JP6514647B2 - 薬物組み合わせ - Google Patents
薬物組み合わせ Download PDFInfo
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- JP6514647B2 JP6514647B2 JP2015560330A JP2015560330A JP6514647B2 JP 6514647 B2 JP6514647 B2 JP 6514647B2 JP 2015560330 A JP2015560330 A JP 2015560330A JP 2015560330 A JP2015560330 A JP 2015560330A JP 6514647 B2 JP6514647 B2 JP 6514647B2
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- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 201000007790 vitelliform macular dystrophy Diseases 0.000 description 1
- 208000020938 vitelliform macular dystrophy 2 Diseases 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Description
本出願は、全体が参照により本明細書に組み込まれる、2013年10月4日に提出された米国仮特許出願第61/887,165号、及び2013年3月1日に提出された米国仮特許出願第61/771,525号の利益を主張する。
本明細書において言及されている全ての公開公報、特許及び特許出願は、あたかも、それぞれ個々の公開公報、特許または特許出願が参照により組み込まれると具体的かつ個々に示されているのと同程度に、参照により本明細書に組み込まれる。
(5−アザシトシン基)−L−(グアニン基)(I)
式中、Lは、リン含有リンカーであり、ここで、Lにおけるリン原子の数が1である;
またはその薬学的に許容可能な塩と;
(a)T細胞活性化剤;
(b)癌ワクチン;及び
(c)アジュバント
から選択される1種以上の補助治療成分と
を含む組み合わせを提供する。
(5−アザシトシン基)−L−(グアニン基)(I)
式中、Lは、リン含有リンカーであり、ここで、Lにおけるリン原子の数が1である;
またはその薬学的に許容可能な塩と;
(a)T細胞活性化剤;
(b)癌ワクチン;
(c)IDO阻害剤;及び
(d)アジュバント
から選択される1種以上の補助治療成分と
を含む組み合わせを提供する。
(式中、R1及びR2は、独立して、H、OH、アルコキシ基、アルコキシアルコキシ基、アシルオキシ基、カーボネート基、カルバメート基、またはハロゲンであり;R3は、Hであるか、またはR3が結合している酸素原子と一緒になって、エーテル、エステル、カーボネート、またはカルバメートを形成し;R4は、Hであるか、またはR4が結合している酸素原子と一緒になって、エーテル、エステル、カーボネート、またはカルバメートを形成し;Xは、Xが結合する酸素原子と一緒になって、ホスホジエステル、ホスホロチオエートジエステル、ボラノホスフェートジエステル、またはメチルホスホネートジエステルを形成する)を有する。いくつかの実施形態において、R1及びR2は、独立して、H、OH、OMe、OEt、OCH2CH2OMe、OBn、またはFであり、Xは、Xが結合する酸素原子と一緒になって、ホスホジエステルを形成する。いくつかの実施形態において、R1及びR2は、Hである。
(a)本明細書に記載の上記化合物またはその塩を含有する第1容器と;
(b)本明細書に記載の実質的に無水の溶媒を含有する第2容器と;
(c)本明細書に記載の1種以上の補助治療成分と
を含むキットを提供する。
(a)上記化合物をDMSOに溶解させて上記化合物のDMSO溶液を生成する予備工程と;
(b)工程(a)の上記溶液を凍結乾燥させて、上記化合物を実質的に無水の粉末として提供する予備工程と
をさらに含む。
(a)骨髄異形成症候群(MDS);
(b)癌;
(c)血液疾患;または
(d)異常ヘモグロビン合成関連疾患
から選択される疾患の免疫療法または該疾患を処置するための方法であって、
本発明の組み合わせ、キット、プロセス、粉末または組成物を、これを必要とするまたは要求する対象に投与することを含む上記方法を提供する。いくつかの実施形態において、上記に定義されている化合物またはその塩は、1種以上の補助治療成分の投与の前に、一緒にまたは後に投与され得る。いくつかの実施形態において、式Iの化合物またはその塩が、まず(プライミング療法として)投与され、続いて、補助治療成分が投与される。
