JP6716585B2 - 結腸直腸癌の処置に使用するためのアピリモド - Google Patents
結腸直腸癌の処置に使用するためのアピリモド Download PDFInfo
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- JP6716585B2 JP6716585B2 JP2017543330A JP2017543330A JP6716585B2 JP 6716585 B2 JP6716585 B2 JP 6716585B2 JP 2017543330 A JP2017543330 A JP 2017543330A JP 2017543330 A JP2017543330 A JP 2017543330A JP 6716585 B2 JP6716585 B2 JP 6716585B2
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- apilimod
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- colorectal cancer
- cancer
- vemurafenib
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Description
[01] 本出願は、U.S. Pat. App. Ser. No. 62/077,127, 2014年11月7日出願、U.S. Pat. App. Ser. No. 62/115,228, 2015年2月12日出願、およびU.S. Pat. App. Ser. No. 62/119,540, 2015年2月23日出願に基づく優先権を主張し、それらの内容を完全に本明細書に援用する。
[02] 本発明は、アピリモド(apilimod)を含む組成物、およびそれを結腸直腸癌(colorectal cancer)の処置に使用する方法に関する。
[39] 本明細書中で用いる用語“医薬的に許容できる塩”は、たとえばアピリモド組成物の酸性基および塩基性基から形成される塩である。具体的な塩類には下記のものが含まれるが、それらに限定されない:硫酸塩、クエン酸塩、酢酸塩、シュウ酸塩、クロリド、ブロミド、ヨージド、硝酸塩、硫酸水素塩、リン酸塩、酸性リン酸塩、イソニコチン酸塩、乳酸塩、サリチル酸塩、酸性クエン酸塩、酒石酸塩、オレイン酸塩、タンニン酸塩、パントテン酸塩、酒石酸水素塩、アスコルビン酸塩、コハク酸塩、マレイン酸塩、ベシル酸塩、ゲンチシン酸塩、フマル酸塩、グルコン酸塩、グルカロン酸塩、サッカリン酸塩、ギ酸塩、安息香酸塩、グルタミン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、p−トルエンスルホン酸塩、およびパモ酸塩(たとえば、1,1’−メチレン−ビス−(2−ヒドロキシ−3−ナフトエート))。
[50] 結腸直腸癌(colorectal cancer)(結腸癌(colon cancer)、直腸癌(rectal cancer)、または腸癌(bowel cancer)としても知られる)は、結腸または直腸における癌の発現である。結腸癌はTNM病期分類システムに従って病期判定される。TNMシステムは最も広く用いられている癌病期分類システムのひとつであり、国際対癌連合(Union for International Cancer Control)(UICC)および対癌米国合同委員会(American Joint Committee on Cancer)(AJCC)により採用されている。TNMシステムは、原発腫瘍のサイズおよび/または範囲(extent)(区域(reach))(T)、近接リンパ節への拡散の量(N)、ならびに身体の他の部分への癌細胞の拡散により形成された転移または続発性腫瘍の存在(M)に基づく。原発腫瘍のサイズおよび/または範囲ならびに癌拡散の程度を示すために、それぞれの文字に数字が加えられる。
[53] 本発明は、療法有効量の本発明のアピリモド組成物を対象に投与することにより処置の必要がある対象において結腸直腸癌を処置するための方法を提供し、その組成物はアピリモド、またはその医薬的に許容できる塩、溶媒和物、包接化合物、水和物、多型、プロドラッグ、アナログもしくは誘導体を含む。一態様において、アピリモド組成物はアピリモド遊離塩基またはアピリモド・ジメシレートを含む。本発明はさらに、結腸直腸癌の処置に有用な医薬の調製のためのアピリモド組成物の使用を提供する。
