amino]quinazolin-7- yl ⁇ oxy)methyl]piperidin-l-yl ⁇ ethyl dihydrogen phosphate; 2- [[3— ⁇ 4— [ ⁇ 5— ⁇ 2— [(2,3-difluorophenyl)amino]-2-oxoethyl ⁇ - lH-pyrazol-3-yl)amino]-quinazolin-7- yl ⁇ oxy)propyl] (ethyl)amino]ethyl dihydrogen phosphate;
  • Yet another preferred compound is any compound selected from :
  • a further particularly preferred compound is any compound selected from:
  • a further preferred compound of formula (I) is any one of:
  • the Aurora B inhibitor used in the disclosure is [AZD1152; barasertib] represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • Aurora B inhibitor used in the disclosure is [AZD1152hqpa] represented by the following formula: or a pharmaceutically acceptable salt thereof, in the form of a nanoparticle.
  • the Aurora B inhibitor used in the disclosure is a nanoparticle [AZD2811] comprising:
  • a diblock poly(lactic) acid- poly(ethylene)glycol copolymer 60 to 78 weight percent a diblock poly(lactic) acid- poly(ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly(ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly(ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle.
  • Aurora B inhibitors such as compounds of formula (I), including AZD1152 and AZD1152hqpa, may be prepared by methods known in the art such as disclosed in W02004/058781.
  • the term "pharmaceutically acceptable salt" of the Aurora B inhibitor used in the present disclosure may be either an acid addition salt or a base addition salt.
  • the acid addition salt can include lower alkanesulfonates such as camsilate (camphorsulfonate), mesilate (methanesulfonate), trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as tosilate (p- toluenesulfonate) and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and sulfate; hydrogen halide salts such as hydrochloride, hydrobromide, hydroiodide, and hydrofluoride; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornithinate, glutamate,
  • the base addition salt can include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkali earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, diethanolamine salt, N- benzyl-N- (2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl)aminomethane salt; and amino acid salts such as alginate.
  • alkali metal salts such as sodium salt, potassium salt, and lithium salt
  • alkali earth metal salts such as calcium salt and magnesium salt
  • the Aurora B inhibitor and pharmaceutically acceptable salt thereof used in the present disclosure may each exist as a solvate, and solvates of them are also included in the meaning of the Aurora B inhibitor and pharmaceutically acceptable salt thereof used in the present disclosure.
  • the anti-HER2 antibody-drug conjugate which is combined with the Aurora B inhibitor is an antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to an anti-HER2 antibody via a thioether bond.
  • the anti-HER2 antibody-drug conjugate as defined above for the first combination embodiment is combined with an Aurora B inhibitor which is a compound of formula (I): wherein
  • Ring A is 5-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms;
  • Z is a group selected from -NR 1 R 2 , phosphonooxy, C3-6cycloalkyl which C3-6cycloalkyl is substituted by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and a 4- to 7-membered ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, which ring may be saturated, partially saturated or unsaturated wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy, and wherein the ring is optionally further substituted on carbon or nitrogen by 1, 2 or 3 halo or C 1-4 alkyl groups;
  • R 1 is a group selected from -COR 8 , -CONR 8 R 9 and C 1-6 alkyl which C 1-6 alkyl is substituted by phosphonooxy or hydroxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 2 is a group selected from is a group selected from hydrogen, -COR 10 , -CONR 10 R 11 and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups or -S(0) p R 11 (where p is 0, 1 or 2) or phosphonooxy, or R 2 is a group selected from C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl and C3-6CycloalkylC 1-4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a 4- to 7-membered ring optionally containing a further nitrogen atom which ring may be saturated, unsaturated or partially saturated wherein the ring is substituted on carbon or nitrogen by a group selected from phosphonooxy and C 1-4 alkyl which C 1-4 alkyl is substituted by phosphonooxy or -NR 8 R 9 , and where the ring is optionally further
  • R 3 is a group selected from hydrogen, halo, cyano, nitro, C 1-6 alkoxy, C 1-6 alkyl, -OR 12 , -CHR 12 R 13 , -0C(0)R 12 , - C (0)R 12 , -NR 12 C (0)R 13 , -C (0)NR 12 R 13 , -NR 12 S0 2 R 13 and -NR 12 R 13 ;
  • R 4 is hydrogen or a group selected from C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, aryl and arylC 1-4 alkyl which group is optionally substituted by 1, 2 or 3 substitutents selected from halo, methyl, ethyl, cyclopropyl and ethynyl;
