WO2024214685A1 - 抗ｂ７－ｈ３抗体－薬物コンジュゲートとａｔｒ阻害剤又はａｔｍ阻害剤との組み合わせ - Google Patents

抗ｂ７－ｈ３抗体－薬物コンジュゲートとａｔｒ阻害剤又はａｔｍ阻害剤との組み合わせ Download PDF

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WO2024214685A1
WO2024214685A1 PCT/JP2024/014351 JP2024014351W WO2024214685A1 WO 2024214685 A1 WO2024214685 A1 WO 2024214685A1 JP 2024014351 W JP2024014351 W JP 2024014351W WO 2024214685 A1 WO2024214685 A1 WO 2024214685A1
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amino acid
seq
acid sequence
cancer
antibody
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PCT/JP2024/014351
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English (en)
French (fr)
Japanese (ja)
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廉 勝又
純 長谷川
服部　千春
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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Priority to EP24788709.4A priority Critical patent/EP4696332A1/en
Priority to CN202480023676.4A priority patent/CN121038817A/zh
Priority to JP2025513954A priority patent/JPWO2024214685A1/ja
Publication of WO2024214685A1 publication Critical patent/WO2024214685A1/ja
Priority to US19/353,836 priority patent/US20260091123A1/en
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Definitions

  • the present invention relates to a pharmaceutical composition in which a specific anti-B7-H3 antibody-drug conjugate is administered in combination with an ATR inhibitor or an ATM inhibitor, and/or a method of treatment in which a specific anti-B7-H3 antibody-drug conjugate is administered in combination with an ATR inhibitor or an ATM inhibitor to an individual.
  • DDR DNA damage response
  • ATM Ataxia telangiectasia-mutated pathway
  • ATR Ataxia-telangiectasia mutated and Rad3-related pathway
  • Inhibitors of the main molecules in these pathways inhibit DNA damage response and reduce cellular function, and are therefore expected to be effective in treating cancer (Non-Patent Document 1).
  • Antibody-drug conjugates which combine a cytotoxic drug with an antibody that binds to an antigen expressed on the surface of cancer cells and can be internalized into the cells, can selectively deliver drugs to cancer cells, allowing the drug to accumulate in the cancer cells and kill them.
  • ADCs Antibody-drug conjugates
  • One known antibody-drug conjugate is one whose components are an anti-B7-H3 antibody and a derivative of exatecan, a topoisomerase I inhibitor (Patent Document 1).
  • the anti-B7-H3 antibody-drug conjugate used in the present invention has been confirmed to exhibit excellent antitumor effects even as a single agent.
  • the present invention aims to provide a pharmaceutical composition characterized by administering a combination of a specific anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor, and/or a treatment method characterized by administering a combination of a specific anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor to an individual.
  • the inventors conducted extensive research to solve the above problems and discovered that administering a specific anti-B7-H3 antibody-drug conjugate in combination with an ATR inhibitor or an ATM inhibitor showed excellent combined effects, leading to the completion of the present invention.
  • the present invention provides the following. [1] A pharmaceutical composition comprising an anti-B7-H3 antibody-drug conjugate, the anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor are administered in combination;
  • the anti-B7-H3 antibody-drug conjugate has the formula
  • a pharmaceutical composition comprising an anti-B7-H3 antibody-drug conjugate, The anti-B7-H3 antibody-drug conjugate is administered in combination with an ATR inhibitor or an ATM inhibitor, and
  • the anti-B7-H3 antibody-drug conjugate is a pharmaceutical composition comprising a drug linker represented by the above formula (Chemical Formula 1) and an anti-B7-H3 antibody or a functional fragment thereof bound via a thioether bond.
  • An anti-B7-H3 antibody or a functional fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 8; a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 9; a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 10; a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 4 ...11
  • composition according to [5], wherein the anti-B7-H3 antibody or a functional fragment thereof comprises a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 of SEQ ID NO: 3, and a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 of SEQ ID NO: 4.
  • An anti-B7-H3 antibody comprising a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 8; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 9; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 10; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 4 ...11; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to
  • the pharmaceutical composition according to [7], wherein the anti-B7-H3 antibody comprises (or consists of) a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 4.
  • the ATR inhibitor is AZD6738, BAY-1895344, or ETP-46464, or a pharma- ceutical acceptable salt thereof.
  • a cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma
  • a pharmaceutical composition comprising an anti-B7-H3 antibody-drug conjugate, the anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor are administered in combination;
  • the anti-B7-H3 antibody-drug conjugate has the formula
  • a pharmaceutical composition comprising an antibody-drug conjugate represented by the formula: [21] A pharmaceutical composition comprising an anti-B7-H3 antibody-drug conjugate, The anti-B7-H3 antibody-drug conjugate is administered in combination with an ATR inhibitor or an ATM inhibitor, and The anti-B7-H3 antibody-drug conjugate is represented by the above formula (Chemical Formula 2): (In the formula, the antibody is an anti-B7-H3 antibody or a functional fragment thereof, each drug linker represented by the structure shown in the formula is bound to the antibody or a functional fragment thereof via a thioether bond, and n represents the average number of drug linkers bound per antibody.) A pharmaceutical composition comprising: [22] The pharmaceutical composition described in [20] or [21], which is
  • a cancer selected from the group consisting of breast cancer, gastric cancer, colore
  • composition for treating a cancer selected from the group consisting of breast cancer, lung cancer, esophageal cancer, head and neck cancer, prostate cancer, and squamous cell cancer.
  • a method for treating an individual in need of treatment comprising administering to the individual an anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor in combination,
  • the antibody-drug conjugate has the formula
  • An anti-B7-H3 antibody or a functional fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 8; a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 9; a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 10; a heavy chain variable region consisting of the amino acid sequence of amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain variable region consisting of the amino acid sequence of amino acid numbers 21 to 128 in SEQ ID NO: 4 ...11
  • An anti-B7-H3 antibody comprising a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 8; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 9; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 10; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to 233 in SEQ ID NO: 4 ...11; a heavy chain having an amino acid sequence of amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain having an amino acid sequence of amino acid numbers 21 to
  • the method for treating a cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, melanoma, and mesothelioma.
  • a cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophage
  • a method for treating an individual in need of treatment comprising administering to the individual an anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor in combination,
  • the anti-B7-H3 antibody-drug conjugate has the formula
  • the antibody is an anti-B7-H3 antibody or a functional fragment thereof, the drug linker is bound to the antibody or a functional fragment thereof via a thioether bond, and n represents the average number of drug linkers bound per antibody.
  • the therapeutic method comprises administering to the patient an antibody-drug conjugate as defined above. [52] The therapeutic method described in [51], wherein the treatment is treatment of cancer. [53] The treatment method according to [51] or [52], wherein the anti-B7-H3 antibody comprises a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 20 to 471 of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 21 to 233 of SEQ ID NO: 4.
  • [54] The method of treatment according to any one of [51] to [53], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.
  • [55] The method of any one of [51] to [54], wherein n is in the range of 3.5 to 4.5.
  • [56] The method of any one of [51] to [55], wherein the anti-B7-H3 antibody-drug conjugate is ifinatamab deruxtecan.
  • the ATR inhibitor is AZD6738, BAY-1895344, or ETP-46464, or a pharma- ceutical acceptable salt thereof.
  • [61] The method of any one of [51] to [60], wherein the anti-B7-H3 antibody-drug conjugate and the ATR inhibitor or ATM inhibitor are contained in different formulations and administered simultaneously or at different times.
  • a cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma
  • a pharmaceutical combination of (i) an anti-B7-H3 antibody-drug conjugate, preferably an anti-B7-H3 antibody-drug conjugate as defined in any one of [1] to [12], and (ii) an ATR inhibitor, preferably an ATR inhibitor as defined in [13] or [14], or an ATM inhibitor, preferably an ATM inhibitor as defined in [15] or [16].
  • a pharmaceutical composition comprising, for administration in combination, (i) an anti-B7-H3 antibody-drug conjugate, preferably an anti-B7-H3 antibody-drug conjugate defined in any one of [1] to [12], and (ii) an ATR inhibitor, preferably an ATR inhibitor defined in [13] or [14], or an ATM inhibitor, preferably an ATM inhibitor defined in [15] or [16].
