JP2020524677A - 標的治療剤を含む併用療法 - Google Patents
標的治療剤を含む併用療法 Download PDFInfo
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Abstract
Description
本開示のさらなる態様は、過剰増殖性疾患の治療薬の調製のための、成分I、又はその薬学的に許容される塩、及び成分II、又はその薬学的に許容される塩の使用である。
本開示の一態様は、がんなどの過剰増殖性疾患を有する対象を治療する併用療法であって、患者に:(A)有効成分として、成分I(又は化合物I)、又はそのプロドラッグ、誘導体、又は薬学的に許容される塩を含む第1の成分;及び(B)有効成分として、成分II(又は化合物II)、又はそのプロドラッグ、誘導体、又は薬学的に許容される塩を含む第2の成分を投与することを含み、前記有効成分の量は、その組合せが前記過剰増殖性疾患の治療において治療上有効となるような量である併用療法を提供する。
いくつかの実施形態において、成分Iは、標的化部分に結合した有効成分又はそのプロドラッグを含むコンジュゲートであり、標的化部分は、HSP90などの熱ショックタンパク質に結合する。標的化部分は、ガネテスピブ、ゲルダナマイシン(タネスピマイシン)、IPI−493、マクベシン、トリプテリン、タネスピマイシン、17−AAG(アルベスピマイシン)、KF−55823、ラジシコール、KF−58333、KF−58332、17−DMAG、IPI−504、BIIB−021、BIIB−028、PU−H64、PU−H71、PU−DZ8、PU−HZ151、SNX−2112、SNX−2321、SNX−5422、SNX−7081、SNX−8891、SNX−0723、SAR−567530、ABI−287、ABI−328、AT−13387、NSC−113497、PF−3823863、PF−4470296、EC−102、EC−154、ARQ−250−RP、BC−274、VER−50589、KW−2478、BHI−001、AUY−922、EMD−614684、EMD−683671、XL−888、VER−51047、KOS−2484、KOS−2539、CUDC−305、MPC−3100、CH−5164840、PU−DZ13、PU−HZ151、PU−DZ13、VER−82576、VER−82160、VER−82576、VER−82160、NXD−30001、NVP−HSP990、SST−0201CL1、SST−0115AA1、SST−0221AA1、SST−0223AA1、ノボビオシン、ヘルビンマイシンA、ラジシコール、CCT018059、PU−H71、セラストロール、又はそれらの互変異性体、アナログ、又は誘導体から選択され得る。
いくつかの実施形態では、成分IIは、成分Iとは異なるがんを治療する治療薬を含む。
腫瘍細胞を排除するための適応免疫応答では、細胞傷害性T細胞の活性化には、特定の抗原からの一次シグナル(すなわち、最初のシグナル)及び1つ以上の共刺激シグナル(すなわち、二次シグナル)の両方が必要である。抗原提示細胞(APC、例えば樹状細胞(DC))は腫瘍関連抗原(TAA)を処理し、TAA(すなわちエピトープ)に由来する抗原性ペプチドをペプチド/MHC分子(クラスI/II)(p/MHC)複合体として細胞表面に提示し、T細胞は、p/MHC複合体を認識するT細胞受容体(TCR)を介してTAAを担持したAPCに結合する。このライゲーションは、がん特異的な細胞傷害性T細胞を活性化する一次シグナルである。さらに、二次共刺激シグナルが、T細胞上の共刺激受容体及びAPC上のそれらのリガンド(又は共受容体)によって提供される。共刺激受容体とそのリガンドとの間の相互作用は、T細胞の活性化を調節し、その活性を高めることができる。CD28、4−1BB(CD137)、及びOX40は、それぞれAPC上のB7−1/2(CD80/CD86)、4−1BB(CD137L)、及びOX−40Lに結合する、T細胞上のよく研究された共刺激受容体である。通常の状況では、過剰なT細胞の増殖を防ぎ、免疫のバランスをとるために、共抑制シグナル(CTLA−4など)が活性化T細胞によって誘導及び発現され、APC上のB7リガンドへの結合においてCD28と競合する。これにより、通常の状況でT細胞の反応を緩和できる。しかし、がんによっては、腫瘍細胞及び腫瘍微小環境に浸潤している制御性T細胞がCTLA−4を恒常的に発現し得る。この共阻害シグナルは、共刺激シグナルを抑制し、したがって、抗がん免疫応答を激減させる。腫瘍細胞によるこの免疫抑制メカニズムは、免疫チェックポイント又はチェックポイント経路と呼ばれる。
