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- JPWO2020154293A5 JPWO2020154293A5 JP2021542443A JP2021542443A JPWO2020154293A5 JP WO2020154293 A5 JPWO2020154293 A5 JP WO2020154293A5 JP 2021542443 A JP2021542443 A JP 2021542443A JP 2021542443 A JP2021542443 A JP 2021542443A JP WO2020154293 A5 JPWO2020154293 A5 JP WO2020154293A5
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上に引用される参考文献ならびに本明細書で引用される参考文献はすべて、それらの全体が参照によって本明細書に組み込まれる。
以下に、出願時の特許請求の範囲の記載を示す。
［請求項１］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖ＣＤＲ１、重鎖ＣＤＲ２、及び重鎖ＣＤＲ３と、軽鎖ＣＤＲ１、軽鎖ＣＤＲ２、及び軽鎖ＣＤＲ３と、を含み、前記抗体が、
（ａ）約５ｎＭ以下（例えば、約３ｎＭ未満）のＥＣ５０で全血中のＴ細胞（ＣＤ４＋ＣＤ４５ＲＡ＋、ＣＤ４＋ＣＤ４５ＲＡ－、ＣＤ８＋ＣＤ４５ＲＡ＋、及び／またはＣＤ８＋ＣＤ４５ＲＡ－）に結合する能力を有するか、
（ｂ）全血中の非Ｔ細胞に結合する能力を有さないか、
（ｃ）胸腺間質性リンパ球新生因子（ＴＳＬＰ）介在性の単球活性化を効果的に遮断する能力を有さないか、
（ｄ）前記ＩＬ－７受容体への結合時にＩＬ－７受容体シグナル伝達をアゴナイズしない（例えば、ｐＳＴＡＴ５活性化が最小限に留まる）か、あるいは
（ｅ）それらが任意に組み合わさったものである、前記抗体またはその抗原結合部分。
［請求項２］
前記重鎖ＣＤＲ３が、配列番号１５に示されるアミノ酸配列（ＤＥＹＳＲＧＹＹＶＬＤＶ）を含む、請求項１に記載の抗体。
［請求項３］
前記抗体が、
（ａ）ヒト及びカニクイザルＩＬ－７受容体（ＩＬ－７Ｒ）のアルファ鎖に選択的に結合する能力を有すること、
（ｂ）可溶性及び膜結合型のＩＬ－７Ｒのアルファ鎖に結合する能力を有すること、
（ｃ）病原性Ｔ細胞の増殖及び／または生存の遮断を必要とする対象に投与されると、前記遮断を行う能力を有すること、
（ｄ）制御性Ｔ細胞（Ｔｒｅｇ）機能の回復及び／またはＴｒｅｇ生存の促進を必要とする対象に投与されると、前記回復及び／または前記促進を行う能力を有すること、
（ｅ）ＣＴＬＡ４－Ｉｇ（ＯＲＥＮＣＩＡ（登録商標））によるものと比較して薬剤フリー寛解を長く維持する能力を有すること、
（ｆ）炎症及び粘膜損傷（例えば、病原性Ｔ細胞によって誘導されるもの）の遮断を必要とする対象の腸組織内で前記遮断を行う能力を有すること、
（ｇ）腸間膜リンパ節（ＭＬＮ）及び／または粘膜固有層（ＬＰ）におけるエフェクターＴ細胞の頻度の低減を必要する対象において前記低減を行う能力を有すること、
（ｈ）Ｔ細胞（例えば、ＣＤ４＋ＣＤ４５ＲＡ＋）のＩＬ－７介在性のｐＳＴＡＴ活性化を低減または阻害する能力を有すること、
（ｉ）ＩＬ－１７及び／またはＩＦＮ－ガンマを産生する細胞の増殖を遮断する能力を有すること、
（ｊ）炎症性疾患（例えば、炎症性腸疾患）を有する対象を治療する能力を有すること、ならびに
（ｋ）それらのいずれかの組み合わせ、
からなる群から選択される１つ以上の特性を有する、請求項１または請求項２に記載の抗体。
［請求項４］
前記重鎖ＣＤＲ１が、配列番号１３に示されるアミノ酸配列（ＤＨＡＭＨ）を含む、請求項１～３のいずれか１項に記載の抗体。
［請求項５］
前記重鎖ＣＤＲ２が、配列番号１４に示されるアミノ酸配列（ＧＩＳＷＮＳＲＧＩＧＹＡＤＳＶＫＧ）を含む、請求項１～４のいずれか１項に記載の抗体。
［請求項６］
前記軽鎖ＣＤＲ１が、配列番号１６に示されるアミノ酸配列（ＲＡＳＱＧＩＳＳＡＬＡ）を含む、請求項１～５のいずれか１項に記載の抗体。
［請求項７］
前記軽鎖ＣＤＲ２が、配列番号１７に示されるアミノ酸配列（ＤＡＳＳＬＥＳ）を含む、請求項１～６のいずれか１項に記載の抗体。
［請求項８］
前記軽鎖ＣＤＲ３が、配列番号１８に示されるアミノ酸配列（ＱＱＦＮＳＹＰＬＷＩＴ）を含む、請求項１～７のいずれか１項に記載の抗体。
［請求項９］
前記抗体が、重鎖可変領域（ＶＨ）及び軽鎖可変領域（ＶＬ）を含み、前記ＶＨが、配列番号１９に示されるアミノ酸配列との同一性が少なくとも約８０％、少なくとも約８５％、少なくとも約９０％、少なくとも約９５％、少なくとも約９６％、少なくとも約９７％、少なくとも約９８％、少なくとも約９９％、または約１００％であるアミノ酸配列を含む、請求項１～８のいずれか１項に記載の抗体。
［請求項１０］
前記ＶＬが、配列番号２０に示されるアミノ酸配列との同一性が少なくとも約８０％、少なくとも約８５％、少なくとも約９０％、少なくとも約９５％、少なくとも約９６％、少なくとも約９７％、少なくとも約９８％、少なくとも約９９％、または約１００％であるアミノ酸配列を含む、請求項１～８のいずれか１項に記載の抗体。
［請求項１１］