  • a pharmaceutical composition comprising an anti-B7-H3 antibody-drug conjugate for administration in combination with an ATR inhibitor or an ATM inhibitor.
  • the pharmaceutical composition according to [67] wherein the drug in the anti-B7-H3 antibody-drug conjugate is a topoisomerase I inhibitor.
  • the pharmaceutical composition according to [68], wherein the anti-tumor compound represented by the formula: [71] The pharmaceutical composition according to [70], wherein the anti-tumor compound is bound to the anti-B7-H3 antibody via a linker via a thioether bond formed at a disulfide bond site present in the anti-B7-H3 antibody. [72] The pharmaceutical composition according to [70] or [71], wherein the linker comprises a tetrapeptide residue of Gly-Gly-Phe-Gly-.
  • the present invention can provide a pharmaceutical composition characterized in that a specific anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor are administered in combination, and/or a treatment method characterized in that a specific anti-B7-H3 antibody-drug conjugate and an ATR inhibitor or an ATM inhibitor are administered in combination to an individual.
  • FIG. 1 shows the amino acid sequence of B7-H3 variant 1 (SEQ ID NO:1).
  • FIG. 2 shows the amino acid sequence of B7-H3 variant 2 (SEQ ID NO:2).
  • FIG. 2 shows the amino acid sequence of the anti-B7-H3 antibody heavy chain (M30-H1 type) (SEQ ID NO: 3).
  • FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (M30-L4 type) (SEQ ID NO: 4).
  • FIG. 5 shows the amino acid sequence of the anti-B7-H3 antibody heavy chain (M30-H2 type) (SEQ ID NO:5).
  • FIG. 1 shows the amino acid sequence of the anti-B7-H3 antibody heavy chain (M30-H3 type) (SEQ ID NO: 6).
  • FIG. 7 shows the amino acid sequence of the anti-B7-H3 antibody heavy chain (M30-H4 type) (SEQ ID NO: 7).
  • FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (M30-L1 type) (SEQ ID NO: 8).
  • FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (M30-L2 type) (SEQ ID NO: 9).
  • FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (M30-L3 type) (SEQ ID NO: 10).
  • FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (M30-L5 type) (SEQ ID NO: 11).
  • FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (M30-L6 type) (SEQ ID NO: 12).
  • FIG. 1 shows the amino acid sequence of the light chain of anti-B7-H3 antibody (M30-L7 type) (SEQ ID NO: 13).
  • This is a diagram showing the cell proliferation inhibitory effect of anti-B7-H3 antibody-drug conjugate (1) alone and anti-B7-H3 antibody-drug conjugate (1) in combination with ATRi (AZD6738) or ATMi (AZD1390) on human lung cancer cells NCI-H322.
  • Black circles indicate groups treated with anti-B7-H3 antibody-drug conjugate (1) alone at each concentration
  • white squares indicate groups treated with anti-B7-H3 antibody-drug conjugate (1) in combination with AZD6738 (final concentration 300 nM) at each concentration
  • white triangles indicate groups treated with anti-B7-H3 antibody-drug conjugate (1) in combination with AZD1390 (final concentration 100 nM).
  • (-) indicates no treatment with anti-B7-H3 antibody-drug conjugate (1).
  • Black circles indicate groups treated with anti-B7-H3 antibody-drug conjugate (1) alone at each concentration
  • white squares indicate groups treated with anti-B7-H3 antibody-drug conjugate (1) in combination with AZD6738 (final concentration 300 nM) at each concentration
  • white triangles indicate groups treated with anti-B7-H3 antibody-drug conjugate (1) in combination with AZD1390 (final concentration 100 nM) at each concentration.
  • (-) indicates no treatment with anti-B7-H3 antibody-drug conjugate (1).
  • This figure shows the in vivo antitumor activity of a solvent control, ATRi (AZD6738) alone, anti-B7-H3 antibody-drug conjugate (1) alone, and a combination treatment of anti-B7-H3 antibody-drug conjugate (1) and ATRi (AZD6738).
  • This figure shows the in vivo antitumor activity of a solvent control, ATMi (AZD1390) alone, anti-B7-H3 antibody-drug conjugate (1) alone, and a combination of anti-B7-H3 antibody-drug conjugate (1) and ATMi (AZD1390).
  • cancer and “tumor” are used interchangeably.
  • the term “gene” includes not only DNA but also its mRNA, cDNA and its cRNA.
  • CDR means a complementarity determining region (CDR). It is known that there are three CDRs in each of the heavy and light chains of an antibody molecule. CDRs are also called hypervariable regions, and are located in the variable regions of the heavy and light chains of an antibody, and are sites with particularly high variability in the primary structure, and are separated into three sites in the primary structure of the heavy and light chain polypeptide chains.
  • the CDRs of the heavy chain are represented as CDRH1, CDRH2, and CDRH3 from the amino terminal side of the heavy chain amino acid sequence
  • the CDRs of the light chain are represented as CDRL1, CDRL2, and CDRL3 from the amino terminal side of the light chain amino acid sequence. These sites are close to each other in the three-dimensional structure, and determine the specificity for the antigen to which they bind.
  • Anti-B7-H3 antibody-drug conjugates used in the present invention are known in the art. Examples of such anti-B7-H3 antibody-drug conjugates include, but are not limited to, vobramitamab duocarmazine (MGC018), mirzotamab clezutoclax (ABBV-155), BAT8009, HS-20093, MHB088C, 7MW3711, and DB-1311.
  • Anti-B7-H3 antibody-drug conjugates are also described in WO2014/057687, WO2023/061457, US11,685,742B2, US20210347894A, US20220233708A, WO2024/022372, WO2022/117040, WO2024/037503, WO2024/037503, and WO2023/241663, all of which are incorporated herein by reference.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention comprises: formula
  • the partial structure of the anti-B7-H3 antibody-drug conjugate consisting of a linker and a drug is referred to as the "drug linker.”
  • This drug linker is bonded to a thiol group (in other words, the sulfur atom of a cysteine residue) generated at the disulfide bond site between the antibody chains (two sites between the heavy chains and the heavy chains, and two sites between the heavy chains and the light chains).
  • the drug linker of the present invention is comprised of the topoisomerase I inhibitor 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]quinoline-10,13-dione, (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]quinoline-10,13(9H,15H)-dione)).
  • Exatecan is formula
  • camptothecin derivative with antitumor effects represented by the formula:
  • the anti-B7-H3 antibody-drug conjugate used in the present invention comprises: formula
  • n is synonymous with the so-called average drug binding number (DAR; Drug-to-Antibody Ratio) and indicates the average number of drug linkers bound per antibody.
  • DAR Drug-to-Antibody Ratio
  • the "average number of drug linkers bound” is also called the Drug-to-Antibody Ratio (DAR) and indicates the average number of drugs (or drug linkers) bound per antibody in the antibody-drug conjugate composition.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention after being transferred into cancer cells, formula
  • the above compound is considered to be the main component of the antitumor activity of the anti-B7-H3 antibody-drug conjugate used in the present invention, and is presumed 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-B7-H3 antibody-drug conjugate used in the present invention is ifinatamab deruxtecan.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention is also presumed to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).
  • This bystander effect is thought to be exerted when the anti-B7-H3 antibody-drug conjugate used in the present invention is internalized in target-expressing cancer cells, and the compound is then released to exert an antitumor effect on nearby cancer cells that do not express the target.
  • Anti-B7-H3 Antibody B7-H3 is a member of the B7 family that is expressed as a costimulatory molecule on antigen-presenting cells, and is thought to promote or suppress immune activity by acting on receptors on T cells.
  • B7-H3 is a protein with a single transmembrane structure and exists in two variants.
  • B7-H3 variant 1 (4Ig-B7-H3) has two V- or C-like Ig domains
  • B7-H3 variant 2 (2Ig-B7-H3) has one V- or C-like Ig domain.
  • the B7-H3 used in the present invention can be directly purified from B7-H3-expressing cells of humans or non-human mammals (rats, mice, etc.) or prepared as a cell membrane fraction of the cells.
  • B7-H3 can also be obtained by synthesizing it in vitro or by producing it in host cells through genetic engineering.
