WO2019230645A1 - 抗her2抗体-薬物コンジュゲート投与によるher2変異がんの治療 - Google Patents
抗her2抗体-薬物コンジュゲート投与によるher2変異がんの治療 Download PDFInfo
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- WO2019230645A1 WO2019230645A1 PCT/JP2019/020886 JP2019020886W WO2019230645A1 WO 2019230645 A1 WO2019230645 A1 WO 2019230645A1 JP 2019020886 W JP2019020886 W JP 2019020886W WO 2019230645 A1 WO2019230645 A1 WO 2019230645A1
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- PLXLYXLUCNZSAA-QLXKLKPCSA-N CC[C@](C(C=C1N2Cc3c([C@H](CCc4c(C)c(F)c5)NC(CO)=O)c4c5nc13)=C(CO1)C2=O)(C1=O)O Chemical compound CC[C@](C(C=C1N2Cc3c([C@H](CCc4c(C)c(F)c5)NC(CO)=O)c4c5nc13)=C(CO1)C2=O)(C1=O)O PLXLYXLUCNZSAA-QLXKLKPCSA-N 0.000 description 1
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Definitions
- the present invention is confirmed to have a therapeutic agent for HER2 mutant cancer and / or a specific anti-HER2 antibody-drug conjugate containing a specific anti-HER2 antibody-drug conjugate and / or a specific anti-HER2 antibody-drug conjugate.
- the present invention relates to a method for treating cancer, characterized by being administered to a patient.
- HER2 Human epidermal growth factor receptor 2
- Non-Patent Documents 1 to 6 Human epidermal growth factor receptor 2
- HER2 is overexpressed in various cancer types such as breast cancer and stomach cancer (Non-Patent Documents 7 to 12), and is reported to be a negative prognostic factor in breast cancer (Non-Patent Documents 13 and 14).
- anti-HER2 drugs effective against HER2-overexpressing cancer trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib and the like are known.
- HER2 has a mutant and is known to be one of cancer driver mutations. It has been reported that such HER2 mutant cancer is present in a ratio of about 2% to 3% of non-small cell lung cancer (Non-Patent Documents 15 to 20). Tests have been conducted to verify the effects of anti-HER2 drugs on HER2 mutant cancer (Non-Patent Documents 21 and 22).
- ADC Antibody-Drug Conjugate
- a cytotoxic drug is bound to an antibody that binds to an antigen that is expressed on the surface of a cancer cell and can be internalized in the cell, is selected for the cancer cell. Therefore, it can be expected that the drug can be delivered in a cancer cell and the cancer cell is killed (Non-patent Documents 23 to 27).
- antibody-drug conjugates comprising anti-HER2 antibody and a derivative of exatecan which is a topoisomerase I inhibitor are known (Patent Documents 1 to 3, Non-patent Documents 28 to 31).
- an anti-HER2 antibody-drug conjugate comprising an anti-HER2 antibody and a derivative of exatecan, which is a topoisomerase I inhibitor, exerts an antitumor effect against cancer in which HER2 overexpression has been confirmed.
- the anti-HER2 antibody-drug conjugate can exert an antitumor effect against HER2 mutant cancer.
- the present invention is confirmed to have a therapeutic agent for HER2 mutant cancer and / or a specific anti-HER2 antibody-drug conjugate containing a specific anti-HER2 antibody-drug conjugate and / or a specific anti-HER2 antibody-drug conjugate. It is an object of the present invention to provide a method for treating cancer, characterized by being administered to a patient.
- a therapeutic agent for HER2 mutant cancer which comprises, as an active ingredient, an anti-HER2 antibody-drug conjugate in which a drug linker represented by the above and an anti-HER2 antibody are bound by a thioether bond.
- HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E745L, 7531 , D769N, D769Y, E770_A 71insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775
- the therapeutic agent according to [2], wherein the HER2 mutation in the HER2 mutant cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, and S310F.
- the therapeutic agent according to [1], wherein the HER2 mutation in the HER2 mutant cancer is an Exon 20 insertion mutation.
- the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V, and I661V.
- the therapeutic agent according to [8], wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4
- the therapeutic agent according to [10] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the therapeutic agent according to [11], wherein the Single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- Non-small cell lung cancer breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer,
- the therapeutic agent according to any one of [1] to [12], wherein the cancer in the HER2 mutant cancer is non-small cell lung cancer.
- the therapeutic agent according to [14], wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- the therapeutic agent according to any one of [15].
- the therapeutic agent as described in.
- a therapeutic agent for HER2 mutant cancer comprising an anti-HER2 antibody-drug conjugate represented by the formula: [24] HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H,
- the therapeutic agent according to [24], wherein the HER2 mutation in the HER2 mutant cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, and S310F.
- the therapeutic agent according to [23], wherein the HER2 mutation in the HER2 mutant cancer is an Exon 20 insertion mutation.
- the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V, and I661V.
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4
- the therapeutic agent according to [32] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the therapeutic agent according to [33] wherein the Single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- Non-small cell lung cancer breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer,
- the therapeutic agent according to any one of [23] to [34] which is at least one selected from the group consisting of ovarian cancer and uterine carcinosarcoma.
- the therapeutic agent according to any one of [23] to [34], wherein the cancer in the HER2 mutant cancer is non-small cell lung cancer.
- the therapeutic agent according to [36] wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- the therapeutic agent according to any one of [37].
- the therapeutic agent as described in.
- A represents the binding position with the anti-HER2 antibody
- An anti-HER2 antibody-drug conjugate in which a drug linker represented by the above and an anti-HER2 antibody are bound by a thioether bond is administered to a patient confirmed to have a HER2 mutant cancer, Method of treatment.
- HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E745L, 7531 , D769N, D769Y, E770_A 71insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4 [54]
- the treatment method according to [54] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the treatment method according to [55] wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- Non-small cell lung cancer breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, The method according to any one of [45] to [56], which is at least one selected from the group consisting of ovarian cancer and uterine carcinosarcoma.
- the method according to any one of [45] to [56], wherein the cancer in the HER2 mutant cancer is non-small cell lung cancer.
- the treatment method according to [58], wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- a method for treating cancer comprising administering the anti-HER2 antibody-drug conjugate represented by the above to a patient confirmed to have a HER2 mutant cancer.
- HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E745L, 7531 , D769N, D769Y, E770_A 71insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4
- the treatment method according to [76] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the treatment method according to [77] wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- Non-small cell lung cancer breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, The treatment method according to any one of [67] to [78], which is at least one selected from the group consisting of ovarian cancer and uterine carcinosarcoma.
- the treatment method according to any one of [67] to [78], wherein the cancer in the HER2 mutant cancer is non-small cell lung cancer.
- the treatment method according to [80] wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E745L, 7531 ,
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4
- the anti-HER2 antibody-drug conjugate according to [98] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the anti-HER2 antibody-drug conjugate according to [99] wherein the Single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- the anti-HER2 antibody-drug conjugate according to any one of [89] to [100] wherein the cancer in the HER2 mutant cancer is non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.
- Anti-HER2 antibody-drug conjugate as described in 1.
- An anti-HER2 antibody-drug conjugate represented by [112] HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E745L
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4
- the anti-HER2 antibody-drug conjugate according to [120] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the anti-HER2 antibody-drug conjugate according to [121] wherein the Single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- the anti-HER2 antibody-drug conjugate according to any one of [111] to [125].
- anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.
- Anti-HER2 antibody-drug conjugate as described in 1.
- HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733
- [135] [134] The use according to [134], wherein the HER2 mutation in the HER2 mutant cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G7776delinsVC, L755S, V777L, and S310F. [136] The use according to [133], wherein the HER2 mutation in the HER2 mutant cancer is an Exon 20 insertion mutation.
- [141] [140] The use according to [140], wherein the Single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.
- [142] The use according to [133], wherein the HER2 mutation in the HER2 mutant cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4
- the use according to [142] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the use according to [143], wherein the Single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- Non-small cell lung cancer breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, The use according to any one of [133] to [144], which is at least one selected from the group consisting of ovarian cancer and uterine carcinosarcoma.
- the use according to any one of [133] to [144], wherein the cancer in the HER2 mutant cancer is non-small cell lung cancer.
- the use according to [146], wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- HER2 mutation in HER2 mutant cancer is Y772_A775dup, G778_P780dup, G7776 delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A243V, D277Y, A293P, D277Y, A293P , S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E745
- [157] [156] The use according to [156], wherein the HER2 mutation in the HER2 mutant cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, and S310F. [158] The use according to [155], wherein the HER2 mutation in the HER2 mutant cancer is an Exon 20 insertion mutation.