本発明の組み合わせにおける使用のための式Iの化合物
(5−アザシトシン基)−L−(グアニン基)(I)
式中、Lは、リン含有リンカーであり、ここで、Lにおけるリン原子の数が1である;またはその薬学的に許容可能な塩を含む組み合わせを提供する。
式中、R1及びR2は、独立して、H、OH、アルコキシ基、アルコキシアルコキシ基、アシルオキシ基、カーボネート基、カルバメート基、またはハロゲンであり;R3は、Hであるか、またはR3が結合している酸素原子と一緒になって、エーテル、エステル、カーボネート、またはカルバメートを形成し;R4は、Hであるか、またはR4が結合している酸素原子と一緒になって、エーテル、エステル、カーボネート、またはカルバメートを形成し;Xは、Xが結合する酸素原子と一緒になって、ホスホジエステル、ホスホロチオエートジエステル、ボラノホスフェートジエステル、またはメチルホスホネートジエステルを形成する。
I−1:
I−2:
I−3:
I−4:
I−5:
I−6:
I−7:
I−8:
I−9:
I−10:
I−11:
I−12:
I−13:
I−14:
I−15:
I−16:
I−17:
I−18:
I−19:
I−20:
I−21:
I−22:
I−23:
I−24:
I−25:
I−26:
I−27:
I−28:
I−29:
I−30:
I−31:
I−32:
I−33:
I−34:
I−35:
I−36:
I−37:
I−38:
I−39:
I−40:
I−41:
I−42:
I−43:
I−44:
及び上記のいずれかの薬学的に許容可能な塩が挙げられる。いくつかの実施形態において、塩は、上記のいずれかのナトリウム塩である。
本発明の組み合わせにおける使用のための製剤
・2種以上の化合物/剤のうち少なくとも1種を、該少なくとも1種の化合物/剤を即座に会合させて該2種以上の化合物/剤の物理的会合を形成するための説明書と一緒に含む材料(例えば、非単一製剤);
・2種以上の化合物/剤のうち少なくとも1種を、該2種以上の化合物/剤による組み合わせ療法のための説明書と一緒に含む材料(例えば、非単一製剤);
・2種以上の化合物/剤のうち少なくとも1種を、該2種以上の化合物/剤の他方が投与された(または投与されている)患者集団への投与のための説明書と一緒に含む材料;
・2種以上の化合物/剤のうち少なくとも1種を、該2種以上の化合物/剤の他方との組み合わせにおける使用に特に適応している量または形態で含む材料
が挙げられる。
(5−アザシトシン基)−L−(グアニン基)(I)
式中、Lは、リン含有リンカーであり、ここで、Lにおけるリン原子の数が1である;またはその薬学的に許容可能な塩と;b)約45%〜約85%のプロピレングリコール;約5%〜約45%のグリセリン;及び0%〜約30%のエタノールを含む溶媒と;c)場合により、薬学的に許容可能な賦形剤とを含む製剤を含む組み合わせを提供する。
ジメチルスルホキシド(DMSO)
投薬及び投与
治療的使用
組み合わせ療法
1.免疫調節抗体を含めたT細胞活性化剤;
2.癌ワクチン;
3.インドールアミン2,3−ジオキシゲナーゼ(IDO)阻害剤;
4.アジュバント;ならびに
5.特に、T細胞活性化剤及び癌ワクチンの組み合わせを含めた、以上のクラスの2種以上の組み合わせ。
1.免疫調節抗体を含めたT細胞活性化剤;
2.癌ワクチン;
3.アジュバント;ならびに
4.特に、T細胞活性化剤及び癌ワクチンの組み合わせを含めた、以上のクラスの2種以上の組み合わせ。
1.免疫調節抗体を含めたT細胞活性化剤
2.癌ワクチン
3.IDO阻害剤
4.アジュバント
実施例
実施例1:マウス癌モデルにおける、免疫刺激mAbと組み合わされたSGI−110の分子、表現、及び機能的インビボ効果
マウス癌におけるインビトロ免疫調節活性SGI−110
免疫刺激mAbと組み合わせたSGI−110の、マウス癌における治療効能
−6日:マウスTS/A細胞を全マウスの側腹部に皮下接種する。
0日:7日の潜伏期の後、明らかに触診可能で目に見える腫瘍移植片(直径≧0.2cm)を担持するマウスを異なる処置グループに分ける(グループあたり6匹)。
グループ1:1〜5日目にビヒクルをqd×5でSQ
グループ2:1〜5日目に、SGI−110、3mg/kgをqd×5でSQ
グループ3:2、5、8日目に抗マウスCTLA−4
グループ4:8、11、14日目に抗マウスCTLA−4
グループ5:SGI−110、3mg/kgをqd×5でSQ(1〜5日目)+抗マウスCTLA−4(2、5、8日目)(同時スケジュール)
グループ6:SGI−110、3mg/kgをqd×5でSQ(1〜5日目)+抗マウスCTLA−4(8、11、14日目)(後続スケジュール)
グループ7:2、5、8日目に抗マウスPD−1
グループ8:8、11、14日目に抗マウスPD−1
