JP2021035962A - がんを治療するための、pd−1アンタゴニスト及びvegfr/fgfr/retチロシンキナーゼ阻害剤の組合せ - Google Patents
がんを治療するための、pd−1アンタゴニスト及びvegfr/fgfr/retチロシンキナーゼ阻害剤の組合せ Download PDFInfo
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- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
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- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
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- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
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- 239000007929 subcutaneous injection Substances 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
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- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
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- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
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- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
Description
R1はC1〜6アルキル又はC3〜8シクロアルキルである。R2は水素原子又はC1〜6アルコキシである。R3は水素原子又はハロゲン原子である。
式中、R1はC1〜6アルキル又はC3〜8シクロアルキルであり、R2は水素原子又はC1〜6アルコキシであり、R3は水素原子又はハロゲン原子である。式(I)で表される化合物は、以下の化合物のうちの1つ又は複数とすることができる:
4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
、4−[3−クロロ−4−(メチルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
、4−[3−クロロ−4−(エチルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
、N6−メトキシ−4−(3−クロロ−4−{[(シクロプロピルアミノ)カルボニル)アミノ]フェノキシ}−7−メトキシ−6−キノリンカルボキシアミド:
、及びN6−メトキシ−4−(3−クロロ−4−{[(エチルアミノ)カルボニル]アミノ}フェノキシ)−7−メトキシ−6−キノリンカルボキシアミド:
。
式中、R1はC1〜6アルキル又はC3〜8シクロアルキルであり、R2は水素原子又はC1〜6アルコキシであり、R3は水素原子又はハロゲン原子である。式(I)で表される化合物は、以下の化合物のうちの1つ又は複数とすることができる:
4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
、4−[3−クロロ−4−(メチルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
、4−[3−クロロ−4−(エチルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
、N6−メトキシ−4−(3−クロロ−4−{[(シクロプロピルアミノ)カルボニル)アミノ]フェノキシ}−7−メトキシ−6−キノリンカルボキシアミド:
、及びN6−メトキシ−4−(3−クロロ−4−{[(エチルアミノ)カルボニル]アミノ}フェノキシ)−7−メトキシ−6−キノリンカルボキシアミド:
。
式中、R1はC1〜6アルキル又はC3〜8シクロアルキルであり、R2は水素原子又はC1〜6アルコキシであり、R3は水素原子又はハロゲン原子である。腫瘍治療剤は、上記の式(I)で表される化合物又はその薬学的に許容される塩、及び抗PD−1抗体を同時に又は別個に投与することができる。腫瘍治療剤は、同時に投与されても別個に投与されてもよい。例えば、組成物は、上記の式(I)で表される化合物又はその薬学的に許容される塩、及び抗PD−1抗体を含む組成物を含みうる。腫瘍治療剤は、上記の式(I)で表される化合物又はその薬学的に許容される塩、及び抗PD−1抗体を含みうる。