２４ＳＱＬＥＶＮＧＳＱＨＳＬＴＣＡＦ３９（配列番号８）、７３ＦＩＥＴＫＫＦＬＬＩＧＫＳＮＩＣ８８（配列番号９）、８９ＶＫＶＧＥＫＳＬＴＣＫＫＩＤＬＴＴ１０５（配列番号１０）、１３６ＱＫＫＹＶＫＶＬＭＨＤＶＡＹ１４９（配列番号１１）、１８１ＹＥＩＫＶＲＳＩＰＤＨＹＦＫＧＦ１９６（配列番号１２）、及びそれらの組み合わせ、からなる群から選択されるエピトープの位置で前記ヒトＩＬ－７受容体の前記アルファ鎖に特異的に結合する、請求項１～１０のいずれか１項に記載の抗体。
［請求項１２］
Ｈ３３、Ｅ７５、Ｆ７９、Ｉ８２、Ｋ８４、Ｍ１４４、Ｒ１８６、Ｈ１９１、Ｙ１９２、及びそれらの組み合わせ、からなる群から選択される１つ以上のアミノ酸残基を含むエピトープの位置で前記ヒトＩＬ－７受容体の前記アルファ鎖に特異的に結合する、請求項１～１１のいずれか１項に記載の抗体。
［請求項１３］
前記抗体が、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、ＩｇＧ４、及びそのバリアントからなる群から選択される、請求項１～１２のいずれか１項に記載の抗体。
［請求項１４］
前記抗体が、ＩｇＧ１抗体である、請求項１３に記載の抗体。
［請求項１５］
エフェクター機能を有さないＩｇＧ１ Ｆｃを含む、請求項１４に記載の抗体。
［請求項１６］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖及び軽鎖を含み、前記重鎖が、配列番号２１に示されるアミノ酸配列を含み、前記軽鎖が、配列番号２２に示されるアミノ酸配列を含む、前記抗体またはその抗原結合部分。
［請求項１７］
表面プラズモン共鳴によって測定すると、１０ｎＭ未満、９ｎＭ未満、８ｎＭ未満、７ｎＭ未満、６ｎＭ未満、５ｎＭ未満、４ｎＭ未満、３ｎＭ未満、２ｎＭ未満、または１ｎＭ未満のＫＤ（例えば、１．３ｎＭ）で前記ヒトＩＬ－７受容体の前記アルファ鎖に結合する、請求項１～１６のいずれか１項に記載の抗体。
［請求項１８］
表面プラズモン共鳴によって測定すると、１０ｎＭ未満、９ｎＭ未満、８ｎＭ未満、７ｎＭ未満、６ｎＭ未満、５ｎＭ未満、４ｎＭ未満、３ｎＭ未満、２ｎＭ未満、または１ｎＭ未満のＫＤ（例えば、１．７ｎＭ）で前記カニクイザルＩＬ－７受容体の前記アルファ鎖に結合する、請求項１～１７のいずれか１項に記載の抗体。
［請求項１９］
前記ヒトＩＬ－７受容体の前記アルファ鎖への結合、または前記カニクイザルＩＬ－７受容体の前記アルファ鎖への結合がｐＨ依存性である、請求項１７または請求項１８に記載の抗体。
［請求項２０］
ｐＨ７．４では約１．３ｎＭのＫＤ、ｐＨ６では約５．３ｎＭのＫＤで前記ヒトＩＬ－７受容体の前記アルファ鎖に結合する、請求項１９に記載の抗体。
［請求項２１］
ｐＨ７．４では約１．７ｎＭのＫＤ、ｐＨ６では約７．０ｎＭのＫＤで前記カニクイザルＩＬ－７受容体の前記アルファ鎖に結合する、請求項１９または請求項２０に記載の抗体。
［請求項２２］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖（ＨＣ）ＣＤＲ１、ＨＣ ＣＤＲ２、及びＨＣ ＣＤＲ３と、軽鎖（ＬＣ）ＣＤＲ１、ＬＣ ＣＤＲ２、及びＬＣ ＣＤＲ３と、を含み、前記ＨＣ ＣＤＲ１が、ＧＸ１Ｘ２ＦＤＤＨＡＸ３Ｈというアミノ酸配列（配列番号２６０）を含み、配列中、Ｘ１が、ＦまたはＹであり、Ｘ２が、Ｔ、Ｐ、Ａ、Ｓ、Ｖ、Ｌ、Ｉ、Ｍ、Ｈ、Ｆ、Ｙ、Ｎ、Ｄ、Ｅ、またはＱであり、Ｘ３が、ＬまたはＭである、前記抗体またはその抗原結合部分。
［請求項２３］
Ｘ２が、ＤまたはＥである、請求項２２に記載の抗体。
［請求項２４］
前記ＨＣ ＣＤＲ２が、ＧＩＸ１ＷＸ２ＳＲＧＸ３ＧＹＸ４Ｘ５Ｘ６Ｘ７Ｘ８Ｘ９というアミノ酸配列（配列番号２６１）を含み、配列中、Ｘ１が、ＳまたはＴであり、Ｘ２が、ＨまたはＮであり、Ｘ３が、ＩまたはＶであり、Ｘ４が、Ｇ、Ａ、Ｓ、Ｔ、Ｖ、Ｌ、Ｉ、Ｒ、Ｈ、またはＮであり、Ｘ５が、Ｐ、Ｔ、Ｎ、Ｄ、Ｅ、Ｑ、Ｓ、Ｈ、またはＹであり、Ｘ６が、Ｐ、Ｇ、Ａ、Ｓ、Ｔ、Ｖ、Ｒ、Ｈ、Ｆ、Ｙ、Ｎ、Ｄ、またはＥであり、Ｘ７が、ＶまたはＩであり、Ｘ８が、Ａ、Ｓ、Ｔ、Ｖ、Ｌ、Ｉ、Ｍ、Ｋ、Ｒ、Ｈ、Ｆ、Ｙ、Ｎ、Ｄ、Ｅ、またはＱであり、Ｘ９が、Ｇ、Ｈ、Ｄ、またはＱである、請求項２２または請求項２３に記載の抗体。
［請求項２５］
Ｘ１が、Ｔである、請求項２４に記載の抗体。
［請求項２６］
前記ＨＣ ＣＤＲ３が、ＤＥＹＸ１Ｘ２ＧＹＹＸ３ＬＤＸ４というアミノ酸配列（配列番号２６２）を含み、配列中、Ｘ１が、Ｓ、Ｔ、Ｎ、Ｄ、またはＥであり、Ｘ２が、Ｌ、Ｍ、Ｒ、またはＳであり、Ｘ３が、Ｇ、Ａ、Ｓ、Ｔ、Ｖ、Ｍ、Ｎ、Ｅ、またはＱであり、Ｘ４が、Ａ、Ｓ、Ｔ、Ｖ、Ｒ、Ｈ、Ｙ、Ｗ、Ｎ、Ｅ、Ｑ、またはＭである、請求項２２～２５のいずれか１項に記載の抗体。
［請求項２７］
Ｘ３が、Ａ、Ｓ、またはＴである、請求項２６に記載の抗体。
［請求項２８］
Ｘ４が、Ｅである、請求項２６または請求項２７に記載の抗体。
［請求項２９］
前記ＬＣ ＣＤＲ１が、Ｘ１Ｘ２Ｘ３Ｘ４Ｘ５Ｘ６Ｘ７ＳＸ８Ｘ９Ａというアミノ酸配列（配列番号２６３）を含み、配列中、Ｘ１が、Ｓ、Ｔ、Ｖ、Ｋ、Ｒ、Ｈ、Ｙ、またはＩであり、Ｘ２が、Ａ、Ｓ、Ｔ、またはＶであり、Ｘ３が、Ｐ、Ｇ、Ａ、Ｓ、Ｔ、Ｖ、Ｌ、Ｉ、Ｍ、Ｋ、Ｒ、Ｈ、Ｎ、Ｅ、またはＱであり、Ｘ４が、Ｐ、Ｇ、Ａ、Ｓ、Ｔ、Ｖ、Ｌ、Ｉ、Ｍ、Ｈ、Ｆ、Ｙ、Ｎ、Ｄ、Ｅ、またはＱであり、Ｘ５が、Ｐ、Ｇ、Ａ、Ｓ、Ｔ、Ｈ、Ｅ、Ｑ、Ｍ、Ｎ、またはＤであり、Ｘ６が、Ｐ、Ｇ、Ａ、Ｓ、Ｔ、Ｖ、Ｌ、Ｉ、またはＮであり、Ｘ７が、Ｓ、Ｔ、Ｖ、Ｌ、Ｉ、Ｍ、Ｈ、Ｆ、Ｙ、Ｎ、Ｄ、Ｅ、またはＱであり、Ｘ８が、ＰまたはＡであり、Ｘ９が、Ａ、Ｌ、またはＶである、請求項２２～２８のいずれか１項に記載の抗体。
