WO2021260583A1 - Association d'un conjugué anticorps-médicament et d'un inhibiteur de la dna-pk - Google Patents

Association d'un conjugué anticorps-médicament et d'un inhibiteur de la dna-pk Download PDF

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WO2021260583A1
WO2021260583A1 PCT/IB2021/055552 IB2021055552W WO2021260583A1 WO 2021260583 A1 WO2021260583 A1 WO 2021260583A1 IB 2021055552 W IB2021055552 W IB 2021055552W WO 2021260583 A1 WO2021260583 A1 WO 2021260583A1
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cancer
pharmaceutical product
antibody
her2
dna
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PCT/IB2021/055552
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Jerome Thomas Mettetal Ii
Stephen Thomas DURANT
Azadeh Cheraghchi Bashi ASTANEH
Elaine B CADOGAN
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Astrazeneca Uk Limited
Daiichi Sankyo Company, Limited
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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
    • A61K47/6801—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
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K47/6835—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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 a DNA-PK inhibitor, and to a therapeutic use and method wherein the specific antibody-drug conjugate and the DNA-PK inhibitor are administered in combination to a subject.
  • DNA-PK is a nuclear serine/threonine protein kinase complex composed of the catalytic subunit DNA-PKcs and a heterodimer of Ku proteins (Ku70/Ku80) and is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinases.
  • PIKK phosphatidylinositol 3-kinase-related kinase
  • DNA-PK has also been implicated in a range of other biological processes, including modulation of chromatin structure, telomere maintenance, transcriptional regulation, and the response to replication stress (Smith and Jackson, Genes and Development 1999; 13: 916-934; Goodwin and Knudsen, Cancer Discovery 2014; 4: 1126-1139).
  • DNA-PK inhibitors such as NU7026, NU7441, KU-0060648 and CC-115 have demonstrated the therapeutic potential of targeting DNA-PK consistent with the known mechanisms of action of the DNA-PK protein.
  • DNA-PK inhibitors are disclosed, for example, in WO2018/114999 and WO2019/238929.
  • 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; Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).
  • HER2-targeting antibody a derivative of exatecan
  • DNA-PK inhibitors no literature is published that describes a test result demonstrating an excellent effect of combined use of the antibody-drug conjugate and a DNA-PK inhibitor or any scientific basis suggesting such a test result.
  • NHEJ non-homologous end joining
  • 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, as a component) 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, a DNA-PK 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 a DNA-PK inhibitor.
  • the present disclosure also provides a therapeutic use and method wherein the anti-HER2 antibody-drug conjugate and DNA-PK inhibitor are administered in combination to a subject.
  • the present disclosure relates to the following [1] to [52]: [1] a pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and a DNA-PK 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; [2] the pharmaceutical product according to [1], wherein the DNA-PK inhibitor is a compound represented by the following formula (I): (I) wherein: R 1 is a cyclohexyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted by one or more groups slected from hydroxyl, methoxy and methyl; and R 2 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof; [3] the pharmaceutical product according to [2] wherein, in formula (I), R 1 is o
  • 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 a DNA-PK inhibitor are administered in combination, and a therapeutic use and method wherein the specific antibody-drug conjugate and the DNA-PK 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).
  • Figures 12A and 12B are diagrams showing combination matrices obtained with high- throughput screens combining DS-8201 with AZD7648 (AZ13880164; DNA-PK inhibitor) in breast cancer cell lines with diverse HER2 expression and one gastric cell line with high HER2 expression.
  • AZD7648 AZ13880164; DNA-PK inhibitor
  • FIGS. 12A and 12B are diagrams showing combination matrices obtained with high- throughput screens combining DS-8201 with AZD7648 (AZ13880164; DNA-PK inhibitor) in breast cancer cell lines with diverse HER2 expression and one gastric cell line with high HER2 expression.
  • inhibitor 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.
  • the terms “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, sarcoma, and melanoma.
  • 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.
  • 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.
  • the term includes 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 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: (1) a stabilization, reduction or elimination of the cancer cell population; (2) a stabilization or reduction in cancer growth; (3) an impairment in the formation of cancer; (4) eradication, removal, or control of primary, regional and/or metastatic cancer; (5) a reduction in mortality; (6) an increase in disease-free, relapse-free, progression-free, and/or overall survival, duration, or rate; (7) an increase in the response rate, the durability of response, or number of patients who respond or are in remission; (8) a decrease in hospitalization rate, (9) a decrease in hospitalization lengths, (10) 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 (11) an increase in the number of patients in remission.