[56] 本発明はまた、併用療法を含む方法を提供する。本明細書中で用いる“併用療法(combination therapy)”または“共療法(co-therapy)”は、アピリモド組成物と追加の有効薬剤との共作用からの有益な効果を得ることを意図した特定の処置計画の一部として、療法有効量のアピリモド組成物を少なくとも1種類の追加の療法剤と共に投与することを含む。“併用療法”は、意図または予測しなかった有益な効果を偶発的または恣意的に生じる2種類以上の療法化合物を別個の単剤療法計画の一部として投与することを含まないものとする。
[64] 複数の態様において、少なくとも1種類の追加薬剤は、モノクローナル抗体、たとえばアレムツヅマブ(alemtuzumab)、ベバシズマブ、カツマキソマブ(catumaxomab)、セツキシマブ(cetuximab)、エドレコロマブ(edrecolomab)、ゲムツヅマブ(gemtuzumab)、オファツムマブ、パニツムマブ(panitumumab),リツキシマブ、トラスツヅマブ(trastuzumab)、エクリズマブ(eculizumab)、エファリズマブ(efalizumab)、muromab−CD3、ナタリズマブ(natalizumab)、アダリムマブ(adalimumab)、アフェリモマブ(afelimomab)、セルトリズマブ ペゴル(certolizumab pegol)、ゴリムマブ(golimumab)、インフリキシマブ(infliximab)、バシリキシマブ(basiliximab)、カナキヌマブ(canakinumab)、ダクリズマブ(daclizumab)、メポリズマブ(mepolizumab)、トシリズマブ(tocilizumab)、ウステキヌマブ(ustekinumab)、イブリツモマブ チウキセタン(ibritumomab tiuxetan)、トシツモマブ、アバゴボマブ(abagovomab)、アデカツムマブ(adecatumumab)、アレムツヅマブ、抗−CD30モノクローナル抗体Xmab2513、抗−METモノクローナル抗体MetMab、アポリズマブ(apolizumab)、アポマブ(apomab)、アルシツモマブ(arcitumomab)、バシリキシマブ、二重特異性抗体2B1、ブリナツモマブ(blinatumomab)、ブレンツキシマブ ベドチン(brentuximab vedotin)、カプロマブ ペンデチド(capromab pendetide)、シクスツムマブ(cixutumumab)、クラウディキシマブ(claudiximab)、コナツムマブ(conatumumab)、ダセツズマブ(dacetuzumab)、デノスマブ(denosumab)、エクリズマブ、エプラツヅマブ(epratuzumab)、エルツマキソマブ(ertumaxomab)、エトラシズマブ(etaracizumab)、フィギツムマブ(figitumumab)、フレソリムマブ(fresolimumab)、ガリキシマブ(galiximab)、ガニツマブ(ganitumab)、ゲムツヅマブ オゾガマイシン(gemtuzumab ozogamicin)、グレムバツムマブ(glembatumumab)、イブリツモマブ、イノツズマブ オゾガマイシン(inotuzumab ozogamicin)、イピリムマブ、レキサツムマブ(lexatumumab)、リンツズマブ(lintuzumab)、リンツズマブ、ルカツムマブ(lucatumumab)、マパツムマブ(mapatumumab)、マツズマブ(matuzumab)、ミラツズマブ(milatuzumab)、モノクローナル抗体CC49、ネシツムマブ(necitumumab)、ニモツズマブ(nimotuzumab)、オファツムマブ、オレゴボマブ(oregovomab)、ペルツズマブ(pertuzumab)、ラマクリマブ(ramacurimab)、ラニビズマブ(ranibizumab)、シプリズマブ(siplizumab)、ソネプシズマブ(sonepcizumab)、タネズマブ(tanezumab)、トシツモマブ、トラスツヅマブ、トレメリムマブ(tremelimumab)、ツコツズマブ セルモロイキン(tucotuzumab celmoleukin)、ベルツズマブ(veltuzumab)、ビシリズマブ(visilizumab)、ボロシキシマブ(volociximab)、およびザルツムマブ(zalutumumab)である。
[87] 本発明は、哺乳類、好ましくはヒトに使用するのに適した医薬的に許容できる医薬組成物であるアピリモド組成物を提供する。これに関して、組成物はさらに少なくとも1種類の医薬的に許容できる賦形剤またはキャリヤーを含むことができ、その量は結腸直腸癌の処置のために有効である。
[89] 一態様において、アピリモド組成物を少なくとも1種類の追加の有効薬剤と単一剤形中で組み合わせる。一態様において、組成物はさらに抗酸化剤を含む。