［請求項３０］
Ｘ６が、Ｐである、請求項２９に記載の抗体。
［請求項３１］
Ｘ８が、Ｐである、請求項２９または請求項３０に記載の抗体。
［請求項３２］
Ｘ７が、ＤまたはＥである、請求項２９～３１のいずれか１項に記載の抗体。
［請求項３３］
前記ＬＣ ＣＤＲ２が、ＤＸ１Ｘ２Ｘ３Ｘ４Ｘ５Ｘ６というアミノ酸配列（配列番号２６４）を含み、配列中、Ｘ１が、Ｇ、Ａ、Ｓ、Ｍ、Ｈ、Ｎ、Ｄ、Ｅ、またはＱであり、Ｘ２が、Ｇ、Ａ、Ｓ、Ｔ、Ｖ、Ｍ、Ｈ、Ｆ、Ｙ、Ｎ、Ｄ、Ｅ、またはＱであり、Ｘ３が、Ａ、Ｓ、Ｆ、Ｙ、Ｗ、Ｎ、Ｄ、Ｅ、またはＬであり、Ｘ４が、Ｐ、Ｓ、Ｔ、Ｌ、Ｋ、Ｈ、またはＮであり、Ｘ５が、Ｄ、Ｅ、またはＱであり、Ｘ６が、Ｇ、Ｓ、Ｔ、Ｎ、Ｄ、Ｑ、Ｐ、またはＥである、請求項２２～３２のいずれか１項に記載の抗体。
［請求項３４］
前記ＬＣ ＣＤＲ３が、Ｘ１Ｘ２ＦＸ３Ｘ４ＹＰＬＸ５Ｘ６Ｘ７というアミノ酸配列（配列番号２６５）を含み、配列中、Ｘ１が、ＭまたはＱであり、Ｘ２が、Ｇ、Ａ、Ｄ、Ｅ、またはＱであり、Ｘ３が、ＮまたはＥであり、Ｘ４が、Ｐ、Ａ、またはＳであり、Ｘ５が、Ｔ、Ｉ、Ｍ、Ｋ、Ｗ、Ｎ、Ｅ、またはＱであり、Ｘ６が、ＬまたはＩであり、Ｘ７が、Ｔ、Ｍ、Ｋ、Ｈ、Ｙ、Ｅ、またはＱである、請求項２２～３３のいずれか１項に記載の抗体。
［請求項３５］
Ｘ２が、Ａである、請求項３４に記載の抗体。
［請求項３６］
Ｘ４が、ＰまたはＡである、請求項３４または請求項３５に記載の抗体。
［請求項３７］
前記重鎖ＣＤＲ１が、配列番号３１～４６に示されるアミノ酸配列のうちの１つを含む、請求項２２～３６のいずれか１項に記載の抗体。
［請求項３８］
前記重鎖ＣＤＲ１が、配列番号４３または配列番号４４に示されるアミノ酸配列を含む、請求項３７に記載の抗体。
［請求項３９］
前記重鎖ＣＤＲ２が、配列番号４７～９６に示されるアミノ酸配列のうちの１つを含む、請求項２２～３８のいずれか１項に記載の抗体。
［請求項４０］
前記重鎖ＣＤＲ２が、配列番号４７に示されるアミノ酸配列を含む、請求項３９に記載の抗体。
［請求項４１］
前記重鎖ＣＤＲ３が、配列番号９７～１２２に示されるアミノ酸配列のうちの１つを含む、請求項２２～４０のいずれか１項に記載の抗体。
［請求項４２］
前記重鎖ＣＤＲ３が、配列番号１０５、配列番号１０６、配列番号１０７、または配列番号１２０に示されるアミノ酸配列を含む、請求項４１に記載の抗体。
［請求項４３］
前記軽鎖ＣＤＲ１が、配列番号１２３～１９４に示されるアミノ酸配列のうちの１つを含む、請求項２２～４２のいずれか１項に記載の抗体。
［請求項４４］
前記軽鎖ＣＤＲ１が、配列番号１７２、配列番号１８９、配列番号１９０、または配列番号１９２に示されるアミノ酸配列を含む、請求項４３に記載の抗体。
［請求項４５］
前記軽鎖ＣＤＲ２が、配列番号１９５～２３７に示されるアミノ酸配列のうちの１つを含む、請求項２２～４４のいずれか１項に記載の抗体。
［請求項４６］
前記軽鎖ＣＤＲ３が、配列番号２３８～２５９に示されるアミノ酸配列のうちの１つを含む、請求項２２～４５のいずれか１項に記載の抗体。
［請求項４７］
前記軽鎖ＣＤＲ３が、配列番号２４０、配列番号２４４、または配列番号２４５に示されるアミノ酸配列を含む、請求項４６に記載の抗体。
［請求項４８］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖（ＨＣ）ＣＤＲ１、ＨＣ ＣＤＲ２、及びＨＣ ＣＤＲ３と、軽鎖（ＬＣ）ＣＤＲ１、ＬＣ ＣＤＲ２、及びＬＣ ＣＤＲ３と、を含み、
（ｉ）前記重鎖ＣＤＲ１が、配列番号３１～４６に示されるアミノ酸配列のうちの１つを含み、
（ｉｉ）前記重鎖ＣＤＲ２が、配列番号１４に示されるアミノ酸配列を含み、
（ｉｉｉ）前記重鎖ＣＤＲ３が、配列番号１５に示されるアミノ酸配列を含み、
（ｉｖ）前記軽鎖ＣＤＲ１が、配列番号１６に示されるアミノ酸配列を含み、
（ｖ）前記軽鎖ＣＤＲ２が、配列番号１７に示されるアミノ酸配列を含み、
（ｖｉ）前記軽鎖ＣＤＲ３が、配列番号１８に示されるアミノ酸配列を含む、
前記抗体またはその抗原結合部分。
［請求項４９］
前記重鎖ＣＤＲ１が、配列番号４３または配列番号４４に示されるアミノ酸配列を含む、請求項４８に記載の抗体。
［請求項５０］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖（ＨＣ）ＣＤＲ１、ＨＣ ＣＤＲ２、及びＨＣ ＣＤＲ３と、軽鎖（ＬＣ）ＣＤＲ１、ＬＣ ＣＤＲ２、及びＬＣ ＣＤＲ３と、を含み、
（ｉ）前記重鎖ＣＤＲ１が、配列番号１３に示されるアミノ酸配列を含み、
（ｉｉ）前記重鎖ＣＤＲ２が、配列番号４７～９６に示されるアミノ酸配列のうちの１つを含み、
（ｉｉｉ）前記重鎖ＣＤＲ３が、配列番号１５に示されるアミノ酸配列を含み、
（ｉｖ）前記軽鎖ＣＤＲ１が、配列番号１６に示されるアミノ酸配列を含み、
（ｖ）前記軽鎖ＣＤＲ２が、配列番号１７に示されるアミノ酸配列を含み、
（ｖｉ）前記軽鎖ＣＤＲ３が、配列番号１８に示されるアミノ酸配列を含む、
前記抗体またはその抗原結合部分。
［請求項５１］
前記重鎖ＣＤＲ２が、配列番号４７に示されるアミノ酸配列を含む、請求項５０に記載の抗体。
［請求項５２］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖（ＨＣ）ＣＤＲ１、ＨＣ ＣＤＲ２、及びＨＣ ＣＤＲ３と、軽鎖（ＬＣ）ＣＤＲ１、ＬＣ ＣＤＲ２、及びＬＣ ＣＤＲ３と、を含み、