[0037]4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
[0038]4−[3−クロロ−4−(メチルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
[0039]4−[3−クロロ−4−(エチルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド:
[0040]N6−メトキシ−4−(3−クロロ−4−{[(シクロプロピルアミノ)カルボニル)アミノ]フェノキシ}−7−メトキシ−6−キノリンカルボキシアミド:
[0041]及びN6−メトキシ−4−(3−クロロ−4−{[(エチルアミノ)カルボニル]アミノ}フェノキシ)−7−メトキシ−6−キノリンカルボキシアミド:
[0042]上記の式(I)で表される化合物は、より好ましくは4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミドである:
(以下で、レンバチニブと示される場合もある)。
[0054]BOR 最良総合効果
[0055]BID 1日2回投与
[0056]CBR 臨床的有効率
[0057]CDR 相補性決定領域
[0058]CHO チャイニーズハムスター卵巣
[0059]CR 完全奏効
[0060]DCR 病勢コントロール率
[0061]DFS 無病生存期間
[0062]DLT 用量制限毒性
[0063]DOR 奏効期間
[0064]DSDR 持続的不変率
[0065]FFPE ホルマリン固定、パラフィン包埋
[0066]FR フレームワーク領域
[0067]IgG 免疫グロブリンG
[0068]IHC 免疫組織化学又は免疫組織化学的
[0069]irRC 免疫関連効果判定基準
[0070]IV 静脈内
[0071]MTD 最大耐用量
[0072]NCBI 国立生物工学情報センター
[0073]NCI 国立がん研究所
[0074]ORR 客観的奏効率
[0075]OS 全生存期間
[0076]PD 進行性疾患
[0077]PD−1 プログラム細胞死1
[0078]PD−L1 プログラム細胞死1リガンド1
[0079]PD−L2 プログラム細胞死1リガンド2
[0080]PFS 無増悪生存期間
[0081]PR 部分奏効
[0082]Q2W 2週間毎に1回投与
[0083]Q3W 3週間毎に1回投与
[0084]QD 1日1回投与
[0085]RECIST 固形癌効果判定基準(Response Evaluation Criteria in Solid Tumors)
[0086]SD 不変疾患
[0087]VH 免疫グロブリン重鎖可変領域
[0088]VK 免疫グロブリンカッパ軽鎖可変領域
[0089]方法、組成物、及び使用がより容易に理解されうるように、特定の専門用語及び科学用語が以下で具体的に定義される。本文書の別の箇所で具体的に定義されない限り、本明細書で使用されるその他の専門用語及び科学用語は全て、当業者が通常理解している意味を有する。
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET(配列番号25)。
式中、R1はC1〜6アルキル又はC3〜8シクロアルキルであり、R2は水素原子又はC1〜6アルコキシであり、R3は水素原子又はハロゲン原子である、を有しえる。
の化合物、又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)としてマルチRTK阻害剤が提供される。
[00161]一態様において、PD−1アンタゴニスト及びマルチRTK阻害剤を含む併用療法を個体に投与するステップを含む、個体のがんを治療する方法が提供される。
1.個体のがんを治療するための方法であって、PD−1アンタゴニスト及びマルチRTK阻害剤を含む併用療法を個体に投与するステップを含む方法。
2.PD−1アンタゴニストがモノクローナル抗体、又はその抗原結合フラグメントである、実施形態1の方法。
3.マルチRTK阻害剤がレンバチニブ又はその薬学的に許容される塩であり、PD−1アンタゴニストがMPDL3280Aでない、実施形態1又は2の方法。
4.個体のがんを治療するためにマルチRTK阻害剤と組み合わせて使用するための、MPDL3280AでないPD−1アンタゴニストを含む医薬であって、PD−1アンタゴニストがモノクローナル抗体、又はその抗原結合フラグメントである、医薬。
5.個体のがんを治療するために、MPDL3280AでないPD−1アンタゴニストと組み合わせて使用するための、マルチRTK阻害剤を含む医薬。
6.薬学的に許容される賦形剤をさらに含む、実施形態4又は5の医薬。
7.マルチRTK阻害剤と組み合わせて投与される場合に個体のがんを治療するための医薬の製造における、MPDL3280AでないPD−1アンタゴニストの使用。
6.MPDL3280AでないPD−1アンタゴニストと組み合わせて投与される場合に個体のがんを治療するための医薬の製造における、マルチRTK阻害剤の使用。
7.個体のがんを治療するための医薬の製造における、MPDL3280AでないPD−1アンタゴニスト、及びマルチRTK阻害剤の使用。