[118] 医薬組成物は、非経口投与に適した無菌の水性液剤または分散液剤であってもよい。本明細書中で用いる非経口という用語は、皮下、皮内、静脈内、筋肉内、関節内、動脈内、滑液包内、胸骨内、クモ膜下、病巣内および頭蓋内への注射法または注入法を含む。
[124] 結腸癌細胞系HCT116(BRAF野生型)およびHT−29(BRAF変異型,V600E)細胞をDMEM(Corning)中で増殖させ、RKO(BRAF変異型,V600E)をMEM(Corning)中で増殖させ、HCT−15(BRAF野生型)、SW1116(BRAF野生型)、SW480(BRAF野生型)およびSW620(BRAF野生型)をRPMI−1640(Corning)中で増殖させ、10% FBS(Sigma Aldrich F2442−500ML,ロット12D370)およびペニシリン/ストレプトマイシン(100×)(CellGro Ref 30−002)を補充した。薬物試験のために、HCT116、HT−29、RKO、HCT−15、SW1116、SW480およびSW620細胞を、それぞれウェル当たり750、8000、300、480、1600、2000、および2000個の密度で、96ウェル−プレートに最終体積50μL中において播種した。
[126] 単剤処理試験のために、播種の24時間後に細胞をアピリモド単独(最終濃度0.5〜10000nM;3倍希釈および合計10種類の希釈液)で、またはベムラフェニブ(最終濃度56.6〜30000nM;2倍希釈および合計10種類の希釈液)、レゴラフェニブ、オキサリプラチン、5−フルオロウラシルまたはイリノテカン(すべての薬物を最終濃度2.5〜50000nMでスクリーニングした;3倍希釈および合計10種類の希釈液)のうちの1種類で処理した。すべての薬物希釈液を2×原液として作成し、50μLを適宜なウェルに添加した。細胞を120時間処理した後、CellTiterGlo(登録商標) (Promega)を用いて生存率を査定し、その際、非処理細胞の相対発光を100%生存率に設定し、各薬物濃度を非処理細胞に対するパーセントとして表わした。GraphPad Prism(GraphPad Software,Inc)を用いてEC50値を決定した。要約すると、生データをlog変換し、次いで非線形回帰(曲線あてはめ)を用いて解析し、その際、データは制約条件付きであった(下=0,上=100)。
オキサリプラチン、イリノテカン、5−フルオロウラシルもしくはレゴラフェニブ単独(すべてについて、最終濃度195〜25000nM;2倍希釈および合計8種類の希釈液)で、または各濃度のアピリモド・ジメシレートと各濃度のベムラフェニブ、オキサリプラチン、イリノテカン、5−フルオロウラシルもしくはレゴラフェニブとの組合わせ(8×8のマトリックス)で処理した。細胞を120時間処理した後、CellTiterGlo(登録商標) (Promega)を用いて生存率を査定し、その際、非処理細胞の相対発光を100%生存率に設定し、各薬物濃度を非処理細胞に対するパーセントとして表わした。
[131] SNX10は、LAM−002に対する耐性を付与する遺伝子を同定するために実施されたハイスループットスクリーニングで同定された、細胞内トラフィッキングに関与する遺伝子である。SNX10の遺伝的アブレーション(genetic ablation)は、LAM−002処理に対する耐性を付与した。これは、SNX10の過剰発現がLAM−002に対する感受性を誘導することを示唆した。この仮説を確証するために、種々の結腸癌系統においてSNX10の発現レベルとLAM−002感受性の相関性を調べた。
[請求項1]
処置の必要がある対象において結腸直腸癌を処置するための組成物であって、療法有効
量のアピリモド、またはその医薬的に許容できる塩、溶媒和物、包接化合物、水和物、多
型、プロドラッグ、アナログもしくは誘導体を含む、前記組成物。
[請求項2]
アピリモドがアピリモド・ジメシレートである、請求項1に記載の組成物。
[請求項3]
結腸直腸癌が難治性または転移性である、請求項1または2に記載の組成物。
[請求項4]
組成物が経口剤形または静脈内投与に適した剤形である、請求項1〜3のいずれか1項
に記載の組成物。
[請求項5]
結腸直腸癌が、世界保健機関のTNM病期分類システムにより規定されるIII期また
はIV期結腸直腸癌である、請求項1〜4のいずれか1項に記載の組成物。
[請求項6]
さらに、少なくとも1種類の追加の有効薬剤を含む、請求項1〜5のいずれか1項に記
載の組成物。
[請求項7]
少なくとも1種類の追加の有効薬剤が療法剤もしくは非療法剤またはその組合わせであ
