JP2021528362A - mTOR阻害剤およびアルブミンのナノ粒子の投与を介して中枢神経系障害を処置する方法 - Google Patents
mTOR阻害剤およびアルブミンのナノ粒子の投与を介して中枢神経系障害を処置する方法 Download PDFInfo
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Abstract
Description
この出願は、2018年3月20日に出願された米国仮特許出願第62/645,634号および2019年3月7日に出願された米国仮特許出願第62/815,346号の優先権の利益を主張する。これらの出願の全内容は、すべての目的のためにこれにより参照により本明細書に組み込まれる。
この出願は、単独でまたは第2の薬剤と組み合わせて、mTOR阻害剤(例えば、リムス薬物、例えば、シロリムスまたはその誘導体)およびアルブミンを含むナノ粒子を含む組成物を投与することによる、CNS障害の処置のための方法および組成物に関する。
中枢神経系疾患は、中枢神経系障害としても公知であり、中枢神経系(CNS)を集合的に形成する、脳または脊髄の構造または機能に影響を及ぼす神経学的障害のスペクトルである。現行の処置には、手術および処方薬が含まれる。しかし、多くのCNS障害は、脳における天然の関門に起因して、処置が困難である。
本明細書で言及されるすべての刊行物、特許、特許出願、および特許出願公開の開示は、参照によりそれらの全体において本明細書に組み込まれる。
本出願は、個体におけるCNS障害(例えば、てんかん、皮質異形成および神経膠芽腫)を処置する方法であって、mTOR阻害剤およびアルブミンを含むナノ粒子を含む有効量の組成物を個体に全身投与するステップを含む、方法を提供する。一部の実施形態では、ナノ粒子組成物中のmTOR阻害剤の量は、各投与について約0.1mg/m2〜約120mg/m2である。一部の実施形態では、ナノ粒子組成物は、1週間ごとに1回、3週間ごとに2回、または4週間ごとに3回投与される。一部の実施形態では、ナノ粒子組成物中のナノ粒子の平均直径は、約200nm以下である。一部の実施形態では、ナノ粒子組成物中のアルブミンのmTOR阻害剤に対する重量比は、約9:1以下である。一部の実施形態では、ナノ粒子は、アルブミンと会合するmTOR阻害剤を含む。一部の実施形態では、ナノ粒子は、アルブミンでコーティングされたmTOR阻害剤を含む。一部の実施形態では、ナノ粒子組成物は、少なくとも約1〜6サイクルにわたり投与され、各サイクルは、21日間または28日間からなる。
本出願は、個体におけるCNS障害(例えば、神経膠芽腫、てんかん、皮質異形成)を処置するための方法であって、mTOR阻害剤(例えば、リムス薬物、例えば、シロリムスまたはその誘導体)およびアルブミンを含む有効量の組成物を個体に全身(例えば、静脈内または皮下)投与するステップを含む、方法を提供する。CNS疾患を処置することが困難であることの1つの重要な理由は、多くの治療剤が血液脳関門(BBB)を通過できないことである。この出願は、mTOR阻害剤(例えば、リムス薬物、例えば、シロリムス)およびアルブミンを含む全身投与されるナノ粒子が、血液脳関門を透過するだけでなく、持続的な期間(例えば、少なくとも120時間)にわたってCNS中にとどまるという、本出願人らの驚くべき知見に基づく。一部の態様では、本出願は、てんかんを処置するための方法を提供する。一部の態様では、本出願は、皮質異形成(例えば、限局性皮質異形成)を処置するための方法を提供する。一部の態様では、本出願は、脳腫瘍、例えば神経膠芽腫を処置するための方法を提供する。
定義
CNS疾患を処置する方法
A.神経膠芽腫を処置する方法
B.てんかんを処置する方法
C.皮質異形成を処置する方法
投薬および投与方法
A.ナノ粒子組成物
B.第2の薬剤
1.抗VEGF抗体
2.プロテアソーム阻害剤
3.アルキル化剤
a)ニトロソウレア化合物
C.放射線療法
CNS障害
A.腫瘍
1.神経膠芽腫
a)再発性神経膠芽腫
b)新たに診断された神経膠芽腫
B.てんかん
C.皮質異形成(例えば、限局性皮質異形成)
個体
ナノ粒子組成物
A.mTOR阻害剤
B.mTOR阻害剤ナノ粒子組成物における他の成分
第2の薬剤
A.抗VEGF抗体
B.プロテアソーム阻害剤
C.アルキル化剤
a)ニトロソウレア化合物
D.抗てんかん薬(AED)
E.VEGFR阻害剤
バイオマーカーの存在に基づく処置方法
本出願は、一態様では、1または複数のmTOR関連遺伝子における1または複数のmTOR活性化異常の状態に基づき、個体におけるCNS障害を処置する方法を提供する。一部の実施形態では、1または複数のバイオマーカーは、mTOR阻害剤による処置に対する都合よい応答を示す。