  • the protein can be obtained by incorporating B7-H3 cDNA into an expression vector, and then synthesizing it in a solution containing enzymes, substrates, and energy materials necessary for transcription and translation, or by expressing B7-H3 by transforming other prokaryotic or eukaryotic host cells.
  • amino acid sequence of the open reading frame (ORF) of the human B7-H3 variant 1 gene is set forth in SEQ ID NO:1 of the sequence listing.
  • sequence of SEQ ID NO:1 is also set forth in Figure 1.
  • amino acid sequence of the ORF of the human B7-H3 variant 2 gene is set forth in SEQ ID NO:2 in the sequence listing.
  • sequence of SEQ ID NO:2 is also set forth in Figure 2.
  • B7-H3 proteins that have the same biological activity as the above B7-H3 proteins, and that have an amino acid sequence in which one or more amino acids have been substituted, deleted, and/or added.
  • Mature human B7-H3 variant 1 from which the signal sequence has been removed corresponds to the amino acid sequence consisting of the 27th to 534th amino acid residues in the amino acid sequence shown in SEQ ID NO:1.
  • Mature human B7-H3 variant 2 from which the signal sequence has been removed corresponds to the amino acid sequence consisting of the 27th to 316th amino acid residues in the amino acid sequence shown in SEQ ID NO:2.
  • the anti-B7-H3 antibody in the anti-B7-H3 antibody-drug conjugate used in the present invention may be derived from any species, but is preferably an antibody derived from human, rat, mouse, and rabbit. If the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques.
  • the antibody of the present invention may be a polyclonal or monoclonal antibody, but is preferably a monoclonal antibody.
  • the anti-B7-H3 antibody in the anti-B7-H3 antibody-drug conjugate used in the present invention preferably has the property of targeting cancer cells, and preferably has the ability to recognize cancer cells, the ability to bind to cancer cells, the ability to be taken up and internalized within cancer cells, and/or cytocidal activity against cancer cells.
  • Binding of antibodies to cancer cells can be confirmed using flow cytometry.
  • Antibody uptake into cancer cells can be confirmed using (1) an assay in which a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody is used to visualize the antibody taken up into the cell using a fluorescent microscope (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay in which a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody is used to measure the amount of fluorescence taken up into the cell (Molecular Biology of the Cell Vol.
  • the antitumor activity of an antibody can be confirmed in vitro by measuring its inhibitory activity against cell proliferation.
  • a cancer cell line that overexpresses the antibody's target protein can be cultured, and the antibody can be added to the culture system at various concentrations to measure the inhibitory activity against focus formation, colony formation, and spheroid proliferation.
  • the antitumor activity can be confirmed by administering the antibody to nude mice transplanted with a cancer cell line that highly expresses the target protein, and measuring changes in the cancer cells.
  • the antibody itself has an antitumor effect, but since the anti-B7-H3 antibody-drug conjugate is bound to a compound that exerts an antitumor effect, the antitumor effect of the anti-B7-H3 antibody itself is not essential.
  • the antibody has the property of being internalized and transferred into the cancer cells.
  • the anti-B7-H3 antibody in the anti-B7-H3 antibody-drug conjugate used in the present invention can be obtained by known means. For example, it can be obtained by immunizing an animal with an antigenic polypeptide and collecting and purifying the antibody produced in the body using a method commonly used in this field.
  • the origin of the antigen is not limited to humans, and animals can also be immunized with antigens derived from animals other than humans, such as mice and rats.
  • antibodies applicable to human diseases can be selected by testing the cross-reactivity of the obtained antibodies that bind to heterologous antigens with human antigens.
  • hybridomas can be established by fusing antibody-producing cells that produce antibodies against an antigen with myeloma cells, thereby obtaining monoclonal antibodies.
  • Antigens can be obtained by genetically manipulating a gene that codes for an antigen protein to produce it in a host cell. Specifically, a vector capable of expressing an antigen gene is prepared, introduced into a host cell to express the gene, and the expressed antigen is purified. Antibodies can also be obtained by immunizing an animal with the above genetically engineered antigen-expressing cells or a cell line expressing the antigen.
  • the anti-B7-H3 antibody in the anti-B7-H3 antibody-drug conjugate used in the present invention is preferably a genetically engineered antibody that has been artificially modified for the purpose of reducing xenoantigenicity to humans, such as a chimeric antibody or a humanized antibody, or an antibody that contains (has) only the genetic sequence of an antibody of human origin, i.e., a human antibody.
  • a genetically engineered antibody that has been artificially modified for the purpose of reducing xenoantigenicity to humans, such as a chimeric antibody or a humanized antibody, or an antibody that contains (has) only the genetic sequence of an antibody of human origin, i.e., a human antibody.
  • These antibodies can be produced using known methods.
  • Chimeric antibodies include antibodies whose variable and constant regions are heterologous, such as chimeric antibodies in which the variable region of a mouse or rat antibody is joined to a constant region of human origin (Proc. Natl. Acad. Sci. U.S.A., 81, 6851-6855, (1984)).
  • Humanized antibodies include antibodies in which only the complementarity determining region (CDR) of a heterologous antibody has been incorporated into a human-derived antibody (Nature (1986) 321, p. 522-525), antibodies in which not only the CDR sequence of a heterologous antibody but also some of the amino acid residues in the framework of the heterologous antibody have been grafted onto a human antibody by the CDR grafting method (WO 90/07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5,821,337).
  • CDR complementarity determining region
  • Human antibodies include antibodies generated using human antibody-producing mice that contain (have) human chromosome fragments that include genes for the heavy and light chains of human antibodies (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 Tec see, for example, Phenotypy: Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K.
  • antibodies obtained by phage display selected from a human antibody library can also be used (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.).
  • the anti-B7-H3 antibody in the anti-B7-H3 antibody-drug conjugate used in the present invention also includes modified antibodies.
  • the modified antibody means an antibody according to the present invention that has been chemically or biologically modified. Chemical modifications include those having a chemical moiety bonded to the amino acid backbone, or a chemical moiety bonded to an N- or O-linked carbohydrate chain.
  • Biological modifications include those that have been post-translationally modified (e.g., addition of an N- or O-linked glycan, processing of the N- or C-terminus, deamidation, isomerization of aspartic acid, oxidation of methionine, etc.), and those that have been expressed using a prokaryotic host cell to add a methionine residue to the N-terminus.
  • those labeled to enable detection or isolation of the antibody or antigen according to the present invention such as enzyme-labeled, fluorescent-labeled, and affinity-labeled antibodies, are also included in the meaning of such modified antibodies.
  • modified antibodies according to the present invention are useful for improving the stability and blood retention of the antibody, reducing antigenicity, and detecting or isolating the antibody or antigen, etc.
  • antibody-dependent cellular cytotoxicity can be enhanced by adjusting the glycan modification (glycosylation, defucosylation, etc.) attached to the antibody of the present invention.
  • glycan modification glycosylation, defucosylation, etc.
  • Known techniques for adjusting the glycan modification of antibodies include, but are not limited to, those described in WO 99/54342, WO 00/61739, WO 02/31140, WO 2007/133855, and WO 2013/120066.
  • the antibodies of the present invention also include antibodies in which the glycan modification has been adjusted.
  • the anti-B7-H3 antibody used in the present invention includes the modified antibody and various functional fragments of the anti-B7-H3 antibody. Furthermore, deletions in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain, and deletions in which the heavy chain is amidated (for example, a heavy chain in which a proline residue at the carboxyl terminus is amidated), etc. are also included. However, as long as the antigen-binding ability and effector function are maintained, the deletions at the carboxyl terminus of the heavy chain of the antibody of the present invention are not limited to the above types.
  • the two heavy chains constituting the antibody used in the present invention may be any one of the heavy chains selected from the group consisting of full-length and the above deletions, or may be a combination of two of them.
  • the quantitative ratio of each deletion may be affected by the type of mammalian cultured cells that produce the antibody of the present invention and the culture conditions, but the antibody of the present invention is preferably one in which one amino acid residue is deleted at the carboxyl terminus of both of the two heavy chains.
  • the term "functional fragment" of an antibody also referred to in one embodiment as "antigen-binding fragment of an antibody” is used to mean a partial fragment of an antibody that has binding activity to an antigen, including, but not limited to, Fab, F(ab') 2 , scFv, diabody, linear antibody, and multispecific antibody formed from antibody fragments.