  • a decrease in the number of adjuvant therapies e.g., chemotherapy or hormonal therapy
  • 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
  • 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 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.
  • 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: (1S,9S)-1-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-methyl- 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 IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro- 1,2,
  • Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula:
  • the 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.
  • Antibody- anti-HER2 antibody
  • 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.
  • 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 a DNA-PK inhibitor according to the present disclosure.
  • Antibody in antibody-drug conjugate 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.
  • 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. 15, 5268- 5282, December 2004), or (3) 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).
  • a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used as the immunotoxin.
  • 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.
  • 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.
  • 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.
  • As the 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.
  • 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 can be exemplified.
  • 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. (2002)43 (7), p.2301-2308; Mé, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1(2), p.189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109(3), p.427-431, etc.) can be exemplified.
  • 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 O-linked carbohydrate chain, etc.
  • the biologically modified variant examples include variants obtained by post-translational modification (such as N-linked or O-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. Further, by regulating the modification of a glycan which is linked to the antibody according to the present disclosure (glycosylation, defucosylation, etc.), it is possible to enhance antibody-dependent cellular cytotoxic activity.
  • a glycan As the technique for regulating the modification of a glycan of antibodies, those disclosed in WO99/54342, WO00/61739, WO02/31140, WO2007/133855, WO2013/120066, etc. are known. However, the technique is not limited thereto.
  • antibodies in which the modification of a glycan is regulated are also included. It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)).
  • deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (the activation of complement, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, in the anti-HER2 antibody according to the present disclosure, antibodies subjected to such modification and functional fragments of the antibody are also included, and 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.
  • isotypes of the anti-HER2 antibody according to the present disclosure for example, IgG (IgG1, IgG2, IgG3, IgG4) can be exemplified, and IgG1 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 (WO01/00245), and trastuzumab can be exemplified as preferred. 3.
  • 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-1H-pyrrol-1- yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2- ⁇ [(1S,9S)- 9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-1H,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, WO
  • 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)).
  • 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 and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA)
  • TCEP tris(2- carboxyethyl)phosphine hydrochloride
  • EDTA ethylenediamine tetraacetic acid
  • 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).
  • 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: 1 and a light chain comprising a light chain variable
  • 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 WO2015/115091 and so on.
  • the anti-HER2 antibody- drug conjugate is trastuzumab deruxtecan (DS-8201). 4.
  • DNA-PK inhibitor refers to an agent that inhibits DNA-PK (nuclear serine/threonine protein kinase complex composed of the catalytic subunit DNA-PKcs and a heterodimer of Ku proteins (Ku70/Ku80)).
  • the DNA-PK inhibitor in the present disclosure may selectively inhibit the kinase DNA-PK, or may non-selectively inhibit DNA-PK and inhibit also kinase(s) other than DNA-PK.
  • the DNA-PK 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 WO2018/114999 and WO2019/238929.
  • DNA-PK inhibitors which may be used according to the present disclosure are selective inhibitors of DNA-PK including M3814/peposertib (Merck) and M9831 (Merck), and non-selective inhibitors of DNA-PK including BR-101801 (Boryung Pharma), SF-2523 (SignalRx Pharmaceuticals), BR-2002/BCN-005 (Boryung Pharma), and CC115 (Celgene).
  • the DNA-PK inhibitor in the present disclosure inhibits DNA-PK selectively.
  • the DNA-PK inhibitor is a compound represented by the following formula (I):
  • R 1 is a cyclohexyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted by one or more groups selected from hydroxyl, methoxy and methyl; and R 2 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
  • cyclohexyl ring refers to carbocyclic ring containing six carbon atoms and no heteroatoms. 1- methoxycyclohex-4-yl groups and 4-methoxycyclohex-1-yl groups have the same structure, as shown below.
  • a cis-1-methoxy-cyclohex-4-yl group is equivalent to a cis-4-methoxy-cyclohex-1-yl and has the following structure: The same conventions apply to other cyclohexyl groups, for example 1-hydroxycyclohex-4-yl groups and 4- hydroxycyclohex-1-yl groups.