8.第1の容器、第2の容器及び添付文書を含むキットであって、第1の容器が、MPDL3280Aでない抗PD−1アンタゴニストを含む少なくとも1回分の用量の医薬を含み、第2の容器が、マルチRTK阻害剤を含む少なくとも1回分の用量の医薬を含み、添付文書が、医薬を使用して個体のがんを治療するための指示書を含むキット。
9.指示書には、医薬が、免疫組織化学的(IHC)アッセイでPD−L1発現について陽性を示すがんを有する個体を治療するのに使用するためのものであることが明記されている、実施形態8のキット。
10.個体がヒトであり、PD−1アンタゴニストが、ヒトPD−L1に特異的に結合し、ヒトPD−L1のヒトPD−1への結合を遮断するモノクローナル抗体、又はその抗原結合フラグメントである、実施形態1〜9のいずれかの方法、医薬、使用又はキット。
11.PD−1アンタゴニストがBMS−936559、MEDI4736、又はMSB0010718Cである、実施形態9の方法、医薬、使用又はキット。
12.個体がヒトであり、PD−1アンタゴニストが、ヒトPD−1に特異的に結合し、ヒトPD−L1のヒトPD−1への結合を遮断するモノクローナル抗体、又はその抗原結合フラグメントである、実施形態1〜9のいずれかの方法、医薬、使用又はキット。
13.PD−1アンタゴニストが、ヒトPD−L2のヒトPD−1への結合も遮断する、実施形態12の方法、医薬、使用又はキット。
14.モノクローナル抗体、又はその抗原結合フラグメントが:(a)配列番号1、2及び3の軽鎖CDR、並びに配列番号4、5及び6の重鎖CDR;又は(b)配列番号7、8及び9の軽鎖CDR、並びに配列番号10、11及び12の重鎖CDRを含む、実施形態13の方法、医薬、使用又はキット。
15.モノクローナル抗体、又はその抗原結合フラグメントが、配列番号7、8及び9の軽鎖CDR、並びに配列番号10、11及び12の重鎖CDRを含む、実施形態13の方法、医薬、使用又はキット。
16.PD−1アンタゴニストが、重鎖及び軽鎖を含む抗PD−1モノクローナル抗体であり、重鎖が配列番号21を含み、軽鎖が配列番号22を含む、実施形態13の方法、医薬、使用又はキット。
17.PD−1アンタゴニストが、重鎖及び軽鎖を含む抗PD−1モノクローナル抗体であり、重鎖が配列番号23を含み、軽鎖が配列番号24を含む、実施形態13の方法、医薬、使用又はキット。
18.がんが固形腫瘍である、実施形態10〜17のいずれかの方法、医薬、使用又はキット。
19.がんが、膀胱がん、乳がん、腎明細胞がん、頭部/頸部扁平上皮細胞癌、肺扁平上皮細胞癌、悪性メラノーマ、非小細胞肺がん(NSCLC)、卵巣がん、膵臓がん、前立腺がん、腎細胞癌(RCC)、小細胞肺がん(SCLC)又はトリプルネガティブ乳がんである、実施形態10〜17のいずれかの方法、医薬、使用又はキット。
20.がんが、NSCLC、RCC、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌又はメラノーマである、実施形態10〜17のいずれかの方法、医薬、使用又はキット。
21.個体が、NSCLC、RCC、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌又はメラノーマで以前に治療を受けたことがない、実施形態10〜17のいずれかの方法、医薬、使用又はキット。
23.がんが、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、びまん性大細胞型B細胞リンパ腫(DLBCL)、濾胞性リンパ腫、ホジキンリンパ腫(HL)、マントル細胞リンパ腫(MCL)、多発性骨髄腫(MM)、骨髄細胞白血病−1タンパク質(Mcl−1)、骨髄異形成症候群(MDS)、非ホジキンリンパ腫(NHL)、又は小リンパ球性リンパ腫(SLL)である、実施形態10〜17のいずれかの方法、医薬、使用又はキット。
24.がんがヒトPD−L1について陽性を示す、実施形態10〜23のいずれかの方法、医薬、使用又はキット。
25.ヒトPD−L1の発現が上昇している、実施形態24の方法、医薬、使用又はキット。
26.PD−1アンタゴニストがペムブロリズマブ、ペムブロリズマブ変異体、ペムブロリズマブバイオシミラー又はニボルマブである、実施形態13の方法、医薬、使用又はキット。
27.ペムブロリズマブが、10mMヒスチジン緩衝液pH5.5中に25mg/mlペムブロリズマブ、7%(w/v)スクロース、0.02%(w/v)ポリソルベート80を含む液体医薬として製剤化されている、実施形態26の方法、医薬、使用又はキット。
28.マルチRTK阻害剤が、レンバチニブ又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)である、実施形態1〜27のいずれかの方法、医薬、使用又はキット。
29.マルチRTK阻害剤がレンバチニブメシル酸塩であり、炭酸カルシウム、マンニトール、微結晶セルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、及びタルクとともに製剤化されている、実施形態1〜28のいずれかの方法、医薬、使用又はキット。