（ｉ）前記重鎖ＣＤＲ１が、配列番号１３に示されるアミノ酸配列を含み、
（ｉｉ）前記重鎖ＣＤＲ２が、配列番号１４に示されるアミノ酸配列を含み、
（ｉｉｉ）前記重鎖ＣＤＲ３が、配列番号９７～１２２に示されるアミノ酸配列のうちの１つを含み、
（ｉｖ）前記軽鎖ＣＤＲ１が、配列番号１６に示されるアミノ酸配列を含み、
（ｖ）前記軽鎖ＣＤＲ２が、配列番号１７に示されるアミノ酸配列を含み、
（ｖｉ）前記軽鎖ＣＤＲ３が、配列番号１８に示されるアミノ酸配列を含む、
前記抗体またはその抗原結合部分。
［請求項５３］
前記重鎖ＣＤＲ３が、配列番号１０５、配列番号１０６、配列番号１０７、または配列番号１２０に示されるアミノ酸配列を含む、請求項５２に記載の抗体。
［請求項５４］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖（ＨＣ）ＣＤＲ１、ＨＣ ＣＤＲ２、及びＨＣ ＣＤＲ３と、軽鎖（ＬＣ）ＣＤＲ１、ＬＣ ＣＤＲ２、及びＬＣ ＣＤＲ３と、を含み、
（ｉ）前記重鎖ＣＤＲ１が、配列番号１３に示されるアミノ酸配列を含み、
（ｉｉ）前記重鎖ＣＤＲ２が、配列番号１４に示されるアミノ酸配列を含み、
（ｉｉｉ）前記重鎖ＣＤＲ３が、配列番号１５に示されるアミノ酸配列を含み、
（ｉｖ）前記軽鎖ＣＤＲ１が、配列番号１２３～１９４に示されるアミノ酸配列のうちの１つを含み、
（ｖ）前記軽鎖ＣＤＲ２が、配列番号１７に示されるアミノ酸配列を含み、
（ｖｉ）前記軽鎖ＣＤＲ３が、配列番号１８に示されるアミノ酸配列を含む、
前記抗体またはその抗原結合部分。
［請求項５５］
前記軽鎖ＣＤＲ１が、配列番号１７２、配列番号１８９、配列番号１９０、または配列番号１９２に示されるアミノ酸配列を含む、請求項５４に記載の抗体。
［請求項５６］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖（ＨＣ）ＣＤＲ１、ＨＣ ＣＤＲ２、及びＨＣ ＣＤＲ３と、軽鎖（ＬＣ）ＣＤＲ１、ＬＣ ＣＤＲ２、及びＬＣ ＣＤＲ３と、を含み、
（ｉ）前記重鎖ＣＤＲ１が、配列番号１３に示されるアミノ酸配列を含み、
（ｉｉ）前記重鎖ＣＤＲ２が、配列番号１４に示されるアミノ酸配列を含み、
（ｉｉｉ）前記重鎖ＣＤＲ３が、配列番号１５に示されるアミノ酸配列を含み、
（ｉｖ）前記軽鎖ＣＤＲ１が、配列番号１６に示されるアミノ酸配列を含み、
（ｖ）前記軽鎖ＣＤＲ２が、配列番号１９５～２３７に示されるアミノ酸配列のうちの１つを含み、
（ｖｉ）前記軽鎖ＣＤＲ３が、配列番号１８に示されるアミノ酸配列を含む、
前記抗体またはその抗原結合部分。
［請求項５７］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する単離された抗体（「抗ＩＬ－７Ｒ抗体」）またはその抗原結合部分であって、前記抗体が、重鎖（ＨＣ）ＣＤＲ１、ＨＣ ＣＤＲ２、及びＨＣ ＣＤＲ３と、軽鎖（ＬＣ）ＣＤＲ１、ＬＣ ＣＤＲ２、及びＬＣ ＣＤＲ３と、を含み、
（ｉ）前記重鎖ＣＤＲ１が、配列番号１３に示されるアミノ酸配列を含み、
（ｉｉ）前記重鎖ＣＤＲ２が、配列番号１４に示されるアミノ酸配列を含み、
（ｉｉｉ）前記重鎖ＣＤＲ３が、配列番号１５に示されるアミノ酸配列を含み、
（ｉｖ）前記軽鎖ＣＤＲ１が、配列番号１６に示されるアミノ酸配列を含み、
（ｖ）前記軽鎖ＣＤＲ２が、配列番号１７に示されるアミノ酸配列を含み、
（ｖｉ）前記軽鎖ＣＤＲ３が、配列番号２３８～２５９に示されるアミノ酸配列のうちの１つを含む、
前記抗体またはその抗原結合部分。
［請求項５８］
前記軽鎖ＣＤＲ３が、配列番号２４０、配列番号２４４、または配列番号２４５に示されるアミノ酸配列を含む、請求項５７に記載の抗体。
［請求項５９］
請求項１～５８のいずれか１項に記載の抗体をコードする核酸。
［請求項６０］
請求項５９に記載の核酸を含むベクター。
［請求項６１］
請求項６０に記載のベクターを含む細胞。
［請求項６２］
前記細胞が、ＣＨＯ細胞、ＨＥＫ２９３細胞、ＨＢＫ細胞、ＣＯＳ細胞、ＮＳＯ細胞、またはＨＴ１０８０細胞である、請求項６１に記載の細胞。
［請求項６３］
請求項１～５８のいずれか１項に記載の抗体が薬剤に連結されたものを含む免疫複合体。
［請求項６４］
請求項１～５８のいずれか１項に記載の抗体、請求項５９に記載の核酸、請求項６０に記載のベクター、請求項６１もしくは請求項６２に記載の細胞、または請求項６３に記載の免疫複合体と、担体と、を含む組成物。
［請求項６５］
請求項１～５８のいずれか１項に記載の抗体、請求項５９に記載の核酸、請求項６０に記載のベクター、請求項６１もしくは請求項６２に記載の細胞、または請求項６３に記載の免疫複合体と、使用のための説明と、を含むキット。
［請求項６６］
ＩＬ－７活性の阻害を必要とする対象において前記阻害を行う方法であって、前記方法が、請求項１～５８のいずれか１項に記載の抗体、請求項５９に記載の核酸、請求項６０に記載のベクター、請求項６１もしくは請求項６２に記載の細胞、または請求項６３に記載の免疫複合体を前記対象に投与することを含む、前記方法。
［請求項６７］
エフェクターＴ細胞の増殖の抑制、ならびに／または制御性Ｔ細胞の発生及び／もしくは生存の誘導を必要とする対象において前記抑制及び／または前記誘導を行う方法であって、前記方法が、請求項１～５８のいずれか１項に記載の抗体、請求項５９に記載の核酸、請求項６０に記載のベクター、請求項６１もしくは請求項６２に記載の細胞、または請求項６３に記載の免疫複合体を前記対象に投与することを含む、前記方法。