  • the term “tetrahydrofuranyl ring” includes tetrahydrofuran-3-yl, the structure of which is shown below. Tetrahydrofuran-3-yl
  • oxanyl ring includes oxan-3-yl and oxan- 4-yl groups, the structures of which are shown below.
  • O xan-4-yl Oxan-3-yl In the above structures the dashed line indicates the bonding position of the relevant group.
  • An oxanyl ring may also be referred to as a tetrahydropyranyl ring.
  • an oxan-4-yl ring may be referred to as a tetrahydropyran-4-yl ring
  • an oxan-3-yl ring may be referred to as a tetrahydropyran-3- yl ring.
  • Values of variable groups in formula (I) are as follows.
  • R 1 is a cyclohexyl ring which is optionally substituted by one or more groups selected from hydroxyl, methoxy and methyl, or R 1 is a tetrahydrofuranyl or oxanyl ring.
  • R 1 is a cyclohexyl ring which is optionally substituted by one or more groups selected from hydroxyl, methoxy and methyl.
  • c)R 1 is a tetrahydrofuranyl or oxanyl ring.
  • R 1 is a cyclohexyl ring which is optionally substituted by one hydroxyl or methoxy group.
  • e)R 1 is a cyclohexyl ring which is optionally substituted by a hydroxyl and a methyl group.
  • f)R 1 is 1-methoxy-cyclohex-4-yl, 1-hydroxy-cyclohex-4- yl, 1-hydroxy-1-methylhex-4yl or 1-hydroxy-4- methyl-cyclohex-4-yl.
  • g)R 1 is 1-methoxy-cyclohex-4-yl, 1-hydroxy-cyclohex-4- yl or 1-hydroxy-1-methyl-cyclohex-4yl.
  • R 1 is 1-hydroxy-1-methyl-cyclohex-4-yl. i)R 1 is cis-1-hydroxy-1-methyl-cyclohex-4-yl. j)R 1 is cis-1-methoxy-cyclobut-4-yl or cis-1-hydroxy- cyclohex-4-yl. k)R 1 is cis-1-hydroxy-cyclohex-4-yl. l)R 1 is an oxetanyl ring. m)R 1 is oxetan-3-yl. n)R 1 is an cyclohexyl ring. o)R 1 is a tetrahydrofuranyl ring.
  • R 1 is tetrahydrofuran-3-yl.
  • q)R 1 is an oxanyl ring.
  • r)R 1 is an oxan-3-yl.
  • s)R 1 is oxan-4-yl.
  • t)R 2 is hydrogen.
  • u)R 2 is methyl.
  • the compound of formula (I) is selected from the group consisting of: 9-((1r,4r)-4-hydroxycyclohexyl)-7-methyl-2-((7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H- purin-8-one; 9-((1s,4s)-4-hydroxycyclohexyl)-7-methyl-2-((7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H- purin-8-one; 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- purin-8-one; 2-((2,7-dimethyl-[1,1,2,
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is selected from the group consisting of: 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- purin-8-one; 9-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one; and 9-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-
  • the compound of formula (I) is selected from the group consisting of: 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- purin-8-one; and 9-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one: or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- purin-8-one, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is 9-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is 9-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof.
  • the DNA-PK inhibitor is a compound represented by the following formula (II): (II) or a pharmaceutically acceptable salt thereof, wherein: A 1 represents N or CR 2A , A 2 represents N or CR 2B and A 3 represents N or CR 2C , where no more than one of A 1 , A 2 and A 3 represent N; R 1 represents C 4-6 cycloalkyl or a 4 to 6 membered heterocycloalkyl containing one heteroatom selected from O, S and N, wherein the C4-6 cycloalkyl or 4 to 6 membered heterocycloalkyl is optionally substituted with one or more groups selected from fluoro, C1-3 alkyl (optionally substituted with a group selected from hydroxyl and C1-2 alkoxy), cyclopropyl, hydroxyl, NH2, dioxo, C(O)C1-2 alkyl, azetidinyl and oxetanyl; and R
  • C4-6 cycloalkyl is a saturated non-aromatic carbocyclic ring containing no heteroatoms.
  • C4-6 cycloalkyl is any such carbocyclic ring containing 4 to 6 carbon atoms.
  • C4-6 cycloalkyl groups include cyclobutyl, cyclopentyl and cyclohexanyl, for example cyclohexanyl.