30.がんと診断されたヒト個体を治療するための方法であって、ペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)を含む併用療法を個体に投与するステップを含み、レンバチニブ又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)が、1日用量でそれぞれレンバチニブとして24mg、20mg又は14mgで投与され、ペムブロリズマブが3週間毎に1回、200mgで投与される、方法。
31.レンバチニブ又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)を、1日用量でそれぞれレンバチニブとして24mg、20mg又は14mgで、及びペムブロリズマブを3週間毎に1回、200mgで個体に投与するステップを含む方法によりヒト個体のがんを治療するために、レンバチニブ又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)と組み合わせて使用するための、ペムブロリズマブを含む医薬。
32.レンバチニブ又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)を、1日用量でそれぞれレンバチニブとして24mg、20mg又は14mgで、及びペムブロリズマブを3週間毎に1回、200mgで個体に投与するステップを含む方法によりヒト個体のがんを治療するために、ペムブロリズマブと組み合わせて使用するための、レンバチニブ又はその薬学的に許容される塩(例えばレンバチニブメシル酸塩)を含む医薬。
33.がんがNSCLC、RCC、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌又はメラノーマである、実施形態30〜32のいずれかの方法又は医薬。
34.個体が、NSCLC、RCC、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌又はメラノーマで以前に治療を受けたことがない、実施形態33の方法又は医薬。
35.併用療法投与前に個体から取り出されたがんの組織切片が、PD−L1発現について陽性を示した、実施形態31〜34のいずれかの方法又は医薬。
36.組織切片の腫瘍細胞のうち少なくとも50%が、免疫組織化学的(IHC)アッセイでPD−L1発現について陽性を示した、実施形態35の方法又は医薬。
37.IHCアッセイで抗体22C3を使用してPD−L1発現を検出した、実施形態36の方法又は医薬。
38.ペムブロリズマブが、IV注入により25〜40分間又は約30分間投与される、実施形態31〜37のいずれかの方法又は医薬。
[00194]分子生物学における標準的な方法が、Sambrook、Fritsch及びManiatis(1982及び1989 第2版、2001 第3版)MOLECULAR CLONING、A LABORATORY MANUAL、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、NY;Sambrook及びRussell(2001)MOLECULAR CLONING、第3版、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、NY;Wu(1993)RECOMBINANT DNA、Vol.217、Academic Press、San Diego、CA)に記載されている。標準的な方法は、Ausbelら(2001)Current Protocols in Molecular Biology、Vols.1〜4、John Wiley及びSons、Inc.New York、NYにも掲載されており、細菌細胞でのクローニング及びDNA突然変異誘発(Vol.1)、哺乳動物細胞及び酵母でのクローニング(Vol.2)、複合糖質及びタンパク質発現(Vol.3)、並びに生物情報学(Vol.4)について記載されている。
腫瘍体積TV(mm3)=長径(mm)×短径(mm)×短径(mm)/2。
腫瘍体積TV(mm3)=長径(mm)×短径(mm)×短径(mm)/2。
腫瘍体積TV(mm3)=長径(mm)×短径(mm)×短径(mm)/2。
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[00217]本明細書で引用される参考文献は全て、個々の刊行物、データベース登録(例えばGenbank配列又はGeneID登録)、特許出願、又は特許がそれぞれ、参照により組み込まれることが明確且つ個別に示される場合と同程度に、参照により組み込まれる。参照による組込みについての明記は、出願者により、米国特許法施行規則第1.57条第(b)項(1)に従って、いずれの個々の刊行物、データベース登録(例えばGenbank配列又はGeneID登録)、特許出願、又は特許にも関連することが意図され、このような引用が参照による組込みについての専用の明記のすぐ隣になくとも、そのそれぞれが米国特許法施行規則第1.57条第(b)項(2)に従って明確に識別される。参照による組込みについての専用の明記を、もしあれば明細書内に含むことで、参照による組込みについてのこの一般的な明記が弱められることはない。本明細書での参考文献の引用は、参考文献が関連先行技術であると認めることとは意図されず、これらの刊行物又は文書の内容又は日付に関して認めるということにもならない。