- the HER2 mutation in the HER2 mutant cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.
- the Single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V, and I661V.
- Single base pair substitution mutations in the extracellular domain of the HER2 protein are S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S13C, R340P, S4
- the use according to [164] which is at least one selected from the group consisting of P627H, A644V, and R647G.
- the use according to [165], wherein the Single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.
- Non-small cell lung cancer breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, The use according to any one of [155] to [166], which is at least one selected from the group consisting of ovarian cancer and uterine carcinosarcoma.
- the use according to any one of [155] to [166], wherein the cancer in HER2 mutant cancer is non-small cell lung cancer.
- the use according to [168], wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- a therapeutic agent for a HER2 gene-mutated cancer comprising, as an active ingredient, an anti-HER2 antibody-drug conjugate in which a drug linker represented by the above and an anti-HER2 antibody are bound by a thioether bond.
- Cancer is non-small cell lung cancer, breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer, Paget's disease, pancreatic cancer, ovarian cancer, and The therapeutic agent according to [1], which is at least one selected from the group consisting of uterine carcinosarcoma.
- the therapeutic agent according to [1], wherein the cancer is non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- Cancer is non-small cell lung cancer, breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer, Paget's disease, pancreatic cancer, ovarian cancer, and The treatment method according to [11], which is at least one selected from the group consisting of uterine carcinosarcoma.
- the treatment method according to [11], wherein the cancer is non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- Any one of [11] to [13], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.
- Cancer is non-small cell lung cancer, breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer, Paget's disease, pancreatic cancer, ovarian cancer, and The anti-HER2 antibody-drug conjugate according to [21], which is at least one selected from the group consisting of uterine carcinosarcoma.
- the anti-HER2 antibody-drug conjugate according to [21] wherein the cancer is non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- Item An anti-HER2 antibody-drug conjugate according to Item.
- Cancer is non-small cell lung cancer, breast cancer, stomach cancer, colon cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, bile duct cancer, Paget's disease, pancreatic cancer, ovarian cancer, and The use according to [31], which is at least one selected from the group consisting of uterine carcinosarcoma.
- the use according to [31], wherein the cancer is non-small cell lung cancer.
- the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence described in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence described in amino acid numbers 1 to 214 in SEQ ID NO: 2.
- a therapeutic agent for HER2 mutant cancer containing a specific anti-HER2 antibody-drug conjugate and / or a specific anti-HER2 antibody-drug conjugate has a HER2 mutant cancer. It is possible to provide a method for treating cancer, characterized by being administered to a patient.
- HER2-ADC The maximum tumor reduction rate is shown as the effectiveness of HER2-ADC (1) for patients with non-small cell lung cancer in which HER2 expression or HER2 mutation is confirmed.
- NE indicates a patient whose HER2 mutation has not been measured or has failed
- E20 indicates a patient in which the Exon 20 insertion mutation has been confirmed in the HER2 protein
- TM indicates the transmembrane of the HER2 protein.
- the domain indicates a patient with a single base pair mutation confirmed, and “EC” indicates a patient with a single base pair mutation confirmed in the extracellular domain of the HER2 protein.
- the time course of tumor reduction rate is shown as the effectiveness of HER2-ADC (1) for patients with non-small cell lung cancer in which HER2 expression or HER2 mutation is confirmed.
- 1 shows the amino acid sequence of HER2 protein (SEQ ID NO: 3).
- HER2 is synonymous with human epidermal growth factor receptor 2 (also sometimes referred to as neu, ErbB-2), HER1 (EGFR, ErbB-1), HER3 (ErbB-3) and It is a transmembrane receptor belonging to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases together with HER4 (ErbB-4).
- EGFR epidermal growth factor receptor
- ErbB-4 epidermal growth factor receptor
- HER2 plays an important role in cell proliferation, differentiation and survival in normal cells and tumor cells by activating and autophosphorylating intracellular tyrosine residues through heterodimer formation with HER1, HER3, or HER4. It is known to fulfill.
- the term “HER2 protein” is used in the same meaning as HER2. The expression of HER2 protein can be detected using methods well known to those skilled in the art, such as immunohistochemistry (IHC).
- the amino acid sequence of the HER2 protein is shown in SEQ ID NO: 3 (FIG. 5).
- SEQ ID NO: 3 the amino acid sequence described in amino acid numbers 1 to 652 is referred to as “extracellular domain of HER2 protein”, and the amino acid sequence described in amino acid numbers 653 to 675 is referred to as “transmembrane domain of HER2 protein”.
- the amino acid sequence described in Nos. 676 to 1255 is referred to as “the intracellular domain of HER2 protein”.
- HER2 gene is synonymous with human epidermal growth factor receptor type 2 related oncogene.
- the HER2 protein is one of the gene products of the HER2 gene.
- the nucleotide sequence of the HER2 gene (cDNA) is shown in SEQ ID NO: 4.
- HER2 mutation means having a mutation in the amino acid sequence of the HER2 protein.
- HER2 mutant cancer means a cancer having a mutation in the amino acid sequence of the HER2 protein. Moreover, even if it does not have HER2 mutation in the whole tumor tissue, if it is cancer containing the cancer cell which has HER2 mutation, it will be included in HER2 mutation cancer.
- HER2 gene mutation means having a mutation in the HER2 gene.
- HER2 gene mutant cancer means a cancer having a mutation in the HER2 gene. Moreover, even if it does not have a HER2 gene mutation in the whole tumor tissue, if it is a cancer containing the cancer cell which has a HER2 gene mutation, it will be included in a HER2 gene mutation cancer.
- HER2 gene mutation affects the amino acid sequence of the HER2 protein, which is a gene product, to cause HER2 mutation.
- HER2 mutation include, for example, a mutation in which YVMA (tyrosine, valine, methionine, alanine), which is the amino acid sequence at positions 772 to 775 of the HER2 protein, is repeated once again (also referred to as “Y772_A775dup” or “A775_G776insYVMA”).
- YVMA tyrosine, valine, methionine, alanine
- GSP glycosyl-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-phenyl-N-N-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(
- HER2 protein A mutation in which L (leucine), the 755th amino acid of S, is replaced by S (serine) ("L755S (Clin Cancer Res. 2006 Jan 1; 12 (1): 57-61, Hum Mutat. 2008 Mar; 29 (3): 441-50, Nature. 2012 Apr 4; 486 (7403): 395-9 , Breast Cancer Res Treat. 2012 Jul; 134 (2): 561-7, Clin Cancer Res. 2012 Sep 15; 18 (18): 4910-8, and CancerettLett.
- V valine
- L leucine
- V valine
- E glutamic acid
- S which is the 310th amino acid of HER2 protein is F (Phenylalanine) substitution (also referred to as “S310F”) (Nature. 2008 Oct 23; 455 (7216): 1069-75, Nature. 2011 Jun 29; 474 (7353): 609-15, Nat Genet. 2011 Oct 30; 43 (12): 1219-23, Nature. 2012 Apr 4; 486 (7403): 395-9, Genome Res. 2012 Nov; 22 (11): 2109-19, and Clin Cancer Res. 2013 May 15 ; 19 (10): 2668-76, etc.).
- F Phhenylalanine
- HER2 mutation a mutation in which A (alanine), which is the 20th amino acid of the HER2 protein, is replaced with T (threonine) (also referred to as “A20T”) (Nature 2010; 466 (7308): 869-73, etc.), a mutation in which A (alanine) which is the 21st amino acid of HER2 protein is replaced with S (serine) (also referred to as “A21S”) (NatureNmedicine 2017; 23 (6): 703- 713, etc.), a mutation in which R (arginine), the 143rd amino acid of the HER2 protein, is replaced with Q (glutamine) (also referred to as “R143Q”) (Nature communications 2015; 6: 10131, and Cancer biology & therapy 2014; 15 (9): 1239-47, etc.), a mutation in which K (lysine), the 200th amino acid of HER2 protein, is replaced with N (asparagine) (also asparagine)
- V valine
- M methionine
- S serotonine
- F phenylalanine
- D aspartic acid
- H histidine
- AYVM alanine, tyrosine, valine, methionine
- E glutamic acid
- A alanine
- a mutation in which YVMA (tyrosine, valine, methionine, alanine) is inserted also referred to as “A775_G776insYVMA”) (ClinCCancer Res.
- G (glycine) which is the 776th amino acid of HER2 protein is AVGC (alanine, valine) , Glycine, cysteine) (also referred to as “G776 delinsAVGC” or “G776> AVGC”) (Nature 2018; 554 (7691): 189-194, and Nature legislator ne 2017; 23 (6): 703-713 etc.), a mutation in which G (glycine), which is the 776th amino acid of HER2 protein, is replaced with VV (valine, valine) (“G776 delinsVV” or “G776> VV”).