  • the term “cyclohexanyl” refers to a carbocyclic ring containing six carbon atoms.
  • 1-hydroxycyclohex-4-yl groups and 4-hydroxycyclohex-1-yl groups have the same structure, as shown below.
  • a cis-1-hydroxy-cyclohex-4-yl group is equivalent to a cis-4-hydroxy-cyclohex-1-yl and has the following structure: In the above structures the dashed line indicates the bonding position of the relevant group.
  • a 4 to 6 membered heterocycloalkyl is a saturated non-aromatic ring comprising one heteroatom independently selected from nitrogen, oxygen or sulphur with the remaining ring members being carbon.
  • 4 to 6 membered heterocycloalkyl groups include piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azetidinyl and oxetanyl, for example piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxetanyl and pyrrolidinyl.
  • substituents on the heterocycloalkyl ring may be linked via either a carbon atom or a heteroatom.
  • dioxo means two oxo substituents which are attached to the same atom.
  • Examples of dioxo substitution include instances where R 1 represents thianyl, which may also be referred to as tetrahydrothiopyranyl, where the sulphur ring atom is substituted with two oxo groups, i.e.tetrahydrothiopyran 1,1-dioxide.
  • the prefix Cp-q in Cp-qalkyl and other terms indicates the range of carbon atoms that are present in the group and unless otherwise stated alkyl and alkoxy groups containing the requisite number of carbon atoms can be branched or unbranched.
  • C 1-3 alkyl groups include methyl (Me), ethyl (Et), n-propyl and i- propyl, for example methyl and ethyl.
  • the term C p-q alkoxy comprises –O-C p-q alkyl groups.
  • C 1- 2 alkoxy groups include methoxy and ethoxy, for example methoxy.
  • R 1 represents cyclohexanyl or a 4 to 6 membered heterocycloalkyl containing one heteroatom selected from O, N or S.
  • R 1 represents a 4 to 6 membered heterocycloalkyl containing one heteroatom selected from O or N.
  • R 1 represents a 4 to 6 membered heterocycloalkyl containing one N heteroatom.
  • R 1 is selected from cyclohexanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl and tetrahydrothiopyranyl.
  • R 1 is selected from pyrrolidinyl and piperidinyl.
  • R 1 is selected from cyclohexanyl, oxetan-3-yl, tetrahydrofuran- 3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-3-yl, piperidin-4-yl and tetrahydrothiopyran- 4-yl.
  • R 1 is selected from pyrrolidin-3-yl and piperidin-4-yl.
  • R 1 is optionally substituted with one or two substituents selected from fluoro, methyl, ethyl, hydroxyl, NH 2 , dioxo, C(O)Me and oxetanyl, wherein the ethyl is optionally substituted with hydroxyl or methoxy.
  • R 1 is optionally substituted with fluoro, methyl, ethyl, hydroxyl, NH2and oxetanyl.
  • R 1 is optionally substituted with fluoro or methyl.
  • R 1 represents pyrrolidinyl or piperidinyl and is optionally substituted with one or two substituents selected from fluoro, methyl, ethyl, hydroxyl, NH2 and oxetanyl.
  • R 1 represents cyclohexanyl optionally substituted with hydroxyl, methyl or NH2.
  • R 1 represents oxetan-3-yl.
  • R 1 represents tetrahydrofuran-3-yl.
  • R 1 represents tetrahydropyran-3-yl or tetrahydropyran-4-yl. In another embodiment, in formula (II), R 1 represents pyrrolidin-3-yl optionally substituted with methyl. In another embodiment, in formula (II), R 1 represents pyrrolidin-3-yl optionally substituted with fluoro. In another embodiment, in formula (II), R 1 represents 4-fluoropyrrolidin-3-yl.
  • R 1 represents piperidin-4-yl optionally substituted with a group selected from methyl, ethyl (unsubstituted or substituted with methoxy or hydroxyl), C(O)Me and oxetan- 3-yl.
  • R 1 represents piperidin-4-yl optionally substituted with methyl.
  • R 1 represents 1-methylpiperidin-4-yl.
  • R 1 represents dioxidotetrahydro-2H-thiopyran-4-yl.
  • a 1 represents CR 2A
  • a 2 represents CR 2B and A 3 represents CR 2C .
  • a 1 represents N
  • a 2 represents CR 2B and A 3 represents CR 2C .