グループ9:SGI−110、3mg/kgをqd×5でSQ(1〜5日目)+抗マウスPD−1(2、5、8日目)(同時スケジュール)
グループ10:SGI−110、3mg/kgをqd×5でSQ(1〜5日目)+抗マウスPD−1(8、11、14日目)(後続スケジュール)
グループ11:1及び8日目にビヒクル(3時間毎に3回の腹腔内注射)
グループ12:1及び8日目にSGI−110、36.6mg/kg/日(3時間毎に3回の腹腔内注射)
グループ13:3、6、9日目に抗マウスCTLA−4
グループ14:1及び8日目にSGI−110、36.6mg/kg/日(3時間毎に3回の腹腔内注射)+抗マウスCTLA−4(3、6、9日目)
SQ5スケジュールの治療効能
グループ1:ビヒクルを週1回SQ(1、8、15日目)
グループ2:SGI−110、24.4mg/kgを週1回SQ(1、8、15日目)
グループ3:3、6、9日目に抗マウスCTLA−4
グループ4:17、20、23日目に抗マウスCTLA−4
グループ5:SGI−110、24.4mg/kgを週1回SQ(1、8、15日目)+抗マウスCTLA−4(3、6、9日目)(同時スケジュール)
グループ6:SGI−110、24.4mg/kgを週1回SQ(1、8、15日目)+抗マウスCTLA−4(17、20、23日目)(後続スケジュール)
グループ7:3、6、9日目に抗マウスPD−1
グループ8:17、20、23日目に抗マウスPD−1
グループ9:SGI−110、24.4mg/kgを週1回SQ(1、8、15日目)+抗マウスPD−1(3、6、9日目)(同時スケジュール)
グループ10:SGI−110、24.4mg/kgを週1回SQ(1、8、15日目)+抗マウスPD−1(17、20、23日目)(後続スケジュール)
グループ11:1及び8日目にビヒクル(3時間毎に3回の腹腔内注射)
グループ12:1及び8日目にSGI−110、36.6mg/kg/日(3時間毎に3回の腹腔内注射)
グループ13:1及び8日目にSGI−110、36.6mg/kg/日(3時間毎に3回の腹腔内注射)+抗マウスCTLA−4(3、6、9日目)
免疫刺激mAbと組み合わされたSGI−110の分子、表現、及び機能的相関
良性組織におけるSGI−110及び免疫刺激mAbの組み合わせ投与のインビボ免疫調節効果
調査した組み合わせ療法の抗腫瘍活性に対する免疫応答の寄与
実施例2:本発明の化合物によるDNAメチル化の阻害
実施例4:実施例3の製剤を用いた動物研究
実施例5:本発明による使用のためのキットの作製
第1容器:注射用の式I−1の化合物100mg
の化合物(本明細書において「SGI−110」とも称する)のナトリウム塩を、US7700567(内容は参照により本明細書に組み込まれる−特に41段の最後の2段落を参照されたい)に記載されているように、1s(式中、R1=カルバメート保護基)をホスホルアミダイト構成ブロック1d:
とカップリングすることによって調製した。
式中、X+=トリエチルアンモニウム(中性化合物C18H24N9O10Pの正確な計算質量は557.14である);のESI−MS(−ve)は、m/z556.1[M−H]-、及び[2M−H]-で1113.1を示した(US7700567の図31の質量スペクトルを参照されたい)。
バルク製剤の配合及び充填
バイアルの凍結乾燥及びキャッピング
ラベル付け及びパッケージング
残存DMSO
第2容器:再構成のためのSGI−110希釈剤、3mL
バルク製剤の配合及び充填
ラベル付け及びパッケージング
実施例6:抗CTLA−4抗体との組み合わせにおけるSGI−110の抗腫瘍活性
材料及び方法
結果及び結論
実施例7:2サイクルの逐次的なSGI−110及び抗CTLA−4の抗腫瘍活性
材料及び方法
結果及び結論
本発明のまた別の態様は、以下のとおりであってもよい。
〔1〕式Iの化合物:
(5−アザシトシン基)−L−(グアニン基)(I)
(式中、Lは、リン含有リンカーであり、Lにおけるリン原子の数が1である)またはその薬学的に許容可能な塩と、
(a)T細胞活性化剤、
(b)癌ワクチン、
(c)IDO阻害剤、及び
(d)アジュバント
から選択される1種以上の補助治療成分と
を含むことを特徴とする組み合わせ。
〔2〕前記式Iの化合物において、Lが、式(II):
(式中、R 1 及びR 2 は、独立して、H、OH、アルコキシ基、アルコキシアルコキシ基、アシルオキシ基、カーボネート基、カルバメート基、またはハロゲンであり;R 3 は、Hであるか、またはR 3 が結合している酸素原子と一緒になって、エーテル、エステル、カーボネート、またはカルバメートを形成し;R 4 は、Hであるか、またはR 4 が結合している酸素原子と一緒になって、エーテル、エステル、カーボネート、またはカルバメートを形成し;Xは、Xが結合する酸素原子と一緒になって、ホスホジエステル、ホスホロチオエートジエステル、ボラノホスフェートジエステル、またはメチルホスホネートジエステルを形成する)を有する、前記〔1〕に記載の組み合わせ。
