JP2020526203A - ヒトにおけるaav遺伝子療法のための手段及び方法 - Google Patents
ヒトにおけるaav遺伝子療法のための手段及び方法 Download PDFInfo
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Abstract
【選択図】 なし
Description
「AAVベクター」とは、分子的方法を用いることによる野生型AAVに由来する組み換えアデノ随伴ウイルス(AAV)ベクターを指す。AAVベクターは、ウイルスゲノムの少なくとも一部が、野生型AAV核酸配列に対して非天然の核酸である導入遺伝子で置き換えられていることから、野生型(wt)AAVベクターとは区別される。
AAV5遺伝子療法ベクターを用いた医学的治療を受ける適格性があるヒト患者を判定するための方法であって、
ヒト患者由来の血清サンプルを用意するステップ、
抗AAV5抗体力価を判定するステップ、
全抗AAV5抗体力価が、実施例において記載される全抗AAV5抗体(TAb)アッセイを用いて判定される0.02〜5の範囲内の値を有する場合、患者は医学的治療を受ける適格性があると考えられ得るステップ
を含む方法が提供される。
適格性があるヒト患者にAAV5遺伝子療法ベクターを投与するステップ
を含む。
ヒト患者由来の血清サンプルを用意するステップ、
抗AAV5抗体力価を判定するステップ、
中和抗AAV5抗体力価が、実施例において記載される中和抗AAV5抗体(NAb)アッセイを用いて判定される3〜10,000の範囲内の値を有する場合、患者は医学的治療を受ける適格性があると考えられ得るステップ
を含む。
適格性があるヒト患者にAAV5遺伝子療法ベクターを投与するステップ
を含む。
別の実施形態において、有効量のAAV5遺伝子療法ベクターをそれを必要とするヒトに投与するステップを含む、ヒトを治療する方法であって、
前記ヒトは、抗AAV5抗体を判定するアッセイを用いた事前スクリーニングに供されず、
前記ヒトは、前記医学的治療の前にAAV5遺伝子療法ベクターを用いた医学的治療に供されていない、方法が提供される。
前記ヒトは、抗AAV5抗体を判定するアッセイを用いた事前スクリーニングに供され、
前記ヒトは、前記医学的治療の前にAAV5遺伝子療法ベクターを用いた医学的治療に供されておらず、
前記ヒトは、ヒト集団において観察される抗AAV5抗体レベルの多くても95番目のパーセンタイルに相当する抗AAV5抗体レベルを有する、方法が提供される。
前記ヒトは、抗AAV5抗体を判定するアッセイを用いた事前スクリーニングに供され、
前記ヒトは、前記医学的治療の前にAAV5遺伝子療法ベクターを用いた医学的治療に供されておらず、
前記ヒトは、ヒト集団において観察される抗AAV5抗体レベルの多くても95番目のパーセンタイルに相当する抗AAV5抗体レベルを有する、方法が提供される。
前記ヒトは、抗AAV5抗体を判定するアッセイを用いた事前スクリーニングに供されず、
前記ヒトは、前記医学的治療の前にAAV5遺伝子療法ベクターを用いた医学的治療に供されていない、方法が提供される。
1)連続的なFIX予防、又は2)要求に応じたFIX、のいずれかを要し、1年あたり≧4回の出血又は血友病性関節症を有する、重度(FIX<1IU/dL)又は中程度〜重度(FIX≦2IU/dL)の血友病Bを有する成人男性を含む、多国籍の非盲検の用量漸増第1/2相調査を行った。試験のさらなる詳細を、NIH clinicaltrials.gov(NCT02396342)のウェブサイトで見い出すことができる。調査は、各センターにおいて施設内審査委員会/施設内倫理委員会によって認可された。すべての参加者は、書面でのインフォームドコンセントを提供した。ヘルシンキ宣言及び医薬品臨床試験の実施基準(Good Clinical Practice)の原則に従って、試験を実施した。
ヒト血清におけるNAbの測定を、導入遺伝子ルシフェラーゼを保持するAAV5(AAV5−luc)及びヒト胎児腎臓細胞株HEK293T(ATCC 11.268)を用いた高感度インビトロアッセイに基づいて査定した。導入遺伝子発現は、ルシフェリン類似体の添加によって明らかになる。