  • Fab' which is a fragment of a monovalent antibody variable region obtained by treating F(ab') 2 under reducing conditions, is also included in the antigen-binding fragment of an antibody.
  • Antigen-binding fragments of antibodies are not limited to these molecules, and include other molecules as long as they have antigen-binding ability. These antigen-binding fragments include not only those obtained by treating the full-length molecule of an antibody protein with an appropriate enzyme, but also proteins produced in an appropriate host cell using a genetically modified antibody gene.
  • the isotype of the antibody according to the present invention can be, for example, IgG (IgG1, IgG2, IgG3, IgG4), etc., with IgG1 or IgG2 being preferred.
  • anti-B7-H3 antibody refers to an antibody that specifically binds to B7-H3 (B cell antigen #7 homolog 3; PD-L3; CD276), and preferably has the activity of being internalized into B7-H3-expressing cells by binding to B7-H3.
  • anti-B7-H3 antibodies include any combination of (1) an amino acid sequence consisting of the 20th to 141st amino acid residues of SEQ ID NO: 3, 5, 6, or 7 in the sequence listing, (2) an amino acid sequence having at least 95% homology to the amino acid sequence of (1) above, and (3) an amino acid sequence in which one or more amino acids have been deleted, substituted, or added in the amino acid sequence of (1) above, and (4) an amino acid sequence consisting of the 21st to 128th amino acid residues of SEQ ID NO: 4, 8, 9, 10, 11, 12, or 13, (5) an amino acid sequence having at least 95% homology to the amino acid sequence of (4) above, and (6) an amino acid sequence in which one or more amino acids have been deleted, substituted, or added in the amino acid sequence of (4) above, and preferably M30-H1-L4 (WO2014/057687).
  • "several" means 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 or 2.
  • amino acid substitutions are substitutions that occur within amino acid groups that are related to the amino acid side chains.
  • an antibody having a suitable combination of the above-mentioned heavy chain and light chain there is provided an antibody having a heavy chain including a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain including a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 in SEQ ID NO: 8; an antibody having a heavy chain including a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 in SEQ ID NO: 3 and a light chain including a light chain variable region consisting of the amino acid sequence set forth in amino acid numbers 21 to 128 in SEQ ID NO: 9 ...
  • antibodies include an antibody having a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 at amino acid numbers 20 to 471 and a light chain consisting of the amino acid sequence described in SEQ ID NO:8 at amino acid numbers 21 to 233; an antibody having a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 at amino acid numbers 20 to 471 and a light chain consisting of the amino acid sequence described in SEQ ID NO:9 at amino acid numbers 21 to 233; an antibody having a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 at amino acid numbers 20 to 471 and a light chain consisting of the amino acid sequence described in SEQ ID NO:10 at amino acid numbers 21 to 233; an antibody having a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 at amino acid numbers 20 to 471 and a light chain consisting of the amino acid sequence described in SEQ ID NO:4 at amino acid numbers 21 to 233; an antibody having a heavy chain consisting of the amino acid sequence described in
  • Suitable combinations include an antibody consisting of a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 and a light chain consisting of the amino acid sequence described in SEQ ID NO:8, an antibody consisting of a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 and a light chain consisting of the amino acid sequence described in SEQ ID NO:9, an antibody consisting of a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 and a light chain consisting of the amino acid sequence described in SEQ ID NO:10, an antibody consisting of a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 and a light chain consisting of the amino acid sequence described in SEQ ID NO:4, an antibody consisting of a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 and a light chain consisting of the amino acid sequence described in SEQ ID NO:11, an antibody consisting of a heavy chain consisting of the amino acid sequence described in SEQ ID NO:3 and a
  • antibodies that have cytotoxic activity equivalent to each of the above antibodies By combining sequences that show high homology with the above heavy chain amino acid sequences and light chain amino acid sequences, it is possible to select antibodies that have cytotoxic activity equivalent to each of the above antibodies. Such homology is generally 80% or more, preferably 90% or more, more preferably 95% or more, and most preferably 99% or more. It is also possible to select antibodies that have cytotoxic activity equivalent to each of the above antibodies by combining amino acid sequences in which one or several amino acid residues have been substituted, deleted, or added to the heavy chain or light chain amino acid sequences.
  • the BLAST ratio can be determined by using the default parameters of the BLAST algorithm (Lipman, 1997, "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs", Nucleic Acids Res. 25:3389-3402).
  • the Blast algorithm can also be accessed on the Internet at www.ncbi.nlm.nih.gov/blast.
  • the amino acid sequence consisting of amino acid residues 1 to 19 is a signal sequence
  • the amino acid sequence consisting of amino acid residues 20 to 141 is a variable region
  • the amino acid sequence consisting of amino acid residues 142 to 471 is a constant region.
  • the sequence of SEQ ID NO:3 is shown in Figure 3
  • the sequence of SEQ ID NO:5 is shown in Figure 5
  • the sequence of SEQ ID NO:6 is shown in Figure 6
  • the sequence of SEQ ID NO:7 is shown in Figure 7.
  • the amino acid sequence consisting of amino acid residues 1 to 20 is a signal sequence
  • the amino acid sequence consisting of amino acid residues 21 to 128 is a variable region
  • the amino acid sequence consisting of amino acid residues 129 to 233 is a constant region.
  • the sequence of SEQ ID NO: 4 is shown in Figure 4, the sequence of SEQ ID NO: 8 in Figure 8, the sequence of SEQ ID NO: 9 in Figure 9, the sequence of SEQ ID NO: 10 in Figure 10, the sequence of SEQ ID NO: 11 in Figure 11, the sequence of SEQ ID NO: 12 in Figure 12, and the sequence of SEQ ID NO: 13 in Figure 13.
  • the above drug linker intermediate is 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': It can be expressed by the chemical name [6,7] indolizino[1,2-b]quinolin-1-yl]amino ⁇ -2-oxoethoxy)methyl]glycinamide, and can be produced with reference to the descriptions in WO 2014/057687, WO 2015/098099, WO 2015/115091, WO 2015/155998, and WO 2019/044947.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention can be produced by reacting the aforementioned drug linker intermediate with an anti-B7-H3 antibody having a thiol group (also called a sulfhydryl group).
  • Antibodies having sulfhydryl groups can be obtained by methods well known to those skilled in the art (Hermanson, G. T, Bioconjugate Techniques, pp.56-136, pp.456-493, Academic Press (1996)).
  • a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) can be used in an amount of 0.3 to 3 molar equivalents per intra-chain disulfide of the antibody, and reacted with the antibody in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), to obtain an antibody having sulfhydryl groups in which the intra-chain disulfides of the antibody have been partially or completely reduced.
  • TCEP tris(2-carboxyethyl)phosphine hydrochloride
  • EDTA ethylenediaminetetraacetic acid
  • 2 to 20 molar equivalents of drug linker intermediate can be used per antibody having a sulfhydryl group to produce antibody-drug conjugates in which 2 to 8 drugs are bound per antibody.
  • the average number of drugs bound per antibody molecule of the produced antibody-drug conjugate can be calculated, for example, by a method in which the UV absorbance of the anti-B7-H3 antibody-drug conjugate and its conjugation precursor are measured at two wavelengths, 280 nm and 370 nm (UV method), or by a method in which the antibody-drug conjugate is treated with a reducing agent, and each of the resulting fragments is quantified by HPLC measurement and calculated (HPLC method).
  • anti-B7-H3 antibody-drug conjugate refers to an antibody-drug conjugate according to the present invention in which the antibody is an anti-B7-H3 antibody.
  • the anti-B7-H3 antibody is preferably an antibody comprising a heavy chain variable region including a CDRH1 consisting of the amino acid sequence set forth in amino acid numbers 50 to 54 in SEQ ID NO: 3, a CDRH2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 85 in SEQ ID NO: 3, and a CDRH3 consisting of the amino acid sequence set forth in amino acid numbers 118 to 130 in SEQ ID NO: 3, and a light chain variable region including a CDRL1 consisting of the amino acid sequence set forth in amino acid numbers 44 to 53 in SEQ ID NO: 4, a CDRL2 consisting of the amino acid sequence set forth in amino acid numbers 69 to 75 in SEQ ID NO: 4, and a CDRL3 consisting of the amino acid sequence set forth in amino acid numbers 108 to 116 in SEQ ID NO: 4, More preferably, the antibody comprises a heavy chain variable region consisting of the amino acid sequence set forth in amino acid numbers 20 to 141 of SEQ ID NO: 3, and a light chain variable region consist
  • the average number of drug linkers bound per antibody in the anti-B7-H3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.