〔3〕R 1 及びR 2 が、独立して、H、OH、OMe、OEt、OCH 2 CH 2 OMe、OBn、またはFである、前記〔1〕または前記〔2〕に記載の組み合わせ。
〔4〕Xが、Xが結合する酸素原子と一緒になって、ホスホジエステルを形成する、前記〔1〕〜〔3〕のいずれか一項に記載の組み合わせ。
〔5〕R 1 及びR 2 が、Hである、前記〔1〕〜〔4〕のいずれか一項に記載の組み合わせ。
〔6〕前記式Iの化合物が、I−(1〜44)のいずれか1つである、前記〔1〕〜〔5〕のいずれか一項に記載の組み合わせ。
〔7〕前記式Iの化合物が、
I−1:
または
I−2:
である、前記〔1〕〜〔6〕のいずれか一項に記載の組み合わせ。
〔8〕前記式Iの化合物が、式:
またはその薬学的に許容可能な塩を有する、前記〔1〕〜〔7〕のいずれか一項に記載の組み合わせ。
〔9〕前記塩が、ナトリウム塩である、前記〔8〕に記載の組み合わせ。
〔10〕前記式Iの化合物またはその塩が、製剤の形態であり、約45%〜約85%のプロピレングリコール、約5%〜約45%のグリセリン、及び0%〜約30%のエタノールを含む実質的に無水の溶媒に溶解されている、前記〔1〕〜〔9〕のいずれか一項に記載の組み合わせ。
〔11〕前記溶媒が、約65%〜約70%のプロピレングリコール、約25%〜約30%のグリセリン、及び0%〜約10%のエタノールを含む、前記〔10〕に記載の組み合わせ。
〔12〕前記溶媒が、65%〜70%のプロピレングリコール及び25%〜30%のグリセリンを含み、任意の残余がエタノールである、前記〔11〕に記載の組み合わせ。
〔13〕前記溶媒が、約65%のプロピレングリコール、約25%のグリセリン、及び約10%のエタノールを含む、前記〔10〕に記載の組み合わせ。
〔14〕前記溶媒が、65%のプロピレングリコール、25%のグリセリン、及び10%のエタノールである、前記〔13〕に記載の組み合わせ。
〔15〕前記溶媒が、約70%のプロピレングリコール及び約30%のグリセリンを含み、エタノールは存在しない、前記〔11〕に記載の組み合わせ。
〔16〕前記溶媒が、
(a)45%〜85%のプロピレングリコール、5%〜45%のグリセリン、及び0%〜30%のエタノール、または
(b)65%〜70%のプロピレングリコール、25%〜30%のグリセリン、及び0%〜10%のエタノール
を含む、前記〔10〕に記載の組み合わせ。
〔17〕前記式Iの化合物またはその塩が、約80mg/mL〜約110mg/mL、場合により約100mg/mLの濃度で前記製剤中に存在する、前記〔10〕〜〔16〕のいずれか一項に記載の組み合わせ。
〔18〕前記製剤が、DMSOを、場合により2:1、1:1、0.5:1、0.3:1または0.2〜0.3:1のDMSO:化合物比で、さらに含む、前記〔10〕〜〔17〕のいずれか一項に記載の組み合わせ。
〔19〕前記製剤が、皮下注射による投与に好適である、前記〔10〕〜〔18〕のいずれか一項に記載の組み合わせ。
〔20〕(a)前記〔1〕〜〔9〕のいずれか一項に定義されている式Iの化合物またはその塩を含有する第1容器と、
(b)前記〔10〕〜〔16〕のいずれか一項に定義されている実質的に無水の溶媒を含有する第2容器と、
(c)前記〔1〕に定義されている1種以上の補助治療成分と
を備えることを特徴とするキット。
〔21〕前記式Iの化合物が、実質的に無水の粉末の形態である、前記〔20〕に記載のキット。
〔22〕前記式Iの化合物が、凍結乾燥されている、前記〔21〕に記載のキット。
〔23〕前記第1容器が、約80mg〜約110mgの前記式Iの化合物またはその塩を含有する、前記〔20〕〜〔22〕のいずれか一項に記載のキット。
〔24〕前記第1容器が、約100mgの前記式Iの化合物またはその塩を含有する、前記〔20〕〜〔23〕のいずれか一項に記載のキット。
〔25〕皮下注射による投与のための説明書をさらに含む、前記〔20〕〜〔24〕のいずれか一項に記載のキット。
〔26〕医薬組成物を調製するためのプロセスであって、前記〔1〕〜〔9〕のいずれか一項に定義されている式Iの化合物またはその塩を、前記〔10〕〜〔16〕のいずれか一項に定義されている実質的に無水の溶媒に溶解する工程と、前記溶解した式Iの化合物を前記〔1〕に定義されている1種以上の補助治療成分と組み合わせる工程とを含むことを特徴とする、プロセス。
〔27〕(a)前記式Iの化合物またはその塩をDMSOに溶解して、前記式Iの化合物のDMSO溶液を生成する予備工程と、
(b)工程(a)の前記溶液を凍結乾燥して、実質的に無水の粉末としての前記式Iの化合物またはその塩を提供する予備工程と
をさらに含む、前記〔26〕に記載のプロセス。