- G (glycine) which is the 776th amino acid of HER2 protein
- V (valine) which is the 777th amino acid sequence.
- a mutation in which L (leucine) is inserted into also referred to as “G776_V777insL”
- G (glycine), which is the 776th amino acid of HER2 protein is L Mutation (also referred to as “G776L”) (see also Lung Cancer.
- G glycine which is the 776th amino acid of HER2 protein and 777 Th Mutation in which VC (valine, cysteine) is inserted between amino acid sequence V (valine) (also referred to as “G776_V777insVC”) (J Clin Oncol. 2013 Jun 1; 31 (16): 1997-2003 etc.
- VGC valine, glycine, cysteine
- G glycine
- V valine
- CG 777th amino acid sequence
- G glycine
- G (glycine) is inserted between V (valine) which is the 777th amino acid of the protein and G (glycine) which is the 777th amino acid sequence (also referred to as “V777_G778insG”) (Nature (2018; 554 (7691): 189-194 etc.)
- G (glycine) is inserted between G (glycine) which is the 778th amino acid of the HER2 protein and S (serine) which is the 779th amino acid sequence.
- S which is the 779th amino acid of the HER2 protein and the 780th amino acid sequence (Also called “S779_P780insVGS”) (Nature 2004; 431 (7008): 525-6, and J Thorac Oncol.col2009 Jan; 4 (1): Refer to 5-11 etc.)
- GSP glycine, serine, proline
- HER2 protein 786th amino acid L is V (valine) Mutation (also referred to as “L786V”) (see Nature 2018; 554 (7691): 189-194 etc.), T (threonine), the 791st amino acid of HER2 protein, is replaced with I (isoleucine). Mutation (also referred to as “T791I”) (Cancer research; 2007; 67 ( 12): 5667-72, etc.), a mutation in which G (glycine), which is the 804th amino acid of HER2 protein, is replaced with S (serine) (also referred to as “G804S”) (Clin Cancer Res.
- L leucine
- F phenylalanine
- V valine
- I isoleucine
- L leucine
- F phenylalanine
- T threonine
- I isoleucine
- R arginine
- W tryptophan
- L leucine
- R arginine
- T threonine
- I isoleucine
- the HER2 mutation in the present invention is not particularly limited as long as it has a mutation in the amino acid sequence of the HER2 protein.
- at least one selected from the group consisting of the HER2 mutations shown above is given as a specific example.
- at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776 delinsVC, L755S, V777L, and S310F can be mentioned.
- Exon 20 insertion mutation refers to a HER2 mutation caused by insertion of a base pair into exon 20 of the HER2 gene.
- Exon 20 of the HER2 gene is represented by the nucleotide sequence set forth in nucleotide numbers 2308 to 2493 of SEQ ID NO: 4, and the HER2 protein encoded thereby is represented by the amino acid sequence set forth in amino acid numbers 770 to 831 of SEQ ID NO: 3. It is.
- the Exon 20 insertion mutation in the present invention is not particularly limited as long as it is a HER2 mutation caused by insertion of a base pair into exon 20 of the HER2 gene.
- the “single base pair mutation” refers to a HER2 mutation that occurs when one base pair in the HER2 gene is replaced with another base pair.
- the single base pair substitution mutation in the present invention is not particularly limited as long as it is a HER2 mutation generated by replacing one base pair in the HER2 gene with another one base pair.
- single base pair substitution mutation in the transmembrane domain of HER2 protein occurs in the transmembrane domain of HER2 protein by replacing one base pair of HER2 gene with another base pair. HER2 mutation is shown.
- the single base pair substitution mutation in the transmembrane domain of the HER2 protein in the present invention is a HER2 mutation that occurs in the transmembrane domain of the HER2 protein by replacing one base pair of the HER2 gene with one other base pair.
- HER2 mutation that occurs in the transmembrane domain of the HER2 protein by replacing one base pair of the HER2 gene with one other base pair.
- at least one selected from the group consisting of V659E, G660D, I654V, I655V, and I661V can be mentioned, and G660D can be preferably mentioned.
- the “single base pair substitution mutation in the extracellular domain of the HER2 protein” is generated in the extracellular domain of the HER2 protein by replacing one base pair of the HER2 gene with another base pair. HER2 mutation is shown.
- the single base pair substitution mutation in the extracellular domain of the HER2 protein in the present invention is a HER2 mutation that occurs in the extracellular domain of the HER2 protein by substituting one base pair of the HER2 gene with another base pair.
- the therapeutic agent and / or treatment method of the present invention can be suitably used for a HER2 mutant cancer in which at least one mutation is confirmed, but is not limited thereto as long as it is a cancer having a mutation in HER2. .
- the presence or absence of the HER2 mutation is confirmed by, for example, collecting tumor tissue from a cancer patient and performing a method such as real-time quantitative PCR (qRT-PCR) or microarray analysis on a formalin-fixed paraffin-embedded specimen (FFPE). be able to.
- qRT-PCR real-time quantitative PCR
- FFPE formalin-fixed paraffin-embedded specimen
- HER2 mutation can also be confirmed by collecting acellular circulating tumor DNA (ctDNA) from a cancer patient and performing a method such as next generation sequencing (NGS) (J Clin Oncol 2013; 31: 1997-2003, Clin CancerRes 2012; 18: 4910-8, J Thorac Oncol 2012; 7: 85-9, Lung Cancer 2011; 74: 139-44, Cancer Res2005; 65: 1642-6, Cancer Sci 2006; 97: 753-9, ESMO Open 2017; 2: e000279, and Annals of Oncology 26: 1421-1427, 2015, etc.).
- NGS next generation sequencing
- HER2 mutation is used in the same meaning as the HER2 gene mutation.
- anti-HER2 antibody means an antibody that specifically binds to HER2, preferably has an activity of internalizing in HER2-expressing cells by binding to HER2, in other words, after binding to HER2, An antibody having an activity of migrating into a HER2-expressing cell is shown.
- Anti-HER2 antibody-drug conjugate The anti-HER2 antibody-drug conjugate used in the present invention has the formula
- A represents the binding position with the antibody
- a partial structure comprising a linker and a drug in the anti-HER2 antibody-drug conjugate is referred to as a “drug linker”.
- This drug linker is a thiol group (in other words, a sulfur atom of a cysteine residue) generated at a disulfide bond site between antibody chains (between two heavy chains and heavy chains and between two heavy chains and light chains). Is bound to.
- the drug linker of the present invention is exatecan (IUPAC name: (1S, 9S) -1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-, a topoisomerase I inhibitor.
- camptothecin derivative having an antitumor effect.
- the anti-HER2 antibody-drug conjugate used in the present invention can also be represented by the following formula.
- N is synonymous with the so-called average drug bond number (DAR; Drug-to-Antibody Ratio), and indicates the average bond number of drug linkers per antibody.
- DAR Drug-to-Antibody Ratio
- the average number of drug linkers per antibody of the anti-HER2 antibody-drug conjugate used in the present invention 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 linker moiety is cleaved after transfer into the tumor cell
- the above compound is considered to be the main body of the antitumor activity of the above-mentioned anti-HER2 antibody-drug conjugate used in the present invention, and has been confirmed to have a topoisomerase I inhibitory action (Ogitani Y. et al ., Clinical Cancer Research, 2016, Oct15; 22 (20): 5097-5108, -5Epub 2016 Mar 29).
- the anti-HER2 antibody-drug conjugate used in the present invention is also known to have a bystander effect (OgitaniY. Et al., Cancer Science (2016) 107, 1039-1046). This bystander effect is obtained when the anti-HER2 antibody-drug conjugate used in the present invention is internalized in a target-expressing cancer cell, and then the above-mentioned compound is against a nearby cancer cell not expressing the target. Is also exerted by exerting an anti-tumor effect.
- the anti-HER2 antibody-drug conjugate used in the present invention can be produced with reference to the description in International Publication No. 2015/115091.
- the HER2 protein used in the present invention can be directly purified from HER2-expressing cells of humans and non-human mammals (rats, mice, etc.) or can be used by preparing a cell membrane fraction of the cells. It can also be obtained by synthesizing HER2 in vitro or by producing it in a host cell by genetic manipulation. Specifically, in genetic manipulation, HER2 cDNA is incorporated into a vector that can be expressed, and then synthesized in a solution containing enzymes, substrates, and energy substances necessary for transcription and translation, or other prokaryotic or true organisms. The protein can be obtained by transforming a nuclear host cell to express HER2.