[1]個体のがんを治療するための方法であって、プログラム細胞死1タンパク質(PD−1)アンタゴニスト及びマルチ受容体チロシンキナーゼ(マルチRTK)阻害剤を含む併用療法を個体に投与するステップを含み、アンタゴニストがMPDL3280Aでない、方法。
[2]個体がヒトである、項[1]に記載の方法。
[3]がんが固形腫瘍である、項[1]又は[2]に記載の方法。
[4]がんが、甲状腺がん、肝細胞癌(HCC)、非小細胞肺がん(NSCLC)、腎細胞癌(RCC)、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌、神経膠芽腫、又はメラノーマである、項[1]又は[2]に記載の方法。
[5]アンタゴニストがモノクローナル抗体、又はその抗原結合フラグメントである、項[1]〜[4]のいずれか一項に記載の方法。
[6]アンタゴニストが抗PD−1抗体である、項[1]〜[5]のいずれか一項に記載の方法。
[7]アンタゴニストがペムブロリズマブ又はニボルマブである、項[1]〜[6]のいずれか一項に記載の方法。
[8]マルチRTK阻害剤が、構造:
を有する4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド、又はその薬学的に許容される塩である、項[1]〜[7]のいずれか一項に記載の方法。
[9]アンタゴニストがペムブロリズマブであり、マルチRTK阻害剤がレンバチニブ又はその薬学的に許容される塩である、項[1]〜[8]のいずれか一項に記載の方法。
[10]ペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩を含む併用療法が、レンバチニブ又はその薬学的に許容される塩の投与後に投与される、項[9]に記載の方法。
[11]ペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩を含む併用療法が、少なくとも7日間のレンバチニブ又はその薬学的に許容される塩の投与後に投与される、項[10]に記載の方法。
[12]ペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩を含む併用療法が、ペムブロリズマブの投与後に投与される、項[9]に記載の方法。
[13]第1の容器、第2の容器及び添付文書を含むキットであって、第1の容器が、プログラム細胞死1タンパク質(PD−1)アンタゴニストを含む少なくとも1回分の用量の医薬を含み、第2の容器が、マルチRTK阻害剤を含む少なくとも1回分の用量の医薬を含み、添付文書が、前記医薬を使用して個体のがんを治療するための指示書を含み、アンタゴニストがMPDL3280Aでない、キット。
[14]指示書には、前記医薬が、免疫組織化学的(IHC)アッセイでPD−L1発現について陽性を示すがんを有する個体を治療するのに使用するためのものであることが明記されている、項[13]に記載のキット。
[15]個体がヒトである、項[13]又は[14]に記載のキット。
[16]マルチ受容体チロシンキナーゼ(マルチRTK)阻害剤が、構造:
を有する4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキシアミド、又はその薬学的に許容される塩である、項[13]〜[15]のいずれか一項に記載のキット。
[17]アンタゴニストが、10mMヒスチジン緩衝液pH5.5中に25mg/mlペムブロリズマブ、7%(w/v)スクロース、0.02%(w/v)ポリソルベート80を含む液体医薬として製剤化されたペムブロリズマブであり、マルチRTK阻害剤が、炭酸カルシウム、マンニトール、微結晶セルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、及びタルクを含む4mg又は10mgのレンバチニブカプセル剤として製剤化されたレンバチニブ又はその薬学的に許容される塩である、項[13]〜[16]のいずれか一項に記載のキット。
[18]がんが、甲状腺がん、HCC、NSCLC、RCC、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌、神経膠芽腫又はメラノーマである、項[13]〜[17]のいずれか一項に記載のキット。
[19]がんと診断されたヒト個体を治療するための方法であって、個体に併用療法を少なくとも24週間投与するステップを含み、併用療法がペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩を含み、レンバチニブ又はその薬学的に許容される塩が、1日用量で、それぞれレンバチニブとして24mg、20mg又は14mgで投与され、ペムブロリズマブが用量200mgで3週間に1回投与される、方法。