〔28〕前記〔1〕〜〔9〕のいずれか一項に定義されている式Iの化合物またはその塩を実質的に無水の粉末の形態で含む医薬組成物を製造するためのプロセスであって、前記式Iの化合物またはその塩をDMSOに溶解して、DMSO溶液を生成する工程と、前記溶液を凍結乾燥して、実質的に無水の粉末としての前記式Iの化合物またはその塩を提供する工程と、次いで、前記粉末を、前記〔1〕に定義されている1種以上の補助治療成分と組み合わせる工程とを含むことを特徴とする、プロセス。
〔29〕前記実質的に無水の粉末が、残存DMSOを含む、前記〔28〕に記載のプロセス。
〔30〕前記残存DMSOが、前記式Iの化合物またはその塩1gあたり約0.1〜約2000mgの量で存在する、前記〔29〕に記載のプロセス。
〔31〕前記残存DMSOが、前記式Iの化合物またはその塩1gあたり約0.1〜約1000mg、約0.1〜約600mg、約0.1〜約500mg、約0.1〜約400mg、約0.1〜約300mgまたは約200〜約300mgの量で存在する、前記〔30〕に記載のプロセス。
〔32〕前記残存DMSOが、前記式Iの化合物またはその塩1gあたり200〜300mgの量で存在する、前記〔31〕に記載のプロセス。
〔33〕前記〔1〕〜〔9〕のいずれか一項に定義されている式Iの化合物またはその塩及びDMSOから本質的になる実質的に無水の粉末であって、前記DMSOが、≦200%w/wの量で存在し、前記〔1〕に定義されている1種以上の補助治療成分と組み合わせるものであることを特徴とする、粉末。
〔34〕前記DMSOが、約0.1%〜約100%、約0.1%〜約60%、約0.1%〜約50%、約0.1%〜約40%または約0.1%〜約30%w/wのDMSO/式Iの化合物またはその塩の量で存在する、前記〔33〕に記載の粉末。
〔35〕前記DMSOが、20〜30%w/wのDMSO/式Iの化合物またはその塩の量で存在する、前記〔34〕に記載の粉末。
〔36〕前記〔26〕〜〔32〕のいずれか一項に記載のプロセスによって得ることができるまたは得られる医薬組成物。
〔37〕前記補助治療成分が、T細胞活性化剤を含む、前記〔1〕〜〔19〕のいずれか一項に記載の組み合わせ、前記〔20〕〜〔25〕のいずれか一項に記載のキット、前記〔26〕〜〔32〕のいずれか一項に記載のプロセス、前記〔33〕〜〔35〕のいずれか一項に記載の粉末または前記〔36〕に記載の組成物。
〔38〕前記補助治療成分が、癌ワクチンを含む、前記〔1〕〜〔19〕のいずれか一項に記載の組み合わせ、前記〔20〕〜〔25〕のいずれか一項に記載のキット、前記〔26〕〜〔32〕のいずれか一項に記載のプロセス、前記〔33〕〜〔35〕のいずれか一項に記載の粉末または前記〔36〕に記載の組成物。
〔39〕前記補助治療成分が、IDO阻害剤を含む、前記〔1〕〜〔19〕のいずれか一項に記載の組み合わせ、前記〔20〕〜〔25〕のいずれか一項に記載のキット、前記〔26〕〜〔32〕のいずれか一項に記載のプロセス、前記〔33〕〜〔35〕のいずれか一項に記載の粉末または前記〔36〕に記載の組成物。
〔40〕前記補助治療成分が、アジュバントを含む、前記〔1〕〜〔19〕のいずれか一項に記載の組み合わせ、前記〔20〕〜〔25〕のいずれか一項に記載のキット、前記〔26〕〜〔32〕のいずれか一項に記載のプロセス、前記〔33〕〜〔35〕のいずれか一項に記載の粉末または前記〔36〕に記載の組成物。
〔41〕前記補助治療成分が、(a)T細胞活性化剤及び癌ワクチン、(b)T細胞活性化剤及びIDO阻害剤、または(c)癌ワクチン及びIDO阻害剤を含み、場合により、前記補助治療成分が、アジュバントをさらに含む、前記〔1〕〜〔19〕のいずれか一項に記載の組み合わせ、前記〔20〕〜〔25〕のいずれか一項に記載のキット、前記〔26〕〜〔32〕のいずれか一項に記載のプロセス、前記〔33〕〜〔35〕のいずれか一項に記載の粉末または前記〔36〕に記載の組成物。
〔42〕前記補助治療成分が、T細胞活性化剤、例えばICOS、GITR、MHC、CD80、CD86、ガレクチン9及びLAG−3のためのアゴニストまたは抗体から選択されるT細胞活性化剤を含む、前記〔1〕〜〔41〕のいずれか一項に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔43〕前記T細胞活性化剤が、抗体、例えば(a)CD137アゴニスト、(b)CD40アゴニスト、(c)OX40アゴニスト、(d)PD−1 mAb、(e)PD−L1 mAb、(f)PD−L2 mAb、(g)CTLA−4 