A.mTOR活性化異常
B.遺伝的異常
C.異常なレベル
D.抵抗性バイオマーカー
製造物品およびキット
例示的な実施形態
再発性神経膠芽腫(rGBM)患者における単一薬物療法としてのまたは第2の薬剤と組み合せたNab−ラパマイシンの使用
ABI−009(「nab−ラパマイシン」)は、注射可能懸濁物のためのラパマイシンタンパク質結合ナノ粒子である(アルブミン結合)。本試験は、BEV、mTOR阻害剤またはMRZへの以前の曝露がない再発性神経膠芽腫を有する対象における、静脈内ABI−009の単剤としての、およびベバシズマブ(BEV)、マリゾミブ(MRZ)、テモゾロミド(TMZ)またはロムスチン(CCNU)と組み合せた安全性および活性を評価するための、以前の治療法後の進行性神経膠芽腫を有するベバシズマブナイーブ対象におけるABI−009(nab−ラパマイシン)の第2相オープンラベル試験である。本試験は、また、対象集団における、ABI−009の単剤としての、またはBEV、MRZ、TMZおよびCCNUと組み合せた安全性および活性を評価することを目標とする。
A.治療法投与
2.単剤としてのnab−ラパマイシンの使用
3.ベバシズマブ(BEV)と組み合せたnab−ラパマイシンの使用
4.マリゾミブ(MRZ)と組み合せたnab−ラパマイシンの使用
5.テモゾロミド(TMZ)と組み合せたnab−ラパマイシンの使用
6.ロムスチン(CCNU)と組み合せたnab−ラパマイシンの使用
B.エンドポイントならびに効力および安全性を評価するための基準
1.エンドポイント
2.効力を評価するための基準
3.安全性を評価するための基準
C.患者
D.処置の持続時間
E.再発性高悪性度グリオーマを有するベバシズマブナイーブ患者におけるABI−009(nab−ラパマイシン)の第2相オープンラベル試験
1.コホート1、100/mg/m2のABI−009
2.コホート2、60/mg/m2のABI−009、50mg/m2のTMZ
3.コホート3、60/mg/m2のABI−009、5mg/kgのBEV
4.コホート4、60/mg/m2のABI−009、90mg/m2のCCNU
(実施例2)
新たに診断された神経膠芽腫(ndGBM)を有する患者における単一薬物療法としてのまたは第2の薬剤と組み合せたNab−ラパマイシンの使用
A.治療法投与
1.開始処置
2.付随処置
3.補助処置
B.エンドポイントならびに効力および安全性を評価するための基準
1.エンドポイント
2.効力を評価するための基準
3.安全性を評価するための基準
C.患者
D.処置の持続時間
(実施例3)
外科的に難治性のてんかんを有する患者におけるNab−ラパマイシンの使用
A.治療法投与
1.ABI−009
2.付随薬物療法
3.対照
B.目的およびエンドポイント
1.目的
2.エンドポイント
C.患者
D.ABI−009で処置される、外科的に難治性のてんかんを有する患者
(実施例4)
ABI−009の単一静脈内投与後の異なる器官へのラパマイシン分布
(実施例5)
スプラーグドーリー(SD)ラットにおけるABI−009の皮下および静脈内投薬後の薬物動態試験
ラットにおける投与後のABI−009の体内分布
(実施例7)
SDラットにおけるABI−009の反復皮下投薬後の毒性学試験
A.試験設計
B.実験手順
1.投薬溶液調製
2.投薬
3.試料収集および解析
C.結果
1.全身性毒性
3.トラフシロリムス血液レベル
Claims (39)
- 個体におけるCNS障害を処置する方法であって、mTOR阻害剤およびアルブミンを含むナノ粒子を含む有効量の組成物を前記個体に全身投与するステップを含む、方法。
- 前記ナノ粒子の組成物中の前記mTOR阻害剤の量が、各投与について約0.1mg/m2〜約120mg/m2である、請求項1に記載の方法。
- 前記ナノ粒子組成物が、1週間ごとに1回、3週間ごとに2回、または4週間ごとに3回投与される、請求項1または請求項2に記載の方法。
- 前記ナノ粒子組成物中の前記ナノ粒子の平均直径が、約200nm以下である、請求項1から3のいずれか一項に記載の方法。
- 前記ナノ粒子組成物中の前記アルブミンの前記mTOR阻害剤に対する重量比が、約9:1以下である、請求項1から4のいずれか一項に記載の方法。
- 前記ナノ粒子が、前記アルブミンと会合する前記mTOR阻害剤を含む、請求項1から5のいずれか一項に記載の方法。
- 前記ナノ粒子が、前記アルブミンでコーティングされた前記mTOR阻害剤を含む、請求項1から6のいずれか一項に記載の方法。