一部の腫瘍では、CD28などのT細胞上の共刺激受容体の関与がない状況でのTCRライゲーションに起因するT細胞内因性のアネルギー及び枯渇が一般的である。
チェックポイント阻害剤
いくつかの実施形態では、成分IIは、チェックポイント経路を遮断する活性剤などのチェックポイント阻害剤を含む。
抑制性チェックポイント受容体PD−1(プログラムドデス−1)は、活性化T細胞上に発現し、通常は上皮細胞、内皮細胞、及び免疫細胞(例えば、DC、マクロファージ及びB細胞)上に発現するプログラムドデスリガンド1及び2(PD−L1、B7−H1、CD274としても知られている)及びPD−L2(B7−DC、CD273としても知られている)によるライゲーションの後、T細胞の抑制及びアポトーシスを誘導することができる。PD−1は主に腫瘍組織を含む末梢組織のエフェクター期にT細胞機能を調節する。PD−1は、活性化T細胞に加え、B細胞及び骨髄細胞上に発現している。多くのヒト腫瘍細胞はPD−L1を発現し、この調節機能を乗っ取って細胞傷害性Tリンパ球による免疫認識と破壊を回避することができる。腫瘍関連PD−L1はエフェクターT細胞のアポトーシスを誘導することが示されており、がんによる免疫回避に寄与すると考えられている。
別の例では、成分IIはPD−1アンタゴニストを含む。
さらに別の例では、成分IIはPD−L1アンタゴニストを含む。
Schlafenファミリーメンバー11(SLFN11)はDNA修復欠損に関与するタンパク質であり、DNA修復タンパク質と相互作用することが示されている。前臨床データに基づくと、これは、イリノテカンを含むDNA損傷剤に対する感受性の潜在的なマーカーである。SLFN11の喪失は、エピジェネティックなサイレンシングを介して発生する可能性があり、このサイレンシングは、DNA損傷を引き起こす化学療法に対する耐性を引き起こす可能性がある。カルボプラチン/シスプラチンに耐性の卵巣がん、非小細胞肺がん(NSCLC)及び乳がん細胞株では、SLFN11遺伝子座はメチル化によってサイレンシングされる。また、このタンパク質を発現する細胞でSLFN11がノックダウンされると、以前は白金製剤に感受性であった細胞の耐性が増加することが分かっている。臨床の場では、白金製剤での生存率が低いNSCLC及び卵巣がん患者の一部は、SLFN11遺伝子座のサイレンシングを示した。化学療法抵抗性のがん患者のSLFN11発現を増加及び/又は回復させることが望ましい。
本開示の併用療法における各成分は、以下のために1つ又は複数の薬学的に許容される賦形剤を使用して製剤化することができる:(1)安定性を向上させる;(2)持続放出又は遅延放出を許容する(例えば、モノマレイミドのデポ製剤から);(3)生体内分布を変更する(例えば、モノマレイミド化合物を特定の組織又は細胞タイプに向ける);(4)in vivoでモノマレイミド化合物の放出プロファイルを変更する。成分I及び成分IIは、それぞれ異なる組成物で投与することができる。
いくつかの実施形態において、併用療法の少なくとも1つの成分は、ポリマー粒子、脂質粒子、無機粒子、又はそれらの組合せ(例えば、脂質安定化ポリマー粒子)などの粒子に製剤化される。いくつかの実施形態において、粒子は固体ポリマー子粒子であるか、ポリマーマトリックスを含む。粒子は、本明細書に記載のポリマー又はその誘導体もしくはコポリマーのいずれを含んでもよい。粒子は一般に1つ以上の生体適合性ポリマーを含む。ポリマーは生分解性ポリマーであり得る。ポリマーは、疎水性ポリマー、親水性ポリマー、又は両親媒性ポリマーであり得る。いくつかの実施形態では、粒子は、追加の標的化部分が結合した1つ又は複数のポリマーを含む。