mAb、及び(h)(a)〜(g)の組み合わせから選択される抗体である、前記〔42〕に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔44〕前記抗体が、(a)トレメリムマブ、(b)イピリムマブ、(c)ニボルマブ、(d)ランブロリズマブ、(e)BMS−936559、(f)MEDI4736、(g)MPDL3280A、及び(h)PF−05082566から選択される抗体を含む、前記〔43〕に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔45〕前記補助治療成分が、CTA癌ワクチンを含み、例えば前記CTA癌ワクチンが、NY−ESO−1、LAGE−1、MAGE−A1、−A2、−A3、−A4、−A6、−A10、−A12、CT7、CT10、GAGE1−6、GAGE1−2、BAGE、SSX1−5、SSX2、HAGE、PRAME、RAGE−1、XAGE−1、MUC2、MUC5B、B7.1/2、CD28、B7−H1、HLA、CD40L及びHMW−MAAから選択されるCTA抗原をベースとし、例えばMAGE−A3(例えば、recMAGE−A3)、NY−ESO−1及びPRAMEをベースとする、前記〔1〕〜〔44〕のいずれか一項に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔46〕前記補助治療成分が、IDO阻害剤、例えばINCB24360、1メチルトリプトファン及びNLG919から選択されるIDO阻害剤を含む、前記〔1〕〜〔45〕のいずれか一項に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔47〕
(a)骨髄異形成症候群(MDS)、
(b)癌、
(c)血液疾患、及び
(d)異常ヘモグロビン合成関連疾患
から選択される疾患の免疫療法または該疾患を処置するための方法であって、
前記〔1〕〜〔46〕のいずれか一項に記載の組み合わせ、キット、プロセス、粉末または組成物を、これを必要とするまたは要求する対象に投与する工程を含むことを特徴とする、方法。
〔48〕前記〔1〕〜〔9〕のいずれか一項に記載の式Iの化合物またはその塩が、前記1種以上の補助治療成分の投与の前に、一緒にまたは後に投与される、前記〔47〕に記載の方法。
〔49〕前記〔1〕〜〔9〕のいずれか一項に記載の式Iの化合物またはその塩が、前記1種以上の補助治療成分の投与の前に投与され、前記1種以上の補助治療成分が、CTLA−4 mAbを含む、前記〔48〕に記載の方法。
〔50〕前記血液疾患が、白血病である、前記〔47〕〜〔49〕のいずれか一項に記載の方法。
〔51〕前記白血病が、急性骨髄性白血病(AML)、急性前骨髄球性白血病、急性リンパ性白血病、及び慢性骨髄性白血病から選択される、前記〔50〕に記載の方法。
〔52〕前記AMLが、高齢者AML、初回再発AML及び第2再発AMLから選択される、前記〔51〕に記載の方法。
〔53〕前記癌が、乳癌、皮膚癌、骨癌、前立腺癌、肝臓癌、肺癌、非小細胞肺癌、扁平上皮・非小細胞肺腺癌、脳腫瘍、咽頭、胆嚢、膵臓、直腸、副甲状腺、甲状腺、副腎、神経組織、頭頸部、結腸、胃、気管支の癌、ならびに腎臓癌、基底細胞癌、潰瘍性及び乳頭状の両方のタイプの扁平上皮細胞癌、転移性皮膚癌、骨肉腫、ユーイング肉腫、細網肉腫、骨髄腫、巨細胞腫、小細胞肺腫瘍、胆石、膵島腫瘍、原発性脳腫瘍、急性及び慢性のリンパ球性及び顆粒球性腫瘍、有毛細胞腫瘍、腺腫、過形成、髄様癌、褐色細胞腫、粘膜神経腫、腸神経節細胞腫、過形成角膜神経腫、マルファン症候群様体質腫瘍、ウィルムス腫瘍、精上皮腫、卵巣腫瘍、白金耐性卵巣癌、平滑筋腫瘍、子宮頸部形成異常及び上皮内癌、神経芽細胞腫、網膜芽細胞腫、軟部組織肉腫、悪性カルチノイド、局所性皮膚病変、菌状息肉腫、横紋筋肉腫、カポジ肉腫、骨肉腫、悪性高カルシウム血症、腎細胞腫瘍、真性赤血球増加症、腺癌、多形膠芽細胞腫、白血病、リンパ腫、黒色腫、類表皮癌、肝細胞癌腫ならびに固形腫瘍から選択される、前記〔47〕〜〔52〕のいずれか一項に記載の方法。
〔54〕前記異常ヘモグロビン合成関連疾患が、鎌状赤血球貧血及びβ−地中海貧血から選択される、前記〔47〕〜〔53〕のいずれか一項に記載の方法。
〔55〕前記MDSが、低、中及び高リスクMDSならびに骨髄増殖性新生物から選択される、前記〔47〕〜〔49〕のいずれか一項に記載の方法。
〔56〕治療または予防に用いられる、前記〔1〕〜〔46〕のいずれか一項に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔57〕免疫療法に用いられる、前記〔56〕に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔58〕前記〔47〕〜〔56〕のいずれか一項に定義されている疾患を処置する方法において使用するための、前記〔1〕〜〔46〕のいずれか一項に記載の組み合わせ、キット、プロセス、粉末または組成物。
