JPWO2019222682A5 - - Google Patents

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JPWO2019222682A5
JPWO2019222682A5 JP2020546149A JP2020546149A JPWO2019222682A5 JP WO2019222682 A5 JPWO2019222682 A5 JP WO2019222682A5 JP 2020546149 A JP2020546149 A JP 2020546149A JP 2020546149 A JP2020546149 A JP 2020546149A JP WO2019222682 A5 JPWO2019222682 A5 JP WO2019222682A5
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JP2021523878A (en
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Priority claimed from PCT/US2019/032956 external-priority patent/WO2019222682A1/en
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本明細書において引用した全ての特許および刊行物は、その全体が参照により本明細書に組み込まれている。
本発明は、例えば以下の項目を提供する。
(項目１)
血友病Ａの処置を必要とするヒト被験体における血友病Ａを処置する方法であって、（ｉ）第ＶＩＩＩ因子（ＦＶＩＩＩ）ポリペプチド、ならびに（ｉｉ）フォンヴィルブランド因子（ＶＷＦ）のＤ’ドメインおよびＶＷＦのＤ３ドメインを含むＶＷＦ断片を含むキメラポリペプチドの複数用量を、ある投薬間隔で、前記被験体に投与することを含み、
前記複数用量の少なくとも１つが、約１５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇであり、前記投薬間隔が、少なくとも約７日である、方法。
(項目２)
前記ＦＶＩＩＩポリペプチドが、共有結合によって前記ＶＷＦ断片と結び付いている、項目１に記載の方法。
(項目３)
前記共有結合が、ペプチド結合またはジスルフィド結合である、項目１または２に記載の方法。
(項目４)
前記ＦＶＩＩＩポリペプチドが、第１の半減期延長部分を含む、項目１～３のいずれか一項に記載の方法。
(項目５)
前記第１の半減期延長部分が、前記ＦＶＩＩＩポリペプチドのＣ末端またはＮ末端に融合されている、項目４に記載の方法。
(項目６)
前記第１の半減期延長部分が、前記ＦＶＩＩＩポリペプチド内に挿入されている、項目４に記載の方法。
(項目７)
前記第１の半減期延長部分が、前記ＦＶＩＩＩポリペプチドのＢドメイン内に挿入されている、項目５または６に記載の方法。
(項目８)
前記第１の半減期延長部分が、配列番号６５のアミノ酸残基７４５に対応するアミノ酸のすぐ下流の前記ＦＶＩＩＩポリペプチド内に挿入されている、項目７に記載の方法。
(項目９)
前記第１の半減期延長部分が、リンカーによって前記ＦＶＩＩＩポリペプチドに融合されている、項目４～８のいずれか一項に記載の方法。
(項目１０)
前記ＶＷＦ断片が、第２の半減期延長部分を含む、項目４～９のいずれか一項に記載の方法。
(項目１１)
前記第２の半減期延長部分が、前記ＶＷＦ断片のＣ末端またはＮ末端に融合されている、項目１０に記載の方法。
(項目１２)
前記第２の半減期延長部分が、前記ＶＷＦ断片内に挿入されている、項目１０に記載の方法。
(項目１３)
前記第２の半減期延長部分が、前記ＶＷＦ断片のＣ末端に融合されている、項目１０または１１に記載の方法。
(項目１４)
前記第２の半減期延長部分が、リンカーによって前記ＶＷＦ断片に融合されている、項目１０～１３のいずれか一項に記載の方法。
(項目１５)
前記第１の半減期延長部分、前記第２の半減期延長部分またはそれらの両方が、アルブミン、免疫グロブリンＦｃ領域、ＸＴＥＮ配列、ヒト絨毛性ゴナドトロピンのβサブユニットのＣ末端ペプチド（ＣＴＰ）、ＰＡＳ配列、ＨＡＰ配列、トランスフェリン、アルブミン結合部分、またはそれらの任意の断片、誘導体、バリアントおよび任意の組合せからなる群より選択される、項目４～１４のいずれか一項に記載の方法。
(項目１６)
前記第１の半減期延長部分が、第１のＸＴＥＮを含む、項目４～１５のいずれか一項に記載の方法。
(項目１７)
前記第１のＸＴＥＮが、配列番号６５のアミノ酸残基７４５に対応するアミノ酸のすぐ下流の前記ＦＶＩＩＩポリペプチド内に挿入されている、項目１６に記載の方法。
(項目１８)
前記第２の半減期延長部分が、第２のＸＴＥＮを含む、項目１０～１７のいずれか一項に記載の方法。
(項目１９)
前記第２のＸＴＥＮが、前記ＶＷＦ断片のＣ末端に融合されている、項目１８に記載の方法。
(項目２０)
前記ＦＶＩＩＩポリペプチドが、第１の免疫グロブリン（Ｉｇ）定常領域またはその部分を含む、項目１～１９のいずれか一項に記載の方法。
(項目２１)
前記第１のＩｇ定常領域またはその部分が、前記ＦＶＩＩＩポリペプチドのＣ末端またはＮ末端に融合されている、項目２０に記載の方法。
(項目２２)
前記第１のＩｇ定常領域またはその部分が、前記ＦＶＩＩＩポリペプチド内に挿入されている、項目２０に記載の方法。
(項目２３)
前記第１のＩｇ定常領域またはその部分が、前記ＦＶＩＩＩポリペプチドのＣ末端に融合されている、項目２０または２１に記載の方法。
(項目２４)
前記第１のＩｇ定常領域またはその部分が、リンカーによって前記ＦＶＩＩＩポリペプチドに融合されている、項目２０～２３のいずれか一項に記載の方法。
(項目２５)
前記第１のＩｇ定常領域またはその部分が、第１のＦｃドメインまたはその部分を含む、項目２０～２４のいずれか一項に記載の方法。
(項目２６)
前記ＶＷＦ断片が、第２のＩｇ定常領域またはその部分を含む、項目１～２５のいずれか一項に記載の方法。
(項目２７)
前記第２のＩｇ定常領域またはその部分が、前記ＶＷＦ断片のＣ末端またはＮ末端に融合されている、項目２６に記載の方法。
(項目２８)
前記第２のＩｇ定常領域またはその部分が、前記ＶＷＦ断片内に挿入されている、項目２６に記載の方法。
(項目２９)
前記第２のＩｇ定常領域またはその部分が、前記ＶＷＦ断片のＣ末端に融合されている、項目２６または２７に記載の方法。
(項目３０)
前記第２のＩｇ定常領域またはその部分が、リンカーによって前記ＶＷＦ断片に融合されている、項目２６～２９のいずれか一項に記載の方法。
(項目３１)
前記リンカーが、切断可能なリンカーである、項目３０に記載の方法。
(項目３２)
前記第２のＩｇ定常領域またはその部分が、第２のＦｃドメインまたはその部分を含む、項目２６～３１のいずれか一項に記載の方法。
(項目３３)
ＦＶＩＩＩタンパク質および前記ＶＷＦ断片が、前記第１のＦｃドメインおよび前記第２のＦｃドメインの間の共有結合により互いに結び付いている、項目３２に記載の方法。
(項目３４)
前記ＦＶＩＩＩタンパク質および前記ＶＷＦ断片が、前記ＦＶＩＩＩタンパク質および前記ＶＷＦ断片の間の非共有結合的な相互作用により互いにさらに結び付いている、項目３３に記載の方法。
(項目３５)
ヒト被験体における血友病Ａを処置する方法であって、キメラポリペプチドの複数用量を、ある投薬間隔で、それを必要とする前記被験体に投与することを含み、前記キメラポリペプチドが、
（ｉ）（ａ）配列番号２１５のアミノ酸配列を含む第１のＦＶＩＩＩポリペプチド断片、
（ｂ）配列番号８（ＡＥ２８８）のアミノ酸配列を含む第１のＸＴＥＮ配列、
（ｃ）配列番号２１６のアミノ酸配列を含む第２のＦＶＩＩＩポリペプチド断片、および
（ｄ）配列番号２１７のアミノ酸配列を含む第１のＦｃ領域
を含むＦＶＩＩＩタンパク質、
（ｉｉ）（ａ）配列番号２１０のアミノ酸配列を含むＶＷＦのＤ’ドメイン、
（ｂ）配列番号２１４のアミノ酸配列を含むＶＷＦのＤ３ドメイン、
（ｃ）配列番号５８（ＡＥ１４４＿５Ａ）のアミノ酸配列を含む第２のＸＴＥＮ配列、
（ｄ）配列番号８８のアミノ酸配列を含むａ２リンカー、および
（ｅ）配列番号２１７のアミノ酸配列を含む第２のＦｃ領域
を含むＶＷＦタンパク質を含み、
前記第１のＦｃ領域が、ジスルフィド結合によって前記第２のＦｃ領域に共有結合的に連結されている、方法。
(項目３６)
前記ＦＶＩＩＩタンパク質が、配列番号６４のアミノ酸配列を含むＦＶＩＩＩシグナルペプチドをさらに含む、項目３５に記載の方法。
(項目３７)
前記ＶＷＦタンパク質が、配列番号２０８のアミノ酸配列を含むＶＷＦシグナルペプチドをさらに含む、項目３５に記載の方法。
(項目３８)
前記ＶＷＦタンパク質が、配列番号２０９のアミノ酸配列を含むＶＷＦのＤ１Ｄ２ドメインをさらに含む、項目３５に記載の方法。
(項目３９)
ヒト被験体における血友病Ａを処置する方法であって、キメラポリペプチドの複数用量を、ある投薬間隔で、それを必要とする前記被験体に投与することを含み、前記キメラポリペプチドが、
（ｉ）配列番号１７３、配列番号２０１、配列番号２０３または配列番号２０７と少なくとも約８０％、９０％、９５％もしくは１００％同一のアミノ酸配列を含むＦＶＩＩＩタンパク質、および
（ｉｉ）配列番号１９７、配列番号２０２または配列番号２０５と少なくとも約８０％、９０％、９５％もしくは１００％同一のアミノ酸配列を含むＶＷＦタンパク質
を含む、方法。
(項目４０)
ヒト被験体における血友病Ａを処置する方法であって、キメラポリペプチドの複数用量を、ある投薬間隔で、それを必要とする前記被験体に投与することを含み、前記キメラポリペプチドが、
（ｉ）配列番号２０３のアミノ酸配列を含むＦＶＩＩＩタンパク質、および
（ｉｉ）配列番号２０５のアミノ酸配列を含むＶＷＦタンパク質