  • "about 4" is preferably 3.8 to 4.2, more preferably 3.9 to 4.1, and even more preferably 4.
  • the average number of drugs or drug linkers bound per antibody in the anti-B7-H3 antibody-drug conjugate is preferably an integer in the range of 2 to 8, more preferably 2, 4, 6, or 8, and most preferably 4.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention can be produced with reference to the descriptions in WO 2014/057687 and WO 2017/002776, etc.
  • ATR inhibitor refers to an agent that inhibits the kinase activity of Ataxia-telangiectacia mutated and Rad3-related (ATR).
  • the ATR inhibitor of the present invention may have the effect of inhibiting kinases other than ATR, but is preferably a drug that selectively inhibits ATR kinase activity.
  • the ATR inhibitor in the present invention is not particularly limited as long as it is a drug having the above-mentioned properties, but preferred examples include AZD6738, BAY-1895344 (CAS number 1876467-74-1), and ETP-46464 (CAS number 1345675-02-6), as well as pharma- ceutical acceptable salts thereof.
  • the ATR inhibitors used in the present invention can be produced according to known methods, for example, AZD6738 can be obtained according to WO2011/154737.
  • ATM inhibitor refers to a drug that inhibits the kinase activity of Ataxia telangiectacia mutated (ATM).
  • the ATM inhibitor of the present invention may have the effect of inhibiting kinases other than ATM, but is preferably a drug that selectively inhibits ATM kinase activity.
  • the ATM inhibitor in the present invention is not particularly limited as long as it is a drug having the above-mentioned properties, but is preferably AZD1390 (WO2017/046216: Example 2), AZD0156 (WO2015/170081: Example 1), KU-55933 (CAS number 587871-26-9; WO2003070726A1), KU-60019 (C Examples of such compounds include CAS number 925701-49-1), KU-59403 (WO2005016919), CP466722 (CAS number 1080622-86-1), and NVP-BEZ235 (dactolisib; CAS number 915019-65-7; WO2006/122806), as well as pharma- ceutical acceptable salts thereof.
  • the ATM inhibitors used in the present invention can be produced according to known methods.
  • AZD1390 and AZD0156 can be obtained according to WO2017/046216 and WO2015/170081.
  • the ATR inhibitor or ATM inhibitor used in the present invention is not particularly limited as long as it is a drug having the above-mentioned properties, but may be a low molecular weight compound, an antibody, a functional fragment of an antibody, a fusion protein, an immunoadhesin, a nucleic acid, an oligonucleotide, an aptamer, or a polypeptide, and is preferably a low molecular weight compound.
  • the low molecular weight compound is preferably an organic compound having a molecular weight of 1000 or less, more preferably a molecular weight of 900 or less, even more preferably a molecular weight of 800 or less, even more preferably a molecular weight of 700 or less, even more preferably a molecular weight of 600 or less, even more preferably a molecular weight of 500 or less, even more preferably a molecular weight of 50 to 500, and even more preferably a molecular weight of 100 to 500.
  • the "pharmacologically acceptable salt" of the ATR inhibitor or ATM inhibitor used in the present invention may be either an acid addition salt or a base addition salt.
  • acid addition salts include lower alkane sulfonates such as camsylate (camphorsulfonate), mesylate (methanesulfonate), trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as tosylate (p-toluenesulfonate) and benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate, and sulfate; hydrohalide 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 ornithine, glutamate
  • base addition salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; organic amine salts such as dibenzylamine salts, morpholine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as arginine salts.
  • alkali metal salts such as sodium salts, potassium salt
  • the ATR inhibitors or ATM inhibitors and their pharma- ceutically acceptable salts used in the present invention may exist as solvates, and these solvates are also included in the ATR inhibitors or ATM inhibitors and their pharma-ceutically acceptable salts used in the present invention.
  • the ATR inhibitor or ATM inhibitor used in the present invention may include a therapeutically effective amount of the ATR inhibitor or ATM inhibitor, a pharma- ceutically acceptable carrier, a diluent, a solubilizer, an emulsifier, a preservative, an adjuvant, etc.
  • the "pharma-ceutically acceptable carrier” etc. may be selected from a wide range of options depending on the type of target disease and the dosage form of the drug.
  • the administration method may be selected as appropriate, for example, by injection, and local injection, intraperitoneal injection, selective intravenous injection, intravenous injection, subcutaneous injection, organ perfusion injection, etc. may be adopted.
  • the solution for injection may be formulated using a carrier consisting of a salt solution, a glucose solution, or a mixture of salt water and glucose solution, various buffer solutions, etc.
  • the solution for injection may be formulated in a powder state, and the injection may be prepared by mixing with the liquid carrier at the time of use.
  • oral liquids powders, pills, capsules, tablets, etc.
  • the liquids can be produced as oral liquid preparations such as suspensions and syrups using water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, oils such as sesame oil and soybean oil, preservatives such as alkyl parahydroxybenzoate, flavors such as strawberry flavor and peppermint, etc.
  • Powders, pills, capsules, and tablets can be formulated using excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, etc. Tablets and capsules are preferred unit dosage forms in that they are easy to administer. When making tablets or capsules, solid manufacturing carriers are used.
  • compositions and a method of treatment characterized in that the anti-B7-H3 antibody-drug conjugate according to the present invention is administered in combination with an ATR inhibitor or an ATM inhibitor will be described.
  • the invention includes a pharmaceutical composition comprising an anti-B7-H3 antibody-drug conjugate used in combination with an ATR inhibitor or an ATM inhibitor, or administered in combination with an ATR inhibitor or an ATM inhibitor.
  • the pharmaceutical composition or treatment method of the present invention may be characterized in that the anti-B7-H3 antibody-drug conjugate and the ATR inhibitor or ATM inhibitor are contained as active ingredients in separate formulations and administered simultaneously or at different times, or the anti-B7-H3 antibody-drug conjugate and the ATR inhibitor or ATM inhibitor are contained as active ingredients in a single formulation and administered.
  • the pharmaceutical composition or treatment method of the present invention may be administered in combination with two or more of the ATR inhibitors or ATM inhibitors used in the present invention.
  • the pharmaceutical composition or method of treatment of the present invention can be used for the treatment of cancer, and is preferably selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer (e.g., small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC)), esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer (e.g., castration-resistant prostate cancer (CRPC)), bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme
  • At least one cancer more preferably at least one cancer selected from the group consisting of breast cancer, lung cancer (e.g., small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC)), esophageal cancer, head and neck cancer, prostate cancer (e.g., castration-resistant prostate cancer (CRPC)), bladder cancer, squamous cell carcinoma, uterine cancer, sarcoma, and melanoma, and even more preferably at least one cancer selected from the group consisting of breast cancer, lung cancer (e.g., small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC)), esophageal cancer, head and neck cancer, prostate cancer (e.g., castration-resistant prostate cancer (CRPC)), and squamous cell carcinoma.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • CRPC castration-resistant prostate cancer
  • the present invention relates to a cancer therapeutic agent used in combination with an ATR inhibitor or an ATM inhibitor, the cancer therapeutic agent comprising an anti-B7-H3 antibody-drug conjugate as an active ingredient, for use in patients who are (already) receiving treatment with an ATR inhibitor or an ATM inhibitor.
  • the present invention relates to a cancer therapeutic agent containing an anti-B7-H3 antibody-drug conjugate as an active ingredient for use in the treatment of cancer, the treatment comprising the administration of an ATR inhibitor or an ATM inhibitor.
  • the present invention relates to an anti-B7-H3 antibody-drug conjugate for treating cancer when administered in combination with an ATR inhibitor or an ATM inhibitor.
  • the present invention relates to the use of an anti-B7-H3 antibody-drug conjugate in the manufacture of a medicament for treating cancer, for use in combination with an ATR inhibitor or an ATM inhibitor.