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6C ycloalkyl and C 3-6C ycloalkylC 1-4 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, halo, C 1-4 alkyl, C 3-6 cycloalkyl, hydroxy and alkoxy;
  • R 8 is C 1-4 alkyl substituted by phosphonooxy and optionally further substituted by 1 or 2 halo or methoxy groups;
  • R 9 is selected from hydrogen and C 1-4 alkyl
  • R 10 is selected from hydrogen and C 1-4 alkyl (optionally substituted by halo, C 1-4 alkoxy, S(0) q (where q is 0,1 or 2) or phosphonooxy);
  • R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, C 1-4 alkyl and heterocyclyl; or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Ring A is a group of formula (a), (b), (c),
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Ring A is a group of formula (a) as defined above.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), X is NH.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Z is -NR 1 R 2 or a 5- to 6-membered saturated ring linked via a carbon atom containing a nitrogen atom and optionally containing a further nitrogen atom, wherein the ring is substituted on carbon or nitrogen by phosphonooxy or C 1-4 alkyl substituted by phosphonooxy.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), in formula (I), R 1 is Ci-salkyl substituted by phosphonooxy and R 2 is a group selected from hydrogen and C 1-6 alkyl which C 1-6 alkyl is optionally substituted by 1,2 or 3 halo or C 1-4 alkoxy groups, or R 2 is a group selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and C 3-6C ycloalkylC 1-4 alkyl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 1 is 2-phosphonooxyethyl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), Z is -NR 1 R 2 and R 1 and R 2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2- phosphonooxyethyl, N-ethyl-N-(2- phosphonooxyethyl)aminomethyl and N-(2— phosphonooxyethyl)aminomethyl and where the ring is optionally further substituted by 1 or 2 methyl.
  • Z is -NR 1 R 2 and R 1 and R 2 together with the nitrogen to which they are attached form a piperidine, pyrrolidine or piperazine ring which is substituted by a group selected from phosphonooxy, phosphonooxymethyl, 2- phosphonooxyethyl, N-ethyl-N-
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 1 and R 2 together with the nitrogen to which they are attached form 2-(phosphonooxymethyl)pyrrolidinyl .
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 4 is 3-fluorophenyl, 3,5-difluorophenyl or 2,3-difluorophenyl .
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein, in formula (I), R 3 is C 1-4 alkoxy, halo or hydrogen.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above, wherein the compound of formula (I) is [AZD1152; barasertib] represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above, wherein the compound of formula (I) is [AZD1152hqpa] represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein the compound of formula (I) is [AZD1152hqpa] in the form of a nanoparticle.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with an Aurora B inhibitor as defined above wherein the compound of formula (I) is [AZD1152hqpa] in the form of a nanoparticle, the nanoparticle comprising:
  • diblock poly(lactic) acid- poly (ethylene)glycol copolymer 7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle [AZD2811].
  • the anti-HER2 antibody comprises a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8.
  • the anti-HER2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10.
  • the anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.
  • the anti-HER2 antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2.
  • the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the Aurora B inhibitor is a nanoparticle [AZD2811] comprising:
  • diblock poly(lactic) acid- poly (ethylene)glycol copolymer 7 to 15 weight percent of pamoic acid; and 60 to 78 weight percent a diblock poly(lactic) acid- poly (ethylene)glycol copolymer; wherein the diblock poly(lactic) acid- poly (ethylene)glycol copolymer has a poly(lactic acid) block having a number average molecular weight of about 16kDa and a poly(ethylene)glycol block having a number average molecular weight of about 5kDa; wherein the poly (ethylene)glycol block comprises about 10 to 30 weight percent of the therapeutic nanoparticle.
  • the pharmaceutical product and therapeutic use and method of the present disclosure may be characterized in that the anti-HER2 antibody-drug conjugate and the Aurora B inhibitor are separately contained as active components in different formulations, and are administered simultaneously or at different times, or characterized in that the antibody-drug conjugate and the Aurora B inhibitor are contained as active components in a single formulation and administered.
  • a single Aurora B inhibitor used in the present disclosure can be administered in combination with the anti-HER2 antibody-drug conjugate, or two or more different Aurora B inhibitors can be administered in combination with the antibody-drug conjugate.