  • a 2 represents N
  • a 1 represents CR 2A and A 3 represents CR 2C .
  • a 3 represents N
  • a 1 represents CR 2A and A 2 represents CR 2C .
  • a 1 represents CR 2A or N
  • R 2A represents hydrogen.
  • R 2B represents hydrogen.
  • R 2C represents hydrogen.
  • one, two or three groups selected from R 2A , R 2B and R 2C is/are independently selected from methyl and methoxy, and any remaining R 2A , R 2B and/or R 2C groups represent hydrogen.
  • one, two or three groups selected from R 2A , R 2B and R 2C represent methyl.
  • one, two or three groups selected from R 2A , R 2B and R 2C represent methoxy.
  • one or two groups selected from R 2A , R 2B and R 2C are independently selected from methyl and methoxy. In another embodiment, in formula (II), one or two groups selected from R 2A , R 2B and R 2C represent methyl. In another embodiment, in formula (II), one or two groups selected from R 2A , R 2B and R 2C represent methoxy. In another embodiment, in formula (II), one group selected from R 2A , R 2B and R 2C represents methyl. In another embodiment, in formula (II), one group selected from R 2A , R 2B and R 2C represents methoxy.
  • the DNA-PK inhibitor is a compound of formula (II), wherein: A 1 represents N or CR 2A , A 2 represents N or CR 2B and A 3 represents N or CR 2C , wherein no more than one of A 1 , A 2 and A 3 represents N; R 1 represents cyclohexanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or tetrahydrothiopyranyl and is optionally substituted with one or two groups selected from fluoro, methyl, ethyl, hydroxyl, NH2, dioxo, C(O)Me and oxetanyl, wherein the ethyl is optionally substituted with hydroxyl or methoxy; and R 2A , R 2B and R 2C each independently represent hydrogen, methyl or methoxy.
  • the DNA-PK inhibitor is a compound of Formula (II), wherein: A 1 represents N or CR 2A , A 2 represents N or CR 2B and A 3 represents N or CR 2C , wherein no more than one of A 1 , A 2 and A 3 represents N; R 1 represents pyrrolidinyl or piperidinyl and is optionally substituted with one or two groups selected from fluoro, methyl, ethyl, hydroxyl, NH 2 , dioxo and oxetanyl, wherein the ethyl is optionally substituted with hydroxyl or methoxy; and R 2A , R 2B and R 2C each independently represent hydrogen, methyl or methoxy.
  • a 1 represents N or CR 2A
  • a 2 represents CR 2B and A 3 represents CR 2C
  • R 1 represents cyclohexanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or tetrahydrothiopyranyl and is optionally substituted with one or two groups selected from fluoro, methyl, ethyl, hydroxyl, NH 2 , dioxo, C(O)Me and oxetanyl, wherein the ethyl is optionally substituted with hydroxyl or methoxy
  • R 2A , R 2B and R 2C each independently represent hydrogen, methyl or methoxy.
  • a 1 represents CR 2A or N
  • a 2 represents CR 2B and A 3 represents CR 2C
  • R 1 represents pyrrolidinyl or piperidinyl and is optionally substituted with one or two groups selected from fluoro, methyl, ethyl, hydroxyl, NH2, dioxo and oxetanyl, wherein the ethyl is optionally substituted with hydroxyl or methoxy
  • R 2A , R 2B and R 2C each independently represent hydrogen, methyl or methoxy.
  • a 1 , A 2 and A 3 each represent CH; and R 1 represents pyrrolidinyl substituted with fluoro.
  • a 1 represents N, and A 2 and A 3 represent CH; and R 1 represents tetrahydrofuranyl.
  • the compound of formula (II) is selected from the group consisting of: 9-(1-acetylpiperidin-4-yl)-7-methyl-2-((7-methylcinnolin- 6-yl)amino)-7,9-dihydro-8H-purin-8-one; 9-(1-acetylpiperidin-4-yl)-7-methyl-2-((7- methylquinoxalin-6-yl)amino)-7,9-dihydro-8H-purin-8-one; 9-(1-acetylpiperidin-4-yl)-7-methyl-2-((7- methylquinazolin-6-yl)amino)-7,9-dihydro-8H-purin-8-one; 9-(1-acetylpiperidin-4-yl)-2-((2,7-dimethylquinoxalin-6- yl)amino)-7-methyl-7,9-dihydro-8H-purin-8-one;
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is 7-methyl-9-(1- methylpiperidin-4-yl)-2-((7-methylquinolin-6-yl)amino)- 7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof.