  • the present invention relates to a pharmaceutical combination of (i) an anti-B7-H3 antibody-drug conjugate and (ii) an ATR inhibitor or an ATM inhibitor.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) an anti-B7-H3 antibody-drug conjugate and (ii) an ATR inhibitor or an ATM inhibitor for administration in combination.
  • the present invention relates to a kit comprising (a) a first composition comprising an anti-B7-H3 antibody-drug conjugate and (b) a second composition comprising an ATR inhibitor or an ATM inhibitor.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention can be suitably used when B7-H3 expression has been confirmed in cancer.
  • the presence or absence of the B7-H3 tumor marker can be confirmed, for example, by collecting tumor tissue from a cancer patient and testing the formalin-fixed, paraffin-embedded (FFPE) specimen at the gene product (protein) level using immunohistochemistry (IHC), a flow cytometer, Western blot, etc., or by testing at the gene transcription level using in situ hybridization (ISH), quantitative PCR (q-PCR), microarray analysis, etc.
  • FFPE formalin-fixed, paraffin-embedded
  • IHC immunohistochemistry
  • ISH in situ hybridization
  • q-PCR quantitative PCR
  • microarray analysis etc.
  • cell-free circulating tumor DNA ctDNA
  • NGS next-generation sequencing
  • the pharmaceutical composition and treatment method of the present invention can be preferably used in mammals, but more preferably in humans.
  • the antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed, for example, by creating a model in which cancer cells are transplanted into a test animal and measuring the reduction in tumor volume and the life-prolonging effect caused by administering the pharmaceutical composition and treatment method of the present invention.
  • the combined effect of the antibody-drug conjugate used in the present invention and the ATR inhibitor or ATM inhibitor can then be confirmed by comparing the antitumor effect with that of the antibody-drug conjugate used in the present invention and the ATR inhibitor or ATM inhibitor when administered alone.
  • the antitumor effect of the pharmaceutical composition and treatment method of the present invention can be confirmed in clinical trials by the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, weight measurement, and other methods, and a complete response (CR), partial response (PR), or other similar results can be obtained.
  • This can be determined using indicators such as progression (progression rate; PR), progression (progressive disease; PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
  • the above-mentioned method makes it possible to confirm the superiority of the antitumor effect of the pharmaceutical composition and treatment method of the present invention over existing pharmaceutical compositions and treatment methods for cancer treatment.
  • the pharmaceutical composition and treatment method of the present invention can slow the growth of cancer cells, inhibit their proliferation, and even destroy them. These actions can relieve cancer patients from symptoms caused by cancer and improve their quality of life, thereby preserving the life of the cancer patient and achieving a therapeutic effect. Even if the destruction of cancer cells is not achieved, the inhibition and control of cancer cell proliferation can enable cancer patients to achieve a higher quality of life and longer survival.
  • the pharmaceutical composition of the present invention can be applied to a patient as a systemic therapy, or can be applied locally to cancer tissue to achieve a therapeutic effect.
  • the pharmaceutical composition of the present invention may be administered containing one or more pharma- ceutical compatible components.
  • the pharma-ceutical compatible components may be appropriately selected from formulation additives and others commonly used in this field depending on the dose and administration concentration of the antibody-drug conjugate and ATR inhibitor or ATM inhibitor used in the present invention.
  • the antibody-drug conjugate used in the present invention may be administered as a pharmaceutical composition containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20.
  • the pharmaceutical composition containing the anti-B7-H3 antibody-drug conjugate used in the present invention may be preferably used as an injection, more preferably used as an aqueous injection or a lyophilized injection, and even more preferably used as a lyophilized injection.
  • the pharmaceutical composition containing the anti-B7-H3 antibody-drug conjugate used in the present invention is an aqueous injection, it can be preferably administered intravenously after diluting with an appropriate diluent.
  • diluents include glucose solution and saline solution, preferably glucose solution, and more preferably 5% glucose solution.
  • the pharmaceutical composition containing the anti-B7-H3 antibody-drug conjugate used in the present invention is a lyophilized injection, it can be preferably dissolved in water for injection, diluted with a required amount of an appropriate diluent, and then administered by intravenous drip.
  • diluents include glucose solution and physiological saline solution, preferably glucose solution, and more preferably 5% glucose solution.
  • the introduction routes that can be used to administer the pharmaceutical composition of the present invention include, for example, intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and preferably, intravenous routes.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention can be administered to a human at about 0.001 to 100 mg/kg once or multiple times at intervals of once every 1 to 180 days.
  • the anti-B7-H3 antibody-drug conjugate can be administered at a dose of preferably 0.1 to 50 mg/kg, more preferably 1 to 50 mg/kg, 1 to 30 mg/kg, 1 to 20 mg/kg, 1 to 15 mg/kg, 2 to 50 mg/kg, 2 to 30 mg/kg, 2 to 20 mg/kg, or 2 to 15 mg/kg multiple times at intervals of once every 1 to 4 weeks, preferably once every 2 to 3 weeks.
  • the anti-B7-H3 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, 4.8 mg/kg, 6.4 mg/kg, 8.0 mg/kg, 10.0 mg/kg, 12.0 mg/kg or 16.0 mg/kg, preferably once every three weeks at a dose of 8.0 mg/kg, 10.0 mg/kg or 12.0 mg/kg.
  • the ATR inhibitor or ATM inhibitor of the present invention can be orally administered to a human at intervals of 1 to 7 days, 1 to 2 times per day, preferably once a day or twice a day.
  • the ATR inhibitor or ATM inhibitor used in the present invention can be orally administered at a dose of 0.1 mg to 3000 mg per administration, preferably at a dose of 2.5 mg to 600 mg per administration.
  • the ATR inhibitor or ATM inhibitor of the present invention can be intravenously administered to a human at intervals of 1 to 180 days, preferably once a week, 2 weeks, 3 weeks, or 4 weeks.
  • the ATR inhibitor or ATM inhibitor used in the present invention can be intravenously administered at a dose of 0.1 mg to 3000 mg per administration, preferably at a dose of 10 mg to 100 mg per administration.
  • the ATR inhibitor or ATM inhibitor used in the present invention may be administered according to the following dosage regimen, but is not limited to these.
  • the ATR inhibitor or ATM inhibitor may be administered at a dose of 5 to 1000 mg once, twice, three times, four times, or five times a day.
  • the ATR or ATM inhibitor can be orally administered at a dose of 20 to 240 mg once a day.
  • the ATR inhibitor or ATM inhibitor can be orally administered at a dose of 20, 40, 80, 120, 160 or 240 mg (preferably 40, 80 or 120 mg) once a day.
  • the ATR or ATM inhibitor can be orally administered at a dose of 120 mg once a day.
  • the ATR inhibitor may be orally administered, preferably twice daily, at a dose of 20 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg or 240 mg per dose.
  • the pharmaceutical composition and treatment method of the present invention may further comprise a cancer therapeutic agent other than the anti-B7-H3 antibody-drug conjugate of the present invention and the ATR inhibitor or ATM inhibitor.
  • the pharmaceutical composition and treatment method of the present invention may be administered in combination with other cancer therapeutic agents, thereby enhancing the antitumor effect.
  • the other cancer therapeutic agent used for such a purpose may be administered to an individual simultaneously with the pharmaceutical composition of the present invention (here, a person skilled in the art will naturally understand that "simultaneously" may mean approximately simultaneously or not), separately, or consecutively, or may be administered at different administration intervals.
  • the individual (subject) is preferably a mammal, more preferably a human.
  • Such cancer therapeutic agents are not limited as long as they have antitumor activity, and examples thereof include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), gemcitabine, and capecitabine.
  • the drug may be at least one selected from the group consisting of oremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, a progesterone formulation, and lapatinib.
  • the pharmaceutical compositions and methods of treatment of the present invention can be used in combination with radiation therapy.
  • a cancer patient can receive radiation therapy before and/or after, or simultaneously with, treatment with the pharmaceutical composition of the present invention.
  • the pharmaceutical compositions and methods of treatment of the present invention can be used as adjuvant chemotherapy in combination with surgery.