- HER2-expressing cell obtained by the above-described genetic manipulation or a cell line expressing HER2 as the HER2 protein.
- the HER2 protein used in the present invention can be directly purified from human HER2-expressing cells, or when used as an antigen, the cell membrane fraction of the cells can be used as the HER2 protein.
- HER2 can be obtained by synthesizing in vitro or by producing it in a host cell by genetic manipulation. Specifically, in genetic manipulation, HER2 is synthesized by incorporating HER2 cDNA into an expressible vector and then incubating the vector in a solution containing enzymes, substrates and energy substances necessary for transcription and translation. be able to.
- the protein can be obtained by transforming another prokaryotic or eukaryotic host cell with the vector and expressing HER2. It is also possible to use a HER2-expressing cell or a cell line expressing HER2 by the aforementioned genetic manipulation as the HER2 protein antigen.
- accession numbers such as M11730 (Genbank) and NP_004439.2 (NCBI).
- the HER2 includes a protein having an amino acid sequence in which one or several amino acids are substituted, deleted, and / or added in the HER2 amino acid sequence, and having the same biological activity as the protein.
- Human HER2 protein is composed of a signal sequence consisting of 22 amino acid residues at the N-terminal, an extracellular domain consisting of 630 amino acid residues, a transmembrane domain consisting of 23 amino acid residues, and an intracellular domain consisting of 580 amino acid residues. .
- the anti-HER2 antibody used in the present invention can be obtained by known means. For example, using a method commonly practiced in this field, an animal is immunized with any polypeptide selected from HER2 or HER2 amino acid sequence serving as an antigen, and antibodies produced in vivo are collected and purified. Can be obtained by: The origin of the antigen is not limited to humans, and animals can be immunized with antigens derived from animals other than humans such as mice and rats. In this case, an anti-HER2 antibody applicable to a human disease can be selected by testing the cross-reactivity between the human antigen and an antibody that binds to the obtained heterologous antigen.
- a hybridoma can be established by fusing an antibody-producing cell that produces an antibody against an antigen and a myeloma cell to obtain a monoclonal antibody.
- the antigen can be obtained by causing a host cell to produce a gene encoding an antigen protein by genetic manipulation.
- a vector capable of expressing an antigen gene may be prepared, introduced into a host cell to express the gene, and the expressed antigen may be purified.
- An antibody can also be obtained by using a method of immunizing an animal with an antigen-expressing cell or a cell line expressing the antigen by genetic manipulation as described above.
- the anti-HER2 antibody used in the present invention is a genetically modified antibody that has been artificially modified for the purpose of reducing the heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody. It is preferable that the antibody has only the gene sequence of a human-derived antibody, that is, a human antibody. These antibodies can be produced using known methods.
- chimeric antibody examples include antibodies in which the variable region and the constant region of the antibody are different from each other, for example, a chimeric antibody in which the variable region of a mouse or rat-derived antibody is joined to a human-derived constant region (Proc.cNatl. Acad). .Sci. USA, 81, 6851-6855, (1984)).
- a humanized antibody an antibody in which only a complementarity determining region (CDR) of a heterologous antibody is incorporated into a human-derived antibody (Nature (1986) 321, p.522-525), heterologous by CDR grafting
- CDR complementarity determining region
- an amino acid residue of a part of the framework of a heterologous antibody is also transplanted to a human antibody (International Publication No. 90/07861), a gene conversion mutagenesis strategy
- An antibody US Pat. No. 5,821,337) that has been humanized by use can be mentioned.
- human antibody an antibody prepared using a human antibody-producing mouse having a human chromosome fragment containing heavy and light chain genes of a human antibody (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., AnimalCell 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.
- antibodies obtained by phage display selected from a human antibody library (Wormstone, I. M. et. Al, Investigative Ophthalmology & VisualScience. (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-HER2 antibody used in the present invention includes antibody modifications.
- the modified product means a product obtained by chemically or biologically modifying the antibody according to the present invention.
- Chemical modifications include chemical modifications having a chemical moiety attached to the amino acid backbone, a chemical moiety attached to an N-linked or O-linked carbohydrate chain, and the like.
- Biological modifications include post-translational modifications (eg, addition of N-linked or O-linked sugar chains, N-terminal or C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, etc. ) And those in which a methionine residue is added to the N-terminus by expression using a prokaryotic host cell.
- the label of the anti-HER2 antibody or antigen used in the present invention to enable detection or isolation for example, an enzyme label, a fluorescent label, and an affinity label are also included in the meaning of such a modified form. It is.
- a modified form of the anti-HER2 antibody used in the present invention is useful for improvement of antibody stability and blood retention, reduction of antigenicity, detection or isolation of antibody or antigen, and the like.
- the anti-HER2 antibody used in the present invention includes an antibody in which the sugar chain modification is regulated.
- the anti-HER2 antibody used in the present invention includes the antibody subjected to the modification and a functional fragment of the antibody, and a deletion in which 1 or 2 amino acids are deleted from the heavy chain carboxyl terminus, and Such amidated deletions (for example, a heavy chain in which the proline residue at the carboxyl terminal site is amidated) and the like are also included.
- the carboxyl-terminal deletion of the heavy chain of the anti-HER2 antibody used in the present invention is not limited to the above type.
- the two heavy chains constituting the anti-HER2 antibody used in the present invention may be any one of a heavy chain selected from the group consisting of a full length and the above-mentioned deletion body, or any two It may be a combination of seeds.
- the amount ratio of each deletion can be affected by the type and culture conditions of the cultured mammalian cells that produce the anti-HER2 antibody used in the present invention.
- the anti-HER2 antibody used in the present invention is preferably 2 There may be mentioned those in which one amino acid residue at the carboxyl terminus is deleted in both heavy chains of the book.
- Examples of the isotype of the anti-HER2 antibody used in the present invention include IgG (IgG1, IgG2, IgG3, IgG4) and the like, and preferably IgG1 or IgG2. These modified forms can also be used as anti-HER2 antibodies according to the present invention.
- anti-HER2 antibody used in the present invention examples include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (WO 01/00245), preferably Trastuzumab.
- “trastuzumab” is a heavy chain consisting of the amino acid sequence of amino acid numbers 1 to 449 in SEQ ID NO: 1 (FIG. 1) and the amino acid sequence of amino acid numbers 1 to 214 in SEQ ID NO: 2 (FIG. 2)
- a humanized anti-HER2 antibody comprising a light chain consisting of
- Suitable anti-HER2 antibodies used in the production of anti-HER2 antibody-drug conjugates according to the present invention are: (1) an antibody comprising a heavy chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in amino acid numbers 1 to 214 in SEQ ID NO: 2, or (2) An antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2.
- the drug linker intermediate used in the production of the anti-HER2 antibody-drug conjugate according to the present invention is represented by the following formula.
- the drug linker intermediate described above 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 ′: 6,7] indolidino [1,2-b] quinolin-1-yl] amino ⁇ -2-oxoethoxy) methyl] glycinamide, It can be produced with reference to the description in WO2015 / 115091.
- the anti-HER2 antibody-drug conjugate used in the present invention can be produced by reacting the above-mentioned drug linker intermediate with an anti-HER2 antibody having a thiol group (or sulfhydryl group).
- An anti-HER2 antibody having a sulfhydryl group 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) is used in an amount of 0.3 to 3 molar equivalents per interchain disulfide within the antibody, and a chelate such as ethylenediaminetetraacetic acid (EDTA).
- TCEP (2-carboxyethyl) phosphine hydrochloride
- EDTA ethylenediaminetetraacetic acid
- an anti-HER2 antibody-drug conjugate in which 2 to 8 drugs are bound per antibody using 2 to 20 molar equivalents of a drug linker intermediate per anti-HER2 antibody having a sulfhydryl group. Can be manufactured.
- Calculation of the average number of drug bonds per antibody molecule of the prepared anti-HER2 antibody-drug conjugate is, for example, measuring UV absorbance of the anti-HER2 antibody-drug conjugate and its conjugation precursor at two wavelengths of 280 nm and 370 nm.
- the method can be carried out by a method (UV method) for calculating by this, or a method (HPLC method) for quantifying and calculating each fragment obtained by treating an antibody-drug conjugate with a reducing agent by HPLC measurement.
- the therapeutic agent and / or therapeutic method of the present invention is characterized by administering a specific anti-HER2 antibody-drug conjugate and can be used for the treatment of HER2 mutant cancer.
- the cancer in HER2 mutant cancer for which the therapeutic agent and / or treatment method of the present invention can be used is preferably lung cancer (including non-small cell lung cancer), breast cancer, stomach cancer (gastric adenocarcinoma).