［請求項６８］
炎症性疾患または自己免疫疾患の治療を必要とする対象において前記治療を行う方法であって、前記方法が、請求項１～５８のいずれか１項に記載の抗体、請求項５９に記載の核酸、請求項６０に記載のベクター、請求項６１もしくは請求項６２に記載の細胞、または請求項６３に記載の免疫複合体を前記対象に投与することを含む、前記方法。
［請求項６９］
前記炎症性疾患または前記自己免疫疾患が、炎症性腸疾患（ＩＢＤ）、過敏性腸症候群、関節リウマチ（ＲＡ）、乾癬、乾癬性関節炎、全身性エリテマトーデス（ＳＬＥ）、ループス腎炎、血管炎、敗血症、全身性炎症反応症候群（ＳＩＲＳ）、Ｉ型糖尿病、グレーブス病、多発性硬化症（ＭＳ）、自己免疫性心筋炎、川崎病、冠動脈疾患、慢性閉塞性肺疾患、間質性肺疾患、自己免疫性甲状腺炎、強皮症、全身性硬化症、変形性関節症、アトピー性皮膚炎、白斑、移植片対宿主病、シェーグレン症候群、自己免疫性腎炎、グッドパスチャー症候群、慢性炎症性脱髄性多発神経炎、アレルギー、喘息、急性または慢性の炎症の結果である他の自己免疫疾患、及びそれらの任意の組み合わせ、からなる群から選択される、請求項６８に記載の方法。
［請求項７０］
前記炎症性疾患または前記自己免疫疾患が、炎症性腸疾患である、請求項６９に記載の方法。
［請求項７１］
前記炎症性腸疾患が、潰瘍性大腸炎またはクローン病である、請求項６９または請求項７０に記載の方法。
［請求項７２］
前記対象が、これまでのＴＮＦ－α阻害剤治療が十分に奏功しなかった対象（抗ＴＮＦ－αの効果が不十分なレスポンダー）である、請求項６６～７１のいずれか１項に記載の方法。
［請求項７３］
１つ以上の追加の治療を施すことをさらに含む、請求項６６～７２のいずれか１項に記載の方法。
［請求項７４］
前記追加の治療が、抗ＴＮＦ－α抗体を含む、請求項７３に記載の方法。
［請求項７５］
前記抗体が、一律用量または体重ベースの用量で前記対象に投与される、請求項６６～７４のいずれか１項に記載の方法。
［請求項７６］
前記抗体が、静脈内、皮下、筋肉内、皮内、または腹腔内に投与される、請求項６６～７５のいずれか１項に記載の方法。
［請求項７７］
前記抗体が、静脈内または皮下に投与される、請求項７６に記載の方法。
［請求項７８］
ヒトＩＬ－７受容体のアルファ鎖に特異的に結合する抗体（「抗ＩＬ－７Ｒ抗体」）の生成方法であって、前記方法が、請求項６１または請求項６２に記載の細胞を適切な条件の下で培養すること、及び前記抗体を単離すること、を含む、前記方法。
All references cited above as well as references cited herein are hereby incorporated by reference in their entirety.
The description of the scope of claims as filed is shown below.
[Claim 1]
An isolated antibody (“anti-IL-7R antibody”) or antigen-binding portion thereof that specifically binds to the alpha chain of the human IL-7 receptor, wherein said antibody comprises heavy chain CDR1, heavy chain CDR2, and a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the antibody comprises
(a) has the ability to bind T cells (CD4+CD45RA+, CD4+CD45RA-, CD8+CD45RA+, and/or CD8+CD45RA-) in whole blood with an EC50 of about 5 nM or less (e.g., less than about 3 nM);
(b) does not have the ability to bind non-T cells in whole blood, or
(c) not capable of effectively blocking thymic stromal lymphopoiesis factor (TSLP)-mediated monocyte activation;
(d) does not agonize IL-7 receptor signaling upon binding to said IL-7 receptor (e.g. pSTAT5 activation is minimal), or (e) any combination thereof. A said antibody or antigen-binding portion thereof.
[Claim 2]
2. The antibody of claim 1, wherein said heavy chain CDR3 comprises the amino acid sequence shown in SEQ ID NO: 15 (DEYSRGYYVLDV).