  • the pharmaceutical compositions of the present invention can be administered prior to surgery to reduce tumor size (referred to as preoperative adjuvant chemotherapy, or neoadjuvant therapy), or after surgery to prevent tumor recurrence (referred to as postoperative adjuvant chemotherapy, or adjuvant therapy).
  • the pharmaceutical compositions and methods of treatment of the present invention can be used as a maintenance therapy.
  • a patient may continue to receive treatment after an initial chemotherapy treatment to prevent recurrence.
  • Production Example 1 Production of anti-B7-H3 antibody-drug conjugate
  • a humanized anti-B7-H3 antibody an antibody comprising a heavy chain consisting of the amino acid sequence represented by amino acid numbers 20 to 471 in SEQ ID NO: 3 and a light chain consisting of the amino acid sequence represented by amino acid numbers 21 to 233 in SEQ ID NO: 4
  • a conjugate was used to produce a conjugate.
  • anti-B7-H3 antibody-drug conjugate (1) An anti-B7-H3 antibody-drug conjugate (hereinafter referred to as "anti-B7-H3 antibody-drug conjugate (1)") was produced in which a drug linker represented by the formula: is linked to an anti-B7-H3 antibody via a thioether bond.
  • the DAR of the anti-B7-H3 antibody-drug conjugate (1) is 4.0.
  • Test Example 1 In vitro cell proliferation inhibition test The cell proliferation inhibition effect was evaluated using human lung cancer cells NCI-H322 and human breast cancer cell line EFM-19.
  • NCI-H322 and EFM-19 cells were cultured in RPMI 1640 (Life Technologies, Cat. No. 11875-119) medium containing 10% (v/v) Fetal Bovine Serum (HyClone, Cat. No. SH30396, Lot AE2916535) and 1% (v/v) Antibiotic-Antimycotic (Life Technologies, Cat. No. 15240-062) in a humidified 5% CO2 environment at 37°C. When each cell reached 70-80% confluence, each cell was detached with TryPLE (Life Technologies, 12605-010) and centrifuged, and then each cell was suspended in medium to a concentration of 1.00x10 5 cells/mL.
  • TryPLE Life Technologies, 12605-010
  • the prepared cell suspension was seeded in each well of a Corning(R) 96-well flat clear bottom black polystyrene TC-treated microplate at 100 ⁇ L each and incubated overnight at 37°C 5% CO 2. The next day, a dilution series of 2000, 600, 200, 60, 20, 6, and 2nM was prepared for the anti-B7-H3 antibody-drug conjugate (1) using the medium.
  • AZD6738 ATR inhibitor; ATRi, WO2011/154737
  • AZD1390 ATM inhibitor; ATMi, WO2017/046216
  • each solution of the dilution series of anti-B7-H3 antibody-drug conjugate (1) was mixed with medium at a 1:1 ratio to give final concentrations of 1000, 300, 100, 30, 10, 3, and 1 nM.
  • each solution of the dilution series of anti-B7-H3 antibody-drug conjugate (1) was mixed with AZD6738 and AZD1390 at a ratio of 1:1, so that the final concentration of each dilution series of anti-B7-H3 antibody-drug conjugate (1) was 1000, 300, 100, 30, 10, 3, 1 nM, and the final concentration of AZD6738 or AZD1390 for each dilution series was 300 or 100 nM, respectively. Then, the entire medium of the cells incubated overnight was aspirated, and for each mixture, 100 ⁇ L of each solution was added to the corresponding well of a 96-well plate containing cells, and incubated at 37 ° C.
  • Test Example 2 In vivo antitumor activity of anti-B7-H3 antibody-drug conjugate (1) in combination with ATR inhibitor: Solvent 1 10 mM acetate buffer (pH 5.5), 5% sorbitol Solvent 2 10% DMSO, 40% Propylene glycol Preparation of Anti-B7-H3 Antibody-Drug Conjugate (1) Administration Solution Anti-B7-H3 antibody-drug conjugate (1) is diluted with solvent 1 to a concentration of 0.1 mg/mL, 0.3 mg/mL, or 1.0 mg/mL.
  • Xenograft model Model 1 Small cell lung cancer cell line NCI-H446 is purchased from ATCC (American Type Culture Collection). 5 x 106 NCI-H446 cells suspended in saline are subcutaneously injected into 5-8 week old female CAnN.Cg- Foxn1nu /CrlCrlj mice (Jackson Laboratory Japan, Inc.).
  • Model 2 Small cell lung cancer cell line NCI-H524 is purchased from ATCC. 4 x 106 NCI-H524 cells suspended in Matrigel/PBS(-) (1:1) are subcutaneously injected into 5-8 week old female CAnN.Cg- Foxn1nu /CrlCrlj mice (Jackson Laboratory Japan, Inc.).
  • Model 3 Human prostate cancer epithelial cell line 22Rv1 is purchased from ATCC. 5 x 10 6 22Rv1 cells suspended in PBS(-) are subcutaneously injected into 5-8 week old castrated male NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice (Jackson Laboratory Japan, Inc.).
  • the tumor-bearing mice were randomly assigned to one of the 16 groups shown below (Day 0).
  • mice in the solvent group are administered solvent 1 and solvent 2.
  • Mice in the anti-B7-H3 antibody-drug conjugate (1) group are administered anti-B7-H3 antibody-drug conjugate (1) administration solution.
  • Mice in the AZD6738 group are administered AZD6738 administration solution.
  • Mice in the anti-B7-H3 antibody-drug conjugate (1) + AZD6738 group are administered anti-B7-H3 antibody-drug conjugate (1) administration solution and AZD6738 administration solution.
  • Solvent 1 is administered intravenously at 10 mL/kg on Day 0 and Day 14.
  • Solvent 2 is administered orally at 10 mL/kg twice a day from Day 0 to Day 14.
  • Anti-B7-H3 antibody-drug conjugate (1) administration solution is administered intravenously at 10 mL/kg on Day 0 and Day 14.
  • the AZD6738 solution is orally administered at 10 mL/kg twice a day from day 0 to day 14. The antitumor effect is confirmed by comparing the tumor volumes of each group.
  • Test Example 3 In vivo antitumor activity of anti-B7-H3 antibody-drug conjugate (1) in combination with ATM inhibitor: Solvent 1 10 mM acetate buffer (pH 5.5), 5% sorbitol solvent 3 0.5% HPMC, 0.1% Tween80
  • Anti-B7-H3 Antibody-Drug Conjugate (1)
  • Administration Solution Anti-B7-H3 antibody-drug conjugate (1) is diluted with solvent 1 to a concentration of 0.1 mg/mL, 0.3 mg/mL, or 1.0 mg/mL.
  • Dosing solutions are prepared to have a concentration of 0.3 mg/mL, 1.0 mg/mL or 3.0 mg/mL AZD1390.
  • Xenograft model Model 1 Small cell lung cancer cell line NCI-H446 is purchased from ATCC. 5 ⁇ 10 6 NCI-H446 cells suspended in saline are subcutaneously injected into 5-8 week old female CAnN.Cg-Foxn1 nu /CrlCrlj mice (Jackson Laboratory Japan, Inc.).
  • Model 2 Small cell lung cancer cell line NCI-H524 is purchased from ATCC. 4 x 106 NCI-H524 cells suspended in Matrigel/PBS(-) (1:1) are subcutaneously injected into 5-8 week old female CAnN.Cg- Foxn1nu /CrlCrlj mice (Jackson Laboratory Japan, Inc.).
  • Model 3 Human prostate cancer epithelial cell line 22Rv1 is purchased from ATCC. 5 x 10 6 22Rv1 cells suspended in PBS(-) are subcutaneously injected into 5-8 week old castrated male NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice (Jackson Laboratory Japan, Inc.).
  • the tumor-bearing mice were randomly assigned to one of the 16 groups shown below (Day 0).
  • mice in the solvent group are administered solvent 1 and solvent 3.
  • Mice in the anti-B7-H3 antibody-drug conjugate (1) group are administered anti-B7-H3 antibody-drug conjugate (1) administration solution.
  • Mice in the AZD1390 group are administered AZD1390 administration solution.
  • Mice in the anti-B7-H3 antibody-drug conjugate (1) + AZD1390 group are administered anti-B7-H3 antibody-drug conjugate (1) administration solution and AZD1390 administration solution.