  • the pharmaceutical product and therapeutic method of the present disclosure can be used for treating cancer, and can be preferably used for treating at least one cancer selected from the group consisting of breast cancer (including triple negative breast cancer and luminal breast cancer), gastric cancer (also called gastric adenocarcinoma), colorectal cancer (also called colon and rectal cancer, and including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head-and-neck cancer (including salivary gland cancer and pharyngeal cancer), esophagogastric junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, uterine cervix cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, corpus uteri carcinoma,
  • the presence or absence of HER2 tumor markers can be determined, for example, by collecting tumor tissue from a cancer patient to prepare a formalin-fixed, paraffin- embedded (FFPE) specimen and subjecting the specimen to a test for gene products (proteins), for example, with an immunohistochemical (IHC) method, a flow cytometer, or Western blotting, or to a test for gene transcription, for example, with an in situ hybridization (ISH) method, a quantitative PCR method (q-PCR), or microarray analysis, or by collecting cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to a test with a method such as next-generation sequencing (NGS).
  • FFPE formalin-fixed, paraffin- embedded
  • IHC immunohistochemical
  • q-PCR quantitative PCR method
  • NGS next-generation sequencing
  • the pharmaceutical product and therapeutic method of the present disclosure can be used for HER2-expressing cancer, which may be HER2-overexpressing cancer (high or moderate) or may be HER2 low-expressing cancer.
  • the term "HER2- overexpressing cancer” is not particularly limited as long as it is recognized as HER2-overexpressing cancer by those skilled in the art.
  • Preferred examples of the HER2-overexpressing cancer can include cancer given a score of 3+ for the expression of HER2 in an IHC method, and cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as positive for the expression of HER2 in an in situ hybridization method (ISH).
  • ISH in situ hybridization method
  • the in situ hybridization method of the present disclosure includes a fluorescence in situ hybridization method (FISH) and a dual color in situ hybridization method (DISH).
  • the term "HER2 low- expressing cancer” is not particularly limited as long as it is recognized as HER2 low-expressing cancer by those skilled in the art.
  • Preferred examples of the HER2 low- expressing cancer can include cancer given a score of 2+ for the expression of HER2 in an IHC method and determined as negative for the expression of HER2 in an in situ hybridization method, and cancer given a score of 1+ for the expression of HER2 in an IHC method.
  • the method for scoring the degree of HER2 expression by the IHC method, or the method for determining positivity or negativity to HER2 expression by the in situ hybridization method is not particularly limited as long as it is recognized by those skilled in the art. Examples of the method can include a method described in the 4th edition of the guidelines for HER2 testing, breast cancer (developed by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer).
  • the cancer may be HER2-overexpressing (high or moderate) or low-expressing breast cancer, or triple negative breast cancer, and/or may have a HER2 status score of IHC 3+, IHC 2+, IHC 1+ or IHC >0 and ⁇ 1+.
  • the pharmaceutical product and therapeutic method of the present disclosure can be preferably used for a mammal, but are more preferably used for a human.
  • the antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed by transplanting cancer cells to a test subject animal to prepare a model and measuring reduction in tumor volume or life-prolonging effect by application of the pharmaceutical product and therapeutic method of the present disclosure. And then, the effect of combined use of the antibody-drug conjugate used in the present disclosure and an Aurora B inhibitor can be confirmed by comparing antitumor effect with single administration of the antibody-drug conjugate used in the present disclosure and that of the Aurora B inhibitor.
  • the antitumor effect of the pharmaceutical product and therapeutic method of the present disclosure can be confirmed in a clinical trial using any of an evaluation method with Response Evaluation Criteria in Solid Tumors (RECIST), a WHO evaluation method, a Macdonald evaluation method, body weight measurement, and other approaches, and can be determined on the basis of indexes of complete response (CR), partial response (PR); progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and so on.
  • RECIST Response Evaluation Criteria in Solid Tumors
  • a WHO evaluation method a Macdonald evaluation method
  • body weight measurement and other approaches
  • CR complete response
  • PR partial response
  • PD progressive disease
  • ORR objective response rate
  • DoR duration of response
  • PFS progression-free survival
  • OS overall survival
  • the pharmaceutical product and therapeutic method of the present disclosure can delay development of cancer cells, inhibit growth thereof, and further kill cancer cells. These effects can allow cancer patients to be free from symptoms caused by cancer or achieve improvement in quality of life (QOL) of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients. Even if the pharmaceutical product and therapeutic method of the present disclosure do not accomplish killing cancer cells, they can achieve higher QOL of cancer patients while achieving longer-term survival, by inhibiting or controlling the growth of cancer cells.
  • QOL quality of life
  • the pharmaceutical product of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues.