る、請求項1〜6のいずれか1項に記載の組成物。
[請求項8]
少なくとも1種類の追加の有効薬剤が、プロテインキナーゼ阻害剤、PD−1/PDL
−1経路阻害剤、白金ベースの抗新生物剤、トポイソメラーゼ阻害剤、ヌクレオシド代謝
阻害剤、アルキル化剤、インターカレート剤、チューブリン結合剤、およびその組合わせ
からなる群から選択される療法剤である、請求項7に記載の組成物。
[請求項9]
療法剤が、ベムラフェニブ、オキサリプラチン、レゴラフェニブ、イリノテカン、5−
フルオロウラシル、ペンブロリズマブ(Keytruda(商標))、アベルマブ、アテ
ゾリズマブ(MPDL3280A)、ニボルマブ(BMS−936558)、ピジリズマ
ブ(MK−3475)、MSB0010718C、MEDI4736、およびその組合わ
せからなる群から選択される、請求項8に記載の組成物。
[請求項10]
療法剤がベムラフェニブである、請求項9に記載の組成物。
[請求項11]
療法剤がレゴラフェニブである、請求項9に記載の組成物。
[請求項12]
癌が難治性または転移性の結腸直腸癌である、請求項10または11に記載の組成物。
[請求項13]
組成物がさらに、アピリモドの1以上の副作用を改善するために選択された非療法剤を
含む、請求項9〜12のいずれか1項に記載の組成物。
[請求項14]
少なくとも1種類の追加薬剤が、アピリモドの1以上の副作用を改善するために選択さ
れた非療法剤である、請求項1〜7のいずれか1項に記載の組成物。
[請求項15]
非療法剤が、オンダンセトロン、グラニセトロン、ドラセトロンおよびパロノセトロン
からなる群から選択される、請求項13または14に記載の組成物。
[請求項16]
非療法剤が、ピンドロールおよびリスペリドンからなる群から選択される、請求項13
または14に記載の組成物。
[請求項17]
対象において結腸直腸癌を処置するための組成物であって、アピリモド・ジメシレート
、ならびにプロテインキナーゼ阻害剤、白金ベースの抗新生物剤、ヌクレオシド代謝阻害
剤、およびBRAF阻害剤のうち1種類以上を含む組成物。
[請求項18]
組成物が、ベムラフェニブ、オキサリプラチン、レゴラフェニブ、イリノテカン、5−
フルオロウラシルのうち1種類以上を含む、請求項17に記載の組成物。
[請求項19]
組成物がベムラフェニブを含む、請求項18に記載の組成物。
[請求項20]
組成物がさらに、オンダンセトロン、グラニセトロン、ドラセトロン、パロノセトロン
、ピンドロールおよびリスペリドンのうち1種類以上を含む、請求項17〜19のいずれ
か1項に記載の組成物。
[請求項21]
難治性または転移性の癌を伴う対象において結腸直腸癌を処置するための組成物であっ
て、アピリモド・ジメシレートおよびベムラフェニブを含む、前記組成物。
[請求項22]
難治性または転移性の癌を伴う対象において結腸直腸癌を処置するための組成物であっ
て、アピリモド・ジメシレートおよびレゴラフェニブを含む、前記組成物。
[請求項23]
対象において結腸直腸癌を処置するための組成物であって、アピリモド・ジメシレート
、ならびにオンダンセトロン、グラニセトロン、ドラセトロン、パロノセトロン、ピンド
ロールおよびリスペリドンのうち1種類以上を含む、前記組成物。
[請求項24]
対象において結腸直腸癌を処置するための組成物であって、アピリモド・ジメシレート
およびキャリヤーを含む、前記組成物。
[請求項25]
結腸直腸癌細胞においてオートファジーまたはアポトーシスを誘発または増強するため
の方法であって、アピリモド・ジメシレートを含む組成物と細胞を接触させることを含む
、前記方法。
[請求項26]
アピリモドおよびベムラフェニブを含む併用療法で処置するためのヒト結腸直腸癌患者
を同定するための方法であって、対象の癌の生体試料をV600E BRAFタンパク質
変異、V600K BRAFタンパク質変異、またはその遺伝学的同等物のうち1以上に
ついてアッセイし、その際、これらの変異のいずれかを有する対象をアピリモドおよびベ
ムラフェニブを含む併用療法で処置するための患者と同定することを含む、前記方法。
[請求項27]
処置の必要がある対象において結腸直腸癌を処置するための方法であって、療法有効量
のアピリモド、またはその医薬的に許容できる塩、溶媒和物、包接化合物、水和物、多型
、プロドラッグ、アナログもしくは誘導体を対象に投与することを含む、前記方法。
[請求項28]
アピリモドがアピリモド・ジメシレートである、請求項27に記載の方法。
[請求項29]
結腸直腸癌をアピリモド処置に対して感受性であると同定するための方法であって、生
検試料などの癌の試料におけるSNX10遺伝子の発現をアッセイすることを含み、その