- Colorectal cancer also called colorectal cancer, including colon cancer and rectal cancer
- esophageal cancer salivary gland cancer
- gastroesophageal junction adenocarcinoma biliary tract cancer (bile duct cancer) Paget's disease
- Peritoneal cancer liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulva cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, head and neck
- the dose per administration of the anti-HER2 antibody-drug conjugate used in the present invention is preferably 5.4 mg / kg (the dose per kg of body weight is 5. 4 mg.kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg, more preferably 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg. Even more preferably, it is 5.4 mg / kg, or 6.4 mg / kg, and even more preferably 6.4 mg / kg.
- the therapeutic agent and the therapeutic method of the present invention are preferably characterized in that the anti-HER2 antibody-drug conjugate used in the present invention is administered once every three weeks.
- the therapeutic agent and therapeutic method of the present invention may contain one or more other drugs (for example, a second drug) other than the anti-HER2 antibody-drug conjugate used in the present invention. That is, the therapeutic agent of the present invention or the anti-HER2 antibody-drug conjugate used in the present invention can be administered in combination with other drugs, thereby enhancing the anticancer effect. Other drugs used for such purposes may be administered to the individual separately or sequentially at the same time as the anti-HER2 antibody-drug conjugate used in the present invention. May be administered in different ways.
- the other drug or the second drug is preferably a cancer therapeutic agent.
- Such a cancer therapeutic agent is not limited as long as it has an antitumor activity, and examples thereof include irinotecan (CPT-11), cisplatin, carboplatin, oxaliplatin, and the like.
- CPT-11 irinotecan
- cisplatin carboplatin
- oxaliplatin irinotecan
- fluorouracil Fluorouracil
- 5-FU gemcitabine
- Gemcitabine Gemcitabine
- Capecitabine Capecitabine
- paclitaxel Paclitaxel
- Docetaxel docetaxel
- doxorubicin (o), doxorubicin (o) Mitomycin C (Mitomycin C), Tegafu Tegafur, Gimeracil, Oteracil, Cetuximab, Panitumumab, Bevacizumab, Remucilfir, Ramiciramib Tipiracil formulation, gefitinib, erlotinib, afat
- the therapeutic agent and treatment method of the present invention can be selected and used as a drug for pharmacotherapy, which is the main treatment method for cancer treatment.
- pharmacotherapy which is the main treatment method for cancer treatment.
- the growth of cancer cells is delayed and proliferated. It can suppress and even destroy cancer cells.
- it is possible to achieve relief from symptoms due to cancer and improvement in QOL, and a therapeutic effect is achieved while maintaining the lives of cancer patients. Even when cancer cells are not destroyed, long-term survival can be achieved while achieving higher QOL in cancer patients by suppressing or controlling the growth of cancer cells.
- the therapeutic agent and treatment method of the present invention can also be used as a drug combined with other therapies in adjuvant therapy, such as surgery, radiation therapy, hormone therapy, etc. Can be combined. Furthermore, it can also be used as a drug for pharmacotherapy in neoadjuvant therapy.
- the therapeutic agent and treatment method of the present invention can be expected to have a preventive effect of suppressing the growth of even fine metastatic cancer cells and further destroying them.
- a preventive effect of suppressing the growth of even fine metastatic cancer cells and further destroying them For example, an effect of suppressing and destroying cancer cells in a body fluid during a metastasis process and an effect of suppressing and destroying fine cancer cells immediately after implantation in any tissue can be expected. Therefore, suppression of cancer metastasis, especially after surgical removal of cancer, can be expected.
- the therapeutic agent and the therapeutic method of the present invention can be applied to a patient as a systemic therapy or applied locally to a cancer tissue to expect a therapeutic effect.
- the therapeutic agent and treatment method of the present invention can be preferably used for mammals, but more preferably can be used for humans.
- the therapeutic agent of the present invention can be administered as a pharmaceutical composition comprising one or more pharmaceutically compatible ingredients.
- the pharmaceutically compatible component is appropriately selected and applied from pharmaceutical additives or the like commonly used in this field according to the dose and concentration of the anti-HER2 antibody-drug conjugate used in the present invention. can do.
- the therapeutic agent of the present invention is a pharmaceutical composition comprising a buffer such as histidine buffer, an excipient such as sucrose, and a surfactant such as polysorbate 80 (hereinafter referred to as “the pharmaceutical composition used in the present invention”). ").).
- the pharmaceutical composition used in the present invention can be preferably used as an injection, more preferably an aqueous injection or a lyophilized injection, and even more preferably, It can be used as a lyophilized injection.
- the pharmaceutical composition used in the present invention is an aqueous injection, it can be preferably administered intravenously after being diluted with an appropriate diluent.
- the diluent include a glucose solution and a physiological saline solution, preferably a glucose solution, and more preferably a 5% glucose solution.
- the pharmaceutical composition used in the present invention is a lyophilized injection
- it can be suitably administered by intravenous infusion after dissolving with water for injection and then diluting the required amount with an appropriate diluent.
- the diluent include a glucose solution and a physiological saline solution, preferably a glucose solution, and more preferably a 5% glucose solution.
- Introduction routes that can be used to administer the pharmaceutical composition used in the present invention can include, for example, intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, preferably Intravenous routes can be mentioned.
- Example 1 Production of anti-HER2 antibody-drug conjugate According to the production method described in International Publication No. 2015/115091, a humanized anti-HER2 antibody (a sequence consisting of amino acid sequences described in amino acid numbers 1 to 449 in SEQ ID NO: 1). An antibody comprising a chain and a light chain consisting of the amino acid sequence of amino acid numbers 1 to 214 in SEQ ID NO: 2)
- HER2-ADC (1) an anti-HER2 antibody-drug conjugate in which an anti-HER2 antibody is bound to an anti-HER2 antibody by a thioether bond was produced.
- the average drug binding number per antibody in HER2-ADC (1) is in the range of 7-8.
- Example 2 Clinical trial (Phase I trial) Phase I trials of HER2-ADC (1) included HER2-positive breast cancer patients (with trastuzumab emtansine history), HER2-positive gastric cancer patients (with trastuzumab treatment history), HER2-low-expressing breast cancer patients (IHC 1+, 2+ and ISH-), and HER2 expression (IHC is 1+ or higher) or other solid cancer patients with confirmed HER2 mutations (confirmed by IHC, FISH, NGS, or other methods) It was. Side effects (AEs), response rate (ORR: CR (complete response) + PR (partial response)), and disease control rate (DCR: CR + PR + SD (stable)) were evaluated.
- AEs Side effects
- ORR CR (complete response) + PR (partial response)
- DCR CR + PR + SD (stable)
- HER2-ADC (1) (6.4 mg / kg).
- the median value of the patient's age is 58.5 years and the patient's previous treatment history is 3 median values.
- 8/12 (66.7%) patients are on medication.
- the median value for the dosing period was 3.663 months.
- the ORR was 62.5% (5/8) and the DCR was 75.0% (6/8).
- PR was 75.0% (3/4).
- the median value for the duration of response was 11.5 months.
- Example 3 Clinical trial (Phase I trial) Subsequent to Example 2, a phase I test of HER2-ADC (1) was conducted. To date, 18 patients with non-small cell lung cancer with confirmed HER2 expression or HER2 mutation who have received HER2-ADC (1) (6.4 mg / kg). The median value of the patient's age is 58.0 years and the patient's previous treatment history is 3 median values. Of the 18 patients, 11 (61.1%) had confirmed HER2 mutations.
- HER2-ADC objective response rate
- ORR Objective Response Rate
- DCR Disease Control Rate
- DoR Duration of Response
- Table 1 shows Time to Response (TTR) and Progression-free Survival (PFS).
- HER2-ADC (1) showed an ORR of 58.8% (10/17) and 88.2% (15 / 17) DCR was shown.
- the median value for DoR was 9.9 months
- the median value for TTR was 1.4 months
- the median value for PFS was 14.1 months.
- HER2-ADC (1) showed an ORR of 72.7% (8/11) and 100% (11/11) in a cohort of 11 non-small cell lung cancer patients with confirmed HER2 mutations DCR was shown.
- the median value for DoR was 11.5 months
- the median value for TTR was 1.4 months
- the median value for PFS was 14.1 months.
- the maximum tumor reduction rate is shown in FIG. 3, and the time course of the tumor reduction rate is shown in FIG.
- Table 2 shows the main adverse events (AE) confirmed under treatment with HER2-ADC (1). All AEs were generally of a low grade.