  • Solvent 1 is administered intravenously at 10 mL/kg on Day 0 and Day 14.
  • Solvent 3 is administered orally at 10 mL/kg once a day from Day 0 to Day 28.
  • Anti-B7-H3 antibody-drug conjugate (1) administration solution is administered intravenously at 10 mL/kg on Day 0 and Day 14.
  • the AZD1390 solution is orally administered at 10 mL/kg once a day from Day 0 to Day 28.
  • the antitumor effect is confirmed by comparing the tumor volumes of each group.
  • Test Example 4 In vivo antitumor activity of anti-B7-H3 antibody-drug conjugate (1) in combination with ATR inhibitors
  • Human prostate cancer epithelial cell line 22Rv1 was purchased from American Type Culture Collection (ATCC) and cultured in RPMI1640 medium (ATCC modification) (Thermo Fisher Scientific) supplemented with 10% heat-inactivated fetal bovine serum (FBS, cytiva) at 37°C in a humidified, 5% CO2 atmosphere.
  • ATCC American Type Culture Collection
  • FBS heat-inactivated fetal bovine serum
  • 22Rv1 cells were trypsinized, washed with D-PBS, and then resuspended in D-PBS at a concentration of 5 x 107 cells/mL.
  • 22Rv1 cells (5 ⁇ 106 cells/mouse) were subcutaneously implanted into the right flank of castrated male NSG mice (NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ, 7 weeks old, The Jackson Laboratory Japan, Inc.).
  • Group 1 Vehicle control Group 2: AZD6738 25 mg/kg Group 3: Anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg Group 4: Anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg + AZD6738 25 mg/kg
  • anti-B7-H3 antibody-drug conjugate (1) was diluted with Soln. A (10 mmol/L histidine buffer [pH 5.9] containing 9% sucrose and 0.02% polysorbate 20).
  • AZD6378 was dissolved in DMSO (10% [v/v] of the total volume of the dosing solution), and the solution was sonicated.
  • Propylene glycol (40% [v/v] of the total volume of the dosing solution) was then added to the solution. After thorough stirring with a magnetic stirrer, water for injection (50% [v/v] of the total volume of the dosing solution) was added to the solution, and the solution was then further thoroughly stirred with a magnetic stirrer.
  • each solution administered was calculated from the individual body weight measured on the day of administration.
  • Soln. A was administered intravenously at 10 mL/kg as a solvent control for anti-B7-H3 antibody-drug conjugate (1) to mice in Group 1 (solvent control) and Group 2 (AZD6738 25 mg/kg) on Days 0 and 15.
  • Soln. B water for injection containing 10% DMSO and 40% propylene glycol was orally administered twice daily at 5 mL/kg as a solvent control for AZD6738 to mice in Group 1 (solvent control) and Group 3 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg) on Days 0, 1, 2, 3, 4, 7, 8, 9, 10, and 11.
  • mice in Group 3 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg) and Group 4 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg + AZD6738 25 mg/kg) were intravenously administered 0.3 mg/mL of anti-B7-H3 antibody-drug conjugate (1) at 10 mL/kg on Days 0 and 15.
  • Mice in Group 2 (AZD6738 25 mg/kg) and Group 4 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg + AZD6738 25 mg/kg) were orally administered 5.0 mg/mL of AZD6738 at 5 mL/kg twice daily on Days 0, 1, 2, 3, 4, 7, 8, 9, 10, and 11.
  • the long and short diameters of the tumor were measured with a digital caliper.
  • the tumor volume and tumor growth inhibition rate (TGI) were calculated using the following formula:
  • C Mean tumor volume of Group 1 (solvent control)
  • T Mean tumor volume of treatment group
  • a Dunnett's test was used to compare tumor volumes in the monotherapy groups with those in the vehicle control group, and to compare tumor volumes in the monotherapy groups with those in the combination group. A P value of less than 0.05 was considered statistically significant.
  • mice in group 4 The following TGI calculations and statistical analyses were performed using data excluding the excluded mice in group 4.
  • Test Example 5 In vivo antitumor activity of anti-B7-H3 antibody-drug conjugate (1) in combination with ATM inhibitors
  • Human prostate cancer epithelial cell line 22Rv1 was purchased from American Type Culture Collection (ATCC) and cultured in RPMI1640 medium (ATCC modification) (Thermo Fisher Scientific) supplemented with 10% heat-inactivated fetal bovine serum (FBS, cytiva) at 37°C in a humidified, 5% CO2 atmosphere.
  • ATCC American Type Culture Collection
  • FBS heat-inactivated fetal bovine serum
  • 22Rv1 cells were trypsinized, washed with D-PBS, and then resuspended in D-PBS at a concentration of 5 x 107 cells/mL.
  • 22Rv1 cells (5 ⁇ 106 cells/mouse) were subcutaneously implanted into the right flank of castrated male NSG mice (NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ, 6 weeks old, The Jackson Laboratory Japan, Inc.).
  • Group 1 Vehicle control Group 2: AZD1390 20 mg/kg Group 3: Anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg Group 4: Anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg + AZD1390 20 mg/kg
  • anti-B7-H3 antibody-drug conjugate (1) was diluted with Soln. A (9% sucrose, 0.02% polysorbate 20 in 10 mmol/L histidine buffer [pH 5.9]).
  • AZD1390 was dissolved in Soln. C (0.5% [w/v] hydroxypropyl methylcellulose [HPMC], 0.1% [v/v] Tween 80), and the solution was then thoroughly stirred with a magnetic stirrer.
  • the amount of each solution administered was calculated from the individual body weight measured on the day of administration.
  • Mice in Group 1 (solvent control) and Group 2 (AZD1390 20 mg/kg) were intravenously administered Soln.
  • Mice in Group 1 (solvent control) and Group 3 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg) were orally administered Soln.
  • C as a solvent control for AZD1390 at 10 mL/kg on Day 1, 2, 3, 4, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 21, 22, 23, 24, and 25.
  • mice in Group 3 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg) and Group 4 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg + AZD1390 20 mg/kg) were intravenously administered 0.3 mg/mL of anti-B7-H3 antibody-drug conjugate (1) at 10 mL/kg on Days 0 and 14.
  • Mice in group 2 (AZD1390 20 mg/kg) and group 4 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg + AZD1390 20 mg/kg) were orally administered 2.0 mg/mL AZD1390 at 10 mL/kg on days 1, 2, 3, 4, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 21, 22, 23, 24, and 25.
  • the long and short diameters of the tumor were measured with digital calipers.
  • Tumor volume and tumor growth inhibition rate (TGI) were calculated using the following formula.
  • C Mean tumor volume of Group 1 (solvent control)
  • T Mean tumor volume of treatment group
  • a Dunnett's test was used to compare tumor volumes in the monotherapy groups with those in the vehicle control group, and to compare tumor volumes in the monotherapy groups with those in the combination group. A P value of less than 0.05 was considered statistically significant.
  • Tumor volumes for each group are shown in Figure 16. Data are the mean tumor volume ⁇ standard error of the mean (SEM). On day 29, TGI was 14%, 63%, and 89% for Group 2 (AZD1390 20 mg/kg), Group 3 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg), and Group 4 (anti-B7-H3 antibody-drug conjugate (1) 3 mg/kg + AZD1390 20 mg/kg), respectively.
  • SEQ ID NO: 1 Amino acid sequence of B7-H3 variant 1
  • SEQ ID NO: 2 Amino acid sequence of B7-H3 variant 2
  • SEQ ID NO: 3 Amino acid sequence of anti-B7-H3 antibody heavy chain (M30-H1 type)
  • SEQ ID NO: 4 Amino acid sequence of anti-B7-H3 antibody light chain (M30-L4 type)
  • SEQ ID NO: 5 Amino acid sequence of anti-B7-H3 antibody heavy chain (M30-H2 type)
  • SEQ ID NO: 7 Amino acid sequence of anti-B7-H3 antibody heavy chain (M30-H4 type)
  • SEQ ID NO: 9 Amino acid sequence of anti-B7-H3 antibody

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WO2026019375A1 (en) * 2024-07-19 2026-01-22 Hummingbird Bioscience Pte. Ltd. B7h3-binding molecules

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