[Claim 3]
the antibody
(a) having the ability to selectively bind to the alpha chain of the human and cynomolgus monkey IL-7 receptor (IL-7R);
(b) having the ability to bind the alpha chain of soluble and membrane-bound forms of IL-7R;
(c) having the ability, when administered to a subject in need of blocking pathogenic T cell proliferation and/or survival, to effect said blocking;
(d) having the ability to restore and/or promote Treg survival when administered to a subject in need of restoring regulatory T cell (Treg) function and/or promoting Treg survival;
(e) having the ability to maintain drug-free remission longer compared to that with CTLA4-Ig (ORENCIA®);
(f) having the ability to block inflammation and mucosal damage (e.g., those induced by pathogenic T cells) within the intestinal tissue of a subject in need thereof;
(g) having the ability to reduce the frequency of effector T cells in the mesenteric lymph node (MLN) and/or lamina propria (LP) in a subject in need thereof;
(h) having the ability to reduce or inhibit IL-7-mediated pSTAT activation of T cells (e.g., CD4+CD45RA+);
(i) having the ability to block the proliferation of cells that produce IL-17 and/or IFN-gamma;
(j) having the ability to treat a subject with an inflammatory disease (e.g., inflammatory bowel disease); and (k) any combination thereof;
3. The antibody of claim 1 or claim 2, having one or more properties selected from the group consisting of:
[Claim 4]
The antibody of any one of claims 1-3, wherein said heavy chain CDR1 comprises the amino acid sequence shown in SEQ ID NO:13 (DHAMH).
[Claim 5]
The antibody of any one of claims 1-4, wherein said heavy chain CDR2 comprises the amino acid sequence shown in SEQ ID NO:14 (GISWNSRGIGYADSVKG).
[Claim 6]
The antibody of any one of claims 1-5, wherein said light chain CDR1 comprises the amino acid sequence shown in SEQ ID NO:16 (RASQGISSALA).
[Claim 7]
The antibody of any one of claims 1-6, wherein said light chain CDR2 comprises the amino acid sequence shown in SEQ ID NO:17 (DASSLES).
[Claim 8]
The antibody of any one of claims 1-7, wherein said light chain CDR3 comprises the amino acid sequence shown in SEQ ID NO:18 (QQFNSYPLWIT).
[Claim 9]
The antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH has at least about 80%, at least about 85%, at least 9. Any one of claims 1-8 comprising an amino acid sequence that is about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% Antibodies as described in.
[Claim 10]
said VL has at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98% identity to the amino acid sequence set forth in SEQ ID NO:20 %, at least about 99%, or about 100%.
[Claim 11]
24SQLEVNGSQHSLTCAF39 (SEQ ID NO:8), 73FIETKKFLLIGKSNIC88 (SEQ ID NO:9), 89VKVGEKSLTCKKIDLTT105 (SEQ ID NO:10), 136QKKYVKVLMHDVAY149 (SEQ ID NO:11), 181YEIKVRSIPDHYFKGF196 (SEQ ID NO:12) selected from the group consisting of epitopes selected from the group and combinations thereof; The antibody of any one of claims 1-10, which specifically binds to said alpha chain of said human IL-7 receptor at.
[Claim 12]
said human IL-7 receptor at an epitope position comprising one or more amino acid residues selected from the group consisting of H33, E75, F79, I82, K84, M144, R186, H191, Y192, and combinations thereof. The antibody of any one of claims 1-11, which specifically binds to the alpha chain of
[Claim 13]
The antibody of any one of claims 1-12, wherein said antibody is selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and variants thereof.
[Claim 14]
14. The antibody of claim 13, wherein said antibody is an IgGl antibody.
[Claim 15]
15. The antibody of claim 14, comprising an IgGl Fc with no effector function.
[Claim 16]
An isolated antibody (“anti-IL-7R antibody”) or antigen-binding portion thereof that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising a heavy chain and a light chain; Said antibody or antigen-binding portion thereof, wherein said heavy chain comprises the amino acid sequence shown in SEQ ID NO:21 and said light chain comprises the amino acid sequence shown in SEQ ID NO:22.
[Claim 17]
said human IL with a KD of less than 10 nM, less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM (e.g., 1.3 nM) as measured by surface plasmon resonance The antibody of any one of claims 1-16, which binds to the alpha chain of the -7 receptor.
[Claim 18]
Said cynomolgus IL with a KD of less than 10 nM, less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM (e.g., 1.7 nM) as measured by surface plasmon resonance The antibody of any one of claims 1-17, which binds to the alpha chain of the -7 receptor.
[Claim 19]
19. The antibody of claim 17 or claim 18, wherein binding of said human IL-7 receptor to said alpha chain or binding of said cynomolgus monkey IL-7 receptor to said alpha chain is pH dependent.
[Claim 20]
20. The antibody of claim 19, which binds to said alpha chain of said human IL-7 receptor with a KD of about 1.3 nM at pH 7.4 and a KD of about 5.3 nM at pH 6.
[Claim 21]
21. The antibody of claim 19 or claim 20, which binds to said alpha chain of said cynomolgus monkey IL-7 receptor with a KD of about 1.7 nM at pH 7.4 and a KD of about 7.0 nM at pH 6.
[Claim 22]
An isolated antibody (“anti-IL-7R antibody”), or antigen-binding portion thereof, that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising the heavy chain (HC) CDR1, HC light chain (LC) CDR1, LC CDR2, and LC CDR3, wherein said HC CDR1 comprises the amino acid sequence GX1X2FDDHAX3H (SEQ ID NO: 260), wherein X1 is F or Y, X2 is T, P, A, S, V, L, I, M, H, F, Y, N, D, E, or Q, and X3 is L or M, An antibody or antigen-binding portion thereof.
[Claim 23]
23. The antibody of claim 22, wherein X2 is D or E.
[Claim 24]
said HC CDR2 comprises the amino acid sequence GIX1WX2SRGX3GYX4X5X6X7X8X9 (SEQ ID NO: 261), wherein X1 is S or T, X2 is H or N, X3 is I or V, and X4 is G, A, S, T, V, L, I, R, H, or N, X5 is P, T, N, D, E, Q, S, H, or Y, and X6 is P, G, A, S, T, V, R, H, F, Y, N, D, or E, X7 is V or I, and X8 is A, S, T, V, L , I, M, K, R, H, F, Y, N, D, E, or Q, and X9 is G, H, D, or Q. antibody.
[Claim 25]
25. The antibody of claim 24, wherein X1 is T.
[Claim 26]
said HC CDR3 comprises the amino acid sequence DEYX1X2GYYX3LDX4 (SEQ ID NO: 262), wherein X1 is S, T, N, D, or E, and X2 is L, M, R, or S; X3 is G, A, S, T, V, M, N, E, or Q and X4 is A, S, T, V, R, H, Y, W, N, E, Q, or 26. The antibody of any one of claims 22-25, which is M.