併用療法の成分は、治療的に有効な結果をもたらす任意の経路で投与することができる。これらには、限定するものではないが、経腸、胃腸、硬膜外、経口、経皮、硬膜外(epidural,peridural)、脳内(大脳内へ)、脳室内(大脳室内へ)、皮膚上(皮膚への塗布)、皮内、(皮膚自体の中へ)、皮下(皮膚の下)、経鼻投与(鼻を通して)、静脈内(静脈の中へ)、動脈内(動脈の中へ)、筋肉内(筋肉の中へ)、心臓内(心臓の中へ)、骨内注入(骨髄の中へ)、髄腔内(脊柱管内へ)、腹腔内、(腹膜内への注入又は注射)、膀胱内注入、硝子体内、(眼を通して)、海綿体内注射、(陰茎の基部へ)、膣内投与、子宮内、羊膜外投与、経皮(全身分布のための無傷の皮膚を介した拡散)、経粘膜(粘膜を介した拡散)、インサフレーション(スノーティング)、舌下、陰唇下、浣腸、点眼(結膜の上)、又は点耳が含まれる。特定の実施形態において、組成物は、それらが血液脳関門、血管関門、又は他の上皮関門を通過することを可能にする方法で投与され得る。
各成分について患者が必要とする正確な量は、対象の種、年齢、及び全身状態、疾患の重症度、個々の組成物、その投与様式、その作用様式等に応じて、対象ごとに異なる。
本開示の一態様は、がんなどの過剰増殖性疾患を有する対象を治療する方法を提供し、この方法は、少なくとも2つの別個の治療薬の併用療法を含む。いくつかの実施形態において、この方法は、患者に:(A)有効成分として、成分I、又はそのプロドラッグ、誘導体、又は薬学的に許容される塩を含む第1の成分;及び(B)有効成分として、成分II、又はそのプロドラッグ、誘導体、又は薬学的に許容される塩を含む第2の成分を投与することを含む。
本開示の併用療法により治療可能ながんは、一般に哺乳動物で発生する。哺乳動物には、例えば、ヒト、非ヒト霊長類、イヌ、ネコ、ラット、マウス、ウサギ、フェレット、モルモット、ウマ、ブタ、ヒツジ、ヤギ、及びウシが含まれる。様々な実施形態において、がんは、肺がん、乳がん、例えば、突然変異体BRCA1及び/又は突然変異型BRCA2乳がん、非BRCA関連乳がん、大腸がん、卵巣がん、膵臓がん、大腸がん、膀胱がん、前立腺がん、子宮頸がん、腎臓がん、白血病、中枢神経系がん、骨髄腫、及び黒色腫である。
本開示の一態様は、本発明の方法を好都合に及び/又は効果的に実施するための様々なキット及びデバイスを提供する。通常、キットは、ユーザが対象の複数の治療を実行できるように、及び/又は複数の実験を実行できるようにするのに十分な量及び/又は数の成分を含む。
本明細書で使用する「化合物」という用語は、描かれた構造のすべての立体異性体、幾何異性体、互変異性体、及び同位体を含むことを意味する。本願において、化合物はコンジュゲートと互換可能に使用される。したがって、本明細書で使用されるコンジュゲートも、描かれた構造のすべての立体異性体、幾何異性体、互変異性体、及び同位体を含むことを意味する。
本明細書で使用する「対象」又は「患者」という用語は、例えば、実験、治療、診断、及び/又は予防目的で併用療法を投与することができる任意の生物を指す。典型的な対象には、動物が含まれる(例えば、マウス、ラット、ウサギ、モルモット、ウシ、ブタ、ヒツジ、ウマ、イヌ、ネコ、ハムスター、ラマ、非ヒト霊長類、及びヒトなどの哺乳類)。
本明細書で使用する「生体適合性」という用語は、一般にレシピエントに無毒であり、レシピエントに重大な悪影響を引き起こさない物質をその代謝産物又は分解生成物とともに指す。一般的には、生体適合性物質は、患者に投与された場合に大きな炎症反応又は免疫反応を誘発しない物質である。
実施例1:コンジュゲート1の合成及びHPLC分析
いくつかの実施形態において、成分Iは、標的化部分に結合した有効成分又はそのプロドラッグを含むコンジュゲートであり、標的化部分はHSP90に結合する。HSP90標的化コンジュゲートの合成及びHPLC分析は、2013年4月16日に出願されたPCT出願番号PCT/US13/36783(WO2013/158644)の実施例1、6、8、1−29に開示された方法で実施することができ、その内容全体が参照により本明細書に組み込まれる。特に、コンジュゲート1又はその薬学的に許容される塩は、PCT/US13/36783の実施例6に従って調製することができる。
Pan02同所性マウスモデル(膵臓がんシンジェニックマウスモデル)における免疫細胞の変化の評価が行われる。この研究では、マウスの免疫細胞の変化を広くプロファイリングすることにより、免疫細胞の変化の幅広い調査を行う。例えば、免疫細胞の数がカウントされる。
T細胞上の免疫チェックポイント受容体及び腫瘍随伴マクロファージ(TAM)上の同族リガンドの発現を分析する。例えば、コンジュゲート1処理時のCD4+及びCD8+T細胞上のCTLA−4発現、PD−1発現を分析する。
実施例3:チェックポイント阻害剤と組み合わせたコンジュゲート1の抗腫瘍効果