を含む、方法。
(項目４１)
ヒト被験体における血友病Ａを処置する方法であって、キメラポリペプチドの複数用量を、ある投薬間隔で、それを必要とする前記被験体に投与することを含み、前記キメラポリペプチドが、
（ｉ）ＦＶＩＩＩ－１６１（配列番号６９）、ＦＶＩＩＩ－１６９（配列番号７０）、ＦＶＩＩＩ－１７０（配列番号７１）、ＦＶＩＩＩ－１７３（配列番号７２）；ＦＶＩＩＩ－１９５（配列番号７３）；ＦＶＩＩＩ－１９６（配列番号７４）、ＦＶＩＩＩ１９９（配列番号７５）、ＦＶＩＩＩ－２０１（配列番号７６）；ＦＶＩＩＩ－２０３（配列番号７７）、ＦＶＩＩＩ－２０４（配列番号７８）、ＦＶＩＩＩ－２０５（配列番号７９）、ＦＶＩＩＩ－２６６（配列番号８０）、ＦＶＩＩＩ－２６７（配列番号８１）、ＦＶＩＩＩ－２６８（配列番号８２）、ＦＶＩＩＩ－２６９（配列番号８３）、ＦＶＩＩＩ－２７１（配列番号８４）、ＦＶＩＩＩ－２７２（配列番号８５）、ＦＶＩＩＩ－３１２（配列番号１７３）、またはＦＶＩＩＩ－３１２Ａ（配列番号２０３）から選択される配列と少なくとも約８０％、９０％、９５％もしくは１００％同一のアミノ酸配列を含むＦＶＩＩＩタンパク質、および
（ｉｉ）ＶＷＦ０３１（配列番号８６）、ＶＷＦ０３４（配列番号８７）、ＶＷＦ０５９（配列番号１９７）、ＶＷＦ０５９Ａ（配列番号２０２）またはＶＷＦ０３６から選択される配列と少なくとも約８０％、９０％、９５％もしくは１００％同一のアミノ酸配列を含むＶＷＦタンパク質
を含む、方法。
(項目４２)
前記複数用量の少なくとも１つが、約１５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇであり、前記投薬間隔が、少なくとも約７日である、項目３９～４１のいずれか一項に記載の方法。
(項目４３)
前記複数用量の少なくとも１つが、約５０ＩＵ／ｋｇ～約６５ＩＵ／ｋｇであり、前記投薬間隔が、少なくとも約５日または約７日である、項目３９～４１のいずれか一項に記載の方法。
(項目４４)
前記複数用量が、少なくとも２用量、少なくとも３用量、少なくとも４用量、少なくとも５用量、少なくとも６用量、少なくとも７用量、少なくとも８用量、少なくとも９用量、少なくとも１０用量、少なくとも１１用量、少なくとも１２用量、少なくとも１３用量、少なくとも１４用量、少なくとも１５用量、少なくとも１６用量、少なくとも１７用量、少なくとも１８用量、少なくとも１９用量、少なくとも２０用量、またはそれよりも多くの用量を含む、項目１～４１のいずれか一項に記載の方法。
(項目４５)
前記血友病Ａの処置が、それを必要とするヒト被験体における出血エピソードの発生率もしくは頻度を制御または減少させることを含む、項目１～４１のいずれか一項に記載の方法。
(項目４６)
前記血友病Ａの処置が、それを必要とするヒト被験体における出血エピソードを予防または処置することを含む、項目１～４１のいずれか一項に記載の方法。
(項目４７)
前記複数用量の少なくとも１つが、約２０ＩＵ／ｋｇ～約９５ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約９０ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約８５ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約８０ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約７５ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約７０ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約６５ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約６０ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約５５ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約５０ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約４５ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約４０ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約３５ＩＵ／ｋｇ、約２０ＩＵ／ｋｇ～約３０ＩＵ／ｋｇ、または約２０ＩＵ／ｋｇ～約２５ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目４８)
前記複数用量の少なくとも１つが、約２０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約２５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約３０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約３５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約４０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約４５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約５０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約５５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約６０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約６５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約７０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約７５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約８０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、約８５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇ、または約９０ＩＵ／ｋｇ～約１００ＩＵ／ｋｇである、項目１～４１５のいずれか一項に記載の方法。
(項目４９)
前記複数用量の少なくとも１つが、約２０ＩＵ／ｋｇ～約８０ＩＵ／ｋｇ、約２５ＩＵ／ｋｇ～約７５ＩＵ／ｋｇ、約３０ＩＵ／ｋｇ～約７０ＩＵ／ｋｇ、約３５ＩＵ／ｋｇ～約６５ＩＵ／ｋｇ、約４０ＩＵ／ｋｇ～約６０ＩＵ／ｋｇ、または約４５ＩＵ／ｋｇ～約５５ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目５０)
前記複数用量の少なくとも１つが、約２５ＩＵ／ｋｇ～約６５ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目５１)
前記複数用量の少なくとも１つが、約２０ＩＵ／ｋｇ、約２５ＩＵ／ｋｇ、約３０ＩＵ／ｋｇ、約３５ＩＵ／ｋｇ、約４０ＩＵ／ｋｇ、約４５ＩＵ／ｋｇ、約５０ＩＵ／ｋｇ、約５５ＩＵ／ｋｇ、約６０ＩＵ／ｋｇ、約６５ＩＵ／ｋｇ、約７０ＩＵ／ｋｇ、約７５ＩＵ／ｋｇ、約８０ＩＵ／ｋｇ、約８５ＩＵ／ｋｇ、約９０ＩＵ／ｋｇ、約９５ＩＵ／ｋｇ、または約１００ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目５２)
前記複数用量の少なくとも１つが、約２５ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目５３)
前記複数用量の少なくとも１つが、約６５ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目５４)
前記複数用量の少なくとも１つが、約８０ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目５５)
前記投薬間隔が、少なくとも約７日、少なくとも約８日、少なくとも約９日、少なくとも約１０日、少なくとも約１１日、少なくとも約１２日、少なくとも約１３日、少なくとも約１４日、少なくとも約１５日、少なくとも約１６日、少なくとも約１７日、少なくとも約１８日、少なくとも約１９日、少なくとも約２０日、少なくとも約２１日、少なくとも約２２日、少なくとも約２３日、少なくとも約２４日、少なくとも約２５日、少なくとも約２６日、少なくとも約２７日、少なくとも約２８日、少なくとも約２９日、少なくとも約３０日、または少なくとも約３１日である、項目１～４１のいずれか一項に記載の方法。
(項目５６)
前記用量の頻度が、１週間ごとに少なくとも１回、２週間ごとに少なくとも１回、３週間ごとに少なくとも１回、または４週間ごとに少なくとも１回である、項目１～４１のいずれか一項に記載の方法。
(項目５７)
前記用量の頻度が、１週間ごとに少なくとも１回である、項目１～４１のいずれか一項に記載の方法。
(項目５８)
前記用量の頻度が、２週間ごとに少なくとも１回である、項目１～４１のいずれか一項に記載の方法。
(項目５９)
前記キメラポリペプチドが、予防的処置のために投与される、項目１～４１のいずれか一項に記載の方法。
(項目６０)
前記キメラポリペプチドが、静脈内注射、静脈内注入、皮下投与、筋肉内投与、経口投与、経鼻投与および肺投与からなる群より選択される経路によって投与される、項目１～４１のいずれか一項に記載の方法。
(項目６１)
前記投与後の前記キメラポリペプチドが、少なくとも約１％、少なくとも約２％、少なくとも約３％、少なくとも約４％、少なくとも約５％、少なくとも約６％、少なくとも約７％、少なくとも約８％、少なくとも約９％、または少なくとも約１０％のＦＶＩＩＩの血漿活性レベルをもたらす、項目１～４１のいずれか一項に記載の方法。
(項目６２)
前記ＦＶＩＩＩの血漿活性レベルが、少なくとも約３％である、項目６１に記載の方法。
(項目６３)
前記ＦＶＩＩＩの血漿活性レベルが、少なくとも約５％である、項目６１に記載の方法。
(項目６４)
前記投与後の前記キメラポリペプチドが、少なくとも約１ＩＵ／ｄＬ、少なくとも約２ＩＵ／ｄＬ、少なくとも約３ＩＵ／ｄＬ、少なくとも約４ＩＵ／ｄＬ、少なくとも約５ＩＵ／ｄＬ、少なくとも約６ＩＵ／ｄＬ、少なくとも約７ＩＵ／ｄＬ、少なくとも約８ＩＵ／ｄＬ、少なくとも約９ＩＵ／ｄＬ、または少なくとも約１０ＩＵ／ｄＬのＦＶＩＩＩの血漿活性レベルをもたらす、項目１～４１のいずれか一項に記載の方法。
(項目６５)
前記ＦＶＩＩＩの血漿活性レベルが、少なくとも約３ＩＵ／ｄＬである、項目６４に記載の方法。
(項目６６)
前記ＦＶＩＩＩの血漿活性レベルが、少なくとも約５ＩＵ／ｄＬである、項目６４に記載の方法。
(項目６７)
前記ＦＶＩＩＩの血漿活性レベルが、前記キメラポリペプチドの前記投与の少なくとも約５日後に、少なくとも約１０ＩＵ／ｄＬである、項目１～４１のいずれか一項に記載の方法。
(項目６８)
前記ＦＶＩＩＩの血漿活性レベルが、前記キメラポリペプチドの前記投与の少なくとも約７日後に、少なくとも約５ＩＵ／ｄＬである、項目１～４１のいずれか一項に記載の方法。
(項目６９)
前記ＦＶＩＩＩの血漿活性レベルが、前記キメラポリペプチドの前記投与の少なくとも約８日後に、少なくとも約３ＩＵ／ｄＬである、項目１～４１のいずれか一項に記載の方法。
(項目７０)
前記ＦＶＩＩＩの血漿活性レベルが、前記キメラポリペプチドの前記投与の少なくとも約１０日後に、少なくとも約１ＩＵ／ｄＬである、項目１～４１のいずれか一項に記載の方法。
(項目７１)
前記複数用量の少なくとも１つが、約５０ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目７２)
前記複数用量が、約５０Ｕ／ｋｇであり、前記投薬間隔が、約７日である、項目１～４１のいずれか一項に記載の方法。
(項目７３)
前記キメラポリペプチドの前記投与が、約７日間、約１０日間、約１１日間、約１２日間、約１３日間、約１４日間、約１５日間、約２０日間、約２４日間、約２５日間、約２８日間、約３０日間、または約３５日間の前記投与後に、ＦＶＩＩＩ阻害剤を誘導しない、項目１～４１のいずれか一項に記載の方法。
(項目７４)
前記キメラポリペプチドの前記投与が、約２８日間の前記投与後に、ＦＶＩＩＩ阻害剤を誘導しない、項目１～４１のいずれか一項に記載の方法。
(項目７５)
前記複数用量の少なくとも１つが、約５０ＩＵ／ｋｇ～約８０ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目７６)
前記複数用量の少なくとも１つが、約５０ＩＵ／ｋｇ～約６５ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目７７)
前記複数用量の少なくとも１つが、約６５ＩＵ／ｋｇ～約８０ＩＵ／ｋｇである、項目１～４１のいずれか一項に記載の方法。
(項目７８)
前記投薬間隔が、少なくとも約７日である、項目１～４１のいずれか一項に記載の方法。
(項目７９)
前記投薬間隔が、約７日～約１４日である、項目１～４１のいずれか一項に記載の方法。
(項目８０)
前記投薬間隔が、少なくとも約１０日である、項目１～４１のいずれか一項に記載の方法。
(項目８１)
前記投薬間隔が、約１０日～約２１日である、項目１～４１のいずれか一項に記載の方法。
(項目８２)
前記投薬間隔が、約１４日～約２１日である、項目１～４１のいずれか一項に記載の方法。
(項目８３)
前記投薬間隔が、約１４日である、項目１～４１のいずれか一項に記載の方法。
(項目８４)
前記ヒト被験体が、女性である、項目１～４１のいずれか一項に記載の方法。
(項目８５)
前記ヒト被験体が、子供である、項目１～４１のいずれか一項に記載の方法。
(項目８６)
前記ヒト被験体が、約１２歳またはそれ未満、約１１歳未満、約１０歳未満、約９歳未満、約８歳未満、約７歳未満、約６歳未満、約５歳未満、約４歳未満、約３歳未満、約２歳未満、または約１歳未満の子供である、項目８５に記載の方法。
(項目８７)
前記投与が、前記ヒト被験体においてＦＶＩＩＩに対する免疫寛容を誘導する、項目１～４１のいずれか一項に記載の方法。
(項目８８)
前記投与が、前記ヒト被験体においてＦＶＩＩＩに対する阻害性免疫応答を低減する、項目１～４１のいずれか一項に記載の方法。
(項目８９)
ＦＶＩＩＩに対する前記阻害性免疫応答が、前記ヒト被験体における高力価の抗ＦＶＩＩＩ抗体を含む、項目８８に記載の方法。 All patents and publications cited herein are incorporated herein by reference in their entirety.
The present invention provides, for example, the following items.
(Item 1)
A method for treating hemophilia A in a human subject in need of treatment for hemophilia A, wherein (i) a factor VIII (FVIII) polypeptide, and (ii) a von Willebrand factor (VWF). Multiple doses of a chimeric polypeptide comprising a VWF fragment comprising the D'domain and the D3 domain of VWF, comprising administering to said subject at certain dosing intervals.
A method in which at least one of the plurality of doses is from about 15 IU / kg to about 100 IU / kg and the dosing interval is at least about 7 days.
(Item 2)
The method of item 1, wherein the FVIII polypeptide is covalently linked to the VWF fragment.
(Item 3)
The method according to item 1 or 2, wherein the covalent bond is a peptide bond or a disulfide bond.
(Item 4)
The method according to any one of items 1 to 3, wherein the FVIII polypeptide comprises a first half-life extension.
(Item 5)
The method of item 4, wherein the first half-life extension is fused to the C-terminus or N-terminus of the FVIII polypeptide.
(Item 6)
The method of item 4, wherein the first half-life extension portion is inserted into the FVIII polypeptide.
(Item 7)
5. The method of item 5 or 6, wherein the first half-life extension portion is inserted within the B domain of the FVIII polypeptide.
(Item 8)
7. The method of item 7, wherein the first half-life extension is inserted into the FVIII polypeptide immediately downstream of the amino acid corresponding to amino acid residue 745 of SEQ ID NO: 65.
(Item 9)
The method of any one of items 4-8, wherein the first half-life extension is fused to the FVIII polypeptide by a linker.
(Item 10)
The method according to any one of items 4 to 9, wherein the VWF fragment comprises a second half-life extension portion.
(Item 11)
10. The method of item 10, wherein the second half-life extension is fused to the C-terminus or N-terminus of the VWF fragment.
(Item 12)
The method of item 10, wherein the second half-life extension portion is inserted into the VWF fragment.
(Item 13)
The method of item 10 or 11, wherein the second half-life extension is fused to the C-terminus of the VWF fragment.
(Item 14)
The method of any one of items 10-13, wherein the second half-life extension is fused to the VWF fragment by a linker.
(Item 15)
The first half-life extension, the second half-life extension, or both are albumin, immunoglobulin Fc region, XTEN sequence, C-terminal peptide (CTP), PAS, β-subunit of human chorionic gonadotropin. The method according to any one of items 4 to 14, selected from the group consisting of sequences, HAP sequences, transferrin, albumin-binding moieties, or any fragments, derivatives, variants and any combinations thereof.
(Item 16)
The method according to any one of items 4 to 15, wherein the first half-life extension portion comprises a first XTEN.
(Item 17)
16. The method of item 16, wherein the first XTEN is inserted into the FVIII polypeptide immediately downstream of the amino acid corresponding to amino acid residue 745 of SEQ ID NO: 65.
(Item 18)
The method according to any one of items 10 to 17, wherein the second half-life extension portion comprises a second XTEN.
(Item 19)
Item 18. The method of item 18, wherein the second XTEN is fused to the C-terminus of the VWF fragment.
(Item 20)
The method according to any one of items 1 to 19, wherein the FVIII polypeptide comprises a first immunoglobulin (Ig) constant region or a portion thereof.
(Item 21)
20. The method of item 20, wherein the first Ig constant region or portion thereof is fused to the C-terminus or N-terminus of the FVIII polypeptide.
(Item 22)
20. The method of item 20, wherein the first Ig constant region or portion thereof is inserted into the FVIII polypeptide.
(Item 23)
The method of item 20 or 21, wherein the first Ig constant region or portion thereof is fused to the C-terminus of the FVIII polypeptide.
(Item 24)
The method of any one of items 20-23, wherein the first Ig constant region or portion thereof is fused to the FVIII polypeptide by a linker.
(Item 25)
The method of any one of items 20-24, wherein the first Ig constant region or portion thereof comprises a first Fc domain or portion thereof.
(Item 26)
The method according to any one of items 1 to 25, wherein the VWF fragment comprises a second Ig constant region or a portion thereof.
(Item 27)
26. The method of item 26, wherein the second Ig constant region or portion thereof is fused to the C-terminus or N-terminus of the VWF fragment.
(Item 28)
26. The method of item 26, wherein the second Ig constant region or portion thereof is inserted into the VWF fragment.
(Item 29)
26 or 27. The method of item 26 or 27, wherein the second Ig constant region or portion thereof is fused to the C-terminus of the VWF fragment.
(Item 30)
The method according to any one of items 26 to 29, wherein the second Ig constant region or a portion thereof is fused to the VWF fragment by a linker.
(Item 31)
30. The method of item 30, wherein the linker is a cleavable linker.
(Item 32)
The method of any one of items 26-31, wherein the second Ig constant region or portion thereof comprises a second Fc domain or portion thereof.
(Item 33)
32. The method of item 32, wherein the FVIII protein and the VWF fragment are covalently linked to each other by a covalent bond between the first Fc domain and the second Fc domain.
(Item 34)
33. The method of item 33, wherein the FVIII protein and the VWF fragment are further linked to each other by a non-covalent interaction between the FVIII protein and the VWF fragment.
(Item 35)
A method of treating hemophilia A in a human subject, comprising administering a plurality of doses of the chimeric polypeptide to the subject in need thereof at certain dosing intervals.
(I) (a) A first FVIII polypeptide fragment comprising the amino acid sequence of SEQ ID NO: 215,
(B) A first XTEN sequence comprising the amino acid sequence of SEQ ID NO: 8 (AE288),
(C) A second FVIII polypeptide fragment comprising the amino acid sequence of SEQ ID NO: 216, and
(D) First Fc region containing the amino acid sequence of SEQ ID NO: 217
FVIII protein, including
(Ii) (a) D'domain of VWF comprising the amino acid sequence of SEQ ID NO: 210,
(B) D3 domain of VWF comprising the amino acid sequence of SEQ ID NO: 214,
(C) A second XTEN sequence comprising the amino acid sequence of SEQ ID NO: 58 (AE144_5A),
(D) An a2 linker containing the amino acid sequence of SEQ ID NO: 88, and
(E) A second Fc region containing the amino acid sequence of SEQ ID NO: 217.
Contains VWF protein, including
A method in which the first Fc region is covalently linked to the second Fc region by a disulfide bond.
(Item 36)
35. The method of item 35, wherein the FVIII protein further comprises an FVIII signal peptide comprising the amino acid sequence of SEQ ID NO: 64.
(Item 37)
35. The method of item 35, wherein the VWF protein further comprises a VWF signal peptide comprising the amino acid sequence of SEQ ID NO: 208.
(Item 38)
35. The method of item 35, wherein the VWF protein further comprises a D1D2 domain of VWF comprising the amino acid sequence of SEQ ID NO: 209.
(Item 39)
A method of treating hemophilia A in a human subject, comprising administering a plurality of doses of the chimeric polypeptide to the subject in need thereof at certain dosing intervals.
(I) An FVIII protein containing an amino acid sequence that is at least about 80%, 90%, 95% or 100% identical to SEQ ID NO: 173, SEQ ID NO: 201, SEQ ID NO: 203 or SEQ ID NO: 207, and.
(Ii) A VWF protein containing an amino acid sequence that is at least about 80%, 90%, 95% or 100% identical to SEQ ID NO: 197, SEQ ID NO: 202 or SEQ ID NO: 205.
Including, how.
(Item 40)
A method of treating hemophilia A in a human subject, comprising administering a plurality of doses of the chimeric polypeptide to the subject in need thereof at certain dosing intervals.
(I) FVIII protein containing the amino acid sequence of SEQ ID NO: 203, and
(Ii) VWF protein containing the amino acid sequence of SEQ ID NO: 205
Including, how.
(Item 41)
A method of treating hemophilia A in a human subject, comprising administering a plurality of doses of the chimeric polypeptide to the subject in need thereof at certain dosing intervals.
(I) FVIII-161 (SEQ ID NO: 69), FVIII-169 (SEQ ID NO: 70), FVIII-170 (SEQ ID NO: 71), FVIII-173 (SEQ ID NO: 72); FVIII-195 (SEQ ID NO: 73); FVIII- 196 (SEQ ID NO: 74), FVIII199 (SEQ ID NO: 75), FVIII-201 (SEQ ID NO: 76); FVIII-203 (SEQ ID NO: 77), FVIII-204 (SEQ ID NO: 78), FVIII-205 (SEQ ID NO: 79), FVIII-266 (SEQ ID NO: 80), FVIII-267 (SEQ ID NO: 81), FVIII-268 (SEQ ID NO: 82), FVIII-269 (SEQ ID NO: 83), FVIII-271 (SEQ ID NO: 84), FVIII-272 (SEQ ID NO: 82) A FVIII protein comprising an amino acid sequence that is at least about 80%, 90%, 95% or 100% identical to the sequence selected from No. 85), FVIII-312 (SEQ ID NO: 173), or FVIII-312A (SEQ ID NO: 203). and
(Ii) At least about 80%, 90%, 95% or 100 with a sequence selected from VWF031 (SEQ ID NO: 86), VWF034 (SEQ ID NO: 87), VWF059 (SEQ ID NO: 197), VWF059A (SEQ ID NO: 202) or VWF036. % VWF protein containing the same amino acid sequence
Including, how.
(Item 42)
The method of any one of items 39-41, wherein at least one of the plurality of doses is from about 15 IU / kg to about 100 IU / kg and the dosing interval is at least about 7 days.
(Item 43)
The method of any one of items 39-41, wherein at least one of the plurality of doses is from about 50 IU / kg to about 65 IU / kg and the dosing interval is at least about 5 days or about 7 days.
(Item 44)
The plurality of doses are at least 2 doses, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses, at least 10 doses, at least 11 doses, at least 12 doses, at least. Any one of items 1-41 comprising 13 doses, at least 14 doses, at least 15 doses, at least 16 doses, at least 17 doses, at least 18 doses, at least 19 doses, at least 20 doses, or more. The method described in.
(Item 45)
The method of any one of items 1-41, wherein the treatment of hemophilia A comprises controlling or reducing the incidence or frequency of bleeding episodes in a human subject in need thereof.
(Item 46)
The method of any one of items 1-41, wherein the treatment of hemophilia A comprises preventing or treating a bleeding episode in a human subject in need thereof.
(Item 47)
At least one of the plurality of doses is about 20 IU / kg to about 95 IU / kg, about 20 IU / kg to about 90 IU / kg, about 20 IU / kg to about 85 IU / kg, about 20 IU / kg to about 80 IU / kg, about 20 IU. / Kg to about 75 IU / kg, about 20 IU / kg to about 70 IU / kg, about 20 IU / kg to about 65 IU / kg, about 20 IU / kg to about 60 IU / kg, about 20 IU / kg to about 55 IU / kg, about 20 IU. / Kg to about 50 IU / kg, about 20 IU / kg to about 45 IU / kg, about 20 IU / kg to about 40 IU / kg, about 20 IU / kg to about 35 IU / kg, about 20 IU / kg to about 30 IU / kg, or about The method according to any one of items 1 to 41, which is 20 IU / kg to about 25 IU / kg.
(Item 48)
At least one of the plurality of doses is about 20 IU / kg to about 100 IU / kg, about 25 IU / kg to about 100 IU / kg, about 30 IU / kg to about 100 IU / kg, about 35 IU / kg to about 100 IU / kg, about 40 IU. / Kg to about 100 IU / kg, about 45 IU / kg to about 100 IU / kg, about 50 IU / kg to about 100 IU / kg, about 55 IU / kg to about 100 IU / kg, about 60 IU / kg to about 100 IU / kg, about 65 IU. / Kg to about 100 IU / kg, about 70 IU / kg to about 100 IU / kg, about 75 IU / kg to about 100 IU / kg, about 80 IU / kg to about 100 IU / kg, about 85 IU / kg to about 100 IU / kg, or about The method according to any one of items 1 to 415, which is 90 IU / kg to about 100 IU / kg.
(Item 49)
At least one of the plurality of doses is about 20 IU / kg to about 80 IU / kg, about 25 IU / kg to about 75 IU / kg, about 30 IU / kg to about 70 IU / kg, about 35 IU / kg to about 65 IU / kg, about 40 IU. The method according to any one of items 1 to 41, which is from / kg to about 60 IU / kg or from about 45 IU / kg to about 55 IU / kg.
(Item 50)
The method of any one of items 1-41, wherein at least one of the plurality of doses is from about 25 IU / kg to about 65 IU / kg.
(Item 51)
At least one of the plurality of doses is about 20 IU / kg, about 25 IU / kg, about 30 IU / kg, about 35 IU / kg, about 40 IU / kg, about 45 IU / kg, about 50 IU / kg, about 55 IU / kg, about 60 IU. Items 1-41 which are / kg, about 65 IU / kg, about 70 IU / kg, about 75 IU / kg, about 80 IU / kg, about 85 IU / kg, about 90 IU / kg, about 95 IU / kg, or about 100 IU / kg. The method described in any one of the above.
(Item 52)
The method according to any one of items 1-41, wherein at least one of the plurality of doses is about 25 IU / kg.
(Item 53)
The method according to any one of items 1-41, wherein at least one of the plurality of doses is about 65 IU / kg.
(Item 54)
The method according to any one of items 1-41, wherein at least one of the plurality of doses is about 80 IU / kg.
(Item 55)
The dosing intervals are at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days. At least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, The method according to any one of items 1-41, which is at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, or at least about 31 days.
(Item 56)
One of items 1-41, wherein the frequency of the dose is at least once per week, at least once every two weeks, at least once every three weeks, or at least once every four weeks. The method described in.
(Item 57)
The method according to any one of items 1-41, wherein the frequency of the dose is at least once per week.
(Item 58)
The method according to any one of items 1-41, wherein the frequency of the dose is at least once every two weeks.
(Item 59)
The method according to any one of items 1-41, wherein the chimeric polypeptide is administered for prophylactic treatment.
(Item 60)
Any of items 1 to 41, wherein the chimeric polypeptide is administered by a route selected from the group consisting of intravenous injection, intravenous injection, subcutaneous administration, intramuscular administration, oral administration, nasal administration and pulmonary administration. The method described in paragraph 1.
(Item 61)
The chimeric polypeptide after the administration is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%. The method according to any one of items 1-41, which results in plasma activity levels of FVIII of at least about 9%, or at least about 10%.
(Item 62)
61. The method of item 61, wherein the plasma activity level of FVIII is at least about 3%.
(Item 63)
61. The method of item 61, wherein the plasma activity level of the FVIII is at least about 5%.
(Item 64)
The chimeric polypeptide after administration is at least about 1 IU / dL, at least about 2 IU / dL, at least about 3 IU / dL, at least about 4 IU / dL, at least about 5 IU / dL, at least about 6 IU / dL, at least about 7 IU /. The method of any one of items 1-41, which results in plasma activity levels of fVIII of dL, at least about 8 IU / dL, at least about 9 IU / dL, or at least about 10 IU / dL.
(Item 65)
64. The method of item 64, wherein the plasma activity level of FVIII is at least about 3 IU / dL.
(Item 66)
64. The method of item 64, wherein the plasma activity level of FVIII is at least about 5 IU / dL.
(Item 67)
The method of any one of items 1-41 wherein the plasma activity level of the FVIII is at least about 10 IU / dL at least about 5 days after said administration of the chimeric polypeptide.
(Item 68)
The method of any one of items 1-41 wherein the plasma activity level of the FVIII is at least about 5 IU / dL at least about 7 days after said administration of the chimeric polypeptide.
(Item 69)
The method of any one of items 1-41 wherein the plasma activity level of the FVIII is at least about 3 IU / dL at least about 8 days after said administration of the chimeric polypeptide.
(Item 70)
The method of any one of items 1-41 wherein the plasma activity level of the FVIII is at least about 1 IU / dL at least about 10 days after said administration of the chimeric polypeptide.
(Item 71)
The method according to any one of items 1-41, wherein at least one of the plurality of doses is about 50 IU / kg.
(Item 72)
The method according to any one of items 1 to 41, wherein the plurality of doses is about 50 U / kg and the dosing interval is about 7 days.
(Item 73)
The administration of the chimeric polypeptide is about 7 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 20 days, about 24 days, about 25 days, about. The method according to any one of items 1-41 which does not induce an FVIII inhibitor after the administration for 28 days, about 30 days, or about 35 days.
(Item 74)
The method according to any one of items 1-41, wherein the administration of the chimeric polypeptide does not induce an FVIII inhibitor after the administration for about 28 days.
(Item 75)
The method of any one of items 1-41, wherein at least one of the plurality of doses is from about 50 IU / kg to about 80 IU / kg.
(Item 76)
The method of any one of items 1-41, wherein at least one of the plurality of doses is from about 50 IU / kg to about 65 IU / kg.
(Item 77)
The method of any one of items 1-41, wherein at least one of the plurality of doses is from about 65 IU / kg to about 80 IU / kg.
(Item 78)
The method according to any one of items 1-41, wherein the dosing interval is at least about 7 days.
(Item 79)
The method according to any one of items 1 to 41, wherein the dosing interval is about 7 days to about 14 days.
(Item 80)
The method according to any one of items 1-41, wherein the dosing interval is at least about 10 days.
(Item 81)
The method according to any one of items 1 to 41, wherein the dosing interval is about 10 days to about 21 days.
(Item 82)
The method according to any one of items 1 to 41, wherein the dosing interval is from about 14 days to about 21 days.
(Item 83)
The method according to any one of items 1 to 41, wherein the dosing interval is about 14 days.
(Item 84)
The method according to any one of items 1 to 41, wherein the human subject is a woman.
(Item 85)
The method according to any one of items 1 to 41, wherein the human subject is a child.
(Item 86)
The human subject is about 12 years old or younger, about 11 years old, about 10 years old, about 9 years old, about 8 years old, about 7 years old, about 6 years old, about 5 years old, about 4 years old. 85. The method of item 85, wherein the child is under the age of, about 3 years, under about 2 years, or under about 1 year.
(Item 87)
The method according to any one of items 1-41, wherein the administration induces immune tolerance to FVIII in the human subject.
(Item 88)
The method of any one of items 1-41, wherein said administration reduces an inhibitory immune response against FVIII in said human subject.
(Item 89)
88. The method of item 88, wherein the inhibitory immune response to FVIII comprises a high titer of an anti-FVIII antibody in said human subject.

Claims (19)

ヒト被験体における血友病Ａを処置するための組成物であって、キメラポリペプチドを含み、
前記キメラポリペプチドが、その必要のある前記被験体に、複数用量で、ある投薬間隔で投与され、
前記キメラポリペプチドが、（ｉ）第ＶＩＩＩ因子（ＦＶＩＩＩ）ポリペプチド、ならびに（ｉｉ）フォンヴィルブランド因子（ＶＷＦ）のＤ’Ｄ３ドメインを含むＶＷＦポリペプチドを含み、前記ＦＶＩＩＩポリペプチドは、ジスルフィド結合によって前記ＶＷＦポリペプチドと結び付いており、
前記キメラポリペプチドの複数用量が、少なくとも約７日の投薬間隔で、前記被験体に投与され、
前記複数用量のそれぞれが、約１５ＩＵ／ｋｇ～約１００ＩＵ／ｋｇであることを特徴とする、組成物。 A composition for treating hemophilia A in a human subject , comprising a chimeric polypeptide.
The chimeric polypeptide is administered to the subject in need thereof in multiple doses at certain dosing intervals.
The chimeric polypeptide comprises a VWF polypeptide comprising (i) a factor VIII (FVIII) polypeptide and (ii) a D' D3 domain of a von Willebrand factor (VWF) , wherein the FVIII polypeptide comprises: It is linked to the VWF polypeptide by a disulfide bond and is linked to the VWF polypeptide.
Multiple doses of the chimeric polypeptide are administered to the subject at a dosing interval of at least about 7 days .
A composition comprising each of the plurality of doses from about 15 IU / kg to about 100 IU / kg. 前記ＦＶＩＩＩポリペプチドが、２つのジスルフィド結合によって前記ＶＷＦポリペプチドと結び付いている、請求項１に記載の組成物。 The composition of claim 1, wherein the FVIII polypeptide is associated with the VWF polypeptide by two disulfide bonds . 前記ＦＶＩＩＩポリペプチドが、配列番号２０７のアミノ酸配列を含む、請求項１または請求項２に記載の組成物。The composition according to claim 1 or 2, wherein the FVIII polypeptide comprises the amino acid sequence of SEQ ID NO: 207. 前記ＶＷＦポリペプチドが、配列番号２０２のアミノ酸配列を含む、請求項１～３のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 3, wherein the VWF polypeptide comprises the amino acid sequence of SEQ ID NO: 202. 前記複数用量のそれぞれが５０ＩＵ／ｋｇであり、前記投薬間隔が少なくとも７日である、請求項１～４のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 4, wherein each of the plurality of doses is 50 IU / kg and the dosing interval is at least 7 days. 前記複数用量の少なくとも１つが、２５ＩＵ／ｋｇである、請求項１～４のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 4, wherein at least one of the plurality of doses is 25 IU / kg. 前記複数用量の少なくとも１つが、５０ＩＵ／ｋｇである、請求項１～４のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 4, wherein at least one of the plurality of doses is 50 IU / kg. 前記複数用量の少なくとも１つが、６５ＩＵ／ｋｇである、請求項１～４のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 4, wherein at least one of the plurality of doses is 65 IU / kg. 予防的処置のためのものである、請求項１～８のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 8, which is for prophylactic treatment. 静脈内投与に適したものである、請求項１～９のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 9, which is suitable for intravenous administration. 前記被験体が、少なくとも１５０曝露日（ＥＤ）にわたって、任意の組換えＦＶＩＩＩ、血漿由来ＦＶＩＩＩ、またはクリオプレシピテートによる血友病Ａについての処置を以前に受けていた、請求項１～１０のいずれか一項に記載の組成物。Claims 1-10, wherein said subject had previously been treated for hemophilia A with any recombinant FVIII, plasma-derived FVIII, or cryoprecipitate for at least 150 exposure days (ED). The composition according to any one. 前記被験体が、The subject
（ａ）販売されているＦＶＩＩＩ製品による予防的処置レジメンを現在受けていて、前記組成物の投与前１２ヶ月間で少なくとも４回の出血エピソードを有したか；または(A) Did you currently receive a prophylactic treatment regimen with an FVIII product on the market and had at least 4 bleeding episodes in the 12 months prior to administration of the composition;
（ｂ）販売されているＦＶＩＩＩ製品によるオンデマンド処置レジメンを現在受けていて、前記組成物の投与前１２ヶ月間で少なくとも１２回の出血エピソードを有したか(B) Did you currently receive an on-demand treatment regimen with a FVIII product on the market and had at least 12 bleeding episodes in the 12 months prior to administration of the composition?
のいずれかである、請求項１～１１のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 11, which is any one of the above. 前記被験体が、少なくとも１００，０００細胞／μＬの血小板数を有する、請求項１～１１のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 11, wherein the subject has a platelet count of at least 100,000 cells / μL. 前記被験体が、血友病Ａに加えて他の凝血障害を有しない、請求項１～１３のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 13, wherein the subject does not have other blood coagulation disorders in addition to hemophilia A. 前記被験体が、ＦＶＩＩＩ製品に対する阻害剤を生じた履歴を有さない、請求項１～１４のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 14, wherein the subject has no history of producing an inhibitor for an FVIII product. 出血エピソードを減らすために、日常的な予防のために使用される、請求項１～１５のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 15, which is used for routine prevention to reduce bleeding episodes. オンデマンド処置のために、そして出血エピソードの制御のために使用される、請求項１～８のいずれか一項に記載の組成物。The composition according to any one of claims 1-8, which is used for on-demand treatment and for the control of bleeding episodes. 出血の術中管理のために使用される、請求項１～８のいずれか一項に記載の組成物。The composition according to any one of claims 1 to 8, which is used for intraoperative management of bleeding. その必要のある被験体において血友病Ａを処置するための組成物であって、A composition for treating hemophilia A in a subject in need thereof.
（ｉ）ＦＶＩＩＩポリペプチド、ならびに（ｉｉ）ＶＷＦのＤ’ドメインおよびＶＷＦのＤ３ドメインを含むＶＷＦ断片を含むキメラポリペプチドを含み、It comprises (i) an FVIII polypeptide and (ii) a chimeric polypeptide comprising a VWF fragment comprising the D'domain of VWF and the D3 domain of VWF.
前記キメラポリペプチドが、前記被験体に、複数用量で、ある投薬間隔で投与され、The chimeric polypeptide is administered to the subject in multiple doses at certain dosing intervals.
前記キメラポリペプチドは２つのポリペプチド配列、配列番号２０７に記載のアミノ酸配列を含む第１のポリペプチド配列および配列番号２０２に記載のアミノ酸配列を含む第２のポリペプチド配列を含み、前記第１のポリペプチドは、ジスルフィド結合によって前記第２のポリペプチドと結び付いており、 The chimeric polypeptide comprises two polypeptide sequences, a first polypeptide sequence comprising the amino acid sequence set forth in SEQ ID NO: 207 and a second polypeptide sequence comprising the amino acid sequence set forth in SEQ ID NO: 202, said first. The polypeptide of the above is bound to the second polypeptide by a disulfide bond.
前記キメラポリペプチドは、日常的な予防のために７日ごとに５０ＩＵ／ｋｇの用量で投与され；The chimeric polypeptide is administered at a dose of 50 IU / kg every 7 days for routine prevention;
前記キメラポリペプチドは、オンデマンド処置のために単回５０ＩＵ／ｋｇの用量として投与され；そしてThe chimeric polypeptide is administered as a single dose of 50 IU / kg for on-demand treatment;
前記キメラポリペプチドは、術中管理のために単回５０ＩＵ／ｋｇの術前用量として投与されることを特徴とする、組成物。The composition, wherein the chimeric polypeptide is administered as a single preoperative dose of 50 IU / kg for intraoperative management.
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* Cited by examiner, † Cited by third party
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Family Cites Families (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4757006A (en) 1983-10-28 1988-07-12 Genetics Institute, Inc. Human factor VIII:C gene and recombinant methods for production
EP0154316B1 (en) 1984-03-06 1989-09-13 Takeda Chemical Industries, Ltd. Chemically modified lymphokine and production thereof
US4965199A (en) 1984-04-20 1990-10-23 Genentech, Inc. Preparation of functional human factor VIII in mammalian cells using methotrexate based selection
US4683195A (en) 1986-01-30 1987-07-28 Cetus Corporation Process for amplifying, detecting, and/or-cloning nucleic acid sequences
US4965188A (en) 1986-08-22 1990-10-23 Cetus Corporation Process for amplifying, detecting, and/or cloning nucleic acid sequences using a thermostable enzyme
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4868112A (en) 1985-04-12 1989-09-19 Genetics Institute, Inc. Novel procoagulant proteins
KR910006424B1 (en) 1985-08-21 1991-08-24 인코텍스 비.브이 Method of manufacturing knitted briefs
WO1987004187A1 (en) 1986-01-03 1987-07-16 Genetics Institute, Inc. METHOD FOR PRODUCING FACTOR VIII:c-TYPE PROTEINS
US5595886A (en) 1986-01-27 1997-01-21 Chiron Corporation Protein complexes having Factor VIII:C activity and production thereof
US4800159A (en) 1986-02-07 1989-01-24 Cetus Corporation Process for amplifying, detecting, and/or cloning nucleic acid sequences
US5610278A (en) 1986-06-24 1997-03-11 Novo Nordisk A/S Process for producing a coagulation active complex of factor VIII fragments
US4912040A (en) 1986-11-14 1990-03-27 Genetics Institute, Inc. Eucaryotic expression system
WO1988007089A1 (en) 1987-03-18 1988-09-22 Medical Research Council Altered antibodies
CA1331157C (en) 1987-04-06 1994-08-02 Randal J. Kaufman Method for producing factor viii:c-type proteins
US6060447A (en) 1987-05-19 2000-05-09 Chiron Corporation Protein complexes having Factor VIII:C activity and production thereof
US6346513B1 (en) 1987-06-12 2002-02-12 Baxter Trading Gmbh Proteins with factor VIII activity: process for their preparation using genetically-engineered cells and pharmaceutical compositions containing them
US5171844A (en) 1987-06-12 1992-12-15 Gist-Brocades N.W. Proteins with factor viii activity: process for their preparation using genetically-engineered cells and pharmaceutical compositions containing them
DE3720246A1 (en) 1987-06-19 1988-12-29 Behringwerke Ag FACTOR VIII: C-LIKE MOLECULE WITH COAGULATION ACTIVITY
FR2619314B1 (en) 1987-08-11 1990-06-15 Transgene Sa FACTOR VIII ANALOG, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
US4994371A (en) 1987-08-28 1991-02-19 Davie Earl W DNA preparation of Christmas factor and use of DNA sequences
US6780613B1 (en) 1988-10-28 2004-08-24 Genentech, Inc. Growth hormone variants
US5004803A (en) 1988-11-14 1991-04-02 Genetics Institute, Inc. Production of procoagulant proteins
CA2006596C (en) 1988-12-22 2000-09-05 Rika Ishikawa Chemically-modified g-csf
EP0461200B1 (en) 1989-02-21 1997-01-22 Washington University Modified forms of reproductive hormones
SE465222C5 (en) 1989-12-15 1998-02-10 Pharmacia & Upjohn Ab A recombinant human factor VIII derivative and process for its preparation
US6552170B1 (en) 1990-04-06 2003-04-22 Amgen Inc. PEGylation reagents and compounds formed therewith
JP3693671B2 (en) 1991-03-15 2005-09-07 アムゲン インコーポレーテッド PEGylation of polypeptides
US5846951A (en) 1991-06-06 1998-12-08 The School Of Pharmacy, University Of London Pharmaceutical compositions
IE922437A1 (en) 1991-07-25 1993-01-27 Idec Pharma Corp Recombinant antibodies for human therapy
US6376463B1 (en) 1992-04-07 2002-04-23 Emory University Modified factor VIII
US5364771A (en) 1992-04-07 1994-11-15 Emory University Hybrid human/porcine factor VIII
US5859204A (en) 1992-04-07 1999-01-12 Emory University Modified factor VIII
US5563045A (en) 1992-11-13 1996-10-08 Genetics Institute, Inc. Chimeric procoagulant proteins
SE504074C2 (en) 1993-07-05 1996-11-04 Pharmacia Ab Protein preparation for subcutaneous, intramuscular or intradermal administration
GB9422383D0 (en) 1994-11-05 1995-01-04 Wellcome Found Antibodies
US6030613A (en) 1995-01-17 2000-02-29 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6485726B1 (en) 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6086875A (en) 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
US6121022A (en) 1995-04-14 2000-09-19 Genentech, Inc. Altered polypeptides with increased half-life
US6096871A (en) 1995-04-14 2000-08-01 Genentech, Inc. Polypeptides altered to contain an epitope from the Fc region of an IgG molecule for increased half-life
US5739277A (en) 1995-04-14 1998-04-14 Genentech Inc. Altered polypeptides with increased half-life
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
SE9503380D0 (en) 1995-09-29 1995-09-29 Pharmacia Ab Protein derivatives
US6458563B1 (en) 1996-06-26 2002-10-01 Emory University Modified factor VIII
EP0918872B1 (en) 1996-08-02 2008-02-20 Bristol-Myers Squibb Company A method for inhibiting immunoglobulin-induced toxicity resulting from the use of immunoglobulins in therapy and in vivo diagnosis
WO1998023289A1 (en) 1996-11-27 1998-06-04 The General Hospital Corporation MODULATION OF IgG BINDING TO FcRn
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
CA2225189C (en) 1997-03-06 2010-05-25 Queen's University At Kingston Canine factor viii gene, protein and methods of use
US6528624B1 (en) 1998-04-02 2003-03-04 Genentech, Inc. Polypeptide variants
US6242195B1 (en) 1998-04-02 2001-06-05 Genentech, Inc. Methods for determining binding of an analyte to a receptor
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
JP2002510481A (en) 1998-04-02 2002-04-09 ジェネンテック・インコーポレーテッド Antibody variants and fragments thereof
GB9809951D0 (en) 1998-05-08 1998-07-08 Univ Cambridge Tech Binding molecules
CA2341029A1 (en) 1998-08-17 2000-02-24 Abgenix, Inc. Generation of modified molecules with increased serum half-lives
EP1006183A1 (en) 1998-12-03 2000-06-07 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Recombinant soluble Fc receptors
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
ES2694002T3 (en) 1999-01-15 2018-12-17 Genentech, Inc. Polypeptide comprising an Fc region of variant human IgG1
AU2001259063A1 (en) 2000-04-12 2001-10-30 Human Genome Sciences, Inc. Albumin fusion proteins
GB0029407D0 (en) 2000-12-01 2001-01-17 Affitech As Product
DK1355919T3 (en) 2000-12-12 2011-03-14 Medimmune Llc Molecules with longer half-lives, compositions and uses thereof
US6888319B2 (en) 2001-03-01 2005-05-03 Palomar Medical Technologies, Inc. Flashlamp drive circuit
US20040106794A1 (en) 2001-04-16 2004-06-03 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
KR101271635B1 (en) 2001-12-21 2013-06-12 휴먼 게놈 사이언시즈, 인코포레이티드 Albumin fusion proteins
US20080194481A1 (en) 2001-12-21 2008-08-14 Human Genome Sciences, Inc. Albumin Fusion Proteins
EP1463751B1 (en) 2001-12-21 2013-05-22 Human Genome Sciences, Inc. Albumin fusion proteins
US20040002587A1 (en) 2002-02-20 2004-01-01 Watkins Jeffry D. Fc region variants
AU2003209446B2 (en) 2002-03-01 2008-09-25 Immunomedics, Inc. Bispecific antibody point mutations for enhancing rate of clearance
US7317091B2 (en) 2002-03-01 2008-01-08 Xencor, Inc. Optimized Fc variants
US20040132101A1 (en) 2002-09-27 2004-07-08 Xencor Optimized Fc variants and methods for their generation
CN100343393C (en) 2002-03-15 2007-10-17 布赖汉姆妇女医院 Central airway administration for systemic delivery of therapeutics
ATE536188T1 (en) 2002-08-14 2011-12-15 Macrogenics Inc FCGAMMARIIB-SPECIFIC ANTIBODIES AND METHODS OF USE THEREOF
DK2345671T3 (en) 2002-09-27 2016-02-15 Xencor Inc Optimized Fc variants and methods for their formation
AU2003286467B2 (en) 2002-10-15 2009-10-01 Abbvie Biotherapeutics Inc. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
GB2395337B (en) 2002-11-14 2005-12-28 Gary Michael Wilson Warning Unit
WO2004063351A2 (en) 2003-01-09 2004-07-29 Macrogenics, Inc. IDENTIFICATION AND ENGINEERING OF ANTIBODIES WITH VARIANT Fc REGIONS AND METHODS OF USING SAME
US7041635B2 (en) 2003-01-28 2006-05-09 In2Gen Co., Ltd. Factor VIII polypeptide
US20090010920A1 (en) 2003-03-03 2009-01-08 Xencor, Inc. Fc Variants Having Decreased Affinity for FcyRIIb
US8388955B2 (en) 2003-03-03 2013-03-05 Xencor, Inc. Fc variants
US7348004B2 (en) 2003-05-06 2008-03-25 Syntonix Pharmaceuticals, Inc. Immunoglobulin chimeric monomer-dimer hybrids
TWI353991B (en) 2003-05-06 2011-12-11 Syntonix Pharmaceuticals Inc Immunoglobulin chimeric monomer-dimer hybrids
GB0324368D0 (en) 2003-10-17 2003-11-19 Univ Cambridge Tech Polypeptides including modified constant regions
US7211559B2 (en) 2003-10-31 2007-05-01 University Of Maryland, Baltimore Factor VIII compositions and methods
EP1697415A1 (en) 2003-11-12 2006-09-06 Biogen Idec MA Inc. NEONATAL Fc RECEPTOR (FcRn)-BINDING POLYPEPTIDE VARIANTS, DIMERIC Fc BINDING PROTEINS AND METHODS RELATED THERETO
WO2005077981A2 (en) 2003-12-22 2005-08-25 Xencor, Inc. Fc POLYPEPTIDES WITH NOVEL Fc LIGAND BINDING SITES
BRPI0506771A (en) 2004-01-12 2007-05-22 Applied Molecular Evolution antibody and pharmaceutical composition
WO2005092925A2 (en) 2004-03-24 2005-10-06 Xencor, Inc. Immunoglobulin variants outside the fc region
WO2005123780A2 (en) 2004-04-09 2005-12-29 Protein Design Labs, Inc. Alteration of fcrn binding affinities or serum half-lives of antibodies by mutagenesis
WO2006085967A2 (en) 2004-07-09 2006-08-17 Xencor, Inc. OPTIMIZED ANTI-CD20 MONOCONAL ANTIBODIES HAVING Fc VARIANTS
CN101987870B (en) 2004-07-15 2013-07-03 赞科股份有限公司 Optimized Fc variants
WO2006047350A2 (en) 2004-10-21 2006-05-04 Xencor, Inc. IgG IMMUNOGLOBULIN VARIANTS WITH OPTIMIZED EFFECTOR FUNCTION
WO2006053299A2 (en) 2004-11-12 2006-05-18 Bayer Healthcare Llc Site-directed modification of fviii
US8048848B2 (en) 2006-02-03 2011-11-01 Prolor Biotech Ltd. Long-acting interferons and derivatives thereof and methods thereof
WO2007104146A1 (en) 2006-03-13 2007-09-20 Tir Technology Lp Adaptive control apparatus and method for a solid-state lighting system
US7939632B2 (en) 2006-06-14 2011-05-10 Csl Behring Gmbh Proteolytically cleavable fusion proteins with high molar specific activity
WO2008077616A1 (en) 2006-12-22 2008-07-03 Csl Behring Gmbh Modified coagulation factors with prolonged in vivo half-life
DK2167117T3 (en) 2007-06-13 2012-11-19 Csl Behring Gmbh Use of VWF stabilized FVIII preparations for extravascular administration for the therapeutic and prophylactic treatment of bleeding disorders
SI2173890T1 (en) 2007-06-21 2011-06-30 Univ Muenchen Tech Biological active proteins having increased in vivo and/or vitro stability
KR101648734B1 (en) 2008-06-24 2016-08-18 체에스엘 베링 게엠베하 Factor VIII, von Willebrand factor or complexes thereof with prolonged in vivo half-life
US8703717B2 (en) 2009-02-03 2014-04-22 Amunix Operating Inc. Growth hormone polypeptides and methods of making and using same
US8680050B2 (en) 2009-02-03 2014-03-25 Amunix Operating Inc. Growth hormone polypeptides fused to extended recombinant polypeptides and methods of making and using same
MX362028B (en) 2009-02-03 2019-01-04 Amunix Pharmaceuticals Inc Extended recombinant polypeptides and compositions comprising same.
ES2705249T3 (en) 2009-06-08 2019-03-22 Amunix Operating Inc Glucose regulating polypeptides and methods for their production and use
MX354555B (en) 2009-06-08 2018-03-09 Amunix Operating Inc Growth hormone polypeptides and methods of making and using same.
AU2010290077C1 (en) 2009-08-24 2015-12-03 Bioverativ Therapeutics Inc. Coagulation factor IX compositions and methods of making and using same
WO2011028344A2 (en) 2009-08-25 2011-03-10 Amunix Operating Inc. Interleukin-1 receptor antagonist compositions and methods of making and using same
WO2011041770A1 (en) 2009-10-02 2011-04-07 The Children's Hospital Of Philadelphia Compositions and methods for enhancing coagulation factor viii function
RS58578B1 (en) * 2011-07-08 2019-05-31 Bioverativ Therapeutics Inc Factor viii chimeric and hybrid polypeptides, and methods of use thereof
CA2850579A1 (en) 2011-10-18 2013-04-25 Carsten Horn Method for improving the stability of purified factor viii after reconstitution
EP3453402B1 (en) 2012-01-12 2021-07-21 Bioverativ Therapeutics Inc. Reducing immunogenicity against factor viii in individuals undergoing factor viii therapy
BR112014017165B1 (en) * 2012-01-12 2023-05-02 Bioverativ Therapeutics Inc CHIMERIC PROTEIN COMPRISING A FACTOR VIII PROTEIN, PHARMACEUTICAL COMPOSITION, AND USES THEREOF
EP2814502B1 (en) 2012-02-15 2017-09-13 CSL Behring GmbH Von willebrand factor variants having improved factor viii binding affinity
ES2771208T3 (en) 2012-02-15 2020-07-06 Bioverativ Therapeutics Inc Factor VIII compositions and methods of preparation and use thereof
CN110054699A (en) 2012-07-11 2019-07-26 比奥贝拉蒂治疗公司 Factor IX compound with XTEN and vWF ELISA albumen, and application thereof
LT2968477T (en) 2013-03-15 2020-03-10 Bioverativ Therapeutics Inc. Factor viii polypeptide formulations
EP2796145B1 (en) 2013-04-22 2017-11-01 CSL Ltd. A covalent complex of von willebrand factor and faktor viii linked by a disulphide bridge
CN105392495A (en) 2013-06-28 2016-03-09 比奥根Ma公司 Thrombin cleavable linker with xten and its uses thereof
EP3013359A4 (en) 2013-06-28 2017-01-25 Biogen MA Inc. Thrombin cleavable linker
US10947269B2 (en) * 2013-08-08 2021-03-16 Bioverativ Therapeutics Inc. Purification of chimeric FVIII molecules
WO2015023891A2 (en) * 2013-08-14 2015-02-19 Biogen Idec Ma Inc. Factor viii-xten fusions and uses thereof
CN106456718A (en) 2014-01-10 2017-02-22 比奥根Ma公司 Factor viii chimeric proteins and uses thereof
RU2714154C2 (en) 2014-06-06 2020-02-12 Октафарма Аг Preparation containing viii factor and von willebrand factor peptides
DK3164150T3 (en) 2014-07-02 2021-02-08 CSL Behring Lengnau AG MODIFIED BY WILLEBRAND FACTOR
PL3193911T3 (en) 2014-07-25 2024-03-11 Csl Behring Gmbh Improved factor viii preparations for use in treating hemophilia a
SG11201701033QA (en) 2014-08-13 2017-03-30 Philadelphia Children Hospital An improved expression cassette for packaging and expression of variant factor viii for the treatment of hemostasis disorders
US11155601B2 (en) 2015-03-06 2021-10-26 CSL Behring Lengnau AG Modified von Willebrand factor having improved half-life
JP6573989B2 (en) 2015-05-22 2019-09-11 ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト A truncated von Willebrand factor polypeptide for the treatment of hemophilia
SG10201912857XA (en) 2016-01-07 2020-02-27 CSL Behring Lengnau AG Mutated von willebrand factor
SG11201805497QA (en) 2016-01-07 2018-07-30 Csl Behring Recombinant Facility Ag Mutated truncated von willebrand factor
CN109790529A (en) 2016-06-24 2019-05-21 财团法人牧岩生命科学研究所 Chimeric protein and application thereof comprising FVIII the and vWF factor
JP2020504082A (en) 2016-11-11 2020-02-06 ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト Truncated von Willebrand factor polypeptide for extravascular administration in the treatment or prevention of blood clotting disorders
BR112019011198A2 (en) 2016-12-02 2019-12-17 Bioverativ Therapeutics Inc methods of inducing immune tolerance to coagulation factors

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