  • the pharmaceutical product of the present disclosure can be administered containing at least one pharmaceutically suitable ingredient.
  • Pharmaceutically suitable ingredients can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration, or the like of the antibody-drug conjugate used in the present disclosure and an Aurora B inhibitor.
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be administered, for example, as a pharmaceutical product containing a buffer such as histidine buffer, a vehicle such as sucrose and trehalose, and a surfactant such as Polysorbates 80 and 20.
  • the pharmaceutical product containing the antibody-drug conjugate used in the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection or a lyophilized injection, and can be even more preferably used as a lyophilized injection.
  • the aqueous injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion.
  • a suitable diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified.
  • a required amount of the lyophilized injection dissolved in advance in water for injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion.
  • a suitable diluent can include dextrose solution and physiological saline, dextrose solution can be preferably exemplified, and 5% dextrose solution can be more preferably exemplified.
  • Examples of the administration route applicable to administration of the pharmaceutical product of the present disclosure can include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and intravenous routes are preferred.
  • the anti-HER2 antibody-drug conjugate used in the present disclosure can be administered to a human with intervals of 1 to 180 days, can be preferably administered with intervals of a week, two weeks, three weeks, or four weeks, and can be more preferably administered with intervals of three weeks.
  • the anti- HER2 antibody-drug conjugate used in the present disclosure can be administered in a dose of about 0.001 to 100 mg/kg per administration, and can be preferably administered in a dose of 0.8 to 12.4 mg/kg per administration.
  • the anti-HER2 antibody-drug conjugate can be administered once every three weeks at a dose of 0.8 mg/kg, 1.6 mg/kg, 3.2 mg/kg, 5.4 mg/kg, 6.4 mg/kg, 7.4 mg/kg, or 8 mg/kg, and can be preferably administered once every three weeks at a dose of 5.4 mg/kg or 6.4 mg/kg.
  • the Aurora B inhibitor according to the present disclosure can be orally administered to a human once or twice in each one to seven days, and can be preferably orally administered once a day or twice per day.
  • the Aurora B inhibitor used in the present disclosure can be orally administered in a dose of 0.1 mg to 4000 mg per administration, and can be preferably administered in a dose of 2.5 mg to 600 mg per administration.
  • the Aurora B inhibitor used in the present disclosure can be administered to a human as an intravenous drip with intervals of 1 to 180 days, and can be preferably administered as an intravenous drip with intervals of a week, two weeks, three weeks, or four weeks.
  • the Aurora B inhibitor used in the present disclosure can be administered as an intravenous drip in a dose of 0.1 mg to 3000 mg per administration, and can be preferably administered as an intravenous drip in a dose of 10 mg to 100 mg per administration.
  • a formulation of an Aurora B inhibitor compound of formula (I) intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4000 mg of the active ingredient, compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of the active ingredient.
  • a daily dose of the Aurora B inhibitor in the range of 0.1-50 mg/kg may be employed.
  • the Aurora B inhibitor used in the present disclosure is AZD2811
  • the Aurora B inhibitor can be administered in a dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg per administration.
  • the total daily dose of AZD2811 is about 200 mg via intravenous administration.
  • the total daily dose is about 500 mg.
  • the total daily dose is about 600 mg.
  • the total daily dose is 300 mg.
  • AZD2811 is administered on day 1 and day 4 of a 28-day cycle.
  • AZD2811 is administered on day 1 of a 21-day cycle.
  • the pharmaceutical product and therapeutic method of the present disclosure can be used as adjuvant chemotherapy combined with surgery operation.
  • the pharmaceutical product of the present disclosure may be administered for the purpose of reducing tumor size before surgical operation (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy), or may be administered for the purpose of preventing recurrence of tumor after surgical operation (referred to as postoperative adjuvant chemotherapy or adjuvant therapy).
  • an anti-HER2 antibody an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 (amino acid residues 1 to 449 of SEQ ID NO: 1) and a light chain consisting of an amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO: 2)
  • an anti- HER2 antibody-drug conjugate in which a drug-linker represented by the following formula: wherein A represents the connecting position to an antibody, is conjugated to the anti-HER2 antibody via a thioether bond was produced (DS-8201: trastuzumab deruxtecan).
  • the DAR of the antibody-drug conjugate is 7.7 or 7.8.