- Example 4 Clinical study (Phase II study) Phase II trials of HER2-ADC (1) have included unresectable and / or metastatic non-small cell lung cancer patients (about 40: Cohort 1) with confirmed HER2 overexpression (IHC 3+ or 2+), and It is performed on unresectable and / or metastatic non-small cell lung cancer patients (about 40: Cohort 2) with confirmed HER2 mutation.
- HER2-ADC (1) is administered at a dose of 6.4 mg / kg once every 3 weeks, and the response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) etc. are evaluated.
- SEQ ID NO: 1 amino acid sequence of humanized anti-HER2 antibody heavy chain
- SEQ ID NO: 2 amino acid sequence of humanized anti-HER2 antibody light chain
- SEQ ID NO: 3 amino acid sequence of HER2 protein
- SEQ ID NO: 4 nucleotide sequence of HER2 gene (cDNA)
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Abstract
Description
HER2は乳がん、胃がん等様々ながん種において過剰発現しており(非特許文献7~12)、乳がんにおいては負の予後因子であることが報告されている(非特許文献13、14)。HER2過剰発現がんに対し有効な抗HER2薬として、トラスツズマブ、トラスツズマブエムタンシン、ペルツズマブ、及びラパチニブ等が知られている。
[1]
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲートを有効成分として含有する、HER2変異がんの治療剤。
[2]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[1]に記載の治療剤。
[3]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[2]に記載の治療剤。
[4]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[1]に記載の治療剤。
[5]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[4]に記載の治療剤。
[6]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[5]に記載の治療剤。
[7]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[1]に記載の治療剤。
[8]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[7]に記載の治療剤。
[9]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[8]に記載の治療剤。
[10]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[1]に記載の治療剤。
[11]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[10]に記載の治療剤。
[12]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[11]に記載の治療剤。
[13]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[1]~[12]のいずれか1項に記載の治療剤。
[14]
HER2変異がんにおけるがんが、非小細胞肺がんである、[1]~[12]のいずれか1項に記載の治療剤。
[15]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[14]に記載の治療剤。
[16]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[1]~[15]のいずれか1項に記載の治療剤。
[17]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[1]~[15]のいずれか1項に記載の治療剤。
[18]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[1]~[17]のいずれか1項に記載の治療剤。
[19]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[1]~[17]のいずれか1項に記載の治療剤。
[20]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[1]~[19]のいずれか1項に記載の治療剤。
[21]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[1]~[19]のいずれか1項に記載の治療剤。
[22]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[1]~[21]のいずれか1項に記載の治療剤。
[23]
式
で示される抗HER2抗体-薬物コンジュゲートを有効成分として含有する、HER2変異がんの治療剤。
[24]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[23]に記載の治療剤。
[25]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[24]に記載の治療剤。
[26]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[23]に記載の治療剤。
[27]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[26]に記載の治療剤。
[28]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[27]に記載の治療剤。
[29]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[23]に記載の治療剤。
[30]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[29]に記載の治療剤。
[31]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[30]に記載の治療剤。
[32]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[23]に記載の治療剤。
[33]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[32]に記載の治療剤。
[34]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[33]に記載の治療剤。
[35]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[23]~[34]のいずれか1項に記載の治療剤。
[36]
HER2変異がんにおけるがんが、非小細胞肺がんである、[23]~[34]のいずれか1項に記載の治療剤。
[37]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[36]に記載の治療剤。
[38]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[23]~[37]のいずれか1項に記載の治療剤。
[39]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[23]~[37]のいずれか1項に記載の治療剤。
[40]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[23]~[39]のいずれか1項に記載の治療剤。
[41]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[23]~[39]のいずれか1項に記載の治療剤。
[42]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[23]~[41]のいずれか1項に記載の治療剤。
[43]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[23]~[41]のいずれか1項に記載の治療剤。
[44]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[23]~[43]のいずれか1項に記載の治療剤。
[45]
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲートを、HER2変異がんを有することが確認された患者に投与することを特徴とする、がんの治療方法。
[46]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[45]に記載の治療方法。
[47]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[46]に記載の治療方法。
[48]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[45]に記載の治療方法。
[49]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[48]に記載の治療方法。
[50]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[49]に記載の治療方法。
[51]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[45]に記載の治療方法。
[52]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[51]に記載の治療方法。
[53]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[52]に記載の治療方法。
[54]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[45]に記載の治療方法。
[55]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[54]に記載の治療方法。
[56]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[55]に記載の治療方法。
[57]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[45]~[56]のいずれか1項に記載の治療方法。
[58]
HER2変異がんにおけるがんが、非小細胞肺がんである、[45]~[56]のいずれか1項に記載の治療方法。
[59]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[58]に記載の治療方法。
[60]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[45]~[59]のいずれか1項に記載の治療方法。
[61]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[45]~[59]のいずれか1項に記載の治療方法。
[62]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[45]~[61]のいずれか1項に記載の治療方法。
[63]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[45]~[61]のいずれか1項に記載の治療方法。
[64]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[45]~[63]のいずれか1項に記載の治療方法。
[65]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[45]~[63]のいずれか1項に記載の治療方法。
[66]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[45]~[65]のいずれか1項に記載の治療方法。
[67]
式
で示される抗HER2抗体-薬物コンジュゲートを、HER2変異がんを有することが確認された患者に投与することを特徴とする、がんの治療方法。
[68]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[67]に記載の治療方法。
[69]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[68]に記載の治療方法。
[70]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[67]に記載の治療方法。
[71]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[70]に記載の治療方法。
[72]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[71]に記載の治療方法。
[73]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[67]に記載の治療方法。
[74]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[73]に記載の治療方法。
[75]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[74]に記載の治療方法。
[76]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[67]に記載の治療方法。
[77]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[76]に記載の治療方法。
[78]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[77]に記載の治療方法。
[79]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[67]~[78]のいずれか1項に記載の治療方法。
[80]
HER2変異がんにおけるがんが、非小細胞肺がんである、[67]~[78]のいずれか1項に記載の治療方法。
[81]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[80]に記載の治療方法。
[82]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[67]~[81]のいずれか1項に記載の治療方法。
[83]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[67]~[81]のいずれか1項に記載の治療方法。
[84]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[67]~[83]のいずれか1項に記載の治療方法。
[85]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[67]~[83]のいずれか1項に記載の治療方法。
[86]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[67]~[85]のいずれか1項に記載の治療方法。
[87]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[67]~[85]のいずれか1項に記載の治療方法。
[88]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[67]~[87]のいずれか1項に記載の治療方法。
[89]
HER2変異がんの治療のための、
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲート。
[90]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[89]に記載の抗HER2抗体-薬物コンジュゲート。
[91]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[90]に記載の抗HER2抗体-薬物コンジュゲート。
[92]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[89]に記載の抗HER2抗体-薬物コンジュゲート。
[93]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[92]に記載の抗HER2抗体-薬物コンジュゲート。
[94]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[93]に記載の抗HER2抗体-薬物コンジュゲート。
[95]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[89]に記載の抗HER2抗体-薬物コンジュゲート。
[96]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[95]に記載の抗HER2抗体-薬物コンジュゲート。
[97]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[96]に記載の抗HER2抗体-薬物コンジュゲート。
[98]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[89]に記載の抗HER2抗体-薬物コンジュゲート。
[99]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[98]に記載の抗HER2抗体-薬物コンジュゲート。
[100]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[99]に記載の抗HER2抗体-薬物コンジュゲート。