〔59〕前記〔47〕〜〔55〕のいずれか一項に定義されている疾患の免疫療法において、または該疾患を処置する方法において使用するための薬物の製造のための、前記〔1〕〜〔46〕のいずれか一項に記載の組み合わせ、キット、プロセス、粉末または組成物の使用。
〔60〕前記製剤、キットまたは組成物を、(a)1週間に1回、2回、3回、4回、5回、6回もしくは7回、または(b)5、6、7、8、9もしくは10日間にわたって毎日、または(c)最大10日間にわたって毎日、または(d)5〜10日間にわたって毎日、または(e)5日間にわたって毎日、直後に2日間の非投与、次いで、次の5日間にわたって毎日、(f)5日間にわたって毎日、直後に2日間の非投与、続いて前記1種以上の補助治療成分の投与、の投薬レジメンに従って、対象に投与することを含む、前記〔47〕〜〔59〕のいずれか一項に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔61〕前記製剤、キットまたは組成物を、5日間にわたって毎日、直後に2日間の非投与、続いてCTLA−4 mAbを含む1種以上の補助治療成分の投与の投薬レジメンに従って、対象に投与することを含む、前記〔60〕に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔62〕前記補助治療成分の前記投与が、前記非投与日の直後である、前記〔60〕または〔61〕に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔63〕前記投与が、皮下投与である、前記〔47〕〜〔62〕のいずれか一項に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔64〕前記1種以上の補助治療成分が、CTLA−4 mAbを含む、前記〔1〕〜〔63〕のいずれか一項に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔65〕前記1種以上の補助治療成分が、イピリムマブを含む、前記〔64〕に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔66〕前記式Iの化合物が、前記〔8〕または前記〔9〕に定義されているとおりである、前記〔64〕または前記〔65〕に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔67〕前記1種以上の補助治療成分が、アジュバントをさらに含む、前記〔64〕〜〔66〕のいずれか一項に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔68〕前記アジュバントが、病原体認識受容体(PRR)リガンドである、前記〔67〕に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔69〕前記アジュバントが、TLRリガンド、例えばTLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10及びTLR11の1つ以上のためのTLRリガンドを含む、前記〔68〕に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
〔70〕前記1種以上の補助治療成分が、(a)CTLA−4 mAb以外のT細胞活性化剤、及び/または(b)癌ワクチン、及び/または(c)IDO阻害剤をさらに含む、前記〔64〕〜〔69〕のいずれか一項に記載の方法、組み合わせ、キット、プロセス、粉末、組成物、または使用。
Claims (40)
- 前記塩が、ナトリウム塩である、請求項1に記載の医薬組成物。
- 前記式Iの化合物またはその塩が、製剤の形態であり、約45%〜約85%のプロピレングリコール、約5%〜約45%のグリセリン、及び0%〜約30%のエタノールを含む実質的に無水の溶媒に溶解されている、請求項1または2に記載の医薬組成物。
- 前記溶媒が、約65%〜約70%のプロピレングリコール、約25%〜約30%のグリセリン、及び0%〜約10%のエタノールを含む、請求項3に記載の医薬組成物。
- 前記溶媒が、65%〜70%のプロピレングリコール及び25%〜30%のグリセリンを含み、任意の残余がエタノールである、請求項4に記載の医薬組成物。
- 前記溶媒が、65%のプロピレングリコール、25%のグリセリン、及び10%のエタノールである、請求項3に記載の医薬組成物。
- 前記溶媒が、約70%のプロピレングリコール及び約30%のグリセリンを含み、エタノールは存在しない、請求項4に記載の医薬組成物。
- 前記溶媒が、
(a)45%〜85%のプロピレングリコール、5%〜45%のグリセリン、及び0%〜30%のエタノール、または
(b)65%〜70%のプロピレングリコール、25%〜30%のグリセリン、及び0%〜10%のエタノール