  • the compound is (S)-7-methyl-2-((7-methylcinnolin-6- yl)amino)-9-(tetrahydrofuran-3-yl)-7,9-dihydro-8H-purin- 8-one, or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients.
  • An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zürich:Wiley-VCH/VHCA, 2002.
  • a suitable pharmaceutically acceptable salt of a compound of formula (I) is, for example, an acid-addition salt.
  • An acid addition salt of a compound of formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid salt.
  • the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulf
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a trifluoroacetic acid, formic acid or methanesulfonic acid salt.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a trifluoroacetic acid or methanesulfonic acid salt.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a methanesulfonic acid salt.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof where the pharmaceutically acceptable salt is a mono-methanesulfonic acid salt, i.e. the stoichiometry of the compound of formula (I) to methanesulfonic acid is 1:1.
  • Compounds and salts described in this specification may exist in solvated forms and unsolvated forms.
  • a solvated form may be a hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or an alternative quantity thereof.
  • the disclosure encompasses all such solvated and unsolvated forms of compounds of formula (I) or (II), particularly to the extent that such forms possess DNA-PK inhibitory activity.
  • Atoms of the compounds and salts described in this specification may exist as their isotopes.
  • the disclosure encompasses all compounds of formula (I) or (II) where an atom is replaced by one or more of its isotopes (for example a compound of formula (I) or (II) where one or more carbon atom is an 11 C or 13 C carbon isotope, or where one or more hydrogen atoms is a 2 H or 3 H isotope, or where one or more nitrogen atoms is a 15 N isotope or where one of more oxygen atoms is an 17 O or 18 O isotope).
  • Compounds and salts described in this specification may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms.
  • a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof is a single optical isomer being in an enantiomeric excess (%ee) of ⁇ 95%, ⁇ 98% or ⁇ 99%.
  • the single optical isomer is present in an enantiomeric excess (%ee) of ⁇ 99%.
  • Some of the compounds of formula (I) or (II) may be crystalline and may have more than one crystalline form. It is to be understood that the disclosure encompasses any crystalline or amorphous form, or mixtures thereof, which possess properties useful in DNA-PK inhibitory activity. It is well known how to determine the efficacy of a crystalline or amorphous form by standard tests. It is generally known that crystalline materials may be analysed using conventional techniques such as, for example, X-Ray Powder Diffraction (hereinafter XRPD) analysis and Differential Scanning Calorimetry (DSC).
  • XRPD X-Ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • the DNA-PK inhibitor used in the disclosure is the compound AZD7648, 7-methyl-2- ((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9- (tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • DNA-PK inhibitor used in the disclosure is the compound 9-((3R,4R)-4- fluoropyrrolidin-3-yl)-7-methyl-2-((7-methylquinolin-6- yl)amino)-7,9-dihydro-8H-purin-8-one, represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • DNA-PK inhibitors such as compounds of formula (I), including AZD7648, may be prepared by methods known in the art such as disclosed in WO2018/114999 and compounds of formula (II) may be prepared by methods known in the art such as disclosed in WO2019/238929. 5.
  • the anti-HER2 antibody-drug conjugate which is combined with the DNA-PK 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 a DNA-PK inhibitor which is a compound represented by the following formula (I): (I) wherein: R 1 is a cyclohexyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted by one or more groups selected from hydroxyl, methoxy and methyl; and R 2 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with a DNA-PK inhibitor which is a compound represented by formula (I) as defined above wherein, in formula (I), R 1 is oxanyl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with a DNA-PK inhibitor as defined above wherein, in formula (I), R 1 is oxan-4-yl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with a DNA-PK inhibitor as defined above wherein, in formula (I), R 1 is cyclohexyl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with a DNA-PK inhibitor as defined above wherein, in formula (I), R 1 is 1-hydroxy-1-methyl-cyclohex-4-yl.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with a DNA-PK inhibitor as defined above wherein, in formula (I), R 2 is hydrogen.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with a DNA-PK inhibitor as defined above, wherein the DNA-PK inhibitor is AZD7648 represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • the anti-HER2 antibody-drug conjugate as defined above is combined with a DNA-PK inhibitor as defined above, wherein the DNA-PK inhibitor is the compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • 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 DNA-PK inhibitor is the compound represented by the following formula: also identified as AZD7648. 6.