[Claim 27]
27. The antibody of claim 26, wherein X3 is A, S, or T.
[Claim 28]
28. The antibody of claim 26 or claim 27, wherein X4 is E.
[Claim 29]
said LC CDR1 comprises the amino acid sequence X1X2X3X4X5X6X7SX8X9A (SEQ ID NO: 263), wherein X1 is S, T, V, K, R, H, Y, or I and X2 is A, S, T , or V, X3 is P, G, A, S, T, V, L, I, M, K, R, H, N, E, or Q, and X4 is P, G, A , S, T, V, L, I, M, H, F, Y, N, D, E, or Q, and X is P, G, A, S, T, H, E, Q, M , N, or D, X6 is P, G, A, S, T, V, L, I, or N, and X7 is S, T, V, L, I, M, H, F , Y, N, D, E, or Q, X8 is P or A, and X9 is A, L, or V.
[Claim 30]
30. The antibody of claim 29, wherein X6 is P.
[Claim 31]
31. The antibody of claim 29 or claim 30, wherein X8 is P.
[Claim 32]
The antibody of any one of claims 29-31, wherein X7 is D or E.
[Claim 33]
said LC CDR2 comprises the amino acid sequence DX1X2X3X4X5X6 (SEQ ID NO: 264), wherein X1 is G, A, S, M, H, N, D, E, or Q and X2 is G, A , S, T, V, M, H, F, Y, N, D, E, or Q, and X3 is A, S, F, Y, W, N, D, E, or L; X4 is P, S, T, L, K, H, or N, X5 is D, E, or Q, and X6 is G, S, T, N, D, Q, P, or The antibody of any one of claims 22-32, which is E.
[Claim 34]
Said LC CDR3 comprises the amino acid sequence X1X2FX3X4YPLX5X6X7 (SEQ ID NO: 265), wherein X1 is M or Q, X2 is G, A, D, E, or Q, and X3 is N or E, X4 is P, A, or S; X5 is T, I, M, K, W, N, E, or Q; X6 is L or I; 34. The antibody of any one of claims 22-33, which is T, M, K, H, Y, E, or Q.
[Claim 35]
35. The antibody of claim 34, wherein X2 is A.
[Claim 36]
36. The antibody of claim 34 or claim 35, wherein X4 is P or A.
[Claim 37]
The antibody of any one of claims 22-36, wherein said heavy chain CDR1 comprises one of the amino acid sequences set forth in SEQ ID NOs:31-46.
[Claim 38]
38. The antibody of claim 37, wherein said heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO:43 or SEQ ID NO:44.
[Claim 39]
The antibody of any one of claims 22-38, wherein said heavy chain CDR2 comprises one of the amino acid sequences set forth in SEQ ID NOs:47-96.
[Claim 40]
40. The antibody of claim 39, wherein said heavy chain CDR2 comprises the amino acid sequence shown in SEQ ID NO:47.
[Claim 41]
The antibody of any one of claims 22-40, wherein said heavy chain CDR3 comprises one of the amino acid sequences set forth in SEQ ID NOS:97-122.
[Claim 42]
42. The antibody of claim 41, wherein said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, or SEQ ID NO:120.
[Claim 43]
The antibody of any one of claims 22-42, wherein said light chain CDR1 comprises one of the amino acid sequences set forth in SEQ ID NOS:123-194.
[Claim 44]
44. The antibody of Claim 43, wherein said light chain CDRl comprises the amino acid sequence set forth in SEQ ID NO:172, SEQ ID NO:189, SEQ ID NO:190, or SEQ ID NO:192.
[Claim 45]
The antibody of any one of claims 22-44, wherein said light chain CDR2 comprises one of the amino acid sequences set forth in SEQ ID NOS:195-237.
[Claim 46]
The antibody of any one of claims 22-45, wherein said light chain CDR3 comprises one of the amino acid sequences set forth in SEQ ID NOS:238-259.
[Claim 47]
47. The antibody of Claim 46, wherein said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO:240, SEQ ID NO:244, or SEQ ID NO:245.
[Claim 48]
An isolated antibody (“anti-IL-7R antibody”), or antigen-binding portion thereof, that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising the heavy chain (HC) CDR1, HC CDR2 and HC CDR3 and light chain (LC) CDR1, LC CDR2 and LC CDR3;
(i) said heavy chain CDR1 comprises one of the amino acid sequences set forth in SEQ ID NOs: 31-46;
(ii) said heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14;
(iii) said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15;
(iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16;
(v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17;
(vi) said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 18;
Said antibody or antigen-binding portion thereof.
[Claim 49]
49. The antibody of Claim 48, wherein said heavy chain CDRl comprises the amino acid sequence set forth in SEQ ID NO:43 or SEQ ID NO:44.
[Claim 50]
An isolated antibody (“anti-IL-7R antibody”), or antigen-binding portion thereof, that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising the heavy chain (HC) CDR1, HC CDR2 and HC CDR3 and light chain (LC) CDR1, LC CDR2 and LC CDR3;
(i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13;
(ii) said heavy chain CDR2 comprises one of the amino acid sequences set forth in SEQ ID NOS: 47-96;
(iii) said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15;
(iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16;
(v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17;
(vi) said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 18;
Said antibody or antigen-binding portion thereof.
[Claim 51]
51. The antibody of claim 50, wherein said heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO:47.
[Claim 52]
An isolated antibody (“anti-IL-7R antibody”), or antigen-binding portion thereof, that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising the heavy chain (HC) CDR1, HC CDR2 and HC CDR3 and light chain (LC) CDR1, LC CDR2 and LC CDR3;
(i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13;
(ii) said heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14;
(iii) said heavy chain CDR3 comprises one of the amino acid sequences set forth in SEQ ID NOs: 97-122;
(iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16;
(v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17;
(vi) said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 18;
Said antibody or antigen-binding portion thereof.
[Claim 53]
53. The antibody of Claim 52, wherein said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, or SEQ ID NO:120.
[Claim 54]
An isolated antibody (“anti-IL-7R antibody”), or antigen-binding portion thereof, that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising the heavy chain (HC) CDR1, HC CDR2 and HC CDR3 and light chain (LC) CDR1, LC CDR2 and LC CDR3;
(i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13;
(ii) said heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14;
(iii) said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15;
(iv) said light chain CDR1 comprises one of the amino acid sequences set forth in SEQ ID NOs: 123-194;
(v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17;
(vi) said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 18;
Said antibody or antigen-binding portion thereof.
[Claim 55]
55. The antibody of Claim 54, wherein said light chain CDRl comprises the amino acid sequence set forth in SEQ ID NO:172, SEQ ID NO:189, SEQ ID NO:190, or SEQ ID NO:192.
[Claim 56]
An isolated antibody (“anti-IL-7R antibody”), or antigen-binding portion thereof, that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising the heavy chain (HC) CDR1, HC CDR2 and HC CDR3 and light chain (LC) CDR1, LC CDR2 and LC CDR3;
(i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13;
(ii) said heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14;
(iii) said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15;
(iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16;
(v) said light chain CDR2 comprises one of the amino acid sequences set forth in SEQ ID NOs: 195-237;
(vi) said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 18;
Said antibody or antigen-binding portion thereof.