  • an Aurora B inhibitor of formula (I) is prepared. Specifically, 2-(3-((7-(3-(ethyl(2- hydroxyethyl)amino)propoxy)quinazolin-4-yl )amino)-1H- pyrazol-5-yl)-N- (3-fluorophenyl)acetamide:
  • a nanoparticle (AZD2811) of 2-(3-((7-(3- (ethyl (2-hydroxyethyl)amino)propoxy)quinazolin-4- yl)amino)-lH-pyrazol-5-yl)-N- (3-fluorophenyl)acetamide (AZD1152hqpa) is prepared.
  • a high-throughput combination screen was run, in which a breast cancer cell line and a gastric cell line with high HER2 expression (Table 1) were treated with combinations of DS-8201 and AZD2811 (Aurora B inhibitor).
  • the readout of the screen was a 7-day cell titer-glo cell viability assay, conducted as a 6 x 6 dose response matrix for each combination (5-point log serial dilution for DS-8201, and half log serial dilution for partners).
  • trastuzumab and exatecan were also screened in parallel with AZD2811. Combination activity was assessed based on a combination of the ⁇ Emax and HSA synergy scores.
  • row A shows matrices of measured cell viability signals.
  • X axes represent drug A (DS-8201), and Y axes represent drug B (AZD2811). Values in the box represent the ratio of cells treated with drug A + B compared to DMSO control at day 7. All values are normalised to cell viability values at day 0. Values between 0 and 100 represent % growth inhibition and values above 100 represent cell death.
  • row B shows HSA excess matrices. Values in the box represent excess values calculated by the HSA (Highest Single Agent) model.
  • Table 2 shows HSA synergy and Loewe additivity scores: Table 2
  • Dose Additivity predicts the expected response if the two compounds act on the same molecular target by means of the same mechanism. It calculates additivity based on the assumption of zero interaction between the compounds and it is independent from the nature of the dose-response relationship.
  • HSA Highest Single Agent
  • Excess Matrix For each well in the concentration matrix, the measured or fitted values are compared to the predicted non-synergistic values for each concentration pair. The predicted values are determined by the chosen model. Differences between the predicted and observed values may indicate synergy or antagonism, and are shown in the Excess Matrix. Excess Matrix values are summarized by the combination scores Excess Volume and Synergy
  • AZD2811 and DS-8201 in combination showed synergistic activity and increased cell death in HER2 + cell lines KPL4 and NCI-N87. Combination activity was observed at Emax (AZD28111 mM and DS-820110 ⁇ g/ml (0.064 mM)) and also at lower concentrations .
  • AZD2811 showed synergistic combination activity and increased cell death in HER2 high cell lines.
  • SEQ ID NO: 1 Amino acid sequence of a heavy chain of an anti-HER2 antibody
  • SEQ ID NO: 2 Amino acid sequence of a light chain of an anti-HER2 antibody

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Abstract

L'invention concerne un produit pharmaceutique pour l'administration d'un conjugué anticorps-médicament anti-HER2 en association avec un inhibiteur de l'Aurora B. Le conjugué anticorps-médicament anti-HER2 est un conjugué anticorps-médicament dans lequel un lieur de médicament représenté par la formule suivante (dans laquelle A représente la position de liaison à un anticorps) est conjugué à un anticorps anti-HER2 par l'intermédiaire d'une liaison thioéther. L'invention concerne également une utilisation thérapeutique et un procédé dans lesquels le conjugué anticorps-médicament et l'inhibiteur de l'Aurora B sont administrés en association à un sujet : formule (I) :
PCT/IB2021/055551 2020-06-24 2021-06-23 Association d'un conjugué anticorps-médicament et d'un inhibiteur d'aurora b Ceased WO2021260582A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023209591A1 (fr) * 2022-04-27 2023-11-02 Daiichi Sankyo Company, Limited Combinaison d'un conjugué anticorps-médicament avec un inhibiteur de l'ezh1 et/ou de l'ezh2
WO2025162211A1 (fr) * 2024-01-29 2025-08-07 正大天晴药业集团股份有限公司 Utilisation d'un conjugué anticorps-médicament anti-her2 dans le traitement du cancer gastrique

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023209591A1 (fr) * 2022-04-27 2023-11-02 Daiichi Sankyo Company, Limited Combinaison d'un conjugué anticorps-médicament avec un inhibiteur de l'ezh1 et/ou de l'ezh2
WO2025162211A1 (fr) * 2024-01-29 2025-08-07 正大天晴药业集团股份有限公司 Utilisation d'un conjugué anticorps-médicament anti-her2 dans le traitement du cancer gastrique

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