HEK293T細胞(HEK293T/ATCC 11.268)
フェノールレッドを含むDMEM(Gibco、参照#31966)/10%FBS(Greiner、参照#758093)/1%PenStrep(Gibco、参照#15140)
フェノールレッドを含まないDMEM(Gibco、参照#21063)/1%Pen−Strep(Gibco、参照#15140)
1×PBS−/−(Gibco、参照#14190)
1×トリプシンEDTA(Gibco、参照#25200)
ポリ−L−リジン(PLL)溶液(2.5%)(Sigma−Aldrich、参照#8920−100)
96ウェル平底黒色培養プレート(costar、参照#3916)
透明の96ウェル平底プレート(corning、参照#3596)
ONE−Glo Luciferase Assay System(Promega、参照#E6120)
Glo Lysis Buffer、1×(Promega、参照#E2661)
AAV5−CMV−luc(例えば、PKOからのAAV5−CMV−73QlucHttを用いた、力価:4e13gc/ml)
AAV5に対する全ヒトAbの定量は、特異的カプシドを用いてプレートをコーティングしたELISAアッセイに基づいた。AAV5カプシドに特異的な全ヒトAbの存在は、プロテインAペルオキシダーゼを用いて明らかになる。ELISAプレート(Nunc MaxiSorpプレート、参照:456537、Thermo Scientific)を炭酸塩バッファー中100ng/ウェルの抗原(AAV5 cap)で4℃に一晩コーティングした。翌日、プレートをPBS tween−20(PBSt)で3回洗浄して抗原の残りを排除し、ブロッキング溶液(PBS+3%FBS)でブロッキングして非特異的結合を防いだ。200μL PBStで3回洗浄した後、100μLの最終容積で、1:9で始まり1:3の希釈系列が後に続く、PBSt中ヒト血清希釈物を添加した。すべてのサンプルを二つ組で試験した。ヒト血清を有しない陰性対照が各プレートに含まれた。血清希釈物を37°で2時間インキュベートした。この後、血清を除去し、プレートをPBStで3回洗浄し、ブロッキング溶液に1:10,000で希釈された100μLのプロテインAペルオキシダーゼを1時間添加した。プレートをPBStで3回洗浄し、反応をTMB基質で明らかにし、30分後にH2SO4 2Nで停止させた。吸光度をマイクロプレートリーダーにて450nmで読み取った。全抗体力価を血清希釈として算出し、全抗体力価は陰性対照よりも5倍高い吸光度を有した。
両コホートにおけるヒト患者すべてが、FIX活性の意味のある向上を呈示し、ほとんどのヒト患者は重度から軽度への表現型の変化によって向上し(表2)、FIXタンパク質の予防的投与の使用の実質的低下又は欠如さえもたらした。患者間及びコホート間で観察されたFIX活性レベルの間に変動が観察された。FIX活性レベルの変動は、ヒト患者のNAb又はTAb状態とは相関しなかった。
Claims (12)
- ヒトの医学的治療における使用のためのAAV5遺伝子療法ベクターであって、前記ヒトは、抗AAV5抗体を判定するアッセイを用いた事前スクリーニングに供されず、前記ヒトは、前記医学的治療の前にAAV5遺伝子療法ベクターを用いた医学的治療に供されていない、AAV5遺伝子療法ベクター。
- ヒトの医学的治療における使用のためのAAV5遺伝子療法ベクターであって、前記ヒトは、抗AAV5抗体を判定するアッセイを用いた事前スクリーニングに供され、前記ヒトは、前記医学的治療の前にAAV5遺伝子療法ベクターを用いた医学的治療に供されておらず、前記ヒトは、ヒト集団において観察される抗AAV5抗体レベルの多くても95番目のパーセンタイルに相当する抗AAV5抗体レベルを有する、AAV5遺伝子療法ベクター。
- 前記ヒトが、抗AAV5抗体(body)に対して陽性の試験結果を示した、請求項3に記載のヒトの医学的治療における使用のためのAAV5遺伝子療法ベクター。
- 少なくとも1012個カプシド/kgに相当する投薬量で投与される、請求項1〜3のいずれか一項に記載のヒトの医学的治療における使用のためのAAV5遺伝子療法ベクター。