[Claim 57]
An isolated antibody (“anti-IL-7R antibody”), or antigen-binding portion thereof, that specifically binds to the alpha chain of the human IL-7 receptor, said antibody comprising the heavy chain (HC) CDR1, HC CDR2 and HC CDR3 and light chain (LC) CDR1, LC CDR2 and LC CDR3;
(i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13;
(ii) said heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14;
(iii) said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15;
(iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16;
(v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17;
(vi) said light chain CDR3 comprises one of the amino acid sequences set forth in SEQ ID NOS:238-259;
Said antibody or antigen-binding portion thereof.
[Claim 58]
58. The antibody of Claim 57, wherein said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO:240, SEQ ID NO:244, or SEQ ID NO:245.
[Claim 59]
A nucleic acid encoding the antibody of any one of claims 1-58.
[Claim 60]
A vector comprising the nucleic acid of claim 59.
[Claim 61]
A cell comprising the vector of claim 60.
[Claim 62]
62. The cells of claim 61, wherein said cells are CHO cells, HEK293 cells, HBK cells, COS cells, NSO cells, or HT1080 cells.
[Claim 63]
An immunoconjugate comprising the antibody of any one of claims 1-58 linked to a drug.
[Claim 64]
The antibody of any one of claims 1 to 58, the nucleic acid of claim 59, the vector of claim 60, the cell of claim 61 or claim 62, or the cell of claim 63. A composition comprising an immunoconjugate and a carrier.
[Claim 65]
The antibody of any one of claims 1 to 58, the nucleic acid of claim 59, the vector of claim 60, the cell of claim 61 or claim 62, or the cell of claim 63. A kit containing an immunoconjugate and instructions for use.
[Claim 66]
A method of effecting said inhibition in a subject in need of inhibition of IL-7 activity, said method comprising the antibody of any one of claims 1-58, the nucleic acid of claim 59, the nucleic acid of claim 59, 64. Said method comprising administering to said subject the vector of claim 60, the cell of claim 61 or claim 62, or the immunoconjugate of claim 63.
[Claim 67]
2. A method for effecting the inhibition and/or induction in a subject in need of inhibition of proliferation of effector T cells and/or induction of development and/or survival of regulatory T cells, said method comprising: 58, the nucleic acid of claim 59, the vector of claim 60, the cell of claim 61 or claim 62, or the immune complex of claim 63 to said subject.
[Claim 68]
A method of administering said treatment in a subject in need of treatment for an inflammatory or autoimmune disease, said method comprising the antibody of any one of claims 1-58, the nucleic acid of claim 59 , the vector of claim 60, the cell of claim 61 or claim 62, or the immunoconjugate of claim 63, to the subject.
[Claim 69]
said inflammatory disease or said autoimmune disease is inflammatory bowel disease (IBD), irritable bowel syndrome, rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, vasculitis, sepsis , systemic inflammatory response syndrome (SIRS), type I diabetes, Graves' disease, multiple sclerosis (MS), autoimmune myocarditis, Kawasaki disease, coronary artery disease, chronic obstructive pulmonary disease, interstitial lung disease, autologous Immune thyroiditis, scleroderma, systemic sclerosis, osteoarthritis, atopic dermatitis, vitiligo, graft-versus-host disease, Sjögren's syndrome, autoimmune nephritis, Goodpasture's syndrome, chronic inflammatory demyelinating 69. The method of claim 68, selected from the group consisting of polyneuritis, allergies, asthma, other autoimmune diseases that are the result of acute or chronic inflammation, and any combination thereof.
[Claim 70]
70. The method of claim 69, wherein said inflammatory disease or said autoimmune disease is inflammatory bowel disease.
[Claim 71]
71. The method of claim 69 or claim 70, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
[Claim 72]
72. The subject according to any one of claims 66 to 71, wherein the subject is a subject for which previous TNF-α inhibitor therapy has not been sufficiently successful (responder with insufficient anti-TNF-α effect). Method.
[Claim 73]
73. The method of any one of claims 66-72, further comprising administering one or more additional treatments.
[Claim 74]
74. The method of claim 73, wherein said additional therapy comprises an anti-TNF-α antibody.
[Claim 75]
75. The method of any one of claims 66-74, wherein the antibody is administered to the subject in a flat dose or a weight-based dose.
[Claim 76]
76. The method of any one of claims 66-75, wherein the antibody is administered intravenously, subcutaneously, intramuscularly, intradermally, or intraperitoneally.
[Claim 77]
77. The method of claim 76, wherein said antibody is administered intravenously or subcutaneously.
[Claim 78]
63. A method of producing an antibody that specifically binds to the alpha chain of the human IL-7 receptor (an "anti-IL-7R antibody"), said method comprising treating the cells of claim 61 or claim 62 with a suitable said method comprising culturing under conditions and isolating said antibody.
Claims (25)
（ｉ）前記重鎖ＣＤＲ１が、配列番号１３に示されるアミノ酸配列を含み、
（ｉｉ）前記重鎖ＣＤＲ２が、配列番号１４に示されるアミノ酸配列を含み、
（ｉｉｉ）前記重鎖ＣＤＲ３が、配列番号１５に示されるアミノ酸配列を含み、
（ｉｖ）前記軽鎖ＣＤＲ１が、配列番号１６に示されるアミノ酸配列を含み、
（ｖ）前記軽鎖ＣＤＲ２が、配列番号１７に示されるアミノ酸配列を含み、
（ｖｉ）前記軽鎖ＣＤＲ３が、配列番号１８に示されるアミノ酸配列を含む、
前記抗ＩＬ－７Ｒ抗体又はその抗原結合部分。 An isolated anti-IL-7R antibody or antigen-binding portion thereof that specifically binds to the alpha chain of the human IL-7 receptor (IL-7R), said anti-IL-7R antibody and antigen-binding portion thereof comprising , heavy chain (HC) CDR1, CDR2 and CDR3 and light chain (LC) CDR1, CDR2 and CDR3;
(i) the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 13;
(ii) said heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14;
(iii) said heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 15;
(iv) the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 16;
(v) the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 17;
(vi) said light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 18;
Said anti-IL-7R antibody or antigen-binding portion thereof.
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| KR20220041111A (en) * | 2019-08-02 | 2022-03-31 | 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 | Compositions and methods for targeting and killing alpha-V beta-3-positive cancer stem cells (CSCs) and for treating drug resistant and metastatic cancer |
| US20220389104A1 (en) | 2021-05-28 | 2022-12-08 | Ose Immunotherapeutics | Method for Treating CD127-Positive Cancers by Administering an Anti-CD127 Agent |
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