[101]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[89]~[100]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[102]
HER2変異がんにおけるがんが、非小細胞肺がんである、[89]~[100]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[103]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[102]に記載の抗HER2抗体-薬物コンジュゲート。
[104]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[89]~[103]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[105]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[89]~[103]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[106]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[89]~[105]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[107]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[89]~[105]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[108]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[89]~[107]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[109]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[89]~[107]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[110]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[89]~[109]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[111]
HER2変異がんの治療のための、
式
で示される抗HER2抗体-薬物コンジュゲート。
[112]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[111]に記載の抗HER2抗体-薬物コンジュゲート。
[113]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[112]に記載の抗HER2抗体-薬物コンジュゲート。
[114]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[111]に記載の抗HER2抗体-薬物コンジュゲート。
[115]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[114]に記載の抗HER2抗体-薬物コンジュゲート。
[116]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[115]に記載の抗HER2抗体-薬物コンジュゲート。
[117]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[111]に記載の抗HER2抗体-薬物コンジュゲート。
[118]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[117]に記載の抗HER2抗体-薬物コンジュゲート。
[119]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[118]に記載の抗HER2抗体-薬物コンジュゲート。
[120]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[111]に記載の抗HER2抗体-薬物コンジュゲート。
[121]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[120]に記載の抗HER2抗体-薬物コンジュゲート。
[122]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[121]に記載の抗HER2抗体-薬物コンジュゲート。
[123]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[111]~[122]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[124]
HER2変異がんにおけるがんが、非小細胞肺がんである、[111]~[122]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[125]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[124]に記載の抗HER2抗体-薬物コンジュゲート。
[126]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[111]~[125]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[127]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[111]~[125]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[128]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[111]~[127]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[129]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[111]~[127]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[130]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[111]~[129]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[131]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[111]~[129]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[132]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[111]~[131]のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
[133]
HER2変異がんの治療用の医薬を製造するための、
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲートの使用。
[134]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[133]に記載の使用。
[135]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[134]に記載の使用。
[136]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[133]に記載の使用。
[137]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[136]に記載の使用。
[138]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[137]に記載の使用。
[139]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[133]に記載の使用。
[140]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[139]に記載の使用。
[141]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[140]に記載の使用。
[142]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[133]に記載の使用。
[143]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[142]に記載の使用。
[144]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[143]に記載の使用。
[145]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[133]~[144]のいずれか1項に記載の使用。
[146]
HER2変異がんにおけるがんが、非小細胞肺がんである、[133]~[144]のいずれか1項に記載の使用。
[147]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[146]に記載の使用。
[148]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[133]~[147]のいずれか1項に記載の使用。
[149]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[133]~[147]のいずれか1項に記載の使用。
[150]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[133]~[149]のいずれか1項に記載の使用。
[151]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[133]~[149]のいずれか1項に記載の使用。
[152]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[133]~[151]のいずれか1項に記載の使用。
[153]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[133]~[151]のいずれか1項に記載の使用。
[154]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[133]~[153]のいずれか1項に記載の使用。
[155]
HER2変異がんの治療用の医薬を製造するための、
式
で示される抗HER2抗体-薬物コンジュゲートの使用。
[156]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、[155]に記載の使用。
[157]
HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、[156]に記載の使用。
[158]
HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、[155]に記載の使用。
[159]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、[158]に記載の使用。
[160]
Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、[159]に記載の使用。
[161]
HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、[155]に記載の使用。
[162]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、[161]に記載の使用。
[163]
HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、[162]に記載の使用。
[164]
HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、[155]に記載の使用。
[165]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、[164]に記載の使用。
[166]
HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、[165]に記載の使用。
[167]
HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、[155]~[166]のいずれか1項に記載の使用。
[168]
HER2変異がんにおけるがんが、非小細胞肺がんである、[155]~[166]のいずれか1項に記載の使用。
[169]
非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、[168]に記載の使用。
[170]
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[155]~[169]のいずれか1項に記載の使用。
[171]
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、[155]~[169]のいずれか1項に記載の使用。
[172]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、[155]~[171]のいずれか1項に記載の使用。
[173]
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、[155]~[171]のいずれか1項に記載の使用。
[174]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、[155]~[173]のいずれか1項に記載の使用。
[175]
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、[155]~[173]のいずれか1項に記載の使用。
[176]
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、[155]~[175]のいずれか1項に記載の使用。
〔1〕
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲートを有効成分として含有する、HER2遺伝子変異がんの治療剤。
〔2〕
がんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆管がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、〔1〕に記載の治療剤。
〔3〕
がんが、非小細胞肺がんである、〔1〕に記載の治療剤。
〔4〕
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔1〕~〔3〕のいずれか1項に記載の治療剤。
〔5〕
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔1〕~〔3〕のいずれか1項に記載の治療剤。
〔6〕
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、〔1〕~〔5〕のいずれか1項に記載の治療剤。
〔7〕
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、〔1〕~〔5〕のいずれか1項に記載の治療剤。
〔8〕
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、〔1〕~〔7〕のいずれか1項に記載の治療剤。
〔9〕
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、〔1〕~〔7〕のいずれか1項に記載の治療剤。
〔10〕
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、〔1〕~〔9〕のいずれか1項に記載の治療剤。
〔11〕
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲートを、HER2遺伝子変異がんを有することが確認された患者に投与することを特徴とする、がんの治療方法。
〔12〕
がんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆管がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、〔11〕に記載の治療方法。
〔13〕
がんが、非小細胞肺がんである、〔11〕に記載の治療方法。
〔14〕
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔11〕~〔13〕のいずれか1項に記載の治療方法。
〔15〕
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔11〕~〔13〕のいずれか1項に記載の治療方法。
〔16〕
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、〔11〕~〔15〕のいずれか1項に記載の治療方法。
〔17〕
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、〔11〕~〔15〕のいずれか1項に記載の治療方法。
〔18〕
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、〔11〕~〔17〕のいずれか1項に記載の治療方法。
〔19〕
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、〔11〕~〔17〕のいずれか1項に記載の治療方法。
〔20〕
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、〔11〕~〔19〕のいずれか1項に記載の治療方法。
〔21〕
HER2遺伝子変異がんの治療のための、
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲート。
〔22〕
がんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆管がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、〔21〕に記載の抗HER2抗体-薬物コンジュゲート。
〔23〕
がんが、非小細胞肺がんである、〔21〕に記載の抗HER2抗体-薬物コンジュゲート。
〔24〕