- 前記ナノ粒子組成物が、少なくとも約1〜6サイクルにわたり投与され、各サイクルが、21日間または28日間からなる、請求項1から7のいずれか一項に記載の方法。
- 前記mTOR阻害剤がリムス薬物である、請求項1から8のいずれか一項に記載の方法。
- 前記mTOR阻害剤がラパマイシンである、請求項9に記載の方法。
- 前記CNS障害がてんかんである、請求項1から10のいずれか一項に記載の方法。
- 前記個体が、てんかん手術を受けている、請求項11に記載の方法。
- 前記個体が、てんかん手術後の30日間に、少なくとも5回のてんかん発作を有する、またはてんかん手術後に1週間のてんかん発作消失を有さない、請求項12に記載の方法。
- 有効量の抗てんかん剤を前記個体に投与するステップをさらに含む、請求項11から13のいずれか一項に記載の方法。
- 前記ナノ粒子組成物中の前記mTOR阻害剤の量が、各投与について約0.1mg/m2〜約25mg/m2である、請求項11から14のいずれか一項に記載の方法。
- 前記CNS障害が神経膠芽腫である、請求項1から10のいずれか一項に記載の方法。
- 前記神経膠芽腫が再発性神経膠芽腫である、請求項16に記載の方法。
- 前記神経膠芽腫が、新たに診断された神経膠芽腫である、請求項16に記載の方法。
- 前記個体が、前記ナノ粒子投与の開始前に、新たに診断された神経膠芽腫の手術的切除を受けている、請求項18に記載の方法。
- 抗VEGF抗体、アルキル化剤およびプロテアソーム阻害剤からなる群から選択される有効量の第2の薬剤を前記個体に投与するステップをさらに含む、請求項1から19のいずれか一項に記載の方法。
- 前記ナノ粒子組成物中の前記mTOR阻害剤の量が、各投与について約20mg/m2〜約100mg/m2である、請求項1から20のいずれか一項に記載の方法。
- 前記第2の薬剤が抗VEGF抗体である、請求項20または請求項21に記載の方法。
- 前記第2の薬剤がプロテアソーム阻害剤である、請求項20または請求項21に記載の方法。
- 前記プロテアソーム阻害剤がマリゾミブである、請求項23に記載の方法。
- 前記第2の薬剤がアルキル化剤である、請求項20または請求項21に記載の方法。
- 前記アルキル化剤がテモゾロミドである、請求項25に記載の方法。
- 放射線療法をさらに含む、請求項26に記載の方法。
- 前記放射線療法が限局放射線療法である、請求項27に記載の方法。
- 前記アルキル化剤がニトロソウレア化合物である、請求項25に記載の方法。
- 前記化合物がロムスチンである、請求項29に記載の方法。
- 前記神経膠芽腫が、mTOR活性化異常を含む、請求項16から30のいずれか一項に記載の方法。
- 前記mTOR活性化異常が、PTEN、TSC1またはTSC2異常を含む、請求項31に記載の方法。
- 前記個体がヒトである、請求項1から32のいずれか一項に記載の方法。
- 前記ナノ粒子組成物が、前記個体に非経口投与される、請求項1から33のいずれか一項に記載の方法。
- 前記ナノ粒子組成物が、前記個体に静脈内投与される、請求項34に記載の方法。
- 前記ナノ粒子組成物が、前記個体に皮下投与される、請求項34に記載の方法。
- CNS障害を処置するための、mTOR阻害剤およびアルブミンを含むナノ粒子組成物を含むキット。
- 抗VEGF抗体、アルキル化剤およびプロテアソーム阻害剤からなる群から選択される薬剤をさらに含む、請求項37に記載のキット。
- mTOR活性化異常を評価するための薬剤をさらに含む、請求項37または38に記載のキット。
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BR112020018910A2 (pt) | 2020-12-29 |
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EP3768268A1 (en) | 2021-01-27 |
CA3094453A1 (en) | 2019-09-26 |
WO2019183146A1 (en) | 2019-09-26 |
IL277402A (en) | 2020-11-30 |
EP3768268A4 (en) | 2022-02-23 |
SG11202009145PA (en) | 2020-10-29 |
KR20200135410A (ko) | 2020-12-02 |
RU2020134124A (ru) | 2022-04-20 |
US20210000752A1 (en) | 2021-01-07 |
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