- 少なくとも1012gc/kg体重に相当する投薬量で使用される、請求項1〜4のいずれか一項に記載のヒトの医学的治療における使用のためのAAV5遺伝子療法ベクター。
- 血友病A又は血友病Bからなる群から選択される疾患の治療において使用される、請求項1〜5のいずれか一項に記載のヒトの医学的治療における使用のためのAAV5遺伝子療法ベクター。
- 血友病の治療において使用され、FIXタンパク質又はそのバリアントをコードする、請求項1〜6のいずれか一項に記載のヒトの医学的治療における使用のためのAAV5遺伝子療法ベクター。
- 前記使用は血流への投与を含む、請求項1〜7のいずれか一項に記載のヒトの医学的治療における使用のためのAAV5遺伝子療法ベクター。
- 前記使用は肝臓への前記ベクターの送達を含む、請求項1〜8のいずれか一項に記載のヒトの医学的治療における使用のためのAAV遺伝子療法ベクター。
- 昆虫細胞において産生される、請求項1〜9のいずれか一項に記載のヒトの医学的治療における使用のためのAAV5遺伝子療法ベクター。
- AAV5遺伝子療法ベクターを用いた医学的治療を受ける適格性があるヒト患者を判定するための方法であって、
ヒト患者由来の血清サンプルを用意するステップ、
抗AAV5抗体力価を判定するステップ、
全抗AAV5抗体力価が、実施例において記載される全抗AAV5(TAb)アッセイを用いて判定される0.02〜5の範囲内の値を有する場合、患者は医学的治療を受ける適格性があると考えられ得るステップ
を含む方法。 - AAV5遺伝子療法ベクターを用いた医学的治療を受ける適格性があるヒト患者を判定するための方法であって、
ヒト患者由来の血清サンプルを用意するステップ、
抗AAV5抗体力価を判定するステップ、
抗AAV5抗体力価が、実施例において記載されるNAbアッセイによって判定される中和抗AAV5抗体アッセイを用いて判定される3〜5,000の範囲内の値を有する場合、患者は医学的治療を受ける適格性があると考えられ得るステップ
を含む方法。
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- 2018-07-10 EA EA202090260A patent/EA202090260A1/ru unknown
- 2018-07-10 EP EP18737622.3A patent/EP3652326A1/en active Pending
- 2018-07-10 US US16/031,906 patent/US11452749B2/en active Active
- 2018-07-10 CA CA3069194A patent/CA3069194A1/en active Pending
- 2018-07-10 KR KR1020207002329A patent/KR20200041310A/ko not_active Application Discontinuation
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2020
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US20190008909A1 (en) | 2019-01-10 |
IL271957A (en) | 2020-02-27 |
AU2018299865A1 (en) | 2020-01-30 |
JP2023123836A (ja) | 2023-09-05 |
EA202090260A1 (ru) | 2020-05-08 |
ZA202000152B (en) | 2021-02-24 |
KR20200041310A (ko) | 2020-04-21 |
IL271957B1 (en) | 2023-10-01 |
WO2019011893A1 (en) | 2019-01-17 |
CA3069194A1 (en) | 2019-01-17 |
EP3652326A1 (en) | 2020-05-20 |
IL271957B2 (en) | 2024-02-01 |
US11452749B2 (en) | 2022-09-27 |
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