  • Therapeutic combined use and method Described in the following are a pharmaceutical product and a therapeutic use and method wherein the anti-HER2 antibody-drug conjugate according to the present disclosure and a DNA-PK inhibitor are administered in combination.
  • 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 DNA-PK 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 DNA-PK inhibitor are contained as active components in a single formulation and administered.
  • a single DNA-PK inhibitor used in the present disclosure can be administered in combination with the anti-HER2 antibody-drug conjugate, or two or more different DNA-PK 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.
  • 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).
  • FISH fluorescence in situ hybridization method
  • DISH dual color in situ hybridization method
  • 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 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.
  • 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.
  • 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.
  • composition 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 a DNA-PK 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 pharmaceutical product containing the anti-HER2 antibody-drug conjugate used in the present disclosure is an aqueous injection
  • the aqueous injection can be preferably diluted with a suitable diluent and then given as an intravenous infusion.
  • the 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.
  • 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 DNA-PK 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 DNA-PK 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 DNA-PK 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 DNA-PK 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 a DNA-PK inhibitor compound of formula (I) or (II) will normally be administered to a warm-blooded animal at a unit dose within the range 2.5-5000 mg/m 2 body area of the animal, or approximately 0.05-100 mg/kg, and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 0.1-250 mg of active ingredient.
  • the size of the dose required for the therapeutic treatment of a particular disease state will necessarily be varied depending on the subject treated, the route of administration and the severity of the illness being treated.
  • 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).
  • preoperative adjuvant chemotherapy or neoadjuvant therapy a preoperative adjuvant chemotherapy or neoadjuvant therapy
  • postoperative adjuvant chemotherapy or adjuvant therapy referred to as postoperative adjuvant chemotherapy or adjuvant therapy.
  • Example 1 Production of antibody-drug conjugate
  • 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:
  • Example 3 Antitumor test Combination of antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) with DNA-PK inhibitor AZD7648 (7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H- purin-8-one) Method: A high-throughput combination screen was run, in which breast cancer cell lines with diverse HER2 expression and one gastric cell line with high HER2 expression (Table 1) were treated with combinations of DS-8201 and AZD7648 (DNA-PK inhibitor).
  • Table 1 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 AZD7648.
  • Combination activity was assessed based on a combination of the ⁇ Emax and HSA synergy scores.
  • Results are shown in Figures 12A and 12B and Table 2.
  • Figure 12A shows matrices of measured cell viability signals.
  • X axes represent drug A (DS-8201)
  • Y axes represent drug B (AZD7648).
  • 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.
  • Figure 12B 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 Loewe 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
  • HSA Highest Single Agent [Berenbaum 1989] quantifies the higher of the two single compound effects at their corresponding concentrations. The combined effect is compared with the effect of each single agent at the concentration used in the combination. Excess over the highest single agent effect indicates cooperativity. HSA does not require the compounds to affect the same target.
  • 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 Score.
  • AZD7648 (AZ13880164) interacted synergistically with DS-8201 and the combination also increased cell death at Emax (10 ⁇ M AZD7648 and 10 ⁇ g/ml (0.064 ⁇ M) DS-8201) in HER2 + cell lines KPL4, NCI-N87 and HCC1419.
  • Emax 10 ⁇ M AZD7648 and 10 ⁇ g/ml (0.064 ⁇ M) DS-8201
  • combination activity was also observed at lower concentrations.
  • AZD7648 and DS-8201 also showed moderate combination activity in HER2 low/ER+ cell line T47D and in HER2 low cell line HCC38.

Abstract

L'invention concerne un produit pharmaceutique permettant l'administration d'un conjugué anticorps anti-HER2-médicament en association avec un inhibiteur de la protéine kinase dépendante de l'ADN, ou DNA-PK. Ledit conjugué anticorps anti-HER2-médicament 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 la DNA-PK sont administrés en association l'un avec l'autre à un sujet.
PCT/IB2021/055552 2020-06-24 2021-06-23 Association d'un conjugué anticorps-médicament et d'un inhibiteur de la dna-pk WO2021260583A1 (fr)

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