このin vivo試験の目的は、膵臓がんのPan02同所性マウスモデルにおけるチェックポイント阻害剤と組み合わせたコンジュゲート1の抗腫瘍効果を評価することであった。
このin vivo試験の目的は、HT−29大腸がん(CRC)モデル及び/又は他のCRCモデルにおける5FU及びロイコボリン(LV)と組み合わせたコンジュゲート1の抗腫瘍効果を評価することであった。
1)ビヒクルでの処理;
2)コンジュゲート1での処理;
3)5FU及びLVでの処理;及び
4)5FU及びLVと組み合わせたコンジュゲート1での処理。
5)5FU及びLVと組み合わせたイリノテカンでの処理;及び
6)イリノテカン単独での処理。
実施例5:タラゾパリブと組み合わせたコンジュゲート1の抗腫瘍効果
NCI−H69(小細胞肺がん)腫瘍を有するマウスを以下で処理した。
2)12.5mpk(mg/kg)のコンジュゲート1を静脈内投与(IV)で週に1度;
3)0.33mpkのタラゾパリブを経口投与(PO)で4日間毎日投薬/3日間の休薬;
4)12.5mpkのコンジュゲート1をIVで週に1度、及びコンジュゲート1投与の24時間後に、0.33mpkのタラゾパリブを4日間毎日投薬/3日間の休薬を開始。
別の同様の研究では、コンジュゲート1及びベリパリブの併用治療がマウスモデルで評価される。
特許請求の範囲において、「1つ」、「その」などの冠詞は、反対の指示がない限り、又は文脈から明白でない限り、1つ又は複数を意味する場合がある。グループのうちの1つ又は複数のメンバー間に「又は」を含む請求項又は説明は、提示された製品又は方法にそのグループメンバーの1つ、2つ以上、又はすべてが存在し、採用され、又は他の態様で関係する場合、反対の指示がない限り、又は文脈から明白でない限り、充足すると見なされる。本発明は、提示された製品又は方法に、グループの厳密に1つのメンバーが存在し、採用され、又は他の態様で関係する実施形態を含む。本発明は、提示された製品又は方法に、グループメンバーのうちの2つ以上又はすべてが存在し、採用され、又は他の態様で関係する実施形態を含む。
Claims (17)
- がんを治療する方法であって:(A)有効成分として、成分I、又はそのプロドラッグ、誘導体、又は薬学的に許容される塩を含む第1の成分;及び(B)有効成分として、成分II、又はそのプロドラッグ、誘導体、又は薬学的に許容される塩を含む第2の成分を投与することを含み、
成分Iは、標的化部分に結合した有効成分又はそのプロドラッグを含むコンジュゲートであり、前記有効成分はチューブリン阻害剤又はそのプロドラッグを含み、
成分IIは成分Iとは異なる、方法。 - 成分Iの標的化部分は、ガネテスピブ又はその互変異性体、アナログ、又は誘導体である、請求項1に記載の方法。
- 成分Iの有効成分は、SN−38又はそのアナログ又は誘導体である、請求項1に記載の方法。
- 成分Iは、
の構造を有するコンジュゲート1である、請求項1に記載の方法。 - 成分IIはチェックポイント阻害剤である、請求項1に記載の方法。
- 成分IIはCTLA−4アンタゴニストを含む、請求項5に記載の方法。
- 成分IIはPD−1及びPD−L1/2チェックポイント経路を遮断する、請求項5に記載の方法。
- 成分IIはPD−1アンタゴニストを含む、請求項7に記載の方法。
- 成分IIはPD−L1アンタゴニストを含む、請求項7に記載の方法。
- 成分IIは5FU及び/又はロイコボリンを含む、請求項1に記載の方法。
- 成分Iはコンジュゲート1であり、成分IIはCTLA−4アンタゴニスト、PD−1アンタゴニスト、PD−L1アンタゴニスト、EZH阻害剤、及び5FU及び/又はロイコボリンからなる群から選択される、請求項1に記載の方法。
- 成分Iは成分IIの前に投与される、請求項1に記載の方法。
- 成分IIは成分Iの前に投与される、請求項1に記載の方法。
- がんは、肺がん、乳がん、大腸がん、卵巣がん、膵臓がん、大腸がん、膀胱がん、前立腺がん、子宮頸がん、腎臓がん、白血病、中枢神経系がん、骨髄腫、及び黒色腫からなる群から選択される、請求項1に記載の方法。
- がんは膵臓がんである、請求項1に記載の方法。
- がんは肺がんである、請求項1に記載の方法。
- がんは大腸がんである、請求項1に記載の方法。
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