[0001]本出願は、その内容が全内容にわたって参照により本明細書に組み込まれる、2015年3月4日出願の日本出願である特願2015−042683号、2015年6月5日出願の日本出願である特願2015−114890号、2015年3月4日出願の米国特許仮出願第62/128,232号、及び2015年6月5日出願の米国特許仮出願第62/171,615号に基づく利益を主張する。
[0002]全内容にわたって参照により本明細書に組み込まれる、配列番号1〜25を含む配列表も添付される。
Claims (21)
- 個体のがんを治療するための、マルチ受容体チロシンキナーゼ(マルチRTK)阻害剤と組み合わせて使用するための、MPDL3280Aでないプログラム細胞死1タンパク質(PD−1)アンタゴニストを含む医薬であって、PD−1アンタゴニストがモノクローナル抗体、又はその抗原結合フラグメントである、医薬。
- 個体のがんを治療するための、MPDL3280Aでないプログラム細胞死1タンパク質(PD−1)アンタゴニストと組み合わせて使用するための、マルチ受容体チロシンキナーゼ(マルチRTK)阻害剤を含む医薬。
- 個体がヒトである、請求項1又は2に記載の医薬。
- がんが固形腫瘍である、請求項1〜3のいずれか一項に記載の医薬。
- がんが、甲状腺がん、肝細胞癌(HCC)、非小細胞肺がん(NSCLC)、腎細胞癌(RCC)、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌、神経膠芽腫、又はメラノーマである、請求項1〜3のいずれか一項に記載の医薬。
- アンタゴニストがモノクローナル抗体、又はその抗原結合フラグメントである、請求項2〜5のいずれか一項に記載の医薬。
- アンタゴニストが抗PD−1抗体である、請求項1〜6のいずれか一項に記載の医薬。
- アンタゴニストがペムブロリズマブ又はニボルマブである、請求項1〜7のいずれか一項に記載の医薬。
- アンタゴニストがペムブロリズマブであり、マルチRTK阻害剤がレンバチニブ又はその薬学的に許容される塩である、請求項1〜9のいずれか一項に記載の医薬。
- ペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩を含む併用療法が、レンバチニブ又はその薬学的に許容される塩の投与後に投与される、請求項10に記載の医薬。
- ペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩を含む併用療法が、少なくとも7日間のレンバチニブ又はその薬学的に許容される塩の投与後に投与される、請求項11に記載の医薬。
- ペムブロリズマブ、及びレンバチニブ又はその薬学的に許容される塩を含む併用療法が、ペムブロリズマブの投与後に投与される、請求項10に記載の医薬。
- 第1の容器、第2の容器及び添付文書を含むキットであって、第1の容器が、プログラム細胞死1タンパク質(PD−1)アンタゴニストを含む少なくとも1回分の用量の医薬を含み、第2の容器が、マルチRTK阻害剤を含む少なくとも1回分の用量の医薬を含み、添付文書が、前記医薬を使用して個体のがんを治療するための指示書を含み、アンタゴニストがMPDL3280Aでない、キット。
- 指示書には、前記医薬が、免疫組織化学的(IHC)アッセイでPD−L1発現について陽性を示すがんを有する個体を治療するのに使用するためのものであることが明記されている、請求項14に記載のキット。
- 個体がヒトである、請求項14又は15に記載のキット。
- アンタゴニストが、10mMヒスチジン緩衝液pH5.5中に25mg/mlペムブロリズマブ、7%(w/v)スクロース、0.02%(w/v)ポリソルベート80を含む液体医薬として製剤化されたペムブロリズマブであり、マルチRTK阻害剤が、炭酸カルシウム、マンニトール、微結晶セルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、及びタルクを含む4mg又は10mgのレンバチニブカプセル剤として製剤化されたレンバチニブ又はその薬学的に許容される塩である、請求項14〜17のいずれか一項に記載のキット。
- がんが、甲状腺がん、HCC、NSCLC、RCC、子宮内膜がん、尿路上皮がん、頭頸部扁平上皮細胞癌、神経膠芽腫又はメラノーマである、請求項14〜18のいずれか一項に記載のキット。
- レンバチニブ又はその薬学的に許容される塩を、1日用量でそれぞれレンバチニブとして24mg、20mg又は14mgで、及びペムブロリズマブを3週間毎に1回、200mgで個体に投与するステップを含む方法により、ヒト個体のがんを治療するための、レンバチニブ又はその薬学的に許容される塩と組み合わせて使用するための、ペムブロリズマブを含む医薬。
- レンバチニブ又はその薬学的に許容される塩を、1日用量でそれぞれレンバチニブとして24mg、20mg又は14mgで、及びペムブロリズマブを3週間毎に1回、200mgで個体に投与するステップを含む方法により、ヒト個体のがんを治療するための、ペムブロリズマブと組み合わせて使用するための、レンバチニブ又はその薬学的に許容される塩を含む医薬。
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