を含む、請求項3に記載の医薬組成物。 - 前記式Iの化合物またはその塩が、約80mg/mL〜約110mg/mLの濃度で前記製剤中に存在する、請求項3〜8のいずれか一項に記載の医薬組成物。
- 前記製剤が、DMSOをさらに含む、請求項3〜9のいずれか一項に記載の医薬組成物。
- 前記製剤が、皮下注射による投与に好適である、請求項3〜10のいずれか一項に記載の医薬組成物。
- 癌を治療するためのキットであって、
(a)請求項1または2に定義されている式Iの化合物またはその塩を含有する第1容器と、
(b)請求項3〜8のいずれか一項に定義されている実質的に無水の溶媒を含有する第2容器と、
(c)請求項1に定義されているT細胞活性化剤と
を備えることを特徴とするキット。 - 前記式Iの化合物が、実質的に無水の粉末の形態である、請求項12に記載のキット。
- 前記式Iの化合物が、凍結乾燥されている、請求項13に記載のキット。
- 前記第1容器が、約80mg〜約110mgの前記式Iの化合物またはその塩を含有する、請求項12〜14のいずれか一項に記載のキット。
- 前記第1容器が、約100mgの前記式Iの化合物またはその塩を含有する、請求項12〜15のいずれか一項に記載のキット。
- 皮下注射による投与のための説明書をさらに含む、請求項12〜16のいずれか一項に記載のキット。
- 癌を治療するための医薬組成物を調製する方法であって、請求項1または2に定義されている式Iの化合物またはその塩を、請求項3〜8のいずれか一項に定義されている実質的に無水の溶媒に溶解する工程と、前記溶解した式Iの化合物を請求項1に定義されているT細胞活性化剤と組み合わせる工程とを含むことを特徴とする、方法。
- 以下の予備工程:
(a)前記式Iの化合物またはその塩をDMSOに溶解して、前記式Iの化合物のDMSO溶液を生成する工程と、
(b)工程(a)の前記溶液を凍結乾燥して、実質的に無水の粉末としての前記式Iの化合物またはその塩を提供する工程と
をさらに含む、請求項18に記載の方法。 - 請求項1に記載の医薬組成物を実質的に無水の粉末の形態で製造する方法であって、前記式Iの化合物またはその塩をDMSOに溶解して、DMSO溶液を生成する工程と、前記溶液を凍結乾燥して、実質的に無水の粉末としての前記式Iの化合物またはその塩を提供する工程と、次いで、前記粉末を、請求項1に定義されているT細胞活性化剤と組み合わせる工程とを含むことを特徴とする、方法。
- 前記実質的に無水の粉末が、残存DMSOを含む、請求項20に記載の方法。
- 前記残存DMSOが、前記式Iの化合物またはその塩1gあたり約0.1〜約2000mgの量で存在する、請求項21に記載の方法。
- 請求項1または2に定義されている式Iの化合物またはその塩及びDMSOのみを含む実質的に無水の粉末を含む組成物であって、前記DMSOが、≦200%w/wの量で存在し、前記組成物が、癌を治療するために使用され、かつ請求項1に定義されているT細胞活性化剤と組み合わせて使用されるものであることを特徴とする、組成物。
- 前記抗体が、(a)トレメリムマブ及び(b)イピリムマブから選択される抗体を含む、請求項1に記載の医薬組成物。
- 前記抗体が、(a)トレメリムマブ及び(b)イピリムマブから選択される抗体を含む、請求項12に記載のキット。
- 前記抗体が、(a)トレメリムマブ及び(b)イピリムマブから選択される抗体を含む、請求項18に記載の方法。
- 前記抗体が、(a)トレメリムマブ及び(b)イピリムマブから選択される抗体を含む、請求項23に記載の組成物。
- 癌の免疫療法において使用するための薬物の製造のための、請求項1に記載の医薬組成物の使用。
- 癌の免疫療法において使用するための薬物の製造のための、請求項12に記載のキットの使用。
- 癌の免疫療法において使用するための薬物の製造のための、請求項18に記載の方法の使用。
- 癌の免疫療法において使用するための薬物の製造のための、請求項23に記載の組成物の使用。
- 前記薬物が、皮下投与に適している、請求項28に記載の医薬組成物の使用。
- 前記薬物が、皮下投与に適している、請求項29に記載のキットの使用。
- 前記薬物が、皮下投与に適している、請求項30に記載の方法の使用。
- 前記薬物が、皮下投与に適している、請求項31に記載の組成物の使用。
- 前記T細胞活性化剤が、イピリムマブである、請求項1に記載の医薬組成物。
- 前記T細胞活性化剤が、イピリムマブである、請求項12に記載のキット。
- 前記T細胞活性化剤が、イピリムマブである、請求項18に記載の方法。
- 前記T細胞活性化剤が、イピリムマブである、請求項23に記載の組成物。
- 前記T細胞活性化剤が、イピリムマブである、請求項28〜35のいずれか一項に記載の使用。
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