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔21〕~〔23〕のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
〔25〕
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔21〕~〔23]〕のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
〔26〕
1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、〔21〕~〔25〕のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
〔27〕
1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、〔21〕~〔25〕のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
〔28〕
1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、〔21〕~〔27〕のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
〔29〕
1回あたりの投与量が6.4mg/kgである、〔21〕~〔27〕のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
〔30〕
3週に1回の間隔で投与される、〔21〕~〔29〕のいずれか1項に記載の抗HER2抗体-薬物コンジュゲート。
〔31〕
HER2遺伝子変異がんの治療用の医薬を製造するための、
式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲートの使用。
〔32〕
がんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆管がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、〔31〕に記載の使用。
〔33〕
がんが、非小細胞肺がんである、〔31〕に記載の使用。
〔34〕
抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔31〕~〔33〕のいずれか1項に記載の使用。
〔35〕
抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、〔31〕~〔33〕のいずれか1項に記載の使用。
〔36〕
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、〔31〕~〔35〕のいずれか1項に記載の使用。
〔37〕
抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、〔31〕~〔35〕のいずれか1項に記載の使用。
〔38〕
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、〔31〕~〔37〕のいずれか1項に記載の使用。
〔39〕
抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、〔31〕~〔37〕のいずれか1項に記載の使用。
〔40〕
抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、〔31〕~〔39〕のいずれか1項に記載の使用。
本発明において、「HER2」とは、ヒト上皮増殖因子受容体2(neu、ErbB-2と呼ばれることもある)と同義であり、HER1(EGFR、ErbB-1)、HER3(ErbB-3)及びHER4(ErbB-4)とともに受容体蛋白質チロシンキナーゼの上皮増殖因子受容体(EGFR)サブファミリーに属する膜貫通受容体である。HER2は、HER1、HER3、又はHER4とのヘテロダイマー形成により細胞内チロシン残基が自己リン酸化されて活性化することにより、正常細胞及び腫瘍細胞において細胞の増殖・分化・生存に重要な役割を果たすことが知られている。
本発明において、「HER2蛋白」という語は、HER2と同じ意味で用いている。HER2蛋白の発現は、免疫組織化学(IHC)法等、当業者に周知の方法を用いて検出することができる。
HER2変異の有無は、例えば、がん患者から腫瘍組織を採取し、ホルマリン固定パラフィン包埋された検体(FFPE)をリアルタイム定量PCR(qRT-PCR)又はマイクロアレイ解析等の方法を行うことにより確認することができる。
[抗HER2抗体-薬物コンジュゲート]
本発明において使用される抗HER2抗体-薬物コンジュゲートは、式
で示される薬物リンカーと、抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲートである。
本発明で用いるHER2蛋白は、ヒト、非ヒト哺乳動物(ラット、マウス等)のHER2発現細胞から直接精製して使用するか、或は当該細胞の細胞膜画分を調製して使用することができ、また、HER2をin vitroにて合成する、或は遺伝子操作によって宿主細胞に産生させることによって得ることができる。遺伝子操作では、具体的には、HER2 cDNAを発現可能なベクターに組み込んだ後、転写と翻訳に必要な酵素、基質及びエネルギー物質を含む溶液中で合成する、或は他の原核生物、又は真核生物の宿主細胞を形質転換してHER2を発現させることによって、該蛋白質を得ることができる。また、前記の遺伝子操作によるHER2発現細胞、或はHER2を発現している細胞株をHER2蛋白として使用することも可能である。
本発明で用いるHER2蛋白質は、ヒトのHER2発現細胞から直接精製して使用するか、或は、抗原として使用する際には、当該細胞の細胞膜画分をHER2蛋白質として使用することができ、また、HER2をin vitroにて合成する、又は遺伝子操作によって宿主細胞に産生させることによって得ることができる。遺伝子操作では、具体的には、HER2 cDNAを発現可能なベクターに組み込んだ後、当該ベクターを転写と翻訳に必要な酵素、基質及びエネルギー物質を含む溶液中でインキュベートすることにより、HER2を合成することができる。或は他の原核生物、又は真核生物の宿主細胞を当該ベクターにて形質転換させ、HER2を発現させることによって、該蛋白質を得ることができる。また、前記の遺伝子操作によるHER2発現細胞、又はHER2を発現している細胞株をHER2蛋白質抗原として使用することも可能である。
HER2のDNA配列及びアミノ酸配列は公的データベース上に公開されており、例えば、M11730(Genbank)、NP_004439.2(NCBI)等のアクセッション番号により参照可能である。
(1)配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体、又は、
(2)配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である。
本発明に係る抗HER2抗体-薬物コンジュゲートの製造に使用される薬物リンカー中間体は、次式で示される。
本発明の治療剤及び/又は治療方法は、特定の抗HER2抗体-薬物コンジュゲートを投与することを特徴とし、HER2変異がんの治療のために使用することができる。
国際公開第2015/115091号に記載の製造方法に従って、ヒト化抗HER2抗体(配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体)を用いて、式
で示される薬物リンカーと、抗HER2抗体とがチオエーテル結合によって結合した抗HER2抗体-薬物コンジュゲート(本発明において「HER2-ADC(1)」と称する)を製造した。HER2-ADC(1)における1抗体あたりの平均薬物結合数は7~8の範囲である。
HER2-ADC(1)のフェーズI試験は、HER2陽性乳がん患者(トラスツズマブエムタンシンの治療歴あり)、HER2陽性胃がん患者(トラスツズマブの治療歴あり)、HER2低発現乳がん患者(IHCが1+、又はIHCが2+でISHがー)、及び、HER2発現(IHCが1+以上)又はHER2変異が確認されたその他の固形がん患者(IHC、FISH、NGS、又はその他の方法により確認)を対象に行われた。副作用(AEs)、奏効率(ORR:CR(完全奏効)+PR(部分奏効))、及び、病勢コントロール率(DCR:CR+PR+SD(安定))を評価した。
実施例2に引き続き、HER2-ADC(1)のフェーズI試験を行った。これまでにHER2-ADC(1)の投与(6.4mg/kg)を受けたHER2発現又はHER2変異が確認された非小細胞肺がんの患者は18人である。患者の年齢のメジアン値は58.0歳であり、患者の前治療歴はメジアン値で3回である。18人の患者のうち、HER2変異が確認された患者は11人(61.1%)である。
HER2-ADC(1)のフェーズII試験は、HER2過剰発現(IHCが3+又は2+)が確認された切除不能及び/又は転移性の非小細胞肺がん患者(約40人: Cohort 1)、及び、HER2変異が確認された切除不能及び/又は転移性の非小細胞肺がん患者(約40人: Cohort 2)を対象に行う。HER2-ADC(1)は6.4mg/kgの投与量を3週に1回の間隔で投与し、奏効率(ORR)、奏効期間(DoR)、無憎悪生存期間(PFS)、全生存期間(OS)等を評価する。
配列番号2:ヒト化抗HER2抗体軽鎖のアミノ酸配列
配列番号3:HER2蛋白のアミノ酸配列
配列番号4:HER2遺伝子(cDNA)のヌクレオチド配列
Claims (44)
- HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、請求項1に記載の治療剤。
- HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、請求項2に記載の治療剤。
- HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、請求項1に記載の治療剤。
- Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、請求項4に記載の治療剤。
- Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、請求項5に記載の治療剤。
- HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、請求項1に記載の治療剤。
- HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、請求項7に記載の治療剤。
- HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、請求項8に記載の治療剤。
- HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、請求項1に記載の治療剤。
- HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、請求項10に記載の治療剤。
- HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、請求項11に記載の治療剤。
- HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、請求項1~12のいずれか1項に記載の治療剤。
- HER2変異がんにおけるがんが、非小細胞肺がんである、請求項1~12のいずれか1項に記載の治療剤。
- 非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、請求項14に記載の治療剤。
- 抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、請求項1~15のいずれか1項に記載の治療剤。
- 抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、請求項1~15のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、請求項1~17のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、請求項1~17のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、請求項1~19のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、請求項1~19のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、請求項1~21のいずれか1項に記載の治療剤。
- HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、V659E、G660D、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、R647G、I654V、I655V、I661V、R678Q、Q680H、V697L、G704R、Q709L、Q711H、G727A、T733I、E744G、N745D、L755P、L755A、L755F、S760F、D769H、D769N、D769Y、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delinsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779P、S779_P780insVGS、P780_Y781insGSP、R784C、R784H、L785R、L786V、T791I、G804S、L807F、S819F、I829T、V842I、L846F、T862I、R868W、L869R、T875I、W906*、T917S、Q943*、S1007*、及びS1151Lからなる群より選択される少なくとも一つである、請求項23に記載の治療剤。
- HER2変異がんにおけるHER2変異が、Y772_A775dup、G778_P780dup、G776delinsVC、L755S、V777L、及びS310Fからなる群より選択される少なくとも一つである、請求項24に記載の治療剤。
- HER2変異がんにおけるHER2変異が、Exon 20 insertion変異である、請求項23に記載の治療剤。
- Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、G776delinsVC、E770_A771insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、G776delinsLC、G776delinsAVGC、G776delinsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780insVGS、及びP780_Y781insGSPからなる群より選択される少なくとも一つである、請求項26に記載の治療剤。
- Exon 20 insertion変異が、Y772_A775dup、G778_P780dup、及びG776delinsVCからなる群より選択される少なくとも一つである、請求項27に記載の治療剤。
- HER2変異がんにおけるHER2変異が、HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異である、請求項23に記載の治療剤。
- HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、V659E、G660D、I654V、I655V、及びI661Vからなる群より選択される少なくとも一つである、請求項29に記載の治療剤。
- HER2蛋白の膜貫通ドメインにおけるSingle base pair substitution変異が、G660Dである、請求項30に記載の治療剤。
- HER2変異がんにおけるHER2変異が、HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異である、請求項23に記載の治療剤。
- HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310F、A20T、A21S、R143Q、K200N、A242V、D277Y、A293P、N302K、V308M、S310Y、N319Y、S335C、R340P、S418T、W452C、V541M、I613V、P627H、A644V、及びR647Gからなる群より選択される少なくとも一つである、請求項32に記載の治療剤。
- HER2蛋白の細胞外ドメインにおけるSingle base pair substitution変異が、S310Fである、請求項33に記載の治療剤。
- HER2変異がんにおけるがんが、非小細胞肺がん、乳がん、胃がん、大腸がん、食道がん、唾液腺がん、胃食道接合部腺がん、胆道がん、ページェット病、膵臓がん、卵巣がん、及び子宮がん肉腫からなる群より選択される少なくとも一つである、請求項23~34のいずれか1項に記載の治療剤。
- HER2変異がんにおけるがんが、非小細胞肺がんである、請求項23~34のいずれか1項に記載の治療剤。
- 非小細胞肺がんが、切除不能及び/又は転移性の非小細胞肺がんである、請求項36に記載の治療剤。
- 抗HER2抗体が、配列番号1においてアミノ酸番号1乃至449に記載のアミノ酸配列からなる重鎖及び配列番号2においてアミノ酸番号1乃至214に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、請求項23~37のいずれか1項に記載の治療剤。
- 抗HER2抗体が、配列番号1に記載のアミノ酸配列からなる重鎖及び配列番号2に記載のアミノ酸配列からなる軽鎖を含んでなる抗体である、請求項23~37のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7から8個の範囲である、請求項23~39のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートにおける1抗体あたりの薬物リンカーの平均結合数が7.5から8個の範囲である、請求項23~39のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が5.4mg/kgから8mg/kgの範囲である、請求項23~41のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートの1回あたりの投与量が6.4mg/kgである、請求項23~41のいずれか1項に記載の治療剤。
- 抗HER2抗体-薬物コンジュゲートが3週に1回の間隔で投与される、請求項23~43のいずれか1項に記載の治療剤。
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SG11202011243XA SG11202011243XA (en) | 2018-05-28 | 2019-05-27 | Treatment of her2-mutated cancer by administering anti-her2 antibody-drug conjugate |
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