際、高いSNX10遺伝子発現はその結腸直腸癌がアピリモド処置に対して感受性である
ことの指標となる、前記方法。
Claims (16)
- 療法有効量のアピリモド、またはその医薬的に許容できる塩を含む、結腸直腸癌を処置
する必要がある対象において結腸直腸癌を処置する方法における使用のための組成物。 - アピリモドがアピリモド・ジメシレートである、請求項1に記載の組成物。
- 結腸直腸癌が難治性または転移性である、請求項1または2に記載の組成物。
- 組成物が経口剤形または静脈内投与に適した剤形である、請求項1〜3のいずれか1項
に記載の組成物。 - 結腸直腸癌が、世界保健機関のTNM病期分類システムにより規定されるIII期また
はIV期結腸直腸癌である、請求項1〜4のいずれか1項に記載の組成物。 - 前記方法が、少なくとも1種類の追加の有効薬剤を投与することをさらに含む、請求項
1〜5のいずれか1項に記載の組成物。 - 少なくとも1種類の追加の有効薬剤が、プロテインキナーゼ阻害剤、PD−1/PDL
−1経路阻害剤、白金ベースの抗新生物剤、トポイソメラーゼ阻害剤、ヌクレオシド代謝
阻害剤、アルキル化剤、インターカレート剤、チューブリン結合剤、およびその組合わせ
からなる群から選択される、請求項6に記載の組成物。 - 前記少なくとも1種類の追加の有効薬剤が、ベムラフェニブ、オキサリプラチン、レゴラフェニブ、イリノテカン、5−フルオロウラシル、ペンブロリズマブ(Keytruda(商標))、アベルマブ、アテゾリズマブ(MPDL3280A)、ニボルマブ(BMS−936558)、ピジリズマブ(MK−3475)、MSB0010718C、MEDI4736、およびその組合わせからなる群から選択される、請求項6に記載の組成物。
- 前記有効薬剤がベムラフェニブ又はレゴラフェニブである、請求項8に記載の組成物で
あって、癌が難治性または転移性の結腸直腸癌であってよい、前記組成物。 - 請求項1に記載の組成物であって、アピリモド・ジメシレートと、プロテインキナーゼ
阻害剤、白金ベースの抗新生物剤、ヌクレオシド代謝阻害剤、およびBRAF阻害剤のう
ちの1種類以上とを含む、前記組成物。 - ベムラフェニブ、オキサリプラチン、レゴラフェニブ、イリノテカン、5−フルオロウ
ラシルのうち1種類以上を含む、請求項10に記載の組成物であって、
ベムラフェニブを含んでもよい、前記組成物。 - さらに、オンダンセトロン、グラニセトロン、ドラセトロン、パロノセトロン、ピンド
ロールおよびリスペリドンのうち1種類以上を含む、請求項10又は11に記載の組成物
。 - 請求項1に記載の組成物であって、
a)当該組成物がアピリモド・ジメシレートおよびベムラフェニブを含む、
b)前記対象が難治性または転移性の癌を有し、当該組成物がアピリモド・ジメシレート
およびレゴラフェニブを含む、
c)当該組成物がアピリモド・ジメシレートと、オンダンセトロン、グラニセトロン、ド
ラセトロン、パロノセトロン、ピンドロールおよびリスペリドンのうち1種類以上とを含
む、又は
d)当該組成物が、アピリモド・ジメシレートおよびキャリヤーを含む、
前記組成物。 - 結腸直腸癌細胞においてアポトーシスを誘発または増強するための方法において使用す
るための、アピリモド・ジメシレートを含む組成物であって、当該方法が、当該組成物と
当該細胞を接触させることを含む、前記組成物。 - アピリモドおよびベムラフェニブを含む併用療法で処置するためのヒト結腸直腸癌患者
を同定するための指標を提供するための方法であって、対象の癌の生体試料をV600E
BRAFタンパク質変異、V600K BRAFタンパク質変異、またはその遺伝学的
同等物のうち1以上についてアッセイすることを含み、その際、これらの変異のいずれか
が、アピリモドおよびベムラフェニブを含む併用療法で処置するための患者を同定するた
めの指標としての役割を果たす、前記方法。 - 結腸直腸癌をアピリモド処置に対して感受性であると同定するための方法であって、生
検試料などの癌の試料におけるSNX10遺伝子の発現をアッセイすることを含み、その
際、高いSNX10遺伝子発現はその結腸直腸癌がアピリモド処置に対して感受性である
ことを示す、前記方法。
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JP2019502707A (ja) * | 2016-01-21 | 2019-01-31 | ラム・セラピューティクス,インコーポレーテッド | 癌をアピリモドで処置するためのバイオマーカー |
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