JPWO2019220369A5 - - Google Patents
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- JPWO2019220369A5 JPWO2019220369A5 JP2020564514A JP2020564514A JPWO2019220369A5 JP WO2019220369 A5 JPWO2019220369 A5 JP WO2019220369A5 JP 2020564514 A JP2020564514 A JP 2020564514A JP 2020564514 A JP2020564514 A JP 2020564514A JP WO2019220369 A5 JPWO2019220369 A5 JP WO2019220369A5
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Description
本明細書に引用又は記載されている各特許、特許出願、及び刊行物の開示は、その全文において本明細書に参考として組み込まれる。
以下に、本願の当初の特許請求の範囲に記載の発明を列挙する。
［発明１］
対象において癌を治療する方法であって、治療に有効な量の抗ＣＤ３８抗体及びＴ細胞リダイレクト治療薬を前記対象に投与して、前記癌を治療することを含む、方法。
［発明２］
癌を有する対象におけるＴ細胞リダイレクト治療薬の有効性を向上させる方法であって、前記対象に抗ＣＤ３８抗体を投与することを含む、方法。
［発明３］
前記抗ＣＤ３８抗体が、前記Ｔ細胞リダイレクト治療薬の投与前に投与される、発明１又は２に記載の方法。
［発明４］
前記Ｔ細胞リダイレクト治療薬が、ＢＣＭＡ、ＧＰＲＣ５Ｄ、ＣＤ３３、ＣＤ１２３、ＣＤ１９、ＰＳＭＡ、ＴＭＥＦＦ２、又はＣＤ２０に結合する、発明１～３のいずれか一つに記載の方法。
［発明５］
前記Ｔ細胞リダイレクト治療薬が、ＣＤ３、ＣＤ３イプシロン（ＣＤ３ε）、ＣＤ８、ＫＩ２Ｌ４、ＮＫＧ２Ｅ、ＮＫＧ２Ｄ、ＮＫＧ２Ｆ、ＢＴＮＬ３、ＣＤ１８６、ＢＴＮＬ８、ＰＤ－１、ＣＤ１９５、又はＮＫＧ２Ｃに結合する、発明１～４のいずれか一つに記載の方法。
［発明６］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号３３の重鎖相補性決定領域１（ＨＣＤＲ１）、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６の軽鎖相補性決定領域１（ＬＣＤＲ１）、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３、
ｂ）配列番号３９の重鎖可変領域（ＶＨ）及び配列番号４０の軽鎖可変領域（ＶＬ）、
ｃ）配列番号７４のＨＣＤＲ１、配列番号７５のＨＣＤＲ２、配列番号７６のＨＣＤＲ３、配列番号７７のＬＣＤＲ１、配列番号７８のＬＣＤＲ２、及び配列番号７９のＬＣＤＲ３、
ｄ）配列番号８０のＶＨ及び配列番号８１のＶＬ、
ｅ）配列番号５３のＣＤ３結合ドメインのＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３、ＬＣＤＲ１、ＬＣＤＲ２、及びＬＣＤＲ３、又は
ｆ）配列番号５３のＣＤ３結合ドメインのＶＨ及びＶＬを含むＣＤ３結合ドメインを含む、発明５に記載の方法。
［発明７］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号２３のＨＣＤＲ１、配列番号２４のＨＣＤＲ２、配列番号２５のＨＣＤＲ３、配列番号２６のＬＣＤＲ１、配列番号２７のＬＣＤＲ２、及び配列番号２８のＬＣＤＲ３を含むＢＣＭＡ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は
ｂ）配列番号２９のＶＨ及び配列番号３０のＶＬを含むＢＣＭＡ結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含む、発明５に記載の方法。
［発明８］
前記Ｔ細胞リダイレクト治療薬が、配列番号３１の第１の重鎖（ＨＣ１）、配列番号３２の第１の軽鎖（ＬＣ１）、配列番号４１の第２の重鎖（ＨＣ２）、及び配列番号４２の第２の軽鎖（ＬＣ２）を含む、発明７に記載の方法。
［発明９］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号４３のＨＣＤＲ１、配列番号４４のＨＣＤＲ２、配列番号４５のＨＣＤＲ３、配列番号４６のＬＣＤＲ１、配列番号４７のＬＣＤＲ２、及び配列番号４８のＬＣＤＲ３を含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は
ｂ）配列番号４９のＶＨ及び配列番号５０のＶＬを含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含む、発明５に記載の方法。
［発明１０］
前記Ｔ細胞リダイレクト治療薬が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、発明９に記載の方法。
［発明１１］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号８４のＨＣＤＲ１、配列番号８５のＨＣＤＲ２、配列番号８６のＨＣＤＲ３、配列番号８７のＬＣＤＲ１、配列番号８８のＬＣＤＲ２、及び配列番号８９のＬＣＤＲ３を含むＣＤ３３結合ドメイン、並びに配列番号７４のＨＣＤＲ１、配列番号７５のＨＣＤＲ２、配列番号７６のＨＣＤＲ３、配列番号７７のＬＣＤＲ１、配列番号７８のＬＣＤＲ２、及び配列番号７９のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は
ｂ）配列番号９０のＶＨ及び配列番号９１のＶＬを含むＣＤ３３結合ドメイン、並びに配列番号８０のＶＨ及び配列番号８１のＶＬを含むＣＤ３結合ドメインを含む、発明５に記載の方法。
［発明１２］
前記Ｔ細胞リダイレクト治療薬が、配列番号９２のＨＣ１、配列番号９３のＬＣ１、配列番号８２のＨＣ２、及び配列番号８３のＬＣ２を含む、発明１１に記載の方法。
［発明１３］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号９４のＨＣＤＲ１、配列番号９５のＨＣＤＲ２、配列番号９６のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号５９のＬＣＤＲ３を含むＣＤ１２３結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は
ｂ）配列番号１００のＶＨ及び配列番号６１のＶＬを含むＣＤ１２３結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含む、発明５に記載の方法。
［発明１４］
前記Ｔ細胞リダイレクト治療薬が、配列番号１０２のＨＣ１、配列番号６３のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、発明１３に記載の方法。
［発明１５］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号５３のＣＤ１９結合ドメインのＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３、ＬＣＤＲ１、ＬＣＤＲ２、及びＬＣＤＲ３を含むＣＤ１９結合ドメイン、並びに配列番号５３のＣＤ３結合ドメインのＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３、ＬＣＤＲ１、ＬＣＤＲ２、及びＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は
ｂ）配列番号５３のアミノ酸配列を含む、発明５に記載の方法。
［発明１６］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号５４のＨＣＤＲ１、配列番号５５のＨＣＤＲ２、配列番号５６のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号５９のＬＣＤＲ３を含むＰＳＭＡ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は
ｂ）配列番号６０のＶＨ及び配列番号６１のＶＬを含むＰＳＭＡ結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含む、発明５に記載の方法。
［発明１７］
前記Ｔ細胞リダイレクト治療薬が、配列番号６２のＨＣ１、配列番号６３のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、発明１６に記載の方法。
［発明１８］
前記Ｔ細胞リダイレクト治療薬が、
ａ）配列番号６４のＨＣＤＲ１、配列番号６５のＨＣＤＲ２、配列番号６６のＨＣＤＲ３、配列番号６７のＬＣＤＲ１、配列番号６８のＬＣＤＲ２、及び配列番号６９のＬＣＤＲ３を含むＴＭＥＦＦ２結合ドメイン、並びに配列番号７４のＨＣＤＲ１、配列番号７５のＨＣＤＲ２、配列番号７６のＨＣＤＲ３、配列番号７７のＬＣＤＲ１、配列番号７８のＬＣＤＲ２、及び配列番号７９のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は
ｂ）配列番号７０のＶＨ及び配列番号７１のＶＬを含むＴＭＥＦＦ２結合ドメイン、並びに配列番号８０のＶＨ及び配列番号８１のＶＬを含むＣＤ３結合ドメインを含む、発明５に記載の方法。
［発明１９］
前記Ｔ細胞リダイレクト治療薬が、配列番号７２のＨＣ１、配列番号７３のＬＣ１、配列番号８２のＨＣ２、及び配列番号８３のＬＣ２を含む、発明１８に記載の方法。
［発明２０］
前記Ｔ細胞リダイレクト治療薬が、多重特異性抗体、キメラ抗原受容体（ＣＡＲ）、又は前記ＣＡＲを含むＴ細胞である、発明１～１９のいずれか一つに記載の方法。
［発明２１］
前記多重特異性抗体が、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、又はＩｇＧ４アイソタイプである、発明２０に記載の方法。
［発明２２］
前記多重特異性抗体が、前記多重特異性抗体のＦｃγ受容体（ＦｃγＲ）への結合を低減する１つ又は２つ以上のＦｃ置換を含む、発明２１に記載の方法。
［発明２３］
前記１つ又は２つ以上のＦｃ置換が、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ、全てのＩｇアイソタイプ上のＮ２９７Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ、ＩｇＧ１上のＫ２１４Ｔ／Ｅ２３３Ｐ／Ｌ２３４Ｖ／Ｌ２３５Ａ／Ｇ２３６欠失／Ａ３２７Ｇ／Ｐ３３１Ａ／Ｄ３６５Ｅ／Ｌ３５８Ｍ、ＩｇＧ２上のＨ２６８Ｑ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ１上のＳ２６７Ｅ／Ｌ３２８Ｆ、ＩｇＧ１上のＬ２３４Ｆ／Ｌ２３５Ｅ／Ｄ２６５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ、及びＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３６欠失／Ｇ２３７Ａ／Ｐ２３８Ｓからなる群から選択され、残基の番号付けが、ＥＵインデックスに従う、発明２２に記載の方法。
［発明２４］
前記多重特異性抗体が、Ｓ２２８Ｐ置換を更に含む、発明２３に記載の方法。
［発明２５］
前記多重特異性抗体が、第１のＣＨ３ドメイン若しくは第２のＣＨ３ドメインに、又は前記第１のＣＨ３ドメイン及び前記第２のＣＨ３ドメインの両方に、１つ又は２つ以上の非対称置換を含む、発明２０～２４のいずれか一つに記載の方法。
［発明２６］
前記１つ又は２つ以上の非対称置換が、Ｆ４５０Ｌ／Ｋ４０９Ｒ、野生型／Ｆ４０９Ｌ＿Ｒ４０９Ｋ、Ｔ３６６Ｙ／Ｆ４０５Ａ、Ｔ３６６Ｗ／Ｆ４０５Ｗ、Ｆ４０５Ｗ／Ｙ４０７Ａ、Ｔ３９４Ｗ／Ｙ４０７Ｔ、Ｔ３９４Ｓ／Ｙ４０７Ａ、Ｔ３６６Ｗ／Ｔ３９４Ｓ、Ｆ４０５Ｗ／Ｔ３９４Ｓ及びＴ３６６Ｗ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、発明２５に記載の方法。
［発明２７］
前記対象が、新たに診断された癌を有する、発明１～２６のいずれか一つに記載の方法。
［発明２８］
前記対象が、以前の抗癌剤療法に対して再発又は難治性である、発明１～２７のいずれか一つに記載の方法。
［発明２９］
前記癌が、血液悪性腫瘍又は固形腫瘍である、発明１～２８のいずれか一つに記載の方法。
［発明３０］
前記血液悪性腫瘍が、多発性骨髄腫、くすぶり型多発性骨髄腫、良性単クローン性γグロブリン血症（ＭＧＵＳ）、急性リンパ性白血病（ＡＬＬ）、びまん性大細胞型Ｂ細胞リンパ腫（ＤＬＢＣＬ）、バーキットリンパ腫（ＢＬ）、濾胞性リンパ腫（ＦＬ）、マントル細胞リンパ腫（ＭＣＬ）、ワルデンストレーム高ガンマグロブリン血症、形質細胞白血病、軽鎖アミロイドーシス（ＡＬ）、前駆体Ｂ細胞リンパ芽球性白血病、前駆体Ｂ細胞リンパ芽球性白血病、急性骨髄性白血病（ＡＭＬ）、骨髄異形成症候群（ＭＤＳ）、慢性リンパ性白血病（ＣＬＬ）、Ｂ細胞悪性腫瘍、慢性骨髄性白血病（ＣＭＬ）、ヘアリー細胞白血病（ＨＣＬ）、芽球性形質細胞様樹状細胞腫瘍、ホジキンリンパ腫、非ホジキンリンパ腫、辺縁帯Ｂ細胞リンパ腫（ＭＺＬ）、又は粘膜関連リンパ組織リンパ腫（ＭＡＬＴ）、形質細胞白血病、未分化大細胞リンパ腫（ＡＬＣＬ）、白血病、又はリンパ腫である、発明２９に記載の方法。
［発明３１］
前記多発性骨髄腫が、新たに診断された多発性骨髄腫である、発明３０に記載の方法。
［発明３２］
前記多発性骨髄腫が、再発又は難治性多発性骨髄腫である、発明３０に記載の方法。
［発明３３］
前記多発性骨髄腫が、高リスク多発性骨髄腫である、発明３１又は３２に記載の方法。
［発明３４］
前記高リスク多発性骨髄腫を有する前記対象が、
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）、
ｃ）ｄｅｌ１７ｐ、
ｄ）１ｑＡｍｐ、
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、発明３３に記載の方法。
［発明３５］
前記多発性骨髄腫が、前記抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ（elotozumab）、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して再発又は難治性である、発明３２に記載の方法。
［発明３６］
前記固形腫瘍が、前立腺癌、肺癌、肝癌、子宮頸癌（cervical cancer）、結腸癌、乳癌、卵巣癌、子宮内膜癌、膵癌、黒色腫、神経膠芽腫、食道癌、胃癌（gastric cancer）、胃癌（stomach cancer）、腎癌、結腸癌、膀胱癌、子宮頸癌（cervical carcinoma）、黒色腫、肝細胞癌、腎細胞癌、尿路上皮癌、頭頸部癌、神経膠腫、又は膠芽腫である、発明２９に記載の方法。
［発明３７］
前記前立腺癌が、再発性、難治性、悪性、若しくは去勢抵抗性前立腺癌、又はこれらの任意の組み合わせである、発明３６に記載の方法。
［発明３８］
前記ＡＭＬが、少なくとも１つの遺伝子異常を伴うＡＭＬ、多系列異形成を伴うＡＭＬ、療法関連ＡＭＬ、未分化ＡＭＬ、最未分化型ＡＭＬ、分化型ＡＭＬ、急性骨髄単球性白血病、急性単球性白血病、急性赤血球性白血病、急性巨核芽球性白血病、急性好塩基球性白血病、線維症を伴う急性汎骨髄症、又は骨髄肉腫である、発明３０に記載の方法。
［発明３９］
前記少なくとも１つの遺伝子異常が、８番染色体と２１番染色体との間の転座、１６番染色体の転座若しくは逆位、１５番染色体と１７番染色体との間の転座、１１番染色体の変化、又はｆｍｓ関連チロシンキナーゼ３（ＦＬＴ３）、ヌクレオフォスミン（ＮＰＭ１）、イソクエン酸デヒドロゲナーゼ１（ＩＤＨ１）、イソクエン酸デヒドロゲナーゼ２（ＩＤＨ２）、ＤＮＡ（シトシン－５）－メチルトランスフェラーゼ３（ＤＮＭＴ３Ａ）、ＣＣＡＡＴ／エンハンサー結合タンパク質アルファ（ＣＥＢＰＡ）、Ｕ２核内低分子ＲＮＡ補助因子１（Ｕ２ＡＦ１）、ｚｅｓｔｅ ２ポリコーム抑制複合体２サブユニットエンハンサー（ＥＺＨ２）、染色体構造維持１Ａ（ＳＭＣ１Ａ）、若しくは染色体構造維持３（ＳＭＣ３）における変異である、発明３８に記載の方法。
［発明４０］
前記少なくとも１つの遺伝子異常が、転座ｔ（８；２１）（ｑ２２；ｑ２２）、逆位ｉｎｖ（１６）（ｐ１３；ｑ２２）、転座ｔ（１６；１６）（ｐ１３；ｑ２２）、転座ｔ（１５；１７）（ｑ２２；ｑ１２）、ＦＬＴ３－ＩＴＤの変異、ＩＤＨ１におけるＲ１３２Ｈ若しくはＲ１００Ｑ／Ｒ１０４Ｖ／Ｆ１０８Ｌ／Ｒ１１９Ｑ／Ｉ１３０Ｖの変異、又はＩＤＨ２におけるＲ１４０Ｑ若しくはＲ１７２の変異である、発明３９に記載の方法。
［発明４１］
前記ＡＬＬが、Ｂ細胞系列ＡＬＬ、Ｔ細胞系列ＡＬＬ、成人ＡＬＬ、又は小児ＡＬＬである、発明３０に記載の方法。
［発明４２］
ＡＬＬを有する前記対象が、フィラデルフィア染色体を有するか、又はＢＣＲ－ＡＢＬキナーゼ阻害剤による治療に対して耐性であるか若しくはそれに対する後天耐性を有する、発明４１に記載の方法。
［発明４３］
前記抗ＣＤ３８抗体が、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、発明１～４２のいずれか一つに記載の方法。
［発明４４］
前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明１～４３のいずれか一つに記載の方法。
［発明４５］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明１～４４のいずれか一つに記載の方法。
［発明４６］
前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明１～４５のいずれか一つに記載の方法。
［発明４７］
前記抗ＣＤ３８抗体が、
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含む、発明１～４２のいずれか一つに記載の方法。
［発明４８］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明４７に記載の方法。
［発明４９］
前記Ｔ細胞リダイレクト治療薬が、ＢＣＭＡ×ＣＤ３二重特異性抗体、ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体、ＣＤ３３×ＣＤ３二重特異性抗体、ＣＤ１９×ＣＤ３二重特異性抗体、ＣＤ１２３×ＣＤ３二重特異性抗体、ＰＳＭＡ×ＣＤ３二重特異性抗体、又はＴＭＥＦＦ２×ＣＤ３二重特異性抗体である、発明１～４８のいずれか一つに記載の方法。
［発明５０］
前記対象に１つ又は２つ以上の抗癌剤療法を投与することを更に含む、発明１～４９のいずれか一つに記載の方法。
［発明５１］
前記１つ又は２つ以上の抗癌剤療法が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、発明５０に記載の方法。
［発明５２］
前記１つ又は２つ以上の抗癌剤療法が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、デキサメタゾン、ビンクリスチン、シクロホスファミド、ヒドロキシダウノルビシン、プレドニゾン、リツキシマブ、イマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ポナチニブ、バフェチニブ、サラカチニブ、トザセルチブ、若しくはダヌセルチブ、シタラビン、ダウノルビシン、イダルビシン、ミトキサントロン、ヒドロキシウレア、デシタビン、クラドリビン、フルダラビン、トポテカン、エトポシド６－チオグアニン、コルチコステロイド、メトトレキサート、６－メルカプトプリン、アザシチジン、三酸化ヒ素、及び全トランス型レチノイン酸、又はこれらの任意の組み合わせからなる群から選択される、発明５１に記載の方法。
［発明５３］
前記抗ＣＤ３８抗体が、約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与される、発明１～５２のいずれか一つに記載の方法。
［発明５４］
前記抗ＣＤ３８抗体が、約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、医薬組成物において投与されるか、又は投与のために提供される、発明１～５３のいずれか一つに記載の方法。
［発明５５］
前記抗ＣＤ３８抗体が、約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供される、発明１～５２のいずれか一つに記載の方法。
［発明５６］
前記抗ＣＤ３８抗体が、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供される、発明５５に記載の方法。
［発明５７］
前記抗ＣＤ３８抗体が、
ａ）約５ｍＭ～約１５ｍＭのヒスチジンと、
ｂ）約１００ｍＭ～約３００ｍＭのソルビトールと、
ｃ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、
ｄ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明５６に記載の方法。
［発明５８］
前記抗ＣＤ３８抗体が、
ａ）約１，８００ｍｇの前記抗ＣＤ３８抗体と、
ｂ）約３０，０００ＵのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明５７に記載の方法。
［発明５９］
前記抗ＣＤ３８抗体が、
ａ）約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明５８に記載の方法。
［発明６０］
対象において癌を治療する方法であって、治療に有効な量のＢＣＭＡ×ＣＤ３二重特異性抗体及び抗ＣＤ３８抗体を前記対象に投与して、前記癌を治療することを含む、方法。
［発明６１］
前記対象が、前記ＢＣＭＡ×ＣＤ３二重特異性抗体の投与前に抗ＣＤ３８抗体で治療されている、発明６０に記載の方法。
［発明６２］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号２３のＨＣＤＲ１、配列番号２４のＨＣＤＲ２、配列番号２５のＨＣＤＲ３、配列番号２６のＬＣＤＲ１、配列番号２７のＬＣＤＲ２、及び配列番号２８のＬＣＤＲ３を含むＢＣＭＡ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメインを含む、発明６０又は６１に記載の方法。
［発明６３］
前記ＢＣＭＡ結合ドメインが、配列番号２９のＶＨ及び配列番号３０のＶＬを含み、前記ＣＤ３結合ドメインが、配列番号３９のＶＨ及び配列番号４０のＶＬを含む、発明６２に記載の方法。
［発明６４］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、ＩｇＧ４アイソタイプであり、ＨＣ１の４０５位にフェニルアラニン及び４０９位にアルギニン、並びにＨＣ２の４０５位にロイシン及び４０９位にリジンを含み、残基の番号付けが、ＥＵインデックスに従う、発明６０～６２のいずれか一つに記載の方法。
［発明６５］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、前記ＨＣ１及び前記ＨＣ２の両方の２２８位にプロリン、２３４位にアラニン、及び２３５位にアラニンを更に含む、発明６４に記載の方法。
［発明６６］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号３１のＨＣ１、配列番号３２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、発明６５に記載の方法。
［発明６７］
前記癌が、ＢＣＭＡ発現癌である、発明６０～６６のいずれか一つに記載の方法。
［発明６８］
前記癌が、血液悪性腫瘍である、発明６０～６７のいずれか一つに記載の方法。
［発明６９］
前記対象が、抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して再発又は難治性である、発明６０～６８のいずれか一つに記載の方法。
［発明７０］
前記対象が、前記抗ＣＤ３８抗体による治療に対して再発又は難治性である、発明６９に記載の方法。
［発明７１］
前記血液悪性腫瘍が、多発性骨髄腫、骨髄腫、ＤＬＢＬＣ、ＣＬＬ、ワルデンストレーム高ガンマグロブリン血症、又は非ホジキンリンパ腫である、発明６８に記載の方法。
［発明７２］
前記多発性骨髄腫が、新たに診断された多発性骨髄腫である、発明７１に記載の方法。
［発明７３］
前記多発性骨髄腫が、再発又は難治性多発性骨髄腫である、発明７１に記載の方法。
［発明７４］
前記多発性骨髄腫が、高リスク多発性骨髄腫である、発明７１～７３のいずれか一つに記載の方法。
［発明７５］
前記高リスク多発性骨髄腫を有する前記対象が、
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）、
ｃ）ｄｅｌ１７ｐ、
ｄ）１ｑＡｍｐ、
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、発明７４に記載の方法。
［発明７６］
前記抗ＣＤ３８抗体が、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、発明６０～７５のいずれか一つに記載の方法。
［発明７７］
前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明６０～７６のいずれか一つに記載の方法。
［発明７８］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明６０～７７のいずれか一つに記載の方法。
［発明７９］
前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明６０～７８のいずれか一つに記載の方法。
［発明８０］
前記抗ＣＤ３８抗体が、
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含む、発明６０～７５のいずれか一つに記載の方法。
［発明８１］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明８０に記載の方法。
［発明８２］
前記抗ＣＤ３８抗体が、約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与される、発明６０～８１のいずれか一つに記載の方法。
［発明８３］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体及び前記抗ＣＤ３８抗体が、静脈内注射によって投与される、発明６０～８２のいずれか一つに記載の方法。
［発明８４］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、静脈内注射によって投与され、前記抗ＣＤ３８抗体が、皮下注射によって投与される、発明６０～８２のいずれか一つに記載の方法。
［発明８５］
前記対象が、ヒトである、発明６０～８４のいずれか一つに記載の方法。
［発明８６］
前記対象に１つ又は２つ以上の抗癌剤療法を投与することを更に含む、発明６０～８５のいずれか一つに記載の方法。
［発明８７］
前記１つ又は２つ以上の抗癌剤療法が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、発明８６に記載の方法。
［発明８８］
前記１つ又は２つ以上の抗癌剤療法が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、プレドニゾン、若しくはデキサメタゾン、又はこれらの任意の組み合わせからなる群から選択される、発明８６に記載の方法。
［発明８９］
前記抗ＣＤ３８抗体が、約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、医薬組成物において投与されるか、又は投与のために提供される、発明６０～８８のいずれか一つに記載の方法。
［発明９０］
前記抗ＣＤ３８抗体が、約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供される、発明６０～８８のいずれか一つに記載の方法。
［発明９１］
前記抗ＣＤ３８抗体が、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供される、発明９０に記載の方法。
［発明９２］
前記抗ＣＤ３８抗体が、
ａ）約５ｍＭ～約１５ｍＭのヒスチジンと、
ｂ）約１００ｍＭ～約３００ｍＭのソルビトールと、
ｃ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、
ｄ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明９１に記載の方法。
［発明９３］
前記抗ＣＤ３８抗体が、
ａ）約１，８００ｍｇの前記抗ＣＤ３８抗体と、
ｂ）約３０，０００ＵのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明９２に記載の方法。
［発明９４］
前記抗ＣＤ３８抗体が、
ａ）約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明９３に記載の方法。
［発明９５］
配列番号２９のＶＨ及び配列番号３０のＶＬを含むＢＣＭＡ結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含むＢＣＭＡｘＣＤ３二重特異性抗体と、配列番号４のＶＨ及び配列番号５のＶＬを含む抗ＣＤ３８抗体とを含む、医薬組成物。
［発明９６］
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号３１のＨＣ１、配列番号３２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含み、前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明９５に記載の医薬組成物。
［発明９７］
非固定組み合わせである、発明９５又は９６に記載の医薬組成物。
［発明９８］
約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、発明９７に記載の医薬組成物。
［発明９９］
約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む、発明９７に記載の医薬組成物。
［発明１００］
約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む、発明９９に記載の医薬組成物。
［発明１０１］
１つ又は２つ以上の賦形剤を更に含む、発明１００に記載の医薬組成物。
［発明１０２］
前記１つ又は２つ以上の賦形剤が、ヒスチジン、メチオニン、ソルビトール、若しくはポリソルベート－２０（ＰＳ－２０）、又はこれらの任意の組み合わせである、発明１０１に記載の医薬組成物。
［発明１０３］
前記医薬組成物が、
ａ）約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約５ｍＭ～約１５ｍＭのヒスチジンと、
ｃ）約１００ｍＭ～約３００ｍＭのソルビトールと、
ｄ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、
ｅ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、発明１０２に記載の医薬組成物。
［発明１０４］
約１０ｍＭのヒスチジンを含む、発明１０３に記載の医薬組成物。
［発明１０５］
約３００ｍＭのソルビトールを含む、発明１０３又は１０４に記載の医薬組成物。
［発明１０６］
約０．０４％（ｗ／ｖ）のＰＳ－２０を含む、発明１０３～１０５のいずれか一つに記載の医薬組成物。
［発明１０７］
約１ｍｇ／ｍＬのメチオニンを含む、発明１０３～１０６のいずれか一つに記載の医薬組成物。
［発明１０８］
ａ）約１，８００ｍｇの前記抗ＣＤ３８抗体と、
ｂ）約３０，０００ＵのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、発明１０３～１０７のいずれか一つに記載の医薬組成物。
［発明１０９］
ａ）約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、発明１０３～１０９のいずれか一つに記載の医薬組成物。
［発明１１０］
発明９５～１０９のいずれか一つに記載の医薬組成物を含む、キット。
［発明１１１］
対象において癌を治療する方法であって、治療に有効な量のＧＰＲＣ５Ｄに結合するＴ細胞リダイレクト治療薬及び抗ＣＤ３８抗体を前記対象に投与して、前記癌を治療することを含む、方法。
［発明１１２］
前記抗ＣＤ３８抗体が、ＧＰＲＣ５Ｄに結合する前記Ｔ細胞リダイレクト治療薬の投与前に対象に投与される、発明１１１に記載の方法。
［発明１１３］
前記対象が、以前の抗癌治療薬による治療に対して再発又は難治性である、発明１１１又は１１２に記載の方法。
［発明１１４］
前記癌が、ＧＰＲＣ５Ｄ発現癌である、発明１１１～１１３のいずれか一つに記載の方法。
［発明１１５］
前記ＧＰＲＣ５Ｄ発現癌が、血液悪性腫瘍又は固形腫瘍である、発明１１４に記載の方法。
［発明１１６］
前記血液悪性腫瘍が、白血病、リンパ腫、又は多発性骨髄腫である、発明１１５に記載の方法。
［発明１１７］
前記固形腫瘍が、卵巣癌、肺癌、胃癌、前立腺癌、腎癌、肝癌、膵癌、結腸癌、食道癌、膀胱癌、子宮頸癌、又は悪性黒色腫である、発明１１６に記載の方法。
［発明１１８］
前記対象が、前記抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して再発又は難治性である、発明１１１～１１７のいずれか一つに記載の方法。
［発明１１９］
前記対象が、前記抗ＣＤ３８抗体による治療に対して再発又は難治性である、発明１１８に記載の方法。
［発明１２０］
前記多発性骨髄腫が、新たに診断された多発性骨髄腫である、発明１１７に記載の方法。
［発明１２１］
前記多発性骨髄腫が、再発又は難治性多発性骨髄腫である、発明１１７に記載の方法。
［発明１２２］
前記多発性骨髄腫が、高リスク多発性骨髄腫である、発明１２０又は１２１に記載の方法。
［発明１２３］
前記高リスク多発性骨髄腫を有する前記対象が、
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）、
ｃ）ｄｅｌ１７ｐ、
ｄ）１ｑＡｍｐ、
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、発明１２２に記載の方法。
［発明１２４］
前記Ｔ細胞リダイレクト治療薬が、ＣＤ３、ＣＤ３イプシロン（ＣＤ３ε）、ＣＤ８、ＫＩ２Ｌ４、ＮＫＧ２Ｅ、ＮＫＧ２Ｄ、ＮＫＧ２Ｆ、ＢＴＮＬ３、ＣＤ１８６、ＢＴＮＬ８、ＰＤ－１、ＣＤ１９５、又はＮＫＧ２Ｃに結合する、発明１１１～１２３のいずれか一つに記載の方法。
［発明１２５］
前記Ｔ細胞リダイレクト治療薬が、配列番号４３のＨＣＤＲ１、配列番号４４のＨＣＤＲ２、配列番号４５のＨＣＤＲ３、配列番号４６のＬＣＤＲ１、配列番号４７のＬＣＤＲ２、及び配列番号４８のＬＣＤＲ３を含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメインを含む、発明１１１～１２４のいずれか一つに記載の方法。
［発明１２６］
前記ＧＰＲＣ５Ｄ結合ドメインが、配列番号４９のＶＨ及び配列番号５０のＶＬを含み、前記ＣＤ３結合ドメインが、配列番号３９のＶＨ及び配列番号４０のＶＬを含む、発明１１１～１２６のいずれか一つに記載の方法。
［発明１２７］
ＧＰＲＣ５Ｃに結合する前記Ｔ細胞リダイレクト治療薬が、多重特異性抗体、ＣＡＲ、又は前記ＣＡＲを発現するＴ細胞である、発明１１１～１２６のいずれか一つに記載の方法。
［発明１２８］
前記多重特異性抗体が、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、又はＩｇＧ４アイソタイプである、発明１２７に記載の方法。
［発明１２９］
前記多重特異性抗体が、前記多重特異性抗体のＦｃγ受容体（ＦｃγＲ）への結合を低減する１つ又は２つ以上のＦｃ置換を含む、発明１２８に記載の方法。
［発明１３０］
前記１つ又は２つ以上のＦｃ置換が、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ、全てのＩｇアイソタイプ上のＮ２９７Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ、ＩｇＧ１上のＫ２１４Ｔ／Ｅ２３３Ｐ／Ｌ２３４Ｖ／Ｌ２３５Ａ／Ｇ２３６欠失／Ａ３２７Ｇ／Ｐ３３１Ａ／Ｄ３６５Ｅ／Ｌ３５８Ｍ、ＩｇＧ２上のＨ２６８Ｑ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ１上のＳ２６７Ｅ／Ｌ３２８Ｆ、ＩｇＧ１上のＬ２３４Ｆ／Ｌ２３５Ｅ／Ｄ２６５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ、及びＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３６欠失／Ｇ２３７Ａ／Ｐ２３８Ｓからなる群から選択され、残基の番号付けが、ＥＵインデックスに従う、発明１２９に記載の方法。
［発明１３１］
前記多重特異性抗体が、Ｓ２２８Ｐ置換を更に含む、発明１３０に記載の方法。
［発明１３２］
前記多重特異性抗体が、第１のＣＨ３ドメイン若しくは第２のＣＨ３ドメインに、又は前記第１のＣＨ３ドメイン及び前記第２のＣＨ３ドメインの両方に、１つ又は２つ以上の非対称置換を含む、発明１２７～１３１のいずれか一つに記載の方法。
［発明１３３］
前記１つ又は２つ以上の非対称置換が、Ｆ４５０Ｌ／Ｋ４０９Ｒ、野生型／Ｆ４０９Ｌ＿Ｒ４０９Ｋ、Ｔ３６６Ｙ／Ｆ４０５Ａ、Ｔ３６６Ｗ／Ｆ４０５Ｗ、Ｆ４０５Ｗ／Ｙ４０７Ａ、Ｔ３９４Ｗ／Ｙ４０７Ｔ、Ｔ３９４Ｓ／Ｙ４０７Ａ、Ｔ３６６Ｗ／Ｔ３９４Ｓ、Ｆ４０５Ｗ／Ｔ３９４Ｓ及びＴ３６６Ｗ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、発明１３２に記載の方法。
［発明１３４］
前記多重特異性抗体が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、発明１１１～１３３のいずれか一つに記載の方法。
［発明１３５］
前記抗ＣＤ３８抗体が、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、発明１１１～１３４のいずれか一つに記載の方法。
［発明１３６］
前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明１１１～１３５のいずれか一つに記載の方法。
［発明１３７］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明１１１～１３６のいずれか一つに記載の方法。
［発明１３８］
前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明１１１～１３７のいずれか一つに記載の方法。
［発明１３９］
前記抗ＣＤ３８抗体が、
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含む、発明１１１～１３８のいずれか一つに記載の方法。
［発明１４０］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明１３９に記載の方法。
［発明１４１］
前記抗ＣＤ３８抗体が、約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与される、発明１１１～１４０のいずれか一つに記載の方法。
［発明１４２］
ＧＰＲＣ５Ｄに結合する前記Ｔ細胞リダイレクト治療薬及び前記抗ＣＤ３８抗体が、静脈内注射によって投与される、発明１１１～１４１のいずれか一つに記載の方法。
［発明１４３］
ＧＰＲＣ５Ｄに結合する前記Ｔ細胞リダイレクト治療薬が、静脈内注射によって投与され、前記抗ＣＤ３８抗体が、皮下注射によって投与される、発明１１１～１４２のいずれか一つに記載の方法。
［発明１４４］
前記対象が、ヒトである、発明１１１～１４３のいずれか一つに記載の方法。
［発明１４５］
ＧＰＲＣ５Ｄに結合する前記Ｔ細胞リダイレクト治療薬が、ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体である、発明１１１～１４４のいずれか一つに記載の方法。
［発明１４６］
前記対象に１つ又は２つ以上の抗癌剤療法を投与することを更に含む、発明１１１～１４５のいずれか一つに記載の方法。
［発明１４７］
前記１つ又は２つ以上の抗癌剤療法が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、発明１４６に記載の方法。
［発明１４８］
前記１つ又は２つ以上の抗癌剤療法が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、デキサメタゾン、又はプレドニゾンからなる群から選択される、発明１４６に記載の方法。
［発明１４９］
前記抗ＣＤ３８抗体が、約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、医薬組成物において投与されるか、又は投与のために提供される、発明１１１～１４８のいずれか一つに記載の方法。
［発明１５０］
前記抗ＣＤ３８抗体が、約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供される、発明１１１～１４９のいずれか一つに記載の方法。
［発明１５１］
前記抗ＣＤ３８抗体が、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供される、発明１５０に記載の方法。
［発明１５２］
前記抗ＣＤ３８抗体が、
ａ）約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約５ｍＭ～約１５ｍＭのヒスチジンと、
ｃ）約１００ｍＭ～約３００ｍＭのソルビトールと、
ｄ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、
ｅ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明１５１に記載の方法。
［発明１５３］
前記抗ＣＤ３８抗体が、
ａ）約１，８００ｍｇの前記抗ＣＤ３８抗体と、
ｂ）約３０，０００ＵのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明１５２に記載の方法。
［発明１５４］
前記抗ＣＤ３８抗体が、
ａ）約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供される、発明１５３に記載の方法。
［発明１５５］
配列番号４３のＨＣＤＲ１、配列番号４４のＨＣＤＲ２、配列番号４５のＨＣＤＲ３、配列番号４６のＬＣＤＲ１、配列番号４７のＬＣＤＲ２、及び配列番号４８のＬＣＤＲ３を含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメインを含むＧＰＲＣ５Ｃ×ＣＤ３二重特異性抗体と、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む抗ＣＤ３８抗体とを含む、医薬組み合わせ。
［発明１５６］
前記ＧＰＲＣ５Ｄ結合ドメインが、配列番号４９のＶＨ及び配列番号５０のＶＬを含み、前記ＣＤ３結合ドメインが、配列番号３９のＶＨ及び配列番号４０のＶＬを含み、前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明１５５に記載の医薬組み合わせ。
［発明１５７］
前記ＧＰＲＣ５Ｃ×ＣＤ３二重特異性抗体が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含み、前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明１５６に記載の医薬組み合わせ。
［発明１５８］
非固定組み合わせである、発明１５５～１５７のいずれか一つに記載の医薬組み合わせ。
［発明１５９］
約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、発明１５８に記載の医薬組み合わせ。
［発明１６０］
約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む、発明１５８に記載の医薬組み合わせ。
［発明１６１］
約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む、発明１５９に記載の医薬組成物。
［発明１６２］
１つ又は２つ以上の賦形剤を更に含む、発明１６１に記載の医薬組み合わせ。
［発明１６３］
前記１つ又は２つ以上の賦形剤が、ヒスチジン、メチオニン、ソルビトール、若しくはポリソルベート－２０（ＰＳ－２０）、又はこれらの任意の組み合わせである、発明１６２に記載の医薬組み合わせ。
［発明１６４］
前記医薬組成物が、
ａ）約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約５ｍＭ～約１５ｍＭのヒスチジンと、
ｃ）約１００ｍＭ～約３００ｍＭのソルビトールと、
ｄ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、
ｅ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、発明１６３に記載の医薬組み合わせ。
［発明１６５］
約１０ｍＭのヒスチジンを含む、発明１６４に記載の医薬組み合わせ。
［発明１６６］
約３００ｍＭのソルビトールを含む、発明１６４又は１６５に記載の医薬組み合わせ。
［発明１６７］
約０．０４％（ｗ／ｖ）のＰＳ－２０を含む、発明１６３～１６６のいずれか一つに記載の医薬組み合わせ。
［発明１６８］
約１ｍｇ／ｍＬのメチオニンを含む、発明１６３～１６７のいずれか一つに記載の医薬組み合わせ。
［発明１６９］
ａ）約１，８００ｍｇの前記抗ＣＤ３８抗体と、
ｂ）約３０，０００ＵのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、発明１６３～１６８のいずれか一つに記載の医薬組み合わせ。
［発明１７０］
ａ）約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、発明１６４～１６９のいずれか一つに記載の医薬組み合わせ。
［発明１７１］
発明１５５～１７１のいずれか一つに記載の医薬組み合わせを含む、キット。
［発明１７２］
対象において癌を治療する方法であって、治療に有効な量のＣＤ１９に結合するＴ細胞リダイレクト治療薬及び抗ＣＤ３８抗体を前記対象に投与して、前記癌を治療することを含む、方法。
［発明１７３］
前記対象が、ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬の投与前に抗ＣＤ３８抗体で治療されている、発明１７２に記載の方法。
［発明１７４］
癌を有する対象におけるＣＤ１９に結合するＴ細胞リダイレクト治療薬の有効性を向上させる方法であって、ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬の投与前に前記対象に抗ＣＤ３８抗体を投与することを含む、方法。
［発明１７５］
前記対象が、以前の抗癌治療薬による治療に対して難治性又は再発性である、発明１７２～１７４のいずれか一つに記載の方法。
［発明１７６］
前記癌が、血液悪性腫瘍又は固形腫瘍である、発明１７２～１７５のいずれか一つに記載の方法。
［発明１７７］
前記血液悪性腫瘍が、リンパ腫、Ｂ細胞悪性腫瘍、ホジキンリンパ腫、非ホジキンリンパ腫、ＤＬＢＬＣ、ＦＬ、ＭＣＬ、辺縁帯Ｂ細胞リンパ腫（ＭＺＬ）、粘膜関連リンパ組織リンパ腫（ＭＡＬＴ）、ＣＬＬ、ＡＬＬ、ＡＭＬ、ワルデンストレーム高ガンマグロブリン血症、又はＴ細胞リンパ腫である、発明１７６に記載の方法。
［発明１７８］
前記固形腫瘍が、肺癌、肝癌、子宮頸癌、結腸癌、乳癌、卵巣癌、膵癌、黒色腫、神経膠芽腫、前立腺癌、食道癌、又は胃癌である、発明１７６に記載の方法。
［発明１７９］
前記Ｔ細胞リダイレクト治療薬が、ＣＤ３イプシロン（ＣＤ３ε）、ＣＤ８、ＫＩ２Ｌ４、ＮＫＧ２Ｅ、ＮＫＧ２Ｄ、ＮＫＧ２Ｆ、ＢＴＮＬ３、ＣＤ１８６、ＢＴＮＬ８、ＰＤ－１、ＣＤ１９５、又はＮＫＧ２Ｃに結合する、発明１７２～１７８のいずれか一つに記載の方法。
［発明１８０］
ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、ブリナツモマブ、アキシカブタゲンシロロイセル、チサゲンレクルユーセル－ｔ、イネビリズマブ、リソカブタゲンマラルユーセル（lisocabtagene maraleucel）、ＸｍＡｂ－５５７４、ＣＩＫ－ＣＡＲ．ＣＤ１９、ＩＣＴＣＡＲ－０１１、ＩＭ－１９、ＪＣＡＲ－０１４、ロンカスツキシマブテシリン、ＭＢ－ＣＡＲＴ２０１９．１、ＯＸＳ－１５５０、ＰＢＣＡＲ－０１９１、ＰＣＡＲ－０１９、ＰＣＡＲ－１１９、Ｓｅｎｌ－００１、ＴＩ－１００７、ＸｍＡｂ－５８７１、ＰＴＧ－０１、ＰＺ０１、Ｓｅｎｌ＿１９０４Ａ、Ｓｅｎｌ＿１９０４Ｂ、ＵＣＡＲＴ－１９、ＣＳＧ－ＣＤ１９、ＤＩ－Ｂ４、ＥＴ－１９０、ＧＣ－００７Ｆ、又はＧＣ－０２２のＣＤ１９結合ドメインを含む、発明１７２～１７９のいずれか一つに記載の方法。
［発明１８１］
ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、ブリナツモマブ、アキシカブタゲンシロロイセル、チサゲンレクルユーセル－ｔ、イネビリズマブ、リソカブタゲンマラルユーセル、ＸｍＡｂ－５５７４、ＣＩＫ－ＣＡＲ．ＣＤ１９、ＩＣＴＣＡＲ－０１１、ＩＭ－１９、ＪＣＡＲ－０１４、ロンカスツキシマブテシリン、ＭＢ－ＣＡＲＴ２０１９．１、ＯＸＳ－１５５０、ＰＢＣＡＲ－０１９１、ＰＣＡＲ－０１９、ＰＣＡＲ－１１９、Ｓｅｎｌ－００１、ＴＩ－１００７、ＸｍＡｂ－５８７１、ＰＴＧ－０１、ＰＺ０１、Ｓｅｎｌ＿１９０４Ａ、Ｓｅｎｌ＿１９０４Ｂ、ＵＣＡＲＴ－１９、ＣＳＧ－ＣＤ１９、ＤＩ－Ｂ４、ＥＴ－１９０、ＧＣ－００７Ｆ、又はＧＣ－０２２を含む、発明１７２～１８０のいずれか一つに記載の方法。
［発明１８２］
ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、多重特異性抗体、ＣＡＲ、又は前記ＣＡＲを発現するＴ細胞である、発明１７２～１８１のいずれか一つに記載の方法。
［発明１８３］
前記抗ＣＤ３８抗体が、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、発明１７２～１８２のいずれか一つに記載の方法。
［発明１８４］
前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明１７２～１８３のいずれか一つに記載の方法。
［発明１８５］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明１７２～１８４のいずれか一つに記載の方法。
［発明１８６］
前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明１７２～１８５のいずれか一つに記載の方法。
［発明１８７］
前記抗ＣＤ３８抗体が、
ａ）配列番号１４のＶＨ及び配列番号１５のＶＬ、
ｂ）配列番号１６のＶＨ及び配列番号１７のＶＬ、
ｃ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は
ｄ）配列番号２０のＶＨ及び配列番号２１のＶＬを含む、発明１７２～１８２のいずれか一つに記載の方法。
［発明１８８］
前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、発明１８７に記載の方法。
［発明１８９］
前記抗ＣＤ３８抗体が、約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与される、発明１７２～１８８のいずれか一つに記載の方法。
［発明１９０］
ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬及び前記抗ＣＤ３８抗体が、静脈内注射によって投与される、発明１７２～１８９のいずれか一つに記載の方法。
［発明１９１］
ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、静脈内注射によって投与され、前記抗ＣＤ３８抗体が、皮下注射によって投与される、発明１７２～１８９のいずれか一つに記載の方法。
［発明１９２］
前記対象が、ヒトである、発明１７２～１９１のいずれか一つに記載の方法。
［発明１９３］
ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、ＣＤ１９×ＣＤ３二重特異性抗体である、発明１７２～１９２のいずれか一つに記載の方法。
［発明１９４］
前記対象に１つ又は２つ以上の抗癌剤療法を投与することを更に含む、発明１７２～１９３のいずれか一つに記載の方法。
［発明１９５］
前記１つ又は２つ以上の抗癌剤療法が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、発明１９４に記載の方法。
［発明１９６］
配列番号５３のブリナツモマブを含むＣＤ１９×ＣＤ３二重特異性抗体、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む抗ＣＤ３８抗体を含む、医薬組み合わせ。
［発明１９７］
前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、発明１９６に記載の医薬組み合わせ。
［発明１９８］
前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、発明１９７に記載の医薬組み合わせ。
［発明１９９］
非固定組み合わせである、発明１９６～１９８のいずれか一つに記載の医薬組み合わせ。
［発明２００］
約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、発明１９９に記載の医薬組み合わせ。
［発明２０１］
約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む、発明１９９に記載の医薬組み合わせ。
［発明２０２］
約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む、発明２０１に記載の医薬組み合わせ。
［発明２０３］
１つ又は２つ以上の賦形剤を更に含む、発明２０２に記載の医薬組み合わせ。
［発明２０４］
前記１つ又は２つ以上の賦形剤が、ヒスチジン、メチオニン、ソルビトール、若しくはポリソルベート－２０（ＰＳ－２０）、又はこれらの任意の組み合わせである、発明２０３に記載の医薬組み合わせ。
［発明２０５］
前記医薬組み合わせが、
ａ）約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約５ｍＭ～約１５ｍＭのヒスチジンと、
ｃ）約１００ｍＭ～約３００ｍＭのソルビトールと、
ｄ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、
ｅ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、発明２０４に記載の医薬組み合わせ。
［発明２０６］
約１０ｍＭのヒスチジンを含む、発明２０５に記載の医薬組み合わせ。
［発明２０７］
約３００ｍＭのソルビトールを含む、発明２０５又は２０６に記載の医薬組み合わせ。
［発明２０８］
約０．０４％（ｗ／ｖ）のＰＳ－２０を含む、発明２０５～２０７のいずれか一つに記載の医薬組み合わせ。
［発明２０９］
約１ｍｇ／ｍＬのメチオニンを含む、発明２０５～２０８のいずれか一つに記載の医薬組み合わせ。
［発明２１０］
ａ）約１，８００ｍｇの前記抗ＣＤ３８抗体と、
ｂ）約３０，０００ＵのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、発明２０５～２０９のいずれか一つに記載の医薬組み合わせ。
［発明２１１］
ａ）約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、
ｂ）約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、
ｃ）約１０ｍＭのヒスチジンと、
ｄ）約３００ｍＭのソルビトールと、
ｅ）約０．０４％（ｗ／ｖ）のＰＳ－２０と、
ｆ）約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、発明２０５～２１０のいずれか一つに記載の医薬組成物。
［発明２１２］
発明１９６～２１１のいずれか一つに記載の医薬組成物を含む、キット。
The disclosure of each patent, patent application, and publication cited or described herein is hereby incorporated by reference in its entirety.
Listed below are the inventions originally claimed in this application.
[Invention 1]
A method of treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of an anti-CD38 antibody and a T-cell redirecting therapeutic agent to treat said cancer.
[Invention 2]
A method of improving the efficacy of a T-cell redirecting therapeutic in a subject with cancer, comprising administering an anti-CD38 antibody to said subject.
[Invention 3]
The method of invention 1 or 2, wherein said anti-CD38 antibody is administered prior to administration of said T cell redirecting therapeutic.
[Invention 4]
4. The method of any one of inventions 1-3, wherein the T cell redirecting therapeutic agent binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, or CD20.
[Invention 5]
5. Any of inventions 1-4, wherein the T cell redirecting therapeutic binds to CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C. or the method described in one.
[Invention 6]
wherein the T-cell redirecting therapeutic is
a) heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38,
b) a heavy chain variable region (VH) of SEQ ID NO:39 and a light chain variable region (VL) of SEQ ID NO:40;
c) HCDR1 of SEQ ID NO:74, HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78 and LCDR3 of SEQ ID NO:79;
d) VH of SEQ ID NO:80 and VL of SEQ ID NO:81,
e) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53, or
f) A method according to invention 5, comprising a CD3 binding domain comprising the VH and VL of the CD3 binding domain of SEQ ID NO:53.
[Invention 7]
wherein the T-cell redirecting therapeutic is
a) a BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27 and LCDR3 of SEQ ID NO:28, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
b) A method according to invention 5, comprising a BCMA binding domain comprising the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.
[Invention 8]
wherein the T-cell redirecting therapeutic comprises the first heavy chain (HC1) of SEQ ID NO:31, the first light chain (LC1) of SEQ ID NO:32, the second heavy chain (HC2) of SEQ ID NO:41, and SEQ ID NO:41 8. The method of invention 7, comprising 42 second light chains (LC2).
[Invention 9]
wherein the T-cell redirecting therapeutic is
a) a GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
b) A method according to invention 5, comprising a GPRC5D binding domain comprising the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.
[Invention 10]
10. The method of claim 9, wherein said T-cell redirecting therapeutic comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.
[Invention 11]
wherein the T-cell redirecting therapeutic is
a) a CD33 binding domain comprising HCDR1 of SEQ ID NO:84, HCDR2 of SEQ ID NO:85, HCDR3 of SEQ ID NO:86, LCDR1 of SEQ ID NO:87, LCDR2 of SEQ ID NO:88 and LCDR3 of SEQ ID NO:89, and HCDR1 of SEQ ID NO:74 , HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78, and LCDR3 of SEQ ID NO:79, and/or
b) A method according to invention 5, comprising a CD33 binding domain comprising the VH of SEQ ID NO:90 and the VL of SEQ ID NO:91, and a CD3 binding domain comprising the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81.
[Invention 12]
12. The method of invention 11, wherein said T-cell redirecting therapeutic comprises HC1 of SEQ ID NO:92, LC1 of SEQ ID NO:93, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83.
[Invention 13]
wherein the T-cell redirecting therapeutic is
a) a CD123 binding domain comprising HCDR1 of SEQ ID NO:94, HCDR2 of SEQ ID NO:95, HCDR3 of SEQ ID NO:96, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:59, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
b) A method according to invention 5, comprising a CD123 binding domain comprising the VH of SEQ ID NO:100 and the VL of SEQ ID NO:61, and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.
[Invention 14]
14. The method of claim 13, wherein said T-cell redirecting therapeutic comprises HC1 of SEQ ID NO:102, LC1 of SEQ ID NO:63, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.
[Invention 15]
wherein the T-cell redirecting therapeutic is
a) a CD19 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD19 binding domain of SEQ ID NO:53 and HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53 a CD3 binding domain comprising, and/or
b) A method according to invention 5, comprising the amino acid sequence of SEQ ID NO:53.
[Invention 16]
wherein the T-cell redirecting therapeutic is
a) a PSMA binding domain comprising HCDR1 of SEQ ID NO:54, HCDR2 of SEQ ID NO:55, HCDR3 of SEQ ID NO:56, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:59, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
b) A method according to invention 5, comprising a PSMA binding domain comprising the VH of SEQ ID NO:60 and the VL of SEQ ID NO:61, and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.
[Invention 17]
17. The method of invention 16, wherein said T-cell redirecting therapeutic comprises HC1 of SEQ ID NO:62, LC1 of SEQ ID NO:63, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.
[Invention 18]
wherein the T-cell redirecting therapeutic is
a) a TMEFF2 binding domain comprising HCDR1 of SEQ ID NO:64, HCDR2 of SEQ ID NO:65, HCDR3 of SEQ ID NO:66, LCDR1 of SEQ ID NO:67, LCDR2 of SEQ ID NO:68, and LCDR3 of SEQ ID NO:69, and HCDR1 of SEQ ID NO:74 , HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78, and LCDR3 of SEQ ID NO:79, and/or
b) A method according to invention 5, comprising a TMEFF2 binding domain comprising the VH of SEQ ID NO:70 and the VL of SEQ ID NO:71, and a CD3 binding domain comprising the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81.
[Invention 19]
19. The method of invention 18, wherein said T-cell redirecting therapeutic comprises HC1 of SEQ ID NO:72, LC1 of SEQ ID NO:73, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83.
[Invention 20]
20. The method of any one of inventions 1-19, wherein said T cell redirecting therapeutic is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell comprising said CAR.
[Invention 21]
The method of invention 20, wherein said multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.
[Invention 22]
The method of invention 21, wherein said multispecific antibody comprises one or more Fc substitutions that reduce binding of said multispecific antibody to Fcγ receptors (FcγR).
[Invention 23]
wherein said one or more Fc substitutions are F234A/L235A on IgG4, L234A/L235A on IgG1, V234A/G237A/P238S/H268A/V309L/A330S/P331S on IgG2, F234A/L235A on IgG4; S228P/F234A/L235A on IgG4, N297A on all Ig isotypes, V234A/G237A on IgG2, K214T/E233P/L234V/L235A/G236 deletion/A327G/P331A/D365E/L358M on IgG1, on IgG2 H268Q/V309L/A330S/P331S, S267E/L328F on IgG1, L234F/L235E/D265A on IgG1, L234A/L235A/G237A/P238S/H268A/A330S/P331S on IgG1, S228A/L2334 on IgG4 G237A/P238S, and S228P/F234A/L235A/G236 deletion on IgG4/G237A/P238S, wherein residue numbering is according to the EU index.
[Invention 24]
The method of invention 23, wherein said multispecific antibody further comprises a S228P substitution.
[Invention 25]
said multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain; The method according to any one of Inventions 20-24.
[Invention 26]
said one or more asymmetric substitutions are ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、発明２５に記載の方法。
[Invention 27]
The method of any one of inventions 1-26, wherein said subject has a newly diagnosed cancer.
[Invention 28]
28. The method of any one of inventions 1-27, wherein the subject is relapsed or refractory to previous anticancer drug therapy.
[Invention 29]
The method of any one of inventions 1-28, wherein said cancer is a hematological malignancy or a solid tumor.
[Invention 30]
The hematological malignancy is multiple myeloma, smoldering multiple myeloma, benign monoclonal gammaglobulinemia (MGUS), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenström hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic Leukemia, precursor B-cell lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancy, chronic myelogenous leukemia (CML), hairy Cellular leukemia (HCL), blastic plasmacytoid dendritic cell tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, marginal zone B-cell lymphoma (MZL), or mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia, undifferentiated 30. The method of invention 29, which is large cell lymphoma (ALCL), leukemia, or lymphoma.
[Invention 31]
31. The method of invention 30, wherein said multiple myeloma is newly diagnosed multiple myeloma.
[Invention 32]
31. The method of invention 30, wherein said multiple myeloma is relapsed or refractory multiple myeloma.
[Invention 33]
33. The method of invention 31 or 32, wherein said multiple myeloma is high-risk multiple myeloma.
[Invention 34]
wherein said subject with said high-risk multiple myeloma is
a) t(4;14)(p16;q32),
b) t(14;16)(q32;q23),
c) del17p,
d) 1qAmp,
e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
f) t(4;14)(p16;q32) and del17p,
g) t(14;16)(q32;q23) and del17p, or
h) having one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, Invention 33 The method described in .
[Invention 35]
said multiple myeloma is relapsed or refractory to treatment with said anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof , invention 32.
[Invention 36]
said solid tumor is prostate cancer, lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer ), stomach cancer, renal cancer, colon cancer, bladder cancer, cervical carcinoma, melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, or The method according to invention 29, which is glioblastoma.
[Invention 37]
37. The method of invention 36, wherein the prostate cancer is recurrent, refractory, malignant, or castration-resistant prostate cancer, or any combination thereof.
[Invention 38]
said AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, therapy-related AML, undifferentiated AML, minimally differentiated AML, differentiated AML, acute myelomonocytic leukemia, acute monocytic 31. The method of invention 30, which is leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelopathy with fibrosis, or myelosarcoma.
[Invention 39]
The at least one genetic abnormality is a translocation between chromosomes 8 and 21, a translocation or inversion on chromosome 16, a translocation between chromosomes 15 and 17, a translocation on chromosome 11 alteration, or fms-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT /enhancer binding protein alpha (CEBPA), U2 small nuclear RNA cofactor 1 (U2AF1), zeste 2 polycomb repressive complex 2 subunit enhancer (EZH2), chromosome structural maintenance 1A (SMC1A), or chromosome structural maintenance 3 ( The method according to invention 38, which is a mutation in SMC3).
[Invention 40]
the at least one genetic abnormality is translocation t(8;21)(q22;q22), inversion inv(16)(p13;q22), translocation t(16;16)(p13;q22), translocation t (15; 17) (q22; q12), FLT3-ITD mutation, R132H or R100Q/R104V/F108L/R119Q/I130V mutation in IDH1, or R140Q or R172 mutation in IDH2, according to Invention 39 Method.
[Invention 41]
31. The method of invention 30, wherein said ALL is B-lineage ALL, T-lineage ALL, adult ALL, or childhood ALL.
[Invention 42]
42. The method of invention 41, wherein said subject with ALL has the Philadelphia chromosome or is resistant to or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.
[Invention 43]
43. The method of inventions 1-42, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11. A method according to any one of the preceding claims.
[Invention 44]
44. The method of any one of inventions 1-43, wherein said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.
[Invention 45]
The method of any one of inventions 1-44, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 46]
46. The method of any one of inventions 1-45, wherein said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.
[Invention 47]
The anti-CD38 antibody is
a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
d) A method according to any one of inventions 1-42, comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21.
[Invention 48]
The method of invention 47, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 49]
wherein said T-cell redirecting therapeutic is a BCMAxCD3 bispecific antibody, a GPRC5DxCD3 bispecific antibody, a CD33xCD3 bispecific antibody, a CD19xCD3 bispecific antibody, a CD123xCD3 bispecific antibody 49. The method of any one of inventions 1-48, wherein the antibody is a PSMAxCD3 bispecific antibody, or a TMEFF2xCD3 bispecific antibody.
[Invention 50]
50. The method of any one of inventions 1-49, further comprising administering one or more anticancer drug therapies to said subject.
[Invention 51]
51. The method of invention 50, wherein said one or more anticancer drug therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies. .
[Invention 52]
The one or more anticancer drug therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib , bosutinib, ponatinib, bafetinib, salacatinib, tozasertib, or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine , azacytidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof.
[Invention 53]
The method of any one of inventions 1-52, wherein said anti-CD38 antibody is administered at a dose of about 8 mg/kg to about 16 mg/kg.
[Invention 54]
wherein said anti-CD38 antibody is about 20 mg/mL to about 120 mg/mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20) 54. The method of any one of inventions 1-53, wherein the anti-CD38 antibody is administered, or provided for administration, in a pharmaceutical composition, which has a pH of about 5.5.
[Invention 55]
53. Any one of Inventions 1-52, wherein the anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20. the method described in Section 1.
[Invention 56]
56. The method of invention 55, wherein said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20. .
[Invention 57]
The anti-CD38 antibody is
a) about 5 mM to about 15 mM histidine;
b) about 100 mM to about 300 mM sorbitol;
c) from about 0.01% w/v to about 0.04% w/v PS-20;
d) administered or provided for administration in a pharmaceutical composition comprising from about 1 mg/mL to about 2 mg/mL methionine and having a pH of from about 5.5 to 5.6; described method.
[Invention 58]
The anti-CD38 antibody is
a) about 1,800 mg of said anti-CD38 antibody;
b) about 30,000 U of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 59]
The anti-CD38 antibody is
a) about 120 mg/mL of said anti-CD38 antibody;
b) about 2,000 U/mL of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 60]
A method of treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody to treat said cancer.
[Invention 61]
The method of invention 60, wherein said subject has been treated with an anti-CD38 antibody prior to administration of said BCMAxCD3 bispecific antibody.
[Invention 62]
A BCMA wherein said BCMAxCD3 bispecific antibody comprises HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28 Invention 60, comprising a binding domain and a CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38 Or the method according to 61.
[Invention 63]
63. The method of invention 62, wherein said BCMA binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, and said CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.
[Invention 64]
said BCMAxCD3 bispecific antibody is of the IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 of HC1 and leucine at position 405 and lysine at position 409 of HC2, and the residue numbering is A method according to any one of inventions 60-62 according to the EU index.
[Invention 65]
65. The method of invention 64, wherein said BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 of both said HC1 and said HC2.
[Invention 66]
66. The method of invention 65, wherein said BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.
[Invention 67]
67. The method of any one of inventions 60-66, wherein said cancer is a BCMA-expressing cancer.
[Invention 68]
68. The method of any one of inventions 60-67, wherein said cancer is a hematologic malignancy.
[Invention 69]
Any of Inventions 60-68, wherein said subject is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof. or the method described in one.
[Invention 70]
The method of invention 69, wherein said subject is relapsed or refractory to treatment with said anti-CD38 antibody.
[Invention 71]
69. The method of invention 68, wherein said hematologic malignancy is multiple myeloma, myeloma, DLBLC, CLL, Waldenström's hypergammaglobulinemia, or non-Hodgkin's lymphoma.
[Invention 72]
72. The method of invention 71, wherein said multiple myeloma is newly diagnosed multiple myeloma.
[Invention 73]
72. The method of invention 71, wherein said multiple myeloma is relapsed or refractory multiple myeloma.
[Invention 74]
The method of any one of inventions 71-73, wherein said multiple myeloma is high-risk multiple myeloma.
[Invention 75]
wherein said subject with said high-risk multiple myeloma is
a) t(4;14)(p16;q32),
b) t(14;16)(q32;q23),
c) del17p,
d) 1qAmp,
e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
f) t(4;14)(p16;q32) and del17p,
g) t(14;16)(q32;q23) and del17p, or
h) having one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, Invention 74 The method described in .
[Invention 76]
The method of Inventions 60-75, wherein said anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11. A method according to any one of the preceding claims.
[Invention 77]
77. The method of any one of inventions 60-76, wherein said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.
[Invention 78]
The method of any one of inventions 60-77, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 79]
79. The method of any one of inventions 60-78, wherein said anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.
[Invention 80]
The anti-CD38 antibody is
a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
d) A method according to any one of inventions 60-75, comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21.
[Invention 81]
The method of invention 80, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 82]
The method of any one of inventions 60-81, wherein said anti-CD38 antibody is administered at a dose of about 8 mg/kg to about 16 mg/kg.
[Invention 83]
The method of any one of inventions 60-82, wherein said BCMAxCD3 bispecific antibody and said anti-CD38 antibody are administered by intravenous injection.
[Invention 84]
The method of any one of inventions 60-82, wherein said BCMAxCD3 bispecific antibody is administered by intravenous injection and said anti-CD38 antibody is administered by subcutaneous injection.
[Invention 85]
The method of any one of Inventions 60-84, wherein said subject is a human.
[Invention 86]
86. The method of any one of inventions 60-85, further comprising administering one or more anti-cancer drug therapies to said subject.
[Invention 87]
87. The method of invention 86, wherein said one or more anticancer drug therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies. .
[Invention 88]
Invention 86, wherein said one or more anticancer drug therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof. The method described in .
[Invention 89]
wherein said anti-CD38 antibody is about 20 mg/mL to about 120 mg/mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20) 89. The method of any one of inventions 60-88, wherein the method is administered or provided for administration in a pharmaceutical composition comprising said anti-CD38 antibody of the pH of about 5.5.
[Invention 90]
88. Any one of Inventions 60-88, wherein said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20. the method described in Section 1.
[Invention 91]
The method of invention 90, wherein said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20. .
[Invention 92]
The anti-CD38 antibody is
a) about 5 mM to about 15 mM histidine;
b) about 100 mM to about 300 mM sorbitol;
c) from about 0.01% w/v to about 0.04% w/v PS-20;
d) administered or provided for administration in a pharmaceutical composition comprising from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6. described method.
[Invention 93]
The anti-CD38 antibody is
a) about 1,800 mg of said anti-CD38 antibody;
b) about 30,000 U of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 94]
The anti-CD38 antibody is
a) about 120 mg/mL of said anti-CD38 antibody;
b) about 2,000 U/mL of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 95]
a BCMAxCD3 bispecific antibody comprising a BCMA binding domain comprising the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30 and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40; and an anti-CD38 antibody comprising the VL of SEQ ID NO:5.
[Invention 96]
The BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42, and the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC2 of SEQ ID NO:12. A pharmaceutical composition according to invention 95, comprising the LC of SEQ ID NO:13.
[Invention 97]
A pharmaceutical composition according to invention 95 or 96, which is a non-fixed combination.
[Invention 98]
about 20 mg/mL to about 120 mg/mL of said anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); 98. The pharmaceutical composition of invention 97, comprising a pH of about 5.5.
[Invention 99]
98. The pharmaceutical composition of invention 97, comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20.
[Invention 100]
99. The pharmaceutical composition of invention 99, comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20.
[Invention 101]
A pharmaceutical composition according to invention 100, further comprising one or more excipients.
[Invention 102]
102. The pharmaceutical composition of invention 101, wherein said one or more excipients is histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.
[Invention 103]
The pharmaceutical composition is
a) from about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
b) about 5 mM to about 15 mM histidine;
c) about 100 mM to about 300 mM sorbitol;
d) from about 0.01% w/v to about 0.04% w/v PS-20;
e) from about 1 mg/mL to about 2 mg/mL of methionine and having a pH of about 5.5-5.6.
[Invention 104]
A pharmaceutical composition according to invention 103, comprising about 10 mM histidine.
[Invention 105]
A pharmaceutical composition according to invention 103 or 104, comprising about 300 mM sorbitol.
[Invention 106]
The pharmaceutical composition according to any one of inventions 103-105, comprising about 0.04% (w/v) PS-20.
[Invention 107]
The pharmaceutical composition according to any one of inventions 103-106, comprising about 1 mg/mL methionine.
[Invention 108]
a) about 1,800 mg of said anti-CD38 antibody;
b) about 30,000 U of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) about 1 mg/mL methionine and a pH of about 5.6.
[Invention 109]
a) about 120 mg/mL of said anti-CD38 antibody;
b) about 2,000 U/mL of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) about 1 mg/mL of methionine and having a pH of about 5.6.
[Invention 110]
A kit comprising a pharmaceutical composition according to any one of Inventions 95-109.
[Invention 111]
A method of treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of a T-cell redirecting therapeutic that binds GPRC5D and an anti-CD38 antibody to treat said cancer.
[Invention 112]
112. The method of invention 111, wherein said anti-CD38 antibody is administered to the subject prior to administration of said T cell redirecting therapeutic that binds to GPRC5D.
[Invention 113]
113. The method of invention 111 or 112, wherein said subject is relapsed or refractory to prior anti-cancer therapeutic treatment.
[Invention 114]
The method according to any one of Inventions 111 to 113, wherein the cancer is GPRC5D-expressing cancer.
[Invention 115]
The method of invention 114, wherein said GPRC5D-expressing cancer is a hematological malignancy or a solid tumor.
[Invention 116]
116. The method of invention 115, wherein said hematologic malignancy is leukemia, lymphoma, or multiple myeloma.
[Invention 117]
117. The method of invention 116, wherein the solid tumor is ovarian cancer, lung cancer, gastric cancer, prostate cancer, renal cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma.
[Invention 118]
of inventions 111-117, wherein said subject is relapsed or refractory to treatment with said anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof A method according to any one of the preceding claims.
[Invention 119]
119. The method of invention 118, wherein said subject is relapsed or refractory to treatment with said anti-CD38 antibody.
[Invention 120]
118. The method of invention 117, wherein said multiple myeloma is newly diagnosed multiple myeloma.
[Invention 121]
118. The method of invention 117, wherein said multiple myeloma is relapsed or refractory multiple myeloma.
[Invention 122]
122. The method of invention 120 or 121, wherein said multiple myeloma is high-risk multiple myeloma.
[Invention 123]
wherein said subject with said high-risk multiple myeloma is
a) t(4;14)(p16;q32),
b) t(14;16)(q32;q23),
c) del17p,
d) 1qAmp,
e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
f) t(4;14)(p16;q32) and del17p,
g) t(14;16)(q32;q23) and del17p, or
h) having one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, invention 122 The method described in .
[Invention 124]
124. Any of inventions 111-123, wherein the T cell redirecting therapeutic binds to CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C. or the method described in one.
[Invention 125]
a GPRC5D binding domain wherein said T-cell redirecting therapeutic comprises HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48; and a CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38. A method according to any one of the preceding claims.
[Invention 126]
any one of inventions 111 to 126, wherein the GPRC5D binding domain comprises the VH of SEQ ID NO: 49 and the VL of SEQ ID NO: 50, and the CD3 binding domain comprises the VH of SEQ ID NO: 39 and the VL of SEQ ID NO: 40 described method.
[Invention 127]
127. The method of any one of inventions 111-126, wherein said T cell redirecting therapeutic agent that binds to GPRC5C is a multispecific antibody, a CAR, or a T cell expressing said CAR.
[Invention 128]
128. The method of invention 127, wherein said multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.
[Invention 129]
129. The method of invention 128, wherein said multispecific antibody comprises one or more Fc substitutions that reduce binding of said multispecific antibody to Fcγ receptors (FcγR).
[Invention 130]
wherein said one or more Fc substitutions are F234A/L235A on IgG4, L234A/L235A on IgG1, V234A/G237A/P238S/H268A/V309L/A330S/P331S on IgG2, F234A/L235A on IgG4; S228P/F234A/L235A on IgG4, N297A on all Ig isotypes, V234A/G237A on IgG2, K214T/E233P/L234V/L235A/G236 deletion/A327G/P331A/D365E/L358M on IgG1, on IgG2 H268Q/V309L/A330S/P331S, S267E/L328F on IgG1, L234F/L235E/D265A on IgG1, L234A/L235A/G237A/P238S/H268A/A330S/P331S on IgG1, S228A/L2334 on IgG4 130. The method of invention 129, wherein the residue numbering is according to the EU index, selected from the group consisting of G237A/P238S, and S228P/F234A/L235A/G236 deletion on IgG4/G237A/P238S.
[Invention 131]
131. The method of invention 130, wherein said multispecific antibody further comprises a S228P substitution.
[Invention 132]
said multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain; The method according to any one of Inventions 127-131.
[Invention 133]
the one or more asymmetric substitutions are ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、発明１３２に記載の方法。
[Invention 134]
134. The method of any one of inventions 111-133, wherein said multispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.
[Invention 135]
The method of inventions 111-134, wherein said anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11 A method according to any one of the preceding claims.
[Invention 136]
The method of any one of inventions 111-135, wherein said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.
[Invention 137]
The method of any one of Inventions 111-136, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 138]
The method of any one of inventions 111-137, wherein said anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.
[Invention 139]
The anti-CD38 antibody is
a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
d) A method according to any one of inventions 111-138, comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21.
[Invention 140]
The method of invention 139, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 141]
The method of any one of inventions 111-140, wherein said anti-CD38 antibody is administered at a dose of about 8 mg/kg to about 16 mg/kg.
[Invention 142]
142. The method of any one of inventions 111-141, wherein said T cell-redirecting therapeutic that binds GPRC5D and said anti-CD38 antibody are administered by intravenous injection.
[Invention 143]
143. The method of any one of inventions 111-142, wherein said T cell redirecting therapeutic that binds to GPRC5D is administered by intravenous injection and said anti-CD38 antibody is administered by subcutaneous injection.
[Invention 144]
The method of any one of Inventions 111-143, wherein said subject is a human.
[Invention 145]
145. The method of any one of inventions 111-144, wherein said T cell redirecting therapeutic that binds to GPRC5D is a GPRC5DxCD3 bispecific antibody.
[Invention 146]
The method of any one of Inventions 111-145, further comprising administering one or more anti-cancer drug therapies to said subject.
[Invention 147]
147. The method of invention 146, wherein said one or more anticancer drug therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies. .
[Invention 148]
147. The method of invention 146, wherein said one or more anticancer drug therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, or prednisone.
[Invention 149]
wherein said anti-CD38 antibody is about 20 mg/mL to about 120 mg/mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20) 148. The method of any one of inventions 111-148, wherein the method is administered or provided for administration in a pharmaceutical composition comprising the anti-CD38 antibody of the method having a pH of about 5.5.
[Invention 150]
149. Any one of Inventions 111-149, wherein said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20. the method described in Section 1.
[Invention 151]
151. The method of invention 150, wherein said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20. .
[Invention 152]
The anti-CD38 antibody is
a) from about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
b) about 5 mM to about 15 mM histidine;
c) about 100 mM to about 300 mM sorbitol;
d) from about 0.01% w/v to about 0.04% w/v PS-20;
e) administered or provided for administration in a pharmaceutical composition comprising from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6. described method.
[Invention 153]
The anti-CD38 antibody is
a) about 1,800 mg of said anti-CD38 antibody;
b) about 30,000 U of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 154]
The anti-CD38 antibody is
a) about 120 mg/mL of said anti-CD38 antibody;
b) about 2,000 U/mL of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 155]
GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and HCDR1 of SEQ ID NO:33, sequence a GPRC5CxCD3 bispecific antibody comprising a CD3 binding domain comprising HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38; An anti-CD38 antibody comprising HCDR1, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.
[Invention 156]
The GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40, and the anti-CD38 antibody comprises 156. A pharmaceutical combination according to invention 155, comprising VH and VL of SEQ ID NO:5.
[Invention 157]
wherein said GPRC5CxCD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42, and said anti-CD38 antibody comprises HC of SEQ ID NO:12 and A pharmaceutical combination according to invention 156, comprising the LC of SEQ ID NO:13.
[Invention 158]
A pharmaceutical combination according to any one of inventions 155-157, which is a non-fixed combination.
[Invention 159]
about 20 mg/mL to about 120 mg/mL of said anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); 158. A pharmaceutical combination according to invention 158, comprising a pH of about 5.5.
[Invention 160]
A pharmaceutical combination according to invention 158, comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20.
[Invention 161]
The pharmaceutical composition of invention 159, comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20.
[Invention 162]
A pharmaceutical combination according to invention 161, further comprising one or more excipients.
[Invention 163]
163. A pharmaceutical combination according to invention 162, wherein said one or more excipients is histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.
[Invention 164]
The pharmaceutical composition is
a) from about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
b) about 5 mM to about 15 mM histidine;
c) about 100 mM to about 300 mM sorbitol;
d) from about 0.01% w/v to about 0.04% w/v PS-20;
e) a pharmaceutical combination according to invention 163, comprising from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6.
[Invention 165]
A pharmaceutical combination according to invention 164, comprising about 10 mM histidine.
[Invention 166]
A pharmaceutical combination according to invention 164 or 165, comprising about 300 mM sorbitol.
[Invention 167]
A pharmaceutical combination according to any one of inventions 163-166, comprising about 0.04% (w/v) PS-20.
[Invention 168]
A pharmaceutical combination according to any one of inventions 163-167, comprising about 1 mg/mL methionine.
[Invention 169]
a) about 1,800 mg of said anti-CD38 antibody;
b) about 30,000 U of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) a pharmaceutical combination according to any one of inventions 163-168, comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 170]
a) about 120 mg/mL of said anti-CD38 antibody;
b) about 2,000 U/mL of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) a pharmaceutical combination according to any one of inventions 164-169, comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 171]
A kit comprising a pharmaceutical combination according to any one of inventions 155-171.
[Invention 172]
A method of treating cancer in a subject, comprising administering to said subject a therapeutically effective amount of a T-cell redirecting therapeutic that binds CD19 and an anti-CD38 antibody to treat said cancer.
[Invention 173]
173. The method of invention 172, wherein said subject has been treated with an anti-CD38 antibody prior to administration of said T cell redirecting therapeutic that binds to CD19.
[Invention 174]
A method of improving the efficacy of a T cell redirecting therapeutic that binds to CD19 in a subject with cancer, comprising administering an anti-CD38 antibody to the subject prior to administering said T cell redirecting therapeutic that binds to CD19. including, method.
[Invention 175]
175. The method of any one of inventions 172-174, wherein said subject is refractory or relapsed to treatment with a previous anti-cancer therapeutic.
[Invention 176]
176. The method of any one of inventions 172-175, wherein said cancer is a hematologic malignancy or a solid tumor.
[Invention 177]
said hematologic malignancy is lymphoma, B-cell malignancy, Hodgkin's lymphoma, non-Hodgkin's lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML , Waldenstrom's hypergammaglobulinemia, or T-cell lymphoma.
[Invention 178]
177. The method of invention 176, wherein the solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer.
[Invention 179]
178. Any one of inventions 172-178, wherein the T cell redirecting therapeutic binds to CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C the method described in Section 1.
[Invention 180]
Said T-cell redirecting therapeutic that binds to CD19 is blinatumomab, axicabtagenciloleucel, tisagenrecleucel-t, inevirizumab, lisocabtagene maraleucel, XmAb-5574, CIK -CAR. CD19, ICTCAR-011, IM-19, JCAR-014, Roncastuximabutecillin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007 , XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F, or the CD19 binding domain of GC-022, inventions 172-179 The method according to any one of
[Invention 181]
Said T-cell redirecting therapeutics that bind to CD19 are blinatumomab, axicabutagensiloleucel, tisagenreclusel-t, inevirizumab, risocabutagenmalarusel, XmAb-5574, CIK-CAR. CD19, ICTCAR-011, IM-19, JCAR-014, Roncastuximabutecillin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007 , XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F, or GC-022. the method described in Section 1.
[Invention 182]
182. The method of any one of inventions 172-181, wherein said T cell redirecting therapeutic that binds CD19 is a multispecific antibody, a CAR, or a T cell expressing said CAR.
[Invention 183]
of inventions 172-182, wherein said anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11 A method according to any one of the preceding claims.
[Invention 184]
183. The method of any one of inventions 172-183, wherein said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.
[Invention 185]
The method of any one of inventions 172-184, wherein said anti-CD38 antibody is of the IgG1 isotype.
[Invention 186]
185. The method of any one of inventions 172-185, wherein said anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.
[Invention 187]
The anti-CD38 antibody is
a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
d) A method according to any one of inventions 172-182, comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21.
[Invention 188]
188. The method of invention 187, wherein said anti-CD38 antibody is of the IgGl isotype.
[Invention 189]
188. The method of any one of inventions 172-188, wherein said anti-CD38 antibody is administered at a dose of about 8 mg/kg to about 16 mg/kg.
[Invention 190]
189. The method of any one of inventions 172-189, wherein said T cell redirecting therapeutic that binds to CD19 and said anti-CD38 antibody are administered by intravenous injection.
[Invention 191]
189. The method of any one of inventions 172-189, wherein said T cell redirecting therapeutic that binds to CD19 is administered by intravenous injection and said anti-CD38 antibody is administered by subcutaneous injection.
[Invention 192]
The method of any one of Inventions 172-191, wherein said subject is a human.
[Invention 193]
193. The method of any one of inventions 172-192, wherein said T cell redirecting therapeutic that binds CD19 is a CD19xCD3 bispecific antibody.
[Invention 194]
193. The method of any one of Inventions 172-193, further comprising administering one or more anti-cancer drug therapies to said subject.
[Invention 195]
195. The method of invention 194, wherein said one or more anticancer drug therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies. .
[Invention 196]
CD19×CD3 bispecific antibody comprising blinatumomab of SEQ ID NO:53, HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and SEQ ID NO:11 A pharmaceutical combination comprising an anti-CD38 antibody comprising LCDR3 of
[Invention 197]
197. A pharmaceutical combination according to invention 196, wherein said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.
[Invention 198]
198. A pharmaceutical combination according to invention 197, wherein said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.
[Invention 199]
A pharmaceutical combination according to any one of inventions 196-198, which is a non-fixed combination.
[Invention 200]
about 20 mg/mL to about 120 mg/mL of said anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); 199. A pharmaceutical combination according to invention 199, comprising and having a pH of about 5.5.
[Invention 201]
199. The pharmaceutical combination of invention 199, comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20.
[Invention 202]
A pharmaceutical combination according to invention 201, comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20.
[Invention 203]
A pharmaceutical combination according to invention 202, further comprising one or more excipients.
[Invention 204]
A pharmaceutical combination according to invention 203, wherein said one or more excipients is histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.
[Invention 205]
wherein the pharmaceutical combination comprises
a) from about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
b) about 5 mM to about 15 mM histidine;
c) about 100 mM to about 300 mM sorbitol;
d) from about 0.01% w/v to about 0.04% w/v PS-20;
e) from about 1 mg/mL to about 2 mg/mL of methionine and at a pH of about 5.5-5.6.
[Invention 206]
A pharmaceutical combination according to invention 205, comprising about 10 mM histidine.
[Invention 207]
A pharmaceutical combination according to invention 205 or 206, comprising about 300 mM sorbitol.
[Invention 208]
The pharmaceutical combination according to any one of inventions 205-207, comprising about 0.04% (w/v) PS-20.
[Invention 209]
The pharmaceutical combination according to any one of inventions 205-208, comprising about 1 mg/mL methionine.
[Invention 210]
a) about 1,800 mg of said anti-CD38 antibody;
b) about 30,000 U of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) a pharmaceutical combination according to any one of inventions 205-209, comprising about 1 mg/mL methionine and having a pH of about 5.6.
[Invention 211]
a) about 120 mg/mL of said anti-CD38 antibody;
b) about 2,000 U/mL of rHuPH20;
c) about 10 mM histidine;
d) about 300 mM sorbitol;
e) about 0.04% (w/v) PS-20;
f) about 1 mg/mL methionine and a pH of about 5.6.
[Invention 212]
A kit comprising a pharmaceutical composition according to any one of Inventions 196-211.
Claims (33)
ｂ）前記Ｔ細胞リダイレクト治療薬が、ＢＣＭＡ、ＧＰＲＣ５Ｄ、ＣＤ３３、ＣＤ１２３、ＣＤ１９、ＰＳＭＡ、ＴＭＥＦＦ２、又はＣＤ２０に結合する、及び／又は b) said T cell redirecting therapeutic binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, or CD20, and/or
ｃ）前記Ｔ細胞リダイレクト治療薬が、ＣＤ３、ＣＤ３イプシロン（ＣＤ３ε）、ＣＤ８、ＫＩ２Ｌ４、ＮＫＧ２Ｅ、ＮＫＧ２Ｄ、ＮＫＧ２Ｆ、ＢＴＮＬ３、ＣＤ１８６、ＢＴＮＬ８、ＰＤ－１、ＣＤ１９５、又はＮＫＧ２Ｃに結合する、 c) the T cell redirecting therapeutic binds to CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C;
請求項１～４のいずれか一項に記載の組成物。A composition according to any one of claims 1-4.
ｉ）配列番号３３の重鎖相補性決定領域１（ＨＣＤＲ１）、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６の軽鎖相補性決定領域１（ＬＣＤＲ１）、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３、 i) heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38,
ｉｉ）配列番号３９の重鎖可変領域（ＶＨ）及び配列番号４０の軽鎖可変領域（ＶＬ）、 ii) a heavy chain variable region (VH) of SEQ ID NO:39 and a light chain variable region (VL) of SEQ ID NO:40;
ｉｉｉ）配列番号７４のＨＣＤＲ１、配列番号７５のＨＣＤＲ２、配列番号７６のＨＣＤＲ３、配列番号７７のＬＣＤＲ１、配列番号７８のＬＣＤＲ２、及び配列番号７９のＬＣＤＲ３、 iii) HCDR1 of SEQ ID NO:74, HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78 and LCDR3 of SEQ ID NO:79;
ｉｖ）配列番号８０のＶＨ及び配列番号８１のＶＬ、 iv) VH of SEQ ID NO:80 and VL of SEQ ID NO:81,
ｖ）配列番号５３のＣＤ３結合ドメインのＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３、ＬＣＤＲ１、ＬＣＤＲ２、及びＬＣＤＲ３、又は v) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53, or
ｖｉ）配列番号５３のＣＤ３結合ドメインのＶＨ及びＶＬを含むＣＤ３結合ドメインを含む、 vi) a CD3 binding domain comprising the VH and VL of the CD3 binding domain of SEQ ID NO:53;
ｂ）前記Ｔ細胞リダイレクト治療薬が、 b) said T-cell redirecting therapeutic is
ｉ）配列番号２３のＨＣＤＲ１、配列番号２４のＨＣＤＲ２、配列番号２５のＨＣＤＲ３、配列番号２６のＬＣＤＲ１、配列番号２７のＬＣＤＲ２、及び配列番号２８のＬＣＤＲ３を含むＢＣＭＡ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は i) a BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
ｉｉ）配列番号２９のＶＨ及び配列番号３０のＶＬを含むＢＣＭＡ結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含み、 ii) a BCMA binding domain comprising the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30 and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40;
場合により、前記Ｔ細胞リダイレクト治療薬が、配列番号３１の第１の重鎖（ＨＣ１）、配列番号３２の第１の軽鎖（ＬＣ１）、配列番号４１の第２の重鎖（ＨＣ２）、及び配列番号４２の第２の軽鎖（ＬＣ２）を含む、 optionally, the T cell redirecting therapeutic agent comprises the first heavy chain (HC1) of SEQ ID NO:31, the first light chain (LC1) of SEQ ID NO:32, the second heavy chain (HC2) of SEQ ID NO:41, and a second light chain (LC2) of SEQ ID NO: 42,
ｃ）前記Ｔ細胞リダイレクト治療薬が、 c) said T-cell redirecting therapeutic is
ｉ）配列番号４３のＨＣＤＲ１、配列番号４４のＨＣＤＲ２、配列番号４５のＨＣＤＲ３、配列番号４６のＬＣＤＲ１、配列番号４７のＬＣＤＲ２、及び配列番号４８のＬＣＤＲ３を含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は i) a GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
ｉｉ）配列番号４９のＶＨ及び配列番号５０のＶＬを含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含み、 ii) a GPRC5D binding domain comprising the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50 and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40;
場合により、前記Ｔ細胞リダイレクト治療薬が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、 optionally, said T cell redirecting therapeutic comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42;
ｄ）前記Ｔ細胞リダイレクト治療薬が、 d) said T-cell redirecting therapeutic is
ｉ）配列番号８４のＨＣＤＲ１、配列番号８５のＨＣＤＲ２、配列番号８６のＨＣＤＲ３、配列番号８７のＬＣＤＲ１、配列番号８８のＬＣＤＲ２、及び配列番号８９のＬＣＤＲ３を含むＣＤ３３結合ドメイン、並びに配列番号７４のＨＣＤＲ１、配列番号７５のＨＣＤＲ２、配列番号７６のＨＣＤＲ３、配列番号７７のＬＣＤＲ１、配列番号７８のＬＣＤＲ２、及び配列番号７９のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は i) a CD33 binding domain comprising HCDR1 of SEQ ID NO:84, HCDR2 of SEQ ID NO:85, HCDR3 of SEQ ID NO:86, LCDR1 of SEQ ID NO:87, LCDR2 of SEQ ID NO:88, and LCDR3 of SEQ ID NO:89, and HCDR1 of SEQ ID NO:74 , HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78, and LCDR3 of SEQ ID NO:79, and/or
ｉｉ）配列番号９０のＶＨ及び配列番号９１のＶＬを含むＣＤ３３結合ドメイン、並びに配列番号８０のＶＨ及び配列番号８１のＶＬを含むＣＤ３結合ドメインを含み、 ii) a CD33 binding domain comprising the VH of SEQ ID NO:90 and the VL of SEQ ID NO:91 and a CD3 binding domain comprising the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81;
場合により、前記Ｔ細胞リダイレクト治療薬が、配列番号９２のＨＣ１、配列番号９３のＬＣ１、配列番号８２のＨＣ２、及び配列番号８３のＬＣ２を含む、 optionally, said T cell redirecting therapeutic comprises HC1 of SEQ ID NO:92, LC1 of SEQ ID NO:93, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83;
ｅ）前記Ｔ細胞リダイレクト治療薬が、 e) said T-cell redirecting therapeutic is
ｉ）配列番号９４のＨＣＤＲ１、配列番号９５のＨＣＤＲ２、配列番号９６のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号５９のＬＣＤＲ３を含むＣＤ１２３結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は i) a CD123 binding domain comprising HCDR1 of SEQ ID NO:94, HCDR2 of SEQ ID NO:95, HCDR3 of SEQ ID NO:96, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:59, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
ｉｉ）配列番号１００のＶＨ及び配列番号６１のＶＬを含むＣＤ１２３結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含み、 ii) a CD123 binding domain comprising the VH of SEQ ID NO: 100 and the VL of SEQ ID NO: 61 and a CD3 binding domain comprising the VH of SEQ ID NO: 39 and the VL of SEQ ID NO: 40;
場合により、前記Ｔ細胞リダイレクト治療薬が、配列番号１０２のＨＣ１、配列番号６３のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、 optionally, said T cell redirecting therapeutic comprises HC1 of SEQ ID NO: 102, LC1 of SEQ ID NO: 63, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42;
ｆ）前記Ｔ細胞リダイレクト治療薬が、 f) said T-cell redirecting therapeutic is
ｉ）配列番号５３のＣＤ１９結合ドメインのＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３、ＬＣＤＲ１、ＬＣＤＲ２、及びＬＣＤＲ３を含むＣＤ１９結合ドメイン、並びに配列番号５３のＣＤ３結合ドメインのＨＣＤＲ１、ＨＣＤＲ２、ＨＣＤＲ３、ＬＣＤＲ１、ＬＣＤＲ２、及びＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は i) a CD19 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD19 binding domain of SEQ ID NO:53 and HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53 a CD3 binding domain comprising, and/or
ｉｉ）配列番号５３のアミノ酸配列を含む、 ii) comprising the amino acid sequence of SEQ ID NO:53;
ｇ）前記Ｔ細胞リダイレクト治療薬が、 g) said T-cell redirecting therapeutic is
ｉ）配列番号５４のＨＣＤＲ１、配列番号５５のＨＣＤＲ２、配列番号５６のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号５９のＬＣＤＲ３を含むＰＳＭＡ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は i) a PSMA binding domain comprising HCDR1 of SEQ ID NO:54, HCDR2 of SEQ ID NO:55, HCDR3 of SEQ ID NO:56, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:59, and HCDR1 of SEQ ID NO:33 , HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and/or
ｉｉ）配列番号６０のＶＨ及び配列番号６１のＶＬを含むＰＳＭＡ結合ドメイン、並びに配列番号３９のＶＨ及び配列番号４０のＶＬを含むＣＤ３結合ドメインを含み、 ii) a PSMA binding domain comprising the VH of SEQ ID NO:60 and the VL of SEQ ID NO:61 and a CD3 binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40;
場合により、前記Ｔ細胞リダイレクト治療薬が、配列番号６２のＨＣ１、配列番号６３のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、 optionally, said T cell redirecting therapeutic comprises HC1 of SEQ ID NO:62, LC1 of SEQ ID NO:63, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42;
ｈ）前記Ｔ細胞リダイレクト治療薬が、 h) said T-cell redirecting therapeutic is
ｉ）配列番号６４のＨＣＤＲ１、配列番号６５のＨＣＤＲ２、配列番号６６のＨＣＤＲ３、配列番号６７のＬＣＤＲ１、配列番号６８のＬＣＤＲ２、及び配列番号６９のＬＣＤＲ３を含むＴＭＥＦＦ２結合ドメイン、並びに配列番号７４のＨＣＤＲ１、配列番号７５のＨＣＤＲ２、配列番号７６のＨＣＤＲ３、配列番号７７のＬＣＤＲ１、配列番号７８のＬＣＤＲ２、及び配列番号７９のＬＣＤＲ３を含むＣＤ３結合ドメイン、並びに／又は i) a TMEFF2 binding domain comprising HCDR1 of SEQ ID NO:64, HCDR2 of SEQ ID NO:65, HCDR3 of SEQ ID NO:66, LCDR1 of SEQ ID NO:67, LCDR2 of SEQ ID NO:68, and LCDR3 of SEQ ID NO:69, and HCDR1 of SEQ ID NO:74 , HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78, and LCDR3 of SEQ ID NO:79, and/or
ｉｉ）配列番号７０のＶＨ及び配列番号７１のＶＬを含むＴＭＥＦＦ２結合ドメイン、並びに配列番号８０のＶＨ及び配列番号８１のＶＬを含むＣＤ３結合ドメインを含み、 ii) a TMEFF2 binding domain comprising the VH of SEQ ID NO:70 and the VL of SEQ ID NO:71 and a CD3 binding domain comprising the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81;
場合により、前記Ｔ細胞リダイレクト治療薬が、配列番号７２のＨＣ１、配列番号７３のＬＣ１、配列番号８２のＨＣ２、及び配列番号８３のＬＣ２を含む、 optionally, said T cell redirecting therapeutic comprises HC1 of SEQ ID NO:72, LC1 of SEQ ID NO:73, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83;
請求項５に記載の組成物。A composition according to claim 5 .
場合により、前記多重特異性抗体が、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、又はＩｇＧ４アイソタイプであり、 optionally, said multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype;
例えば、前記多重特異性抗体が、前記多重特異性抗体のＦｃγ受容体（ＦｃγＲ）への結合を低減する１つ又は２つ以上のＦｃ置換を含み、 For example, said multispecific antibody comprises one or more Fc substitutions that reduce binding of said multispecific antibody to Fcγ receptors (FcγR),
場合により、前記１つ又は２つ以上のＦｃ置換が、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ、全てのＩｇアイソタイプ上のＮ２９７Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ、ＩｇＧ１上のＫ２１４Ｔ／Ｅ２３３Ｐ／Ｌ２３４Ｖ／Ｌ２３５Ａ／Ｇ２３６欠失／Ａ３２７Ｇ／Ｐ３３１Ａ／Ｄ３６５Ｅ／Ｌ３５８Ｍ、ＩｇＧ２上のＨ２６８Ｑ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ１上のＳ２６７Ｅ／Ｌ３２８Ｆ、ＩｇＧ１上のＬ２３４Ｆ／Ｌ２３５Ｅ／Ｄ２６５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ、及びＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３６欠失／Ｇ２３７Ａ／Ｐ２３８Ｓからなる群から選択され、残基の番号付けが、ＥＵインデックスに従うものであり、 Optionally, said one or more Fc substitutions are F234A/L235A on IgG4, L234A/L235A on IgG1, V234A/G237A/P238S/H268A/V309L/A330S/P331S on IgG2, F234A on IgG4 /L235A, S228P/F234A/L235A on IgG4, N297A on all Ig isotypes, V234A/G237A on IgG2, K214T/E233P/L234V/L235A/G236 deletion/A327G/P331A/D365E/L358M on IgG1, H268Q/V309L/A330S/P331S on IgG2, S267E/L328F on IgG1, L234F/L235E/D265A on IgG1, L234A/L235A/G237A/P238S/H268A/A330S/P331S on IgG1, S23AF on IgG/4 /L235A/G237A/P238S, and S228P/F234A/L235A/G236 deletion on IgG4/G237A/P238S, wherein residue numbering is according to the EU index;
ａ）例えば、前記多重特異性抗体が、Ｓ２２８Ｐ置換を更に含む、及び／又は、第１のＣＨ３ドメイン若しくは第２のＣＨ３ドメインに、又は前記第１のＣＨ３ドメイン及び前記第２のＣＨ３ドメインの両方に、１つ又は２つ以上の非対称置換を含む、 a) for example said multispecific antibody further comprises a S228P substitution and/or in said first CH3 domain or said second CH3 domain or both said first CH3 domain and said second CH3 domain contains one or more asymmetric substitutions,
ｂ）場合により、前記１つ又は２つ以上の非対称置換が、Ｆ４５０Ｌ／Ｋ４０９Ｒ、野生型／Ｆ４０９Ｌ＿Ｒ４０９Ｋ、Ｔ３６６Ｙ／Ｆ４０５Ａ、Ｔ３６６Ｗ／Ｆ４０５Ｗ、Ｆ４０５Ｗ／Ｙ４０７Ａ、Ｔ３９４Ｗ／Ｙ４０７Ｔ、Ｔ３９４Ｓ／Ｙ４０７Ａ、Ｔ３６６Ｗ／Ｔ３９４Ｓ、Ｆ４０５Ｗ／Ｔ３９４Ｓ及びＴ３６６Ｗ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、 b) optionally, said one or more asymmetric substitutions are F450L/K409R, wildtype/F409L_R409K, T366Y/F405A, T366W/F405W, F405W/Y407A, T394W/Y407T, T394S/Y407A, T366W/T394S, Ｆ４０５Ｗ／Ｔ３９４Ｓ及びＴ３６６Ｗ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、
請求項１～６のいずれか一項に記載の組成物。A composition according to any one of claims 1-6.
ｂ）前記対象が、以前の抗癌剤療法に対して再発又は難治性である、及び／又は b) said subject is relapsed or refractory to prior anticancer therapy, and/or
ｃ）前記癌が、血液悪性腫瘍又は固形腫瘍であり、 c) said cancer is a hematologic malignancy or solid tumor;
場合により、前記血液悪性腫瘍が、多発性骨髄腫、くすぶり型多発性骨髄腫、良性単クローン性γグロブリン血症（ＭＧＵＳ）、急性リンパ性白血病（ＡＬＬ）、びまん性大細胞型Ｂ細胞リンパ腫（ＤＬＢＣＬ）、バーキットリンパ腫（ＢＬ）、濾胞性リンパ腫（ＦＬ）、マントル細胞リンパ腫（ＭＣＬ）、ワルデンストレーム高ガンマグロブリン血症、形質細胞白血病、軽鎖アミロイドーシス（ＡＬ）、前駆体Ｂ細胞リンパ芽球性白血病、前駆体Ｂ細胞リンパ芽球性白血病、急性骨髄性白血病（ＡＭＬ）、骨髄異形成症候群（ＭＤＳ）、慢性リンパ性白血病（ＣＬＬ）、Ｂ細胞悪性腫瘍、慢性骨髄性白血病（ＣＭＬ）、ヘアリー細胞白血病（ＨＣＬ）、芽球性形質細胞様樹状細胞腫瘍、ホジキンリンパ腫、非ホジキンリンパ腫、辺縁帯Ｂ細胞リンパ腫（ＭＺＬ）、又は粘膜関連リンパ組織リンパ腫（ＭＡＬＴ）、形質細胞白血病、未分化大細胞リンパ腫（ＡＬＣＬ）、白血病、又はリンパ腫であり、 Optionally, said hematological malignancy is multiple myeloma, smoldering multiple myeloma, benign monoclonal gammaglobulinemia (MGUS), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma ( DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenström hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoma Blastic leukemia, precursor B-cell lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myelogenous leukemia (CML) ), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, marginal zone B-cell lymphoma (MZL), or mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia , anaplastic large cell lymphoma (ALCL), leukemia, or lymphoma;
ｉ）例えば、前記多発性骨髄腫が、新たに診断された多発性骨髄腫であり、 i) for example, said multiple myeloma is newly diagnosed multiple myeloma,
場合により、前記多発性骨髄腫が、高リスク多発性骨髄腫であり、 Optionally, said multiple myeloma is high-risk multiple myeloma,
Ｉ．例えば、前記高リスク多発性骨髄腫を有する前記対象が、 I. For example, if said subject with said high-risk multiple myeloma is
Ａ．ｔ（４；１４）（ｐ１６；ｑ３２）、 A. t(4;14)(p16;q32),
Ｂ．ｔ（１４；１６）（ｑ３２；ｑ２３）、 B. t(14;16)(q32;q23),
Ｃ．ｄｅｌ１７ｐ、 C. del17p,
Ｄ．１ｑＡｍｐ、 D. 1 qAmp,
Ｅ．ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、 E. t(4;14)(p16;q32) and t(14;16)(q32;q23),
Ｆ．ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、 F. t(4;14)(p16;q32) and del17p,
Ｇ．ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は G. t(14;16)(q32;q23) and del17p, or
Ｈ．ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、 H. have one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof;
ＩＩ．前記多発性骨髄腫が、再発又は難治性多発性骨髄腫であり、場合により、 II. wherein said multiple myeloma is relapsed or refractory multiple myeloma, optionally
Ａ．前記多発性骨髄腫が、高リスク多発性骨髄腫であり、例えば、前記高リスク多発性骨髄腫を有する前記対象が、 A. said multiple myeloma is high-risk multiple myeloma, e.g., said subject having said high-risk multiple myeloma is
ａ）ｔ（４；１４）（ｐ１６；ｑ３２）、 a) t(4;14)(p16;q32),
ｂ）ｔ（１４；１６）（ｑ３２；ｑ２３）、 b) t(14;16)(q32;q23),
ｃ）ｄｅｌ１７ｐ、 c) del17p,
ｄ）１ｑＡｍｐ、 d) 1qAmp,
ｅ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、 e) t(4;14)(p16;q32) and t(14;16)(q32;q23),
ｆ）ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、 f) t(4;14)(p16;q32) and del17p,
ｇ）ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は g) t(14;16)(q32;q23) and del17p, or
ｈ）ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、又は、 h) has one or more chromosomal abnormalities including t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof, or
Ｂ．前記多発性骨髄腫が、前記抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ（elotozumab）、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して再発又は難治性であり、 B. said multiple myeloma is relapsed or refractory to treatment with said anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof ,
前記ＡＭＬが、少なくとも１つの遺伝子異常を伴うＡＭＬ、多系列異形成を伴うＡＭＬ、療法関連ＡＭＬ、未分化ＡＭＬ、最未分化型ＡＭＬ、分化型ＡＭＬ、急性骨髄単球性白血病、急性単球性白血病、急性赤血球性白血病、急性巨核芽球性白血病、急性好塩基球性白血病、線維症を伴う急性汎骨髄症、又は骨髄肉腫であり、 said AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, therapy-related AML, undifferentiated AML, minimally differentiated AML, differentiated AML, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelopathy with fibrosis, or myelosarcoma,
場合により、前記少なくとも１つの遺伝子異常が、８番染色体と２１番染色体との間の転座、１６番染色体の転座若しくは逆位、１５番染色体と１７番染色体との間の転座、１１番染色体の変化、又はｆｍｓ関連チロシンキナーゼ３（ＦＬＴ３）、ヌクレオフォスミン（ＮＰＭ１）、イソクエン酸デヒドロゲナーゼ１（ＩＤＨ１）、イソクエン酸デヒドロゲナーゼ２（ＩＤＨ２）、ＤＮＡ（シトシン－５）－メチルトランスフェラーゼ３（ＤＮＭＴ３Ａ）、ＣＣＡＡＴ／エンハンサー結合タンパク質アルファ（ＣＥＢＰＡ）、Ｕ２核内低分子ＲＮＡ補助因子１（Ｕ２ＡＦ１）、ｚｅｓｔｅ ２ポリコーム抑制複合体２サブユニットエンハンサー（ＥＺＨ２）、染色体構造維持１Ａ（ＳＭＣ１Ａ）、若しくは染色体構造維持３（ＳＭＣ３）における変異である、 optionally, the at least one genetic abnormality is a translocation between chromosomes 8 and 21; a translocation or inversion on chromosome 16; a translocation between chromosomes 15 and 17; Chromosome 3 alterations or fms-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A) ), CCAAT/enhancer binding protein alpha (CEBPA), U2 small nuclear RNA cofactor 1 (U2AF1), zeste 2 polycomb repressive complex 2 subunit enhancer (EZH2), chromosome structure maintenance 1A (SMC1A), or chromosome structure a mutation in maintenance 3 (SMC3),
ＩＩＩ．例えば、前記少なくとも１つの遺伝子異常が、転座ｔ（８；２１）（ｑ２２；ｑ２２）、逆位ｉｎｖ（１６）（ｐ１３；ｑ２２）、転座ｔ（１６；１６）（ｐ１３；ｑ２２）、転座ｔ（１５；１７）（ｑ２２；ｑ１２）、ＦＬＴ３－ＩＴＤの変異、ＩＤＨ１におけるＲ１３２Ｈ若しくはＲ１００Ｑ／Ｒ１０４Ｖ／Ｆ１０８Ｌ／Ｒ１１９Ｑ／Ｉ１３０Ｖの変異、又はＩＤＨ２におけるＲ１４０Ｑ若しくはＲ１７２の変異である、又は、 III. For example, the at least one genetic abnormality is translocation t(8;21)(q22;q22), inversion inv(16)(p13;q22), translocation t(16;16)(p13;q22), translocation t(15;17)(q22;q12), a mutation in FLT3-ITD, a R132H or R100Q/R104V/F108L/R119Q/I130V mutation in IDH1, or a R140Q or R172 mutation in IDH2, or
前記ＡＬＬが、Ｂ細胞系列ＡＬＬ、Ｔ細胞系列ＡＬＬ、成人ＡＬＬ、又は小児ＡＬＬである、 said ALL is B-lineage ALL, T-lineage ALL, adult ALL, or childhood ALL;
ＩＶ．場合により、ＡＬＬを有する前記対象が、フィラデルフィア染色体を有するか、又はＢＣＲ－ＡＢＬキナーゼ阻害剤による治療に対して耐性であるか若しくはそれに対する後天耐性を有する、又は IV. optionally, said subject with ALL has the Philadelphia chromosome or is resistant to or has acquired resistance to treatment with a BCR-ABL kinase inhibitor, or
ｉｉ）前記固形腫瘍が、前立腺癌、肺癌、肝癌、子宮頸癌（cervical cancer）、結腸癌、乳癌、卵巣癌、子宮内膜癌、膵癌、黒色腫、神経膠芽腫、食道癌、胃癌（gastric cancer）、胃癌（stomach cancer）、腎癌、結腸癌、膀胱癌、子宮頸癌（cervical carcinoma）、黒色腫、肝細胞癌、腎細胞癌、尿路上皮癌、頭頸部癌、神経膠腫、又は膠芽腫であり、場合により、前記前立腺癌が、再発性、難治性、悪性、若しくは去勢抵抗性前立腺癌、又はこれらの任意の組み合わせである、 ii) said solid tumor is prostate cancer, lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer ( gastric cancer, stomach cancer, renal cancer, colon cancer, bladder cancer, cervical carcinoma, melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma or glioblastoma, and optionally the prostate cancer is relapsed, refractory, malignant, or castration-resistant prostate cancer, or any combination thereof.
請求項１～７のいずれか一項に記載の組成物。A composition according to any one of claims 1-7.
ｉ）配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含み、場合により、 i) HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11, optionally
Ｉ．前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、 I. wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5;
ＩＩ．前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、及び／又は、 II. said anti-CD38 antibody is of the IgG1 isotype, and/or
ＩＩＩ．前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、 III. wherein said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13;
ｉｉ）前記抗ＣＤ３８抗体が、 ii) said anti-CD38 antibody is
Ｉ）配列番号１４のＶＨ及び配列番号１５のＶＬ、 I) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
ＩＩ）配列番号１６のＶＨ及び配列番号１７のＶＬ、 II) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
ＩＩＩ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は III) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
ＩＶ）配列番号２０のＶＨ及び配列番号２１のＶＬを含み、 IV) comprising VH of SEQ ID NO:20 and VL of SEQ ID NO:21;
場合により、前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 optionally, said anti-CD38 antibody is of the IgG1 isotype;
ｂ）前記Ｔ細胞リダイレクト治療薬が、ＢＣＭＡ×ＣＤ３二重特異性抗体、ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体、ＣＤ３３×ＣＤ３二重特異性抗体、ＣＤ１９×ＣＤ３二重特異性抗体、ＣＤ１２３×ＣＤ３二重特異性抗体、ＰＳＭＡ×ＣＤ３二重特異性抗体、又はＴＭＥＦＦ２×ＣＤ３二重特異性抗体であり、 b) said T cell-redirecting therapeutic is a BCMAxCD3 bispecific antibody, a GPRC5DxCD3 bispecific antibody, a CD33xCD3 bispecific antibody, a CD19xCD3 bispecific antibody, a CD123xCD3 bispecific antibody a bispecific antibody, a PSMAxCD3 bispecific antibody, or a TMEFF2xCD3 bispecific antibody,
前記対象に１つ又は２つ以上の抗癌剤療法を投与することと組み合わせて用いるものであり、 for use in combination with administering to said subject one or more anti-cancer drug therapies;
場合により、前記１つ又は２つ以上の抗癌剤療法が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、 optionally, the one or more anticancer drug therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies;
ｃ）例えば、前記１つ又は２つ以上の抗癌剤療法が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、デキサメタゾン、ビンクリスチン、シクロホスファミド、ヒドロキシダウノルビシン、プレドニゾン、リツキシマブ、イマチニブ、ダサチニブ、ニロチニブ、ボスチニブ、ポナチニブ、バフェチニブ、サラカチニブ、トザセルチブ、若しくはダヌセルチブ、シタラビン、ダウノルビシン、イダルビシン、ミトキサントロン、ヒドロキシウレア、デシタビン、クラドリビン、フルダラビン、トポテカン、エトポシド６－チオグアニン、コルチコステロイド、メトトレキサート、６－メルカプトプリン、アザシチジン、三酸化ヒ素、及び全トランス型レチノイン酸、又はこれらの任意の組み合わせからなる群から選択される、及び／又は c) for example, said one or more anticancer drug therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib , dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, salacatinib, tozasertib, or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, selected from the group consisting of 6-mercaptopurine, azacytidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof; and/or
ｄ）前記抗ＣＤ３８抗体が、 d) said anti-CD38 antibody is
ｉ） i)
Ｉ．約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与されるものである、及び／又は I. is administered at a dose of about 8 mg/kg to about 16 mg/kg; and/or
ＩＩ．約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、医薬組成物において投与されるか、又は投与のために提供されるものであり、又は II. about 20 mg/mL to about 120 mg/mL of said anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); administered or provided for administration in a pharmaceutical composition comprising and having a pH of about 5.5, or
約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供されるものであり、 administered or provided for administration in a pharmaceutical composition comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20;
場合により、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供されるものである、 optionally administered or provided for administration in a pharmaceutical composition comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20;
ｉｉ）例えば、前記抗ＣＤ３８抗体が、 ii) for example, said anti-CD38 antibody is
Ｉ）約５ｍＭ～約１５ｍＭのヒスチジンと、 I) about 5 mM to about 15 mM histidine;
ＩＩ）約１００ｍＭ～約３００ｍＭのソルビトールと、 II) about 100 mM to about 300 mM sorbitol;
ＩＩＩ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、 III) from about 0.01% w/v to about 0.04% w/v PS-20;
ＩＶ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、医薬組成物において投与されるか、又は投与のために提供されるものであり、 IV) administered or provided for administration in a pharmaceutical composition comprising from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6;
場合により、前記抗ＣＤ３８抗体が、 Optionally, said anti-CD38 antibody is
Ａ．約１，８００ｍｇの前記抗ＣＤ３８抗体と、 A. about 1,800 mg of said anti-CD38 antibody;
Ｂ．約３０，０００ＵのｒＨｕＰＨ２０と、 B. about 30,000 U of rHuPH20;
Ｃ．約１０ｍＭのヒスチジンと、 C. about 10 mM histidine;
Ｄ．約３００ｍＭのソルビトールと、 D. about 300 mM sorbitol; and
Ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 E. about 0.04% (w/v) PS-20;
Ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供されるものであり、 F. administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6;
例えば、前記抗ＣＤ３８抗体が、 For example, the anti-CD38 antibody is
ａ．約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 a. about 120 mg/mL of said anti-CD38 antibody;
ｂ．約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、 b. rHuPH20 at about 2,000 U/mL;
ｃ．約１０ｍＭのヒスチジンと、 c. about 10 mM histidine;
ｄ．約３００ｍＭのソルビトールと、 d. about 300 mM sorbitol; and
ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 e. about 0.04% (w/v) PS-20;
ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供されるものである、 f. is administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6;
請求項１～８のいずれか一項に記載の組成物。A composition according to any one of claims 1-8.
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号２３のＨＣＤＲ１、配列番号２４のＨＣＤＲ２、配列番号２５のＨＣＤＲ３、配列番号２６のＬＣＤＲ１、配列番号２７のＬＣＤＲ２、及び配列番号２８のＬＣＤＲ３を含むＢＣＭＡ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメインを含む、 A BCMA wherein said BCMAxCD3 bispecific antibody comprises HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28 a binding domain and a CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38;
ｂ）場合により、前記ＢＣＭＡ結合ドメインが、配列番号２９のＶＨ及び配列番号３０のＶＬを含み、前記ＣＤ３結合ドメインが、配列番号３９のＶＨ及び配列番号４０のＶＬを含み、 b) optionally, said BCMA binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, said CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40;
前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、ＩｇＧ４アイソタイプであり、ＨＣ１の４０５位にフェニルアラニン及び４０９位にアルギニン、並びにＨＣ２の４０５位にロイシン及び４０９位にリジンを含み、残基の番号付けが、ＥＵインデックスに従うものであり、 said BCMAxCD3 bispecific antibody is of the IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 of HC1 and leucine at position 405 and lysine at position 409 of HC2, and the residue numbering is subject to the EU index;
場合により、前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、前記ＨＣ１及び前記ＨＣ２の両方の２２８位にプロリン、２３４位にアラニン、及び２３５位にアラニンを更に含む、 optionally, said BCMAxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 of both said HC1 and said HC2;
ｃ）例えば、前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、配列番号３１のＨＣ１、配列番号３２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、 c) for example, said BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42,
ｄ）前記癌が、ＢＣＭＡ発現癌であり、 d) the cancer is a BCMA-expressing cancer;
前記対象が、抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して再発又は難治性である、 said subject is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof;
ｅ）場合により、前記対象が、前記抗ＣＤ３８抗体による治療に対して再発又は難治性である、及び／又は e) optionally, said subject is relapsed or refractory to treatment with said anti-CD38 antibody, and/or
前記癌が、血液悪性腫瘍である、 wherein the cancer is a hematologic malignancy;
ｆ）場合により、前記血液悪性腫瘍が、多発性骨髄腫、骨髄腫、ＤＬＢＬＣ、ＣＬＬ、ワルデンストレーム高ガンマグロブリン血症、又は非ホジキンリンパ腫であり、例えば、 f) optionally, said hematologic malignancy is multiple myeloma, myeloma, DLBLC, CLL, Waldenström's hypergammaglobulinemia, or non-Hodgkin's lymphoma, for example
ｉ）前記多発性骨髄腫が、 i) said multiple myeloma is
Ｉ．新たに診断された多発性骨髄腫である、 I. Newly diagnosed multiple myeloma,
ＩＩ．再発又は難治性多発性骨髄腫である、又は II. have relapsed or refractory multiple myeloma, or
ＩＩＩ．前記多発性骨髄腫が、高リスク多発性骨髄腫である、 III. wherein said multiple myeloma is high-risk multiple myeloma;
ｉｉ）例えば、前記高リスク多発性骨髄腫を有する前記対象が、 ii) for example, said subject with said high-risk multiple myeloma is
Ｉ．ｔ（４；１４）（ｐ１６；ｑ３２）、 I. t(4;14)(p16;q32),
ＩＩ．ｔ（１４；１６）（ｑ３２；ｑ２３）、 II. t(14;16)(q32;q23),
ＩＩＩ．ｄｅｌ１７ｐ、 III. del17p,
ＩＶ．１ｑＡｍｐ、 IV. 1 qAmp,
Ｖ．ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、 V. t(4;14)(p16;q32) and t(14;16)(q32;q23),
ＶＩ．ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、 VI. t(4;14)(p16;q32) and del17p,
ＶＩＩ．ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は VII. t(14;16)(q32;q23) and del17p, or
ＶＩＩＩ．ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、 VIII. have one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof;
請求項１０～１２のいずれか一項に記載の組成物。A composition according to any one of claims 10-12.
ｂ）前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、 b) said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5;
ｃ）前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 c) said anti-CD38 antibody is of the IgG1 isotype;
ｄ）前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、 d) said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13;
ｅ）前記抗ＣＤ３８抗体が、 e) said anti-CD38 antibody is
ｉ）配列番号１４のＶＨ及び配列番号１５のＶＬ、 i) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
ｉｉ）配列番号１６のＶＨ及び配列番号１７のＶＬ、 ii) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
ｉｉｉ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は iii) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
ｉｖ）配列番号２０のＶＨ及び配列番号２１のＶＬを含み、 iv) comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21;
場合により、前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 optionally, said anti-CD38 antibody is of the IgG1 isotype;
ｆ）前記抗ＣＤ３８抗体が、約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与されるものであり、 f) said anti-CD38 antibody is administered at a dose of about 8 mg/kg to about 16 mg/kg;
前記ＢＣＭＡ×ＣＤ３二重特異性抗体及び前記抗ＣＤ３８抗体が、静脈内注射によって投与されるものである、 wherein said BCMAxCD3 bispecific antibody and said anti-CD38 antibody are administered by intravenous injection;
ｇ）前記ＢＣＭＡ×ＣＤ３二重特異性抗体が、静脈内注射によって投与され、前記抗ＣＤ３８抗体が、皮下注射によって投与されるものである、 g) said BCMAxCD3 bispecific antibody is administered by intravenous injection and said anti-CD38 antibody is administered by subcutaneous injection;
ｈ）前記対象が、ヒトであり、 h) said subject is a human;
ｉ）前記対象に１つ又は２つ以上の抗癌剤療法を投与することと組み合わせて用いるものである、 i) in combination with administering one or more anticancer drug therapies to said subject,
場合により、前記１つ又は２つ以上の抗癌剤療法が、 Optionally, said one or more anticancer drug therapies are
ｉ）自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、又は i) selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapy, or
ｉｉ）レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、プレドニゾン、若しくはデキサメタゾン、又はこれらの任意の組み合わせからなる群から選択される、 ii) selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof;
ｊ）前記抗ＣＤ３８抗体が、約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、医薬組成物において投与されるか、又は投与のために提供されるものである、及び／又は j) the anti-CD38 antibody is from about 20 mg/mL to about 120 mg in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); /mL of said anti-CD38 antibody and having a pH of about 5.5, and/or
前記抗ＣＤ３８抗体が、約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供されるものであり、 said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20;
場合により、前記抗ＣＤ３８抗体が、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供されるものである、 optionally, the anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 120 mg/mL of the anti-CD38 antibody and about 2,000 U/mL of rHuPH20;
ｋ）例えば、前記抗ＣＤ３８抗体が、 k) for example, said anti-CD38 antibody is
ｉ）約５ｍＭ～約１５ｍＭのヒスチジンと、 i) about 5 mM to about 15 mM histidine;
ｉｉ）約１００ｍＭ～約３００ｍＭのソルビトールと、 ii) about 100 mM to about 300 mM sorbitol;
ｉｉｉ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、 iii) from about 0.01% w/v to about 0.04% w/v PS-20;
ｉｖ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、医薬組成物において投与されるか、又は投与のために提供されるものである、 iv) administered or provided for administration in a pharmaceutical composition comprising from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6;
場合により前記抗ＣＤ３８抗体が、 Optionally, said anti-CD38 antibody is
Ｉ．約１，８００ｍｇの前記抗ＣＤ３８抗体と、 I. about 1,800 mg of said anti-CD38 antibody;
ＩＩ．約３０，０００ＵのｒＨｕＰＨ２０と、 II. about 30,000 U of rHuPH20;
ＩＩＩ．約１０ｍＭのヒスチジンと、 III. about 10 mM histidine;
ＩＶ．約３００ｍＭのソルビトールと、 IV. about 300 mM sorbitol; and
Ｖ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 V. about 0.04% (w/v) PS-20;
ＶＩ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供されるものである、 VI. is administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6;
例えば、前記抗ＣＤ３８抗体が、 For example, the anti-CD38 antibody is
Ａ．約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 A. about 120 mg/mL of said anti-CD38 antibody;
Ｂ．約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、 B. rHuPH20 at about 2,000 U/mL;
Ｃ．約１０ｍＭのヒスチジンと、 C. about 10 mM histidine;
Ｄ．約３００ｍＭのソルビトールと、 D. about 300 mM sorbitol; and
Ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 E. about 0.04% (w/v) PS-20;
Ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供されるものである、 F. is administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6;
請求項１０～１２のいずれか一項に記載の組成物。A composition according to any one of claims 10-12.
前記医薬組成物が、非固定組み合わせである、 wherein said pharmaceutical composition is a non-fixed combination;
ｂ）場合により、 b) as the case may be,
ｉ）約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、又は i) about 20 mg/mL to about 120 mg/mL of said anti-CD38 in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); comprising an antibody and having a pH of about 5.5, or
約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含み、 about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20;
場合により、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含み、 optionally about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20;
例えば、前記医薬組成物は、１つ又は２つ以上の賦形剤を更に含み、 For example, the pharmaceutical composition further comprises one or more excipients,
場合により、前記１つ又は２つ以上の賦形剤が、ヒスチジン、メチオニン、ソルビトール、若しくはポリソルベート－２０（ＰＳ－２０）、又はこれらの任意の組み合わせである、 optionally, said one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof;
ｉｉ）前記医薬組成物が、 ii) the pharmaceutical composition is
Ｉ．約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 I. about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
ＩＩ．約５ｍＭ～約１５ｍＭのヒスチジンと、 II. about 5 mM to about 15 mM histidine;
ＩＩＩ．約１００ｍＭ～約３００ｍＭのソルビトールと、 III. about 100 mM to about 300 mM sorbitol;
ＩＶ．約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、 IV. PS-20 from about 0.01% w/v to about 0.04% w/v;
Ｖ．約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６であり、 V. from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6;
場合により、前記医薬組成物が、 Optionally, the pharmaceutical composition comprises
Ａ．約１０ｍＭのヒスチジンを含む、 A. containing about 10 mM histidine;
Ｂ．約３００ｍＭのソルビトールを含む、 B. containing about 300 mM sorbitol;
Ｃ．約０．０４％（ｗ／ｖ）のＰＳ－２０を含む、 C. containing about 0.04% (w/v) PS-20;
Ｄ．約１ｍｇ／ｍＬのメチオニンを含む、 D. containing about 1 mg/mL methionine;
Ｅ．下記： E. the below described:
ａ．約１，８００ｍｇの前記抗ＣＤ３８抗体と、 a. about 1,800 mg of said anti-CD38 antibody;
ｂ．約３０，０００ＵのｒＨｕＰＨ２０と、 b. about 30,000 U of rHuPH20;
ｃ．約１０ｍＭのヒスチジンと、 c. about 10 mM histidine;
ｄ．約３００ｍＭのソルビトールと、 d. about 300 mM sorbitol; and
ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 e. about 0.04% (w/v) PS-20;
ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、 f. about 1 mg/mL methionine and a pH of about 5.6;
Ｆ．下記： F. the below described:
ａ．約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 a. about 120 mg/mL of said anti-CD38 antibody;
ｂ．約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、 b. rHuPH20 at about 2,000 U/mL;
ｃ．約１０ｍＭのヒスチジンと、 c. about 10 mM histidine;
ｄ．約３００ｍＭのソルビトールと、 d. about 300 mM sorbitol; and
ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 e. about 0.04% (w/v) PS-20;
ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、 f. about 1 mg/mL methionine and a pH of about 5.6;
請求項１５に記載の医薬組成物。16. A pharmaceutical composition according to claim 15.
ｂ）前記対象が、以前の抗癌治療薬による治療に対して再発又は難治性である、 b) the subject is relapsed or refractory to prior anticancer therapy treatment;
ｃ）前記癌が、ＧＰＲＣ５Ｄ発現癌であり、場合により、前記ＧＰＲＣ５Ｄ発現癌が、血液悪性腫瘍又は固形腫瘍であり、 c) said cancer is a GPRC5D-expressing cancer, optionally said GPRC5D-expressing cancer is a hematological malignancy or a solid tumor;
ｉ）場合により、前記血液悪性腫瘍が、白血病、リンパ腫、又は多発性骨髄腫であり、例えば、前記多発性骨髄腫が、 i) optionally, said hematologic malignancy is leukemia, lymphoma, or multiple myeloma, for example, said multiple myeloma is
Ｉ．新たに診断された多発性骨髄腫、又は I. Newly diagnosed multiple myeloma, or
ＩＩ．再発又は難治性多発性骨髄腫であり、 II. Relapsed or refractory multiple myeloma,
場合により、前記多発性骨髄腫が、高リスク多発性骨髄腫であり、例えば、前記高リスク多発性骨髄腫を有する前記対象が、 Optionally, said multiple myeloma is high-risk multiple myeloma, e.g., said subject with said high-risk multiple myeloma is
Ａ．ｔ（４；１４）（ｐ１６；ｑ３２）、 A. t(4;14)(p16;q32),
Ｂ．ｔ（１４；１６）（ｑ３２；ｑ２３）、 B. t(14;16)(q32;q23),
Ｃ．ｄｅｌ１７ｐ、 C. del17p,
Ｄ．１ｑＡｍｐ、 D. 1 qAmp,
Ｅ．ｔ（４；１４）（ｐ１６；ｑ３２）及びｔ（１４；１６）（ｑ３２；ｑ２３）、 E. t(4;14)(p16;q32) and t(14;16)(q32;q23),
Ｆ．ｔ（４；１４）（ｐ１６；ｑ３２）及びｄｅｌ１７ｐ、 F. t(4;14)(p16;q32) and del17p,
Ｇ．ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又は G. t(14;16)(q32;q23) and del17p, or
Ｈ．ｔ（４；１４）（ｐ１６；ｑ３２）、ｔ（１４；１６）（ｑ３２；ｑ２３）及びｄｅｌ１７ｐ、又はこれらの任意の組み合わせを含む１つ又は２つ以上の染色体異常を有する、 H. have one or more chromosomal abnormalities comprising t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof;
ｉｉ）場合により、前記固形腫瘍が、卵巣癌、肺癌、胃癌、前立腺癌、腎癌、肝癌、膵癌、結腸癌、食道癌、膀胱癌、子宮頸癌、又は悪性黒色腫であり、 ii) optionally the solid tumor is ovarian cancer, lung cancer, gastric cancer, prostate cancer, renal cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma;
前記対象が、前記抗ＣＤ３８抗体、レナリドミド、ボルテゾミブ、ポマリドミド、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、若しくはサリドマイド、又はこれらの任意の組み合わせによる治療に対して再発又は難治性である、 said subject is relapsed or refractory to treatment with said anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof;
ｄ）例えば、前記対象が、前記抗ＣＤ３８抗体による治療に対して再発又は難治性である、 d) for example, said subject is relapsed or refractory to treatment with said anti-CD38 antibody;
ｅ）前記Ｔ細胞リダイレクト治療薬が、ＣＤ３、ＣＤ３イプシロン（ＣＤ３ε）、ＣＤ８、ＫＩ２Ｌ４、ＮＫＧ２Ｅ、ＮＫＧ２Ｄ、ＮＫＧ２Ｆ、ＢＴＮＬ３、ＣＤ１８６、ＢＴＮＬ８、ＰＤ－１、ＣＤ１９５、又はＮＫＧ２Ｃに結合する、 e) the T cell redirecting therapeutic binds to CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C;
ｆ）前記Ｔ細胞リダイレクト治療薬が、配列番号４３のＨＣＤＲ１、配列番号４４のＨＣＤＲ２、配列番号４５のＨＣＤＲ３、配列番号４６のＬＣＤＲ１、配列番号４７のＬＣＤＲ２、及び配列番号４８のＬＣＤＲ３を含むＧＰＲＣ５Ｄ結合ドメイン、並びに配列番号３３のＨＣＤＲ１、配列番号３４のＨＣＤＲ２、配列番号３５のＨＣＤＲ３、配列番号３６のＬＣＤＲ１、配列番号３７のＬＣＤＲ２、及び配列番号３８のＬＣＤＲ３を含むＣＤ３結合ドメインを含む、 f) a GPRC5D binding wherein said T cell redirecting therapeutic comprises HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48 domain and a CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38;
ｇ）前記ＧＰＲＣ５Ｄ結合ドメインが、配列番号４９のＶＨ及び配列番号５０のＶＬを含み、前記ＣＤ３結合ドメインが、配列番号３９のＶＨ及び配列番号４０のＶＬを含む、 g) said GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and said CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40;
ｈ）ＧＰＲＣ５Ｃに結合する前記Ｔ細胞リダイレクト治療薬が、多重特異性抗体、ＣＡＲ、又は前記ＣＡＲを発現するＴ細胞であり、 h) said T cell redirecting therapeutic that binds to GPRC5C is a multispecific antibody, a CAR, or a T cell expressing said CAR;
場合により、前記多重特異性抗体が、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、又はＩｇＧ４アイソタイプであり、 optionally, said multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype;
場合により、前記多重特異性抗体が、前記多重特異性抗体のＦｃγ受容体（ＦｃγＲ）への結合を低減する１つ又は２つ以上のＦｃ置換を含み、 optionally, said multispecific antibody comprises one or more Fc substitutions that reduce binding of said multispecific antibody to Fcγ receptors (FcγR);
例えば、前記１つ又は２つ以上のＦｃ置換が、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＦ２３４Ａ／Ｌ２３５Ａ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ、全てのＩｇアイソタイプ上のＮ２９７Ａ、ＩｇＧ２上のＶ２３４Ａ／Ｇ２３７Ａ、ＩｇＧ１上のＫ２１４Ｔ／Ｅ２３３Ｐ／Ｌ２３４Ｖ／Ｌ２３５Ａ／Ｇ２３６欠失／Ａ３２７Ｇ／Ｐ３３１Ａ／Ｄ３６５Ｅ／Ｌ３５８Ｍ、ＩｇＧ２上のＨ２６８Ｑ／Ｖ３０９Ｌ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ１上のＳ２６７Ｅ／Ｌ３２８Ｆ、ＩｇＧ１上のＬ２３４Ｆ／Ｌ２３５Ｅ／Ｄ２６５Ａ、ＩｇＧ１上のＬ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ／Ｈ２６８Ａ／Ａ３３０Ｓ／Ｐ３３１Ｓ、ＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３７Ａ／Ｐ２３８Ｓ、及びＩｇＧ４上のＳ２２８Ｐ／Ｆ２３４Ａ／Ｌ２３５Ａ／Ｇ２３６欠失／Ｇ２３７Ａ／Ｐ２３８Ｓからなる群から選択され、残基の番号付けが、ＥＵインデックスに従うものであり、 For example, the one or more Fc substitutions are F234A/L235A on IgG4, L234A/L235A on IgG1, V234A/G237A/P238S/H268A/V309L/A330S/P331S on IgG2, F234A/ L235A, S228P/F234A/L235A on IgG4, N297A on all Ig isotypes, V234A/G237A on IgG2, K214T/E233P/L234V/L235A/G236 deletion/A327G/P331A/D365E/L358M on IgG1, IgG2 H268Q/V309L/A330S/P331S on IgG1, S267E/L328F on IgG1, L234F/L235E/D265A on IgG1, L234A/L235A/G237A/P238S/H268A/A330S/P331S on IgG1, S2248P/F23 on IgG4 L235A/G237A/P238S, and S228P/F234A/L235A/G236 deletion/G237A/P238S on IgG4, wherein residue numbering is according to the EU index;
ｉ）前記多重特異性抗体が、Ｓ２２８Ｐ置換を更に含む、及び／又は i) said multispecific antibody further comprises a S228P substitution, and/or
前記多重特異性抗体が、第１のＣＨ３ドメイン若しくは第２のＣＨ３ドメインに、又は前記第１のＣＨ３ドメイン及び前記第２のＣＨ３ドメインの両方に、１つ又は２つ以上の非対称置換を含む、 said multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain;
ｉｉ）場合により、前記１つ又は２つ以上の非対称置換が、Ｆ４５０Ｌ／Ｋ４０９Ｒ、野生型／Ｆ４０９Ｌ＿Ｒ４０９Ｋ、Ｔ３６６Ｙ／Ｆ４０５Ａ、Ｔ３６６Ｗ／Ｆ４０５Ｗ、Ｆ４０５Ｗ／Ｙ４０７Ａ、Ｔ３９４Ｗ／Ｙ４０７Ｔ、Ｔ３９４Ｓ／Ｙ４０７Ａ、Ｔ３６６Ｗ／Ｔ３９４Ｓ、Ｆ４０５Ｗ／Ｔ３９４Ｓ及びＴ３６６Ｗ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、 ii) optionally, said one or more asymmetric substitutions are F450L/K409R, wild-type/F409L_R409K, T366Y/F405A, T366W/F405W, F405W/Y407A, T394W/Y407T, T394S/Y407A, T366W/T394S, Ｆ４０５Ｗ／Ｔ３９４Ｓ及びＴ３６６Ｗ／Ｔ３６６Ｓ＿Ｌ３６８Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３９４Ｗ、Ｔ３６６Ｉ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｔ３６６Ｌ＿Ｋ３９２Ｍ＿Ｔ３９４Ｗ／Ｆ４０５Ａ＿Ｙ４０７Ｖ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、Ｌ３５１Ｙ＿Ｙ４０７Ａ／Ｔ３６６Ｖ＿Ｋ４０９Ｆ、Ｙ４０７Ａ／Ｔ３６６Ａ＿Ｋ４０９Ｆ、並びにＴ３５０Ｖ＿Ｌ３５１Ｙ＿Ｆ４０５Ａ＿Ｙ４０７Ｖ／Ｔ３５０Ｖ＿Ｔ３６６Ｌ＿Ｋ３９２Ｌ＿Ｔ３９４Ｗからなる群から選択される、
ｉ）前記多重特異性抗体が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含む、 i) said multispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42,
ｊ）前記抗ＣＤ３８抗体が、配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、 j) said anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11;
ｋ）前記抗ＣＤ３８抗体が、配列番号４のＶＨ及び配列番号５のＶＬを含む、 k) said anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5;
ｌ）前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 l) said anti-CD38 antibody is of the IgG1 isotype;
ｍ）前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、 m) said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13;
ｎ）前記抗ＣＤ３８抗体が、 n) said anti-CD38 antibody is
ｉ）配列番号１４のＶＨ及び配列番号１５のＶＬ、 i) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
ｉｉ）配列番号１６のＶＨ及び配列番号１７のＶＬ、 ii) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
ｉｉｉ）配列番号１８のＶＨ及び配列番号１９のＶＬ、又は iii) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
ｉｖ）配列番号２０のＶＨ及び配列番号２１のＶＬを含み、 iv) comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21;
場合により、前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 optionally, said anti-CD38 antibody is of the IgG1 isotype;
ｏ）前記抗ＣＤ３８抗体が、約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与されるものである、 o) the anti-CD38 antibody is administered at a dose of about 8 mg/kg to about 16 mg/kg;
ｐ）ＧＰＲＣ５Ｄに結合する前記Ｔ細胞リダイレクト治療薬及び前記抗ＣＤ３８抗体が、静脈内注射によって投与されるものである、 p) said T cell-redirecting therapeutic that binds to GPRC5D and said anti-CD38 antibody are administered by intravenous injection;
ｑ）ＧＰＲＣ５Ｄに結合する前記Ｔ細胞リダイレクト治療薬が、静脈内注射によって投与され、前記抗ＣＤ３８抗体が、皮下注射によって投与されるものである、 q) said T cell redirecting therapeutic that binds to GPRC5D is administered by intravenous injection and said anti-CD38 antibody is administered by subcutaneous injection;
ｒ）前記対象が、ヒトである、 r) said subject is a human
ｓ）ＧＰＲＣ５Ｄに結合する前記Ｔ細胞リダイレクト治療薬が、ＧＰＲＣ５Ｄ×ＣＤ３二重特異性抗体である、 s) said T cell redirecting therapeutic that binds to GPRC5D is a GPRC5DxCD3 bispecific antibody;
ｔ）前記対象に１つ又は２つ以上の抗癌剤療法を投与することと組み合わせて用いるものであり、 t) in combination with administering to said subject one or more anti-cancer drug therapies;
場合により、前記１つ又は２つ以上の抗癌剤療法が、 Optionally, said one or more anticancer drug therapies are
ｉ）自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、又は i) selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapy, or
ｉｉ）前記１つ又は２つ以上の抗癌剤療法が、レナリドミド、サリドマイド、ポマリドミド、ボルテゾミブ、カルフィルゾミブ、エロトズマブ、イキサゾミブ、メルファラン、デキサメタゾン、又はプレドニゾンからなる群から選択される、 ii) the one or more anticancer drug therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, or prednisone;
ｕ）前記抗ＣＤ３８抗体が、約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、医薬組成物において投与されるか、又は投与のために提供されるものである、及び／又は u) the anti-CD38 antibody is from about 20 mg/mL to about 120 mg in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); /mL of said anti-CD38 antibody and having a pH of about 5.5, and/or
前記抗ＣＤ３８抗体が、約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供されるものであり、 said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20;
場合により、前記抗ＣＤ３８抗体が、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含む医薬組成物において投与されるか、又は投与のために提供されるものである、 optionally, said anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20;
ｖ）例えば、前記抗ＣＤ３８抗体が、 v) for example, said anti-CD38 antibody is
ｉ）約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 i) from about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
ｉｉ）約５ｍＭ～約１５ｍＭのヒスチジンと、 ii) about 5 mM to about 15 mM histidine;
ｉｉｉ）約１００ｍＭ～約３００ｍＭのソルビトールと、 iii) about 100 mM to about 300 mM sorbitol;
ｉｖ）約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、 iv) from about 0.01% w/v to about 0.04% w/v PS-20;
ｖ）約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６である、医薬組成物において投与されるか、又は投与のために提供されるものであり、 v) administered or provided for administration in a pharmaceutical composition comprising from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6;
場合により、前記抗ＣＤ３８抗体が、 Optionally, said anti-CD38 antibody is
Ｉ．約１，８００ｍｇの前記抗ＣＤ３８抗体と、 I. about 1,800 mg of said anti-CD38 antibody;
ＩＩ．約３０，０００ＵのｒＨｕＰＨ２０と、 II. about 30,000 U of rHuPH20;
ＩＩＩ．約１０ｍＭのヒスチジンと、 III. about 10 mM histidine;
ＩＶ．約３００ｍＭのソルビトールと、 IV. about 300 mM sorbitol; and
Ｖ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 V. about 0.04% (w/v) PS-20;
ＶＩ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供されるものであり、 VI. administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6;
場合により、前記抗ＣＤ３８抗体が、 Optionally, said anti-CD38 antibody is
Ａ．約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 A. about 120 mg/mL of said anti-CD38 antibody;
Ｂ．約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、 B. rHuPH20 at about 2,000 U/mL;
Ｃ．約１０ｍＭのヒスチジンと、 C. about 10 mM histidine;
Ｄ．約３００ｍＭのソルビトールと、 D. about 300 mM sorbitol; and
Ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 E. about 0.04% (w/v) PS-20;
Ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、医薬組成物において投与されるか、又は投与のために提供されるものである、 F. is administered or provided for administration in a pharmaceutical composition comprising about 1 mg/mL methionine and having a pH of about 5.6;
請求項１８～２０のいずれか一項に記載の組成物。A composition according to any one of claims 18-20.
ａ）場合により、前記ＧＰＲＣ５Ｃ×ＣＤ３二重特異性抗体が、配列番号５１のＨＣ１、配列番号５２のＬＣ１、配列番号４１のＨＣ２、及び配列番号４２のＬＣ２を含み、前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、及び／又は a) Optionally, said GPRC5CxCD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42, and said anti-CD38 antibody comprises the sequence comprising the HC of number 12 and the LC of SEQ ID NO: 13, and/or
非固定組み合わせである、 is a non-fixed combination,
ｂ）場合により、前記組み合わせ医薬が、 b) optionally, said combination medicament is
ｉ）約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、又は i) about 20 mg/mL to about 120 mg/mL of said anti-CD38 in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); comprising an antibody and having a pH of about 5.5, or
約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含み、 about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20;
場合により、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含み、 optionally about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20;
例えば、前記組み合わせ医薬が、１つ又は２つ以上の賦形剤を更に含み、 For example, said combination medicament further comprises one or more excipients,
場合により、前記１つ又は２つ以上の賦形剤が、ヒスチジン、メチオニン、ソルビトール、若しくはポリソルベート－２０（ＰＳ－２０）、又はこれらの任意の組み合わせである、 optionally, said one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof;
ｉｉ）例えば、前記組み合わせ医薬が、 ii) for example, said combination medicament is
Ｉ．下記： I. the below described:
Ａ．約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 A. about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
Ｂ．約５ｍＭ～約１５ｍＭのヒスチジンと、 B. about 5 mM to about 15 mM histidine;
Ｃ．約１００ｍＭ～約３００ｍＭのソルビトールと、 C. about 100 mM to about 300 mM sorbitol;
Ｄ．約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、 D. PS-20 from about 0.01% w/v to about 0.04% w/v;
Ｅ．約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６であり、 E. from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6;
場合により、前記組み合わせ医薬が、 Optionally, said combination pharmaceutical is
ａ．約１０ｍＭのヒスチジンを含む、 a. containing about 10 mM histidine;
ｂ．約３００ｍＭのソルビトールを含む、 b. containing about 300 mM sorbitol;
ｃ．下記： c. the below described:
１．約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 1. about 120 mg/mL of said anti-CD38 antibody;
２．約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、 2. rHuPH20 at about 2,000 U/mL;
３．約１０ｍＭのヒスチジンと、 3. about 10 mM histidine;
４．約３００ｍＭのソルビトールと、 4. about 300 mM sorbitol; and
５．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 5. about 0.04% (w/v) PS-20;
６．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、 6. about 1 mg/mL methionine and a pH of about 5.6;
ＩＩ．約０．０４％（ｗ／ｖ）のＰＳ－２０を含む、 II. containing about 0.04% (w/v) PS-20;
ＩＩＩ．約１ｍｇ／ｍＬのメチオニンを含む、及び／又は III. containing about 1 mg/mL methionine, and/or
ＩＶ．下記： IV. the below described:
Ａ．約１，８００ｍｇの前記抗ＣＤ３８抗体と、 A. about 1,800 mg of said anti-CD38 antibody;
Ｂ．約３０，０００ＵのｒＨｕＰＨ２０と、 B. about 30,000 U of rHuPH20;
Ｃ．約１０ｍＭのヒスチジンと、 C. about 10 mM histidine;
Ｄ．約３００ｍＭのソルビトールと、 D. about 300 mM sorbitol; and
Ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 E. about 0.04% (w/v) PS-20;
Ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、 F. about 1 mg/mL methionine and a pH of about 5.6;
請求項２２に記載の組み合わせ医薬。23. A pharmaceutical combination according to claim 22.
ｂ）前記癌が、血液悪性腫瘍又は固形腫瘍であり、 b) said cancer is a hematological malignancy or solid tumor,
ｉ）場合により、前記血液悪性腫瘍が、リンパ腫、Ｂ細胞悪性腫瘍、ホジキンリンパ腫、非ホジキンリンパ腫、ＤＬＢＬＣ、ＦＬ、ＭＣＬ、辺縁帯Ｂ細胞リンパ腫（ＭＺＬ）、粘膜関連リンパ組織リンパ腫（ＭＡＬＴ）、ＣＬＬ、ＡＬＬ、ＡＭＬ、ワルデンストレーム高ガンマグロブリン血症、又はＴ細胞リンパ腫である、又は i) optionally the hematological malignancy is lymphoma, B-cell malignancy, Hodgkin's lymphoma, non-Hodgkin's lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT); have CLL, ALL, AML, Waldenström hypergammaglobulinemia, or T-cell lymphoma, or
ｉｉ）前記固形腫瘍が、肺癌、肝癌、子宮頸癌、結腸癌、乳癌、卵巣癌、膵癌、黒色腫、神経膠芽腫、前立腺癌、食道癌、又は胃癌である、 ii) the solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer;
ｃ）前記Ｔ細胞リダイレクト治療薬が、ＣＤ３イプシロン（ＣＤ３ε）、ＣＤ８、ＫＩ２Ｌ４、ＮＫＧ２Ｅ、ＮＫＧ２Ｄ、ＮＫＧ２Ｆ、ＢＴＮＬ３、ＣＤ１８６、ＢＴＮＬ８、ＰＤ－１、ＣＤ１９５、又はＮＫＧ２Ｃに結合する、 c) the T cell redirecting therapeutic binds to CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C;
ｄ）ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、ブリナツモマブ、アキシカブタゲンシロロイセル、チサゲンレクルユーセル－ｔ、イネビリズマブ、リソカブタゲンマラルユーセル（lisocabtagene maraleucel）、ＸｍＡｂ－５５７４、ＣＩＫ－ＣＡＲ．ＣＤ１９、ＩＣＴＣＡＲ－０１１、ＩＭ－１９、ＪＣＡＲ－０１４、ロンカスツキシマブテシリン、ＭＢ－ＣＡＲＴ２０１９．１、ＯＸＳ－１５５０、ＰＢＣＡＲ－０１９１、ＰＣＡＲ－０１９、ＰＣＡＲ－１１９、Ｓｅｎｌ－００１、ＴＩ－１００７、ＸｍＡｂ－５８７１、ＰＴＧ－０１、ＰＺ０１、Ｓｅｎｌ＿１９０４Ａ、Ｓｅｎｌ＿１９０４Ｂ、ＵＣＡＲＴ－１９、ＣＳＧ－ＣＤ１９、ＤＩ－Ｂ４、ＥＴ－１９０、ＧＣ－００７Ｆ、又はＧＣ－０２２のＣＤ１９結合ドメインを含む、 d) said T-cell redirecting therapeutic that binds to CD19 is blinatumomab, axicabtagen ciloleucel, tisagen reclusel-t, inevirizumab, lisocabtagene maraleucel, XmAb-5574 , CIK-CAR. CD19, ICTCAR-011, IM-19, JCAR-014, Roncastuximabutecillin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007 , XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F, or the CD19 binding domain of GC-022;
ｅ）ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、ブリナツモマブ、アキシカブタゲンシロロイセル、チサゲンレクルユーセル－ｔ、イネビリズマブ、リソカブタゲンマラルユーセル、ＸｍＡｂ－５５７４、ＣＩＫ－ＣＡＲ．ＣＤ１９、ＩＣＴＣＡＲ－０１１、ＩＭ－１９、ＪＣＡＲ－０１４、ロンカスツキシマブテシリン、ＭＢ－ＣＡＲＴ２０１９．１、ＯＸＳ－１５５０、ＰＢＣＡＲ－０１９１、ＰＣＡＲ－０１９、ＰＣＡＲ－１１９、Ｓｅｎｌ－００１、ＴＩ－１００７、ＸｍＡｂ－５８７１、ＰＴＧ－０１、ＰＺ０１、Ｓｅｎｌ＿１９０４Ａ、Ｓｅｎｌ＿１９０４Ｂ、ＵＣＡＲＴ－１９、ＣＳＧ－ＣＤ１９、ＤＩ－Ｂ４、ＥＴ－１９０、ＧＣ－００７Ｆ、又はＧＣ－０２２を含む、 e) said T-cell redirecting therapeutic that binds to CD19 is blinatumomab, axicabutagenciloleucel, tisagenreclusel-t, inevirizumab, risocabutagenmalarusel, XmAb-5574, CIK-CAR . CD19, ICTCAR-011, IM-19, JCAR-014, Roncastuximabutecillin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007 , XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F, or GC-022,
ｆ）ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、多重特異性抗体、ＣＡＲ、又は前記ＣＡＲを発現するＴ細胞である、 f) said T-cell redirecting therapeutic that binds to CD19 is a multispecific antibody, a CAR, or a T-cell expressing said CAR;
ｇ）前記抗ＣＤ３８抗体が、 g) said anti-CD38 antibody is
ｉ）下記： i) below:
Ｉ．配列番号６のＨＣＤＲ１、配列番号７のＨＣＤＲ２、配列番号８のＨＣＤＲ３、配列番号９のＬＣＤＲ１、配列番号１０のＬＣＤＲ２、及び配列番号１１のＬＣＤＲ３を含む、 I. HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11;
ＩＩ．配列番号４のＶＨ及び配列番号５のＶＬを含む、 II. comprising the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5;
ＩＩＩ．ＩｇＧ１アイソタイプである、及び／又は III. is of the IgG1 isotype, and/or
ＩＶ．配列番号１２のＨＣ及び配列番号１３のＬＣを含む、又は IV. comprising HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13, or
ｉｉ）下記： ii) below:
Ｉ．配列番号１４のＶＨ及び配列番号１５のＶＬ、 I. VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15,
ＩＩ．配列番号１６のＶＨ及び配列番号１７のＶＬ、 II. VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17,
ＩＩＩ．配列番号１８のＶＨ及び配列番号１９のＶＬ、又は III. VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or
ＩＶ．配列番号２０のＶＨ及び配列番号２１のＶＬを含み、 IV. comprising the VH of SEQ ID NO:20 and the VL of SEQ ID NO:21;
場合により、前記抗ＣＤ３８抗体が、ＩｇＧ１アイソタイプである、 optionally, said anