JPWO2021127525A5

JPWO2021127525A5 -

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Publication number: JPWO2021127525A5
Application number: JP2022538201A
Authority: JP
Publication date: 2023-12-15

Description

等価物
本開示は、その主旨または必須の特徴から逸脱することなく、他の特定の形態に具体化することができる。したがって、前述の実施形態は、全ての観点で、本明細書に記載の本開示を限定するものではなく、例示するものであるとみなされるべきである。異なる実施形態の種々の構造要素および種々の開示された方法のステップを種々の組合せおよび順列で利用することができ、また、そのような変形はすべて、本開示の形態であるとみなされるべきである。したがって、本開示の範囲は、前述の説明によってではなく、添付の特許請求の範囲によって示され、特許請求の範囲と同等の意味および範囲の中に入る変化は全て特許請求の範囲に包含されるものとする。
特定の実施形態では、例えば、以下が提供される：
（項目１）
（ａ）治療有効量の単離された抗第ＸＩ因子（ＦＸＩ）および／または抗活性化第ＸＩ因子（ＦＸＩａ）抗体またはその抗原結合性断片；
（ｂ）ヒスチジン緩衝剤；
（ｃ）糖または糖アルコール；および
（ｄ）ポリソルベート
を含むｐＨ５．０～６．０の薬物送達製剤を含むバイアルであって、
前記抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片の治療有効量を完全に抜き取れるように過剰充填分を含む、バイアル。
（項目２）
前記単離された抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片の前記治療有効量が、１２０ｍｇ／ｍｌから１８０ｍｇ／ｍｌの間の濃度である、項目１に記載のバイアル。
（項目３）
前記単離された抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片の前記治療有効量が、約１５０ｍｇ／ｍｌの濃度である、項目１または２に記載のバイアル。
（項目４）
前記ヒスチジン緩衝剤が、ヒスチジンおよびヒスチジン塩を含む、項目１から３までのいずれか一項に記載のバイアル。
（項目５）
前記ヒスチジンが、Ｌ－ヒスチジンである、項目４に記載のバイアル。
（項目６）
前記ヒスチジン塩が、ヒスチジンＨＣｌ一水和物である、項目４または５に記載のバイアル。
（項目７）
前記ヒスチジン緩衝剤の濃度が、１０ｍＭから３０ｍＭの間である、項目４から６までのいずれか一項に記載のバイアル。
（項目８）
前記ヒスチジン緩衝剤の濃度が、約２０ｍＭである、項目７に記載のバイアル。
（項目９）
前記糖または糖アルコールが、二糖である、項目１から８までのいずれか一項に記載のバイアル。
（項目１０）
前記二糖が、スクロースである、項目９に記載のバイアル。
（項目１１）
前記スクロースの濃度が、１７０ｍＭから２７０ｍＭの間である、項目１０に記載のバイアル。
（項目１２）
前記スクロースの濃度が、約２２０ｍＭである、項目１１に記載のバイアル。
（項目１３）
前記ポリソルベートが、ポリソルベート２０である、項目１から１２までのいずれか一項に記載のバイアル。
（項目１４）
前記ポリソルベート２０の濃度が、０．０２％（ｖ／ｖ）から０．０６％（ｖ／ｖ）の間である、項目１３に記載のバイアル。
（項目１５）
前記ポリソルベート２０の濃度が、約０．０４％（ｖ／ｖ）である、項目１４に記載のバイアル。
（項目１６）
前記ｐＨが、５．３～５．７である、項目１から１５までのいずれか一項に記載のバイアル。
（項目１７）
前記ｐＨが、約５．５である、項目１から１６までのいずれか一項に記載のバイアル。
（項目１８）
前記過剰充填分が、前記薬物送達製剤の１０％（ｖ／ｖ）から３０％（ｖ／ｖ）の間を構成し、必要に応じて、前記バイアルが、前記薬物送達製剤を１．１ｍＬ～１．３ｍＬ含む、項目１から１７までのいずれか一項に記載のバイアル。
（項目１９）
前記過剰充填分が、前記薬物送達製剤の約２０％（ｖ／ｖ）を構成し、必要に応じて、前記バイアルが、前記薬物送達製剤を約１．２ｍＬ含む、項目１８に記載のバイアル。
（項目２０）
前記抗体またはその抗原結合性断片が、配列番号９または２９における相補性決定領域ＨＣＤＲ１、ＨＣＤＲ２、およびＨＣＤＲ３を含む重鎖可変領域（ＶＨ）；ならびに配列番号１９または３９における相補性決定領域ＬＣＤＲ１、ＬＣＤＲ２、ＬＣＤＲ３を含む軽鎖可変領域（ＶＬ）を含む、項目１から１９までのいずれか一項に記載のバイアル。
（項目２１）
前記抗体またはその抗原結合性断片が、
ｉ．配列番号２３の重鎖可変領域ＣＤＲ１；配列番号２４の重鎖可変領域ＣＤＲ２；配列番号２５の重鎖可変領域ＣＤＲ３；配列番号３３の軽鎖可変領域ＣＤＲ１；配列番号３４の軽鎖可変領域ＣＤＲ２；および配列番号３５の軽鎖可変領域ＣＤＲ３；
ｉｉ．配列番号２６の重鎖可変領域ＣＤＲ１；配列番号２７の重鎖可変領域ＣＤＲ２；配列番号２８の重鎖可変領域ＣＤＲ３；配列番号３６の軽鎖可変領域ＣＤＲ１；配列番号３７の軽鎖可変領域ＣＤＲ２；および配列番号３８の軽鎖可変領域ＣＤＲ３；
ｉｉｉ．配列番号４３の重鎖可変領域ＣＤＲ１；配列番号４４の重鎖可変領域ＣＤＲ２；配列番号４５の重鎖可変領域ＣＤＲ３；配列番号４７の軽鎖可変領域ＣＤＲ１；配列番号３７の軽鎖可変領域ＣＤＲ２；および配列番号１５の軽鎖可変領域ＣＤＲ３；または
ｉｖ．配列番号４６の重鎖可変領域ＣＤＲ１；配列番号４の重鎖可変領域ＣＤＲ２；配列番号５の重鎖可変領域ＣＤＲ３；配列番号３３の軽鎖可変領域ＣＤＲ１；配列番号１４の軽鎖可変領域ＣＤＲ２；および配列番号１５の軽鎖可変領域ＣＤＲ３
を含む、項目１から２０までのいずれか一項に記載のバイアル。
（項目２２）
前記抗体またはその抗原結合性断片が、配列番号９、２９からなる群から選択される重鎖可変領域（ＶＨ）、およびそれに対して９０％の同一性を有するＶＨ；ならびに、配列番号１９、３９からなる群から選択される軽鎖可変領域（ＶＬ）、およびそれに対して９０％の同一性を有するＶＬを含む、項目１から２１までのいずれか一項に記載のバイアル。
（項目２３）
前記抗体またはその抗原結合性断片が、配列番号９および２９からなる群から選択される重鎖可変領域（ＶＨ）；ならびに配列番号１９および３９からなる群から選択される軽鎖可変領域（ＶＬ）を含む、項目１から２２までのいずれか一項に記載のバイアル。
（項目２４）
前記抗体が、配列番号３１、１１からなる群から選択されるアミノ酸配列を含む重鎖、およびそれに対して９０％の同一性を有する重鎖；ならびに、配列番号４１、２１からなる群から選択されるアミノ酸配列を含む軽鎖、およびそれに対して９０％の同一性を有する軽鎖を含む、項目１から２３までのいずれか一項に記載のバイアル。
（項目２５）
前記抗体が、配列番号３１のアミノ酸配列を含む重鎖および配列番号４１のアミノ酸配列を含む軽鎖を含む、項目１から２４までのいずれか一項に記載のバイアル。
（項目２６）
前記抗体が、ヒトモノクローナル抗体である、項目１から２５までのいずれか一項に記載のバイアル。
（項目２７）
前記抗体が、ヒトＩｇＧ１アイソタイプである、項目２６に記載のバイアル。
（項目２８）
前記抗体が、Ｆｃドメイン内にＤ２６５Ａ置換およびＰ３２９Ａ置換を含み、必要に応じて、１２０ｍｇ～１８０ｍｇが、対象に投与するための前記抗第ＸＩ因子（ＦＸＩ）および／または抗活性化第ＸＩ因子（ＦＸＩａ）抗体またはその抗原結合性断片の前記治療有効量である、項目２６または２７に記載のバイアル。
（項目２９）
（ａ）約１５０ｍｇの濃度の、治療有効量の単離された抗第ＸＩ因子（ＦＸＩ）および／または抗活性化第ＸＩ因子（ＦＸＩａ）抗体またはその抗原結合性断片；
（ｂ）約２０ｍＭの濃度のヒスチジン緩衝剤；
（ｃ）約２２０ｍＭの濃度のスクロース；および
（ｄ）約０．０４％（ｖ／ｖ）の濃度のポリソルベート２０
を含むｐＨ５．５の薬物送達製剤を含むバイアルであって、
前記抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片の治療有効量を完全に抜き取れるように過剰充填分を含む、バイアル。
（項目３０）
（ａ）治療有効量の単離された抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片；
（ｂ）ヒスチジン緩衝剤；
（ｃ）糖または糖アルコール；
（ｄ）ポリソルベート、ならびに
（ｅ）希釈剤
を含むｐＨ５．０～６．０の静脈内薬物送達製剤であって、
前記希釈剤が、第２の糖および水を含む溶液である、
静脈内薬物送達製剤。
（項目３１）
前記単離された抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片の前記治療有効量の濃度が、１．２０ｍｇ／ｍｌから１．８０ｍｇ／ｍｌの間である、項目３０に記載の静脈内薬物送達製剤。
（項目３２）
前記単離された抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片の前記治療有効量の濃度が、約１．５０ｍｇ／ｍｌである、項目３０または３１に記載の静脈内薬物送達製剤。
（項目３３）
前記ヒスチジン緩衝剤が、ヒスチジンおよびヒスチジン塩を含む、項目３０から３２までのいずれか一項に記載の静脈内薬物送達製剤。
（項目３４）
前記ヒスチジンが、Ｌ－ヒスチジンである、項目３３に記載の静脈内薬物送達製剤。
（項目３５）
前記ヒスチジン塩が、ヒスチジンＨＣｌ一水和物である、項目３３または３４に記載の静脈内薬物送達製剤。
（項目３６）
前記ヒスチジン緩衝剤の濃度が、０．１０ｍＭから０．３０ｍＭの間である、項目３０から３５までのいずれか一項に記載の静脈内薬物送達製剤。
（項目３７）
前記ヒスチジン緩衝剤の濃度が、約０．２０ｍＭである、項目３０から３６までのいずれか一項に記載の静脈内薬物送達製剤。
（項目３８）
前記糖または糖アルコールが、二糖である、項目３０から３７までのいずれか一項に記載の静脈内薬物送達製剤。
（項目３９）
前記二糖が、スクロースである、項目３８に記載の静脈内薬物送達製剤。
（項目４０）
前記スクロースの濃度が、１．７０ｍＭから２．７０ｍＭの間である、項目３９に記載の静脈内薬物送達製剤。
（項目４１）
前記スクロースの濃度が、約２．２０ｍＭである、項目４０に記載の静脈内薬物送達製剤。
（項目４２）
前記ポリソルベートが、ポリソルベート２０である、項目３０から４１までのいずれか一項に記載の静脈内薬物送達製剤。
（項目４３）
前記ポリソルベート２０の濃度が、０．００１％（ｖ／ｖ）未満である、項目４２に記載の静脈内薬物送達製剤。
（項目４４）
前記ポリソルベート２０の濃度が、約０．０００４％（ｖ／ｖ）である、項目４３に記載の静脈内薬物送達製剤。
（項目４５）
前記ｐＨが５．３～５．７である、項目３０から４４までのいずれか一項に記載の静脈内薬物送達製剤。
（項目４６）
前記ｐＨが約５．５である、項目３０から４５までのいずれか一項に記載の静脈内薬物送達製剤。
（項目４７）
前記希釈剤中の前記第２の糖が、単糖である、項目３０から４６までのいずれか一項に記載の静脈内薬物送達製剤。
（項目４８）
前記単糖が、ブドウ糖である、項目４７に記載の静脈内薬物送達製剤。
（項目４９）
前記ブドウ糖の濃度が、２．５％（ｖ／ｖ）から７．５％（ｖ／ｖ）の間である、項目４８に記載の静脈内薬物送達製剤。
（項目５０）
前記ブドウ糖の濃度が、約５％（ｖ／ｖ）である、項目４８または４９に記載の静脈内薬物送達製剤。
（項目５１）
前記抗体またはその抗原結合性断片が、配列番号９または２９における相補性決定領域ＨＣＤＲ１、ＨＣＤＲ２、およびＨＣＤＲ３を含む重鎖可変領域（ＶＨ）；ならびに配列番号１９または３９における相補性決定領域ＬＣＤＲ１、ＬＣＤＲ２、ＬＣＤＲ３を含む軽鎖可変領域（ＶＬ）を含む、項目３０から５０までのいずれか一項に記載の静脈内薬物送達製剤。
（項目５２）
前記抗体またはその抗原結合性断片が、
ｉ．配列番号２３の重鎖可変領域ＣＤＲ１；配列番号２４の重鎖可変領域ＣＤＲ２；配列番号２５の重鎖可変領域ＣＤＲ３；配列番号３３の軽鎖可変領域ＣＤＲ１；配列番号３４の軽鎖可変領域ＣＤＲ２；および配列番号３５の軽鎖可変領域ＣＤＲ３；
ｉｉ．配列番号２６の重鎖可変領域ＣＤＲ１；配列番号２７の重鎖可変領域ＣＤＲ２；配列番号２８の重鎖可変領域ＣＤＲ３；配列番号３６の軽鎖可変領域ＣＤＲ１；配列番号３７の軽鎖可変領域ＣＤＲ２；および配列番号３８の軽鎖可変領域ＣＤＲ３；
ｉｉｉ．配列番号４３の重鎖可変領域ＣＤＲ１；配列番号４４の重鎖可変領域ＣＤＲ２；配列番号４５の重鎖可変領域ＣＤＲ３；配列番号４７の軽鎖可変領域ＣＤＲ１；配列番号３７の軽鎖可変領域ＣＤＲ２；および配列番号１５の軽鎖可変領域ＣＤＲ３；または
ｉｖ．配列番号４６の重鎖可変領域ＣＤＲ１；配列番号４の重鎖可変領域ＣＤＲ２；配列番号５の重鎖可変領域ＣＤＲ３；配列番号３３の軽鎖可変領域ＣＤＲ１；配列番号１４の軽鎖可変領域ＣＤＲ２；および配列番号１５の軽鎖可変領域ＣＤＲ３
を含む、項目３０から５１までのいずれか一項に記載の静脈内薬物送達製剤。
（項目５３）
前記抗体またはその抗原結合性断片が、配列番号９、２９からなる群から選択される重鎖可変領域（ＶＨ）、およびそれに対して９０％の同一性を有するＶＨ；ならびに、配列番号１９、３９からなる群から選択される軽鎖可変領域（ＶＬ）、およびそれに対して９０％の同一性を有するＶＬを含む、項目３０から２５までのいずれか一項に記載の静脈内薬物送達製剤。
（項目５４）
前記抗体またはその抗原結合性断片が、配列番号９および２９からなる群から選択される重鎖可変領域（ＶＨ）；ならびに配列番号１９および３９からなる群から選択される軽鎖可変領域（ＶＬ）を含む、項目３０から５３までのいずれか一項に記載の静脈内薬物送達製剤。
（項目５５）
前記抗体が、配列番号３１、１１からなる群から選択されるアミノ酸配列を含む重鎖、およびそれに対して９０％の同一性を有する重鎖；ならびに、配列番号４１、２１からなる群から選択されるアミノ酸配列を含む軽鎖、およびそれに対して９０％の同一性を有する軽鎖を含む、項目３０から５４までのいずれか一項に記載の静脈内薬物送達製剤。
（項目５６）
前記抗体が、配列番号３１のアミノ酸配列を含む重鎖および配列番号４１のアミノ酸配列を含む軽鎖を含む、項目３０から５５までのいずれか一項に記載の静脈内薬物送達製剤。
（項目５７）
前記抗体が、ヒトモノクローナル抗体である、項目３０から５６までのいずれか一項に記載の静脈内薬物送達製剤。
（項目５８）
前記抗体が、ヒトＩｇＧ１アイソタイプである、項目５７に記載の静脈内薬物送達製剤。
（項目５９）
前記抗体が、Ｆｃドメイン内にＤ２６５Ａ置換およびＰ３２９Ａ置換を含み、必要に応じて、１２０ｍｇ～１８０ｍｇが、対象に投与するための前記抗第ＸＩ因子（ＦＸＩ）および／または抗活性化第ＸＩ因子（ＦＸＩａ）抗体またはその抗原結合性断片の前記治療有効量である、項目５７または５８に記載の静脈内薬物送達製剤。
（項目６０）
（ａ）約１．５ｍｇの濃度の、治療有効量の単離された抗ＦＸＩおよび／または抗ＦＸＩａ抗体またはその抗原結合性断片；
（ｂ）約０．２０ｍＭの濃度のヒスチジン緩衝剤；
（ｃ）約２．２０ｍＭの濃度のスクロース；
（ｄ）約０．０００４％（ｖ／ｖ）の濃度のポリソルベート２０、および
（ｅ）希釈剤
を含むｐＨ５．５の静脈内薬物送達製剤であって、
前記希釈剤が、水中５％ブドウ糖（Ｄ５Ｗ）である、静脈内薬物送達製剤。
（項目６１）
血栓塞栓性障害に罹患しているか、またはそれが発生するリスクがある対象を処置する方法であって、項目１から２８までのいずれか一項に記載のバイアル中に存在する前記薬物送達製剤または項目３０から５９までのいずれか一項に記載の静脈内薬物送達製剤を治療有効量でそれを必要とする対象に投与するステップを含む方法。
（項目６２）
前記血栓塞栓性障害が、心房細動または心房粗動、一過性脳虚血発作、虚血性脳卒中、血栓塞栓性脳卒中、出血性卒中、静脈血栓塞栓症（ＶＴＥ）、小児ＶＴＥ、全身性塞栓症、非中枢神経系性塞栓症、心筋梗塞、深部静脈血栓症、重症プロテインＳ欠乏症、脳血管発作、およびがんからなる群から選択される、項目６１に記載の方法。
（項目６３）
前記バイアル中に存在する前記薬物送達製剤または前記静脈内薬物送達製剤を月１回投与する、項目６１または６２に記載の方法。
（項目６４）
前記バイアル中に存在する前記薬物送達製剤または前記静脈内薬物送達製剤を、約３０ｍｇ、約６０ｍｇ、約９０ｍｇ、約１２０ｍｇ、約１５０ｍｇ、および約１８０ｍｇからなる群から選択される用量で投与する、項目６１から６３までのいずれか一項に記載の方法。
（項目６５）
前記バイアル中に存在する前記薬物送達製剤を約１２０ｍｇの用量で投与する、項目６１から６４までのいずれか一項に記載の方法。
（項目６６）
前記バイアル中に存在する前記薬物送達製剤を約１５０ｍｇの用量で投与する、項目６１から６４までのいずれか一項に記載の方法。
（項目６７）
前記バイアル中に存在する前記薬物送達製剤を皮下投与する、項目６１から６６までのいずれか一項に記載の方法。
（項目６８）
前記血栓塞栓性障害が、心房細動または心房粗動である、項目６１から６７までのいずれか一項に記載の方法。
（項目６９）
前記心房細動または心房粗動が、発作性心房細動（ＰＡＦ）である、項目６８に記載の方法。
（項目７０）
前記バイアル中に存在する前記薬物送達製剤を、１カ月に１回、３カ月の期間にわたって投与する、項目６１から６９までのいずれか一項に記載の方法。
（項目７１）
前記対象が、脳卒中のリスクが低い状態である、項目６１から７０までのいずれか一項に記載の方法。
（項目７２）
前記対象のＣＨＡ _２ＤＳ _２ＶＡＳｃリスクスコアが、０～１である、項目７１に記載の方法。
（項目７３）
前記対象が、脳卒中のリスクが中程度の状態である、項目６１から７０までのいずれか一項に記載の方法。
（項目７４）
前記対象が、脳卒中のリスクが高い状態である、項目６１から７０までのいずれか一項に記載の方法。
（項目７５）
前記対象のＣＨＡ _２ＤＳ _２ＶＡＳｃリスクスコアが、男性対象については≧２であり、
女性対象については≧３である、項目７４に記載の方法。
（項目７６）
前記バイアル中に存在する前記薬物送達製剤の有効性を、前記薬物送達製剤の３回目の用量後のトラフ時の第ＸＩ因子の阻害を測定することによって評価するステップをさらに含む、項目６１から７５までのいずれか一項に記載の方法。
（項目７７）
前記バイアル中に存在する前記薬物送達製剤の有効性を、遊離の第ＸＩ因子、総第ＸＩ因子、第ＸＩ因子凝固活性、活性化部分トロンボプラスチン時間、およびＤ－ダイマーからなる一覧から選択される１つまたは複数のバイオマーカーを評価することによって評価するステップをさらに含む、項目６１から７６までのいずれか一項に記載の方法。
（項目７８）
前記バイアル中に存在する前記薬物送達製剤の有害事象を、出血事象または抗薬物抗体の存在を測定することによって評価するステップをさらに含む、項目６１から７７までのいずれか一項に記載の方法。
（項目７９）
出血事象である有害事象が生じている患者に、以下：（ｉ）コロイド、晶質、ヒト血漿もしくはアルブミンなどの血漿タンパク質を使用した補液；（ｉｉ）濃厚赤血球もしくは全血を用いた輸血；または（ｉｉｉ）新鮮凍結血漿（ＦＦＰ）、濃縮プロトロンビン複合体（ＰＣＣ）、活性化ＰＣＣ（ＡＰＣＣ）、例えば、第ＶＩＩＩ因子阻害薬など、および／もしくは組換え活性化第ＶＩＩ因子の投与、のうちの１つまたは複数を適用するステップをさらに含む、項目７８に記載の方法。
（項目８０）
血栓塞栓性障害に罹患しているか、またはそれが発生するリスクがあり、外科手技を受ける対象を処置する方法であって、項目３０から５９までのいずれか一項に記載の静脈内薬物送達製剤をそれを必要とする対象に投与するステップを含み、前記対象に、前記静脈内薬物送達製剤を前記外科手技と同日に投与する、方法。
（項目８１）
前記外科手技が、膝関節置換術、人工股関節置換術、整形外科手術、ペースメーカー設置、カテーテル設置、胸部外科手術、および腹部外科手術からなる群から選択される、項目８０に記載の方法。
（項目８２）
前記静脈内薬物送達製剤を、月１回投与する、項目８０または８１に記載の方法。
（項目８３）
前記静脈内薬物送達製剤を、約３０ｍｇ、約６０ｍｇ、約９０ｍｇ、約１２０ｍｇ、約１５０ｍｇ、および約１８０ｍｇからなる群から選択される用量で投与する、項目８０から８２までのいずれか一項に記載の方法。
（項目８４）
前記静脈内薬物送達製剤を、約３０ｍｇの用量で投与する、項目８０から８３までのいずれか一項に記載の方法。
（項目８５）
前記静脈内薬物送達製剤を、約６０ｍｇの用量で投与する、項目８０から８３までのいずれか一項に記載の方法。
（項目８６）
前記静脈内薬物送達製剤を、約１５０ｍｇの用量で投与する、項目８０から８３までのいずれか一項に記載の方法。
（項目８７）
前記静脈内薬物送達製剤を、約７５ｍｇの用量で投与する、項目８０から８２までのいずれか一項に記載の方法。
（項目８８）
前記静脈内薬物送達製剤を、外科手術のおよそ４～８時間後に投与する、項目８０から８７までのいずれか一項に記載の方法。
（項目８９）
血栓塞栓性障害に罹患しているか、またはそれが発生するリスクがあり、非ステロイド性抗炎症薬（ＮＳＡＩＤ）を受けている対象を処置する方法であって、項目１から２８までのいずれか一項に記載のバイアル中に存在する前記薬物送達製剤または項目３０から５９までのいずれか一項に記載の静脈内薬物送達製剤を治療有効量で、プロトンポンプ阻害薬と組み合わせて、それを必要とする対象に投与するステップを含む、方法。
（項目９０）
前記バイアル中に存在する前記薬物送達製剤または前記静脈内薬物送達製剤を、月１回投与する、項目８９に記載の方法。
（項目９１）
前記バイアル中に存在する前記薬物送達製剤または前記静脈内薬物送達製剤を、約３０ｍｇ、約６０ｍｇ、約９０ｍｇ、約１２０ｍｇ、約１５０ｍｇ、および約１８０ｍｇからなる群から選択される用量で投与する、項目８９または９０に記載の方法。
（項目９２）
前記バイアル中に存在する前記薬物送達製剤または前記静脈内薬物送達製剤を、約７５ｍｇの用量で投与する、項目８８または８９に記載の方法。
（項目９３）
前記バイアル中に存在する前記薬物送達製剤を、皮下投与する、項目８９から９１までのいずれか一項に記載の方法。 Equivalents This disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the embodiments described above are to be considered in all respects as illustrative rather than limiting on the disclosure described herein. Various structural elements of different embodiments and steps of various disclosed methods may be utilized in various combinations and permutations, and all such variations should be considered forms of the present disclosure. be. The scope of the disclosure is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope. shall be taken as a thing.
In certain embodiments, for example, the following is provided:
(Item 1)
(a) a therapeutically effective amount of an isolated anti-factor XI (FXI) and/or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof;
(b) histidine buffer;
(c) a sugar or sugar alcohol; and
(d) Polysorbate
A vial comprising a drug delivery formulation with a pH of 5.0 to 6.0 comprising:
A vial containing an overfill to allow complete withdrawal of the therapeutically effective amount of said anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof.
(Item 2)
Vial according to item 1, wherein said therapeutically effective amount of said isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is at a concentration between 120 mg/ml and 180 mg/ml.
(Item 3)
Vial according to item 1 or 2, wherein the therapeutically effective amount of the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is at a concentration of about 150 mg/ml.
(Item 4)
4. The vial of any one of items 1 to 3, wherein the histidine buffer comprises histidine and histidine salts.
(Item 5)
The vial according to item 4, wherein the histidine is L-histidine.
(Item 6)
The vial according to item 4 or 5, wherein the histidine salt is histidine HCl monohydrate.
(Item 7)
Vial according to any one of items 4 to 6, wherein the concentration of the histidine buffer is between 10 mM and 30 mM.
(Item 8)
8. The vial of item 7, wherein the concentration of the histidine buffer is about 20 mM.
(Item 9)
9. The vial according to any one of items 1 to 8, wherein the sugar or sugar alcohol is a disaccharide.
(Item 10)
The vial according to item 9, wherein the disaccharide is sucrose.
(Item 11)
The vial of item 10, wherein the concentration of sucrose is between 170mM and 270mM.
(Item 12)
12. The vial of item 11, wherein the concentration of sucrose is about 220 mM.
(Item 13)
13. The vial according to any one of items 1 to 12, wherein the polysorbate is polysorbate 20.
(Item 14)
14. The vial of item 13, wherein the concentration of polysorbate 20 is between 0.02% (v/v) and 0.06% (v/v).
(Item 15)
15. The vial of item 14, wherein the concentration of polysorbate 20 is about 0.04% (v/v).
(Item 16)
The vial according to any one of items 1 to 15, wherein the pH is between 5.3 and 5.7.
(Item 17)
17. The vial of any one of items 1 to 16, wherein the pH is about 5.5.
(Item 18)
The overfill comprises between 10% (v/v) and 30% (v/v) of the drug delivery formulation, and optionally the vial contains between 1.1 mL and 30% (v/v) of the drug delivery formulation. The vial according to any one of items 1 to 17, containing 1.3 mL.
(Item 19)
19. The vial of item 18, wherein the overfill constitutes about 20% (v/v) of the drug delivery formulation, and optionally the vial contains about 1.2 mL of the drug delivery formulation.
(Item 20)
The antibody or antigen-binding fragment thereof has a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and complementarity determining regions LCDR1, LCDR2 in SEQ ID NO: 19 or 39. 20. The vial of any one of items 1 to 19, comprising a light chain variable region (VL) comprising , LCDR3.
(Item 21)
The antibody or antigen-binding fragment thereof is
i. Heavy chain variable region CDR1 of SEQ ID NO: 23; heavy chain variable region CDR2 of SEQ ID NO: 24; heavy chain variable region CDR3 of SEQ ID NO: 25; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 34; and light chain variable region CDR3 of SEQ ID NO: 35;
ii. Heavy chain variable region CDR1 of SEQ ID NO: 26; heavy chain variable region CDR2 of SEQ ID NO: 27; heavy chain variable region CDR3 of SEQ ID NO: 28; light chain variable region CDR1 of SEQ ID NO: 36; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 38;
iii. Heavy chain variable region CDR1 of SEQ ID NO: 43; heavy chain variable region CDR2 of SEQ ID NO: 44; heavy chain variable region CDR3 of SEQ ID NO: 45; light chain variable region CDR1 of SEQ ID NO: 47; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 15; or
iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15.
21. The vial according to any one of items 1 to 20, comprising:
(Item 22)
The antibody or antigen-binding fragment thereof has a heavy chain variable region (VH) selected from the group consisting of SEQ ID NO: 9, 29, and a VH having 90% identity thereto; and SEQ ID NO: 19, 39. 22. The vial of any one of items 1 to 21, comprising a light chain variable region (VL) selected from the group consisting of: and a VL having 90% identity thereto.
(Item 23)
The antibody or antigen-binding fragment thereof has a heavy chain variable region (VH) selected from the group consisting of SEQ ID NO: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NO: 19 and 39. 23. The vial according to any one of items 1 to 22, comprising:
(Item 24)
The antibody has a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 11, and a heavy chain having 90% identity thereto; and a heavy chain selected from the group consisting of SEQ ID NO: 41, 21. 24. A vial according to any one of items 1 to 23, comprising a light chain comprising an amino acid sequence of 90% identity thereto.
(Item 25)
25. The vial of any one of items 1 to 24, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 41.
(Item 26)
26. The vial according to any one of items 1 to 25, wherein the antibody is a human monoclonal antibody.
(Item 27)
27. The vial of item 26, wherein the antibody is of the human IgG1 isotype.
(Item 28)
The antibody comprises a D265A substitution and a P329A substitution in the Fc domain, and optionally 120 mg to 180 mg of the anti-factor XI (FXI) and/or anti-activated factor XI ( FXIa) Vial according to item 26 or 27, said therapeutically effective amount of antibody or antigen-binding fragment thereof.
(Item 29)
(a) a therapeutically effective amount of an isolated anti-factor XI (FXI) and/or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof at a concentration of about 150 mg;
(b) histidine buffer at a concentration of about 20 mM;
(c) sucrose at a concentration of about 220 mM; and
(d) Polysorbate 20 at a concentration of about 0.04% (v/v)
A vial containing a drug delivery formulation at pH 5.5 comprising:
A vial containing an overfill to allow complete withdrawal of the therapeutically effective amount of said anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof.
(Item 30)
(a) a therapeutically effective amount of an isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof;
(b) histidine buffer;
(c) sugar or sugar alcohol;
(d) polysorbate, and
(e) Diluent
An intravenous drug delivery formulation with a pH of 5.0 to 6.0, comprising:
the diluent is a solution containing a second sugar and water;
Intravenous drug delivery formulations.
(Item 31)
Intravenous according to item 30, wherein the concentration of the therapeutically effective amount of the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is between 1.20 mg/ml and 1.80 mg/ml. Internal drug delivery formulation.
(Item 32)
32. The intravenous drug delivery formulation of item 30 or 31, wherein the concentration of the therapeutically effective amount of the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is about 1.50 mg/ml.
(Item 33)
33. The intravenous drug delivery formulation of any one of items 30-32, wherein the histidine buffer comprises histidine and a histidine salt.
(Item 34)
34. The intravenous drug delivery formulation according to item 33, wherein the histidine is L-histidine.
(Item 35)
35. The intravenous drug delivery formulation according to item 33 or 34, wherein the histidine salt is histidine HCl monohydrate.
(Item 36)
36. The intravenous drug delivery formulation according to any one of items 30 to 35, wherein the concentration of the histidine buffer is between 0.10 mM and 0.30 mM.
(Item 37)
37. The intravenous drug delivery formulation of any one of items 30-36, wherein the concentration of the histidine buffer is about 0.20 mM.
(Item 38)
38. The intravenous drug delivery formulation according to any one of items 30 to 37, wherein the sugar or sugar alcohol is a disaccharide.
(Item 39)
39. The intravenous drug delivery formulation of item 38, wherein the disaccharide is sucrose.
(Item 40)
40. The intravenous drug delivery formulation of item 39, wherein the concentration of sucrose is between 1.70mM and 2.70mM.
(Item 41)
41. The intravenous drug delivery formulation of item 40, wherein the concentration of sucrose is about 2.20 mM.
(Item 42)
42. The intravenous drug delivery formulation according to any one of items 30 to 41, wherein the polysorbate is polysorbate 20.
(Item 43)
43. The intravenous drug delivery formulation of item 42, wherein the concentration of polysorbate 20 is less than 0.001% (v/v).
(Item 44)
44. The intravenous drug delivery formulation of item 43, wherein the concentration of polysorbate 20 is about 0.0004% (v/v).
(Item 45)
45. The intravenous drug delivery formulation according to any one of items 30 to 44, wherein the pH is between 5.3 and 5.7.
(Item 46)
46. The intravenous drug delivery formulation according to any one of items 30 to 45, wherein the pH is about 5.5.
(Item 47)
47. The intravenous drug delivery formulation of any one of items 30-46, wherein the second sugar in the diluent is a monosaccharide.
(Item 48)
48. The intravenous drug delivery formulation according to item 47, wherein the monosaccharide is glucose.
(Item 49)
49. The intravenous drug delivery formulation of item 48, wherein the concentration of glucose is between 2.5% (v/v) and 7.5% (v/v).
(Item 50)
50. The intravenous drug delivery formulation of item 48 or 49, wherein the concentration of glucose is about 5% (v/v).
(Item 51)
The antibody or antigen-binding fragment thereof has a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and complementarity determining regions LCDR1, LCDR2 in SEQ ID NO: 19 or 39. 51. The intravenous drug delivery formulation of any one of items 30 to 50, comprising a light chain variable region (VL) comprising , LCDR3.
(Item 52)
The antibody or antigen-binding fragment thereof is
i. Heavy chain variable region CDR1 of SEQ ID NO: 23; heavy chain variable region CDR2 of SEQ ID NO: 24; heavy chain variable region CDR3 of SEQ ID NO: 25; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 34; and light chain variable region CDR3 of SEQ ID NO: 35;
ii. Heavy chain variable region CDR1 of SEQ ID NO: 26; heavy chain variable region CDR2 of SEQ ID NO: 27; heavy chain variable region CDR3 of SEQ ID NO: 28; light chain variable region CDR1 of SEQ ID NO: 36; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 38;
iii. Heavy chain variable region CDR1 of SEQ ID NO: 43; heavy chain variable region CDR2 of SEQ ID NO: 44; heavy chain variable region CDR3 of SEQ ID NO: 45; light chain variable region CDR1 of SEQ ID NO: 47; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 15; or
iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15.
52. The intravenous drug delivery formulation according to any one of items 30 to 51, comprising:
(Item 53)
The antibody or antigen-binding fragment thereof has a heavy chain variable region (VH) selected from the group consisting of SEQ ID NO: 9, 29, and a VH having 90% identity thereto; and SEQ ID NO: 19, 39. 26. The intravenous drug delivery formulation of any one of items 30 to 25, comprising a light chain variable region (VL) selected from the group consisting of:
(Item 54)
The antibody or antigen-binding fragment thereof has a heavy chain variable region (VH) selected from the group consisting of SEQ ID NO: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NO: 19 and 39. 54. The intravenous drug delivery formulation according to any one of items 30 to 53, comprising:
(Item 55)
The antibody has a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 11, and a heavy chain having 90% identity thereto; and a heavy chain selected from the group consisting of SEQ ID NO: 41, 21. 55. An intravenous drug delivery formulation according to any one of items 30 to 54, comprising a light chain comprising an amino acid sequence of 90% identity thereto.
(Item 56)
56. The intravenous drug delivery formulation of any one of items 30-55, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 41.
(Item 57)
57. The intravenous drug delivery formulation of any one of items 30 to 56, wherein the antibody is a human monoclonal antibody.
(Item 58)
58. The intravenous drug delivery formulation of item 57, wherein the antibody is of the human IgG1 isotype.
(Item 59)
The antibody comprises a D265A substitution and a P329A substitution in the Fc domain, and optionally 120 mg to 180 mg of the anti-factor XI (FXI) and/or anti-activated factor XI ( FXIa) Intravenous drug delivery formulation according to item 57 or 58, wherein said therapeutically effective amount of an antibody or antigen-binding fragment thereof.
(Item 60)
(a) a therapeutically effective amount of an isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof at a concentration of about 1.5 mg;
(b) histidine buffer at a concentration of about 0.20 mM;
(c) sucrose at a concentration of about 2.20 mM;
(d) polysorbate 20 at a concentration of about 0.0004% (v/v), and
(e) Diluent
A pH 5.5 intravenous drug delivery formulation comprising:
An intravenous drug delivery formulation, wherein the diluent is 5% dextrose in water (D5W).
(Item 61)
29. A method of treating a subject suffering from or at risk of developing a thromboembolic disorder, the drug delivery formulation being present in a vial according to any one of items 1 to 28 or 60. A method comprising administering a therapeutically effective amount of an intravenous drug delivery formulation according to any one of items 30 to 59 to a subject in need thereof.
(Item 62)
The thromboembolic disorder is atrial fibrillation or atrial flutter, transient ischemic attack, ischemic stroke, thromboembolic stroke, hemorrhagic stroke, venous thromboembolism (VTE), pediatric VTE, systemic embolism. 62. The method of item 61, wherein the method is selected from the group consisting of: disease, non-central nervous system embolism, myocardial infarction, deep vein thrombosis, severe protein S deficiency, cerebrovascular accident, and cancer.
(Item 63)
63. The method of item 61 or 62, wherein the drug delivery formulation or the intravenous drug delivery formulation present in the vial is administered once a month.
(Item 64)
administering the drug delivery formulation or the intravenous drug delivery formulation present in the vial at a dose selected from the group consisting of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, and about 180 mg. 64. The method according to any one of 61 to 63.
(Item 65)
65. The method of any one of items 61-64, wherein the drug delivery formulation present in the vial is administered at a dose of about 120 mg.
(Item 66)
65. The method of any one of items 61-64, wherein the drug delivery formulation present in the vial is administered at a dose of about 150 mg.
(Item 67)
67. The method of any one of items 61-66, wherein the drug delivery formulation present in the vial is administered subcutaneously.
(Item 68)
68. The method of any one of items 61 to 67, wherein the thromboembolic disorder is atrial fibrillation or atrial flutter.
(Item 69)
69. The method of item 68, wherein the atrial fibrillation or atrial flutter is paroxysmal atrial fibrillation (PAF).
(Item 70)
70. The method of any one of items 61 to 69, wherein the drug delivery formulation present in the vial is administered once a month for a period of three months.
(Item 71)
71. The method of any one of items 61-70, wherein the subject is at low risk of stroke.
(Item 72)
72. The method of item 71, wherein the subject has a CHA ₂ DS ₂ VASc risk score of 0-1.
(Item 73)
71. The method according to any one of items 61 to 70, wherein the subject is at intermediate risk of stroke.
(Item 74)
71. The method of any one of items 61-70, wherein the subject is at high risk for stroke.
(Item 75)
the subject's CHA ₂ DS ₂ VASc risk score is ≧2 for male subjects;
The method according to item 74, wherein for female subjects ≧3.
(Item 76)
Items 61-75, further comprising evaluating the effectiveness of the drug delivery formulation present in the vial by measuring inhibition of Factor XI during the trough after a third dose of the drug delivery formulation. The method described in any one of the preceding paragraphs.
(Item 77)
The efficacy of the drug delivery formulation present in the vial is determined by one selected from the list consisting of free factor XI, total factor XI, factor XI clotting activity, activated partial thromboplastin time, and D-dimer. 77. The method of any one of items 61 to 76, further comprising evaluating by evaluating one or more biomarkers.
(Item 78)
78. The method of any one of items 61-77, further comprising assessing adverse events of the drug delivery formulation present in the vial by measuring bleeding events or the presence of anti-drug antibodies.
(Item 79)
Patients experiencing an adverse event that is a bleeding event are given: (i) fluid replacement using colloids, crystalloids, human plasma, or plasma proteins such as albumin; (ii) transfusion using packed red blood cells or whole blood; or (iii) administration of fresh frozen plasma (FFP), concentrated prothrombin complex (PCC), activated PCC (APCC), such as a factor VIII inhibitor, and/or recombinant activated factor VII; 79. The method of item 78, further comprising applying one or more.
(Item 80)
59. A method of treating a subject suffering from or at risk of developing a thromboembolic disorder undergoing a surgical procedure, the intravenous drug delivery formulation according to any one of items 30 to 59. administering to a subject in need thereof the intravenous drug delivery formulation on the same day as the surgical procedure.
(Item 81)
81. The method of item 80, wherein the surgical procedure is selected from the group consisting of knee replacement, hip replacement, orthopedic surgery, pacemaker placement, catheter placement, thoracic surgery, and abdominal surgery.
(Item 82)
82. The method of item 80 or 81, wherein the intravenous drug delivery formulation is administered once a month.
(Item 83)
83, wherein the intravenous drug delivery formulation is administered at a dose selected from the group consisting of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, and about 180 mg. the method of.
(Item 84)
84. The method of any one of items 80-83, wherein the intravenous drug delivery formulation is administered at a dose of about 30 mg.
(Item 85)
84. The method of any one of items 80-83, wherein the intravenous drug delivery formulation is administered at a dose of about 60 mg.
(Item 86)
84. The method of any one of items 80-83, wherein the intravenous drug delivery formulation is administered at a dose of about 150 mg.
(Item 87)
83. The method of any one of items 80-82, wherein the intravenous drug delivery formulation is administered at a dose of about 75 mg.
(Item 88)
88. The method of any one of items 80-87, wherein the intravenous drug delivery formulation is administered approximately 4-8 hours after surgery.
(Item 89)
A method of treating a subject suffering from or at risk of developing a thromboembolic disorder and receiving nonsteroidal anti-inflammatory drugs (NSAIDs), the method comprising: in combination with a proton pump inhibitor in a therapeutically effective amount of said drug delivery formulation present in a vial as described in paragraph 30 or intravenous drug delivery formulation as described in any one of paragraphs 30 to 59, in combination with a proton pump inhibitor, A method comprising the step of administering to a subject.
(Item 90)
90. The method of item 89, wherein the drug delivery formulation or the intravenous drug delivery formulation present in the vial is administered once a month.
(Item 91)
administering the drug delivery formulation or the intravenous drug delivery formulation present in the vial at a dose selected from the group consisting of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, and about 180 mg. 89 or 90.
(Item 92)
90. The method of item 88 or 89, wherein the drug delivery formulation or the intravenous drug delivery formulation present in the vial is administered at a dose of about 75 mg.
(Item 93)
92. The method of any one of items 89-91, wherein the drug delivery formulation present in the vial is administered subcutaneously.

Claims

(a) a therapeutically effective amount of an isolated anti-factor XI (FXI) and/or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof;
(b) histidine buffer;
(c) a sugar or sugar alcohol; and
(d) Polysorbate
A vial containing a formulation with a pH of 5.0 to 6.0 comprising:
A vial containing an overfill to allow complete withdrawal of the therapeutically effective amount of said anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof.

(a) the concentration of said isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is (i) between 120 mg/mL and 180 mg/mL, and/or (ii) about 150 mg/mL; be;
(b) the histidine buffer comprises histidine and histidine salt;
(c) the sugar or sugar alcohol is a disaccharide;
(d) the polysorbate is polysorbate 20;
(e) the pH is (i) 5.3 to 5.7 and/or (ii) about 5.5;
(f) said overfill constitutes between 10% (v/v) and 30% (v/v) of said formulation;
(g) a heavy chain variable region (VH) in which the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof comprises the complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and a light chain variable region (VL) comprising the complementarity determining regions LCDR1, LCDR2, LCDR3 in SEQ ID NO: 19 or 39;
(h) the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof,
i. Heavy chain variable region CDR1 of SEQ ID NO: 23; heavy chain variable region CDR2 of SEQ ID NO: 24; heavy chain variable region CDR3 of SEQ ID NO: 25; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 34; and light chain variable region CDR3 of SEQ ID NO: 35;
ii. Heavy chain variable region CDR1 of SEQ ID NO: 26; heavy chain variable region CDR2 of SEQ ID NO: 27; heavy chain variable region CDR3 of SEQ ID NO: 28; light chain variable region CDR1 of SEQ ID NO: 36; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 38;
iii. Heavy chain variable region CDR1 of SEQ ID NO: 43; heavy chain variable region CDR2 of SEQ ID NO: 44; heavy chain variable region CDR3 of SEQ ID NO: 45; light chain variable region CDR1 of SEQ ID NO: 47; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 15; or
iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15.
including;
(i) the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof has a VH selected from the group consisting of SEQ ID NOs: 9 and 29, and a VH having 90% identity thereto; and a VL selected from the group consisting of SEQ ID NO: 19, 39, and a VL having 90% identity thereto;
(j) said isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is a VH selected from the group consisting of SEQ ID NO: 9 and 29; and a VH selected from the group consisting of SEQ ID NO: 19 and 39; Contains VL;
(k) the isolated anti-FXI and/or anti-FXIa antibody has a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31 and 11, and a heavy chain having 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21, and having 90% identity thereto;
(l) said isolated anti-FXI and/or anti-FXIa antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 41;
(m) said isolated anti-FXI and/or anti-FXIa antibody is a human monoclonal antibody; and/or
(n) The vial according to claim 1, wherein the vial is a syringe.

(a) the histidine is L-histidine;
(b) the histidine salt is histidine HCl monohydrate;
(c) the concentration of said histidine buffer is (i) between 10mM and 30mM, or (ii) about 20mM;
(d) the disaccharide is sucrose;
(e) the concentration of polysorbate 20 is (i) between 0.02% (v/v) and 0.06% (v/v), and/or (ii) about 0.04% (v/v). ) is;
(f) said vial contains 1.1 mL to 1.3 mL of said formulation;
(g) said overfill constitutes about 20% (v/v) of said formulation;
(h) the antibody is of the human IgG1 isotype;
(i) said antibody comprises a D265A substitution and a P329A substitution within the Fc domain; and/or
(j) The vial of claim 2, wherein the vial is a prefilled syringe.

(a) the concentration of sucrose is (i) between 170mM and 270mM and/or (ii) about 220mM;
(b) said vial contains about 1.2 mL of said formulation; and/or
4. The vial of claim 3, wherein (c) 120 mg to 180 mg is the therapeutically effective amount of the anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof.

(a) a therapeutically effective amount of an isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof at a concentration of about 150 mg;
(b) histidine buffer at a concentration of about 20 mM;
(c) sucrose at a concentration of about 220 mM; and
(d) Polysorbate 20 at a concentration of about 0.04% (v/v)
A vial containing a pH 5.5 formulation comprising:
A vial containing an overfill to allow complete withdrawal of the therapeutically effective amount of said anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof.

6. The vial of claim 5, wherein the vial is a syringe.

7. The vial of claim 6, wherein the syringe is a prefilled syringe.

(a) a therapeutically effective amount of an isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof;
(b) histidine buffer;
(c) sugar or sugar alcohol;
(d) polysorbate, and
(e) a diluent solution containing a second sugar and water;
An intravenous formulation with a pH of 5.0 to 6.0 containing.

(a) the concentration of said isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is between 1.20 mg/mL and 1.80 mg/mL;
(b) the concentration of the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is about 1.50 mg/mL;
(c) the histidine buffer comprises histidine and histidine salt;
(d) the concentration of said histidine buffer is between 0.10mM and 0.30mM;
(e) the concentration of the histidine buffer is about 0.20 mM;
(f) the sugar or sugar alcohol is a disaccharide;
(g) the polysorbate is polysorbate 20;
(h) the pH is (i) 5.3 to 5.7 and/or (ii) about 5.5;
(i) the second sugar in the diluent is a monosaccharide;
(j) a VH in which the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof comprises the complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and SEQ ID NO: 19 or 39; Contains VL including complementarity determining regions LCDR1, LCDR2, and LCDR3;
(k) the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof,
i. Heavy chain variable region CDR1 of SEQ ID NO: 23; heavy chain variable region CDR2 of SEQ ID NO: 24; heavy chain variable region CDR3 of SEQ ID NO: 25; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 34; and light chain variable region CDR3 of SEQ ID NO: 35;
ii. Heavy chain variable region CDR1 of SEQ ID NO: 26; heavy chain variable region CDR2 of SEQ ID NO: 27; heavy chain variable region CDR3 of SEQ ID NO: 28; light chain variable region CDR1 of SEQ ID NO: 36; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 38;
iii. Heavy chain variable region CDR1 of SEQ ID NO: 43; heavy chain variable region CDR2 of SEQ ID NO: 44; heavy chain variable region CDR3 of SEQ ID NO: 45; light chain variable region CDR1 of SEQ ID NO: 47; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region CDR3 of SEQ ID NO: 15; or
iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15.
including;
(l) the isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof has a VH selected from the group consisting of SEQ ID NOs: 9 and 29, and a VH having 90% identity thereto; and a VL selected from the group consisting of SEQ ID NO: 19, 39, and a VL having 90% identity thereto;
(m) said isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is a VH selected from the group consisting of SEQ ID NO: 9 and 29; and a VH selected from the group consisting of SEQ ID NO: 19 and 39; Contains VL;
(n) the isolated anti-FXI and/or anti-FXIa antibody has a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31 and 11, and a heavy chain having 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21, and having 90% identity thereto;
(o) said isolated anti-FXI and/or anti-FXIa antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 41; and/or
9. The intravenous formulation of claim 8, wherein (p) the isolated anti-FXI and/or anti-FXIa antibody is a human monoclonal antibody.

(a) the histidine is L-histidine;
(b) the histidine salt is histidine HCl monohydrate;
(c) the disaccharide is sucrose;
(d) the concentration of polysorbate 20 is (i) less than 0.001% (v/v) and/or about 0.0004% (v/v);
(e) the monosaccharide is glucose;
(f) said antibody is of the human IgG1 isotype; and/or
(g) The intravenous formulation of claim 9, wherein the antibody comprises a D265A substitution and a P329A substitution within the Fc domain.

(a) the concentration of sucrose is (i) between and/or about 2.20 mM;
(b) the concentration of said glucose is (i) between 2.5% (v/v) and 7.5% (v/v) and/or (ii) about 5% (v/v);
11. The intravenous formulation of claim 10, wherein (c) 120 mg to 180 mg is the therapeutically effective amount of the anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof.

(a) said therapeutically effective amount of isolated anti-FXI and/or anti-FXIa antibody or antigen-binding fragment thereof is at a concentration of about 1.5 mg;
(b) the concentration of the histidine buffer is about 0.20 mM;
(c) the concentration of sucrose is about 2.20mM;
(d) the concentration of the polysorbate 20 is about 0.0004% (v/v), and
12. The intravenous formulation of claim 10 or 11, wherein (e) the diluent is 5% dextrose in water (D5W) at pH 5.5.

The formulation present in a vial according to any one of claims 1 to 7 or claim 8 for the treatment of a subject suffering from or at risk of developing a thromboembolic disorder. 13. A composition comprising an intravenous formulation according to any one of claims 1 to 12.

(a) the subject is (i) severely obese and/or (ii) has a body mass index ≧35 kg/m ^２2 is; and/or
14. The composition of claim 13, wherein (b) the subject's body weight is between about 50 kg and about 130 kg.

The thromboembolic disorder is
(a) atrial fibrillation or atrial flutter;
(b) transient ischemic attack,
(c) ischemic stroke;
(d) thromboembolic stroke;
(e) hemorrhagic stroke;
(f) venous thromboembolism (VTE);
(g) Pediatric VTE;
(h) systemic embolism;
(i) non-central nervous system embolism;
(j) myocardial infarction;
(k) deep vein thrombosis;
(l) severe protein S deficiency;
(m) cerebrovascular accident, and
(n) cancer
15. The composition according to claim 13 or 14, selected from the group consisting of.

(a) the composition is
(i) Once a month;
(ii) once a month for a period of three months;
(iii) at a dose of about 1 mg to about 600 mg;
(iv) at a dose of about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, or about 90 mg to about 160 mg;
(v) at a dose selected from the group consisting of about 30 mg, about 40 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg and about 240 mg;
(vi) at a dose of about 120 mg;
(vii) at a dose of about 150 mg;
(viii) at a dose of about 180 mg;
(ix) subcutaneously or intravenously;
(x) subcutaneously, once a month at a dose of about 120 mg for a period of three months; and/or
(xi) at a dose of about 180 mg subcutaneously once a month for a period of three months;
characterized by being administered;
(b) said thromboembolic disorder is atrial fibrillation or atrial flutter; and/or
(c) The composition of any one of claims 13 to 15, wherein the subject is at low, intermediate, or high risk for stroke.

(a) the atrial fibrillation or atrial flutter is paroxysmal atrial fibrillation (PAF);
(b) CHA of said target _２2 DS _２2 VASc risk score is between 0 and 1; and/or
(c) CHA of said target _２2 DS _２2 the VASc risk score is 0-1 for male subjects and 1-2 for female subjects; and/or
(d) CHA of said target _２2 DS _２2 17. The composition of claim 16, wherein the VASc risk score is ≧2 for male subjects and ≧3 for female subjects.

13. Intravenous formulation according to any one of claims 8 to 12 for the treatment of a subject suffering from or at risk of developing a thromboembolic disorder and undergoing a surgical procedure. , wherein the intravenous formulation is administered to the subject on the same day as the surgical procedure.

(a) the surgical procedure is
(i) knee joint replacement;
(ii) total hip replacement;
(iii) orthopedic surgery;
(iv) pacemaker installation;
(v) catheter placement;
(vi) thoracic surgery, and
(vii) Abdominal surgery
selected from the group consisting of and/or
(b) the intravenous formulation comprises:
(i) once a month;
(ii) once a month for a period of three months;
(iii) at a dose of about 1 mg to about 600 mg;
(iv) at a dose of about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, or about 90 mg to about 160 mg;
(v) at a dose selected from the group consisting of about 30 mg, about 40 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg and about 240 mg;
(vi) at a dose of about 120 mg;
(vii) at a dose of about 150 mg;
(viii) at a dose of about 180 mg;
(ix) subcutaneously or intravenously;
(x) subcutaneously, once a month at a dose of about 120 mg over a period of 3 months;
(xi) subcutaneously, once a month at a dose of about 180 mg over a period of three months; and/or
(xii) Approximately 4 to 8 hours after surgery
19. A formulation according to claim 18, characterized in that it is administered.

(a) the knee joint replacement surgery is a unilateral knee joint replacement surgery;
(b) the subject is (i) severely obese and/or (ii) has a body mass index ≧35 kg/m ^２2 is; and/or
20. The formulation of claim 19, wherein (c) the subject's body weight is between about 50 kg and about 130 kg.

Any one of claims 1 to 7 for treating a subject suffering from or at risk of developing a thromboembolic disorder and receiving non-steroidal anti-inflammatory drugs (NSAIDs). 13. A composition comprising said formulation present in a vial as described in 1. or an intravenous formulation as claimed in any one of claims 8 to 12 in combination with a proton pump inhibitor.

The composition is
(a) Once a month;
(b) once a month for a period of three months;
(c) at a dose of about 1 mg to about 600 mg;
(d) at a dose of about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, or about 90 mg to about 160 mg;
(e) at a dose selected from the group consisting of about 30 mg, about 40 mg, about 60 mg, about 75 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg and about 240 mg;
(f) at a dose of about 120 mg;
(g) at a dose of about 150 mg;
(h) at a dose of about 180 mg;
(i) subcutaneously or intravenously;
(p) subcutaneously, once a month at a dose of about 120 mg for a period of three months; and/or
(q) subcutaneously once a month at a dose of about 180 mg for a period of 3 months;
Composition according to claim 21, characterized in that it is administered.

A composition comprising said formulation present in a vial according to any one of claims 1 to 7 or an intravenous formulation according to any one of claims 8 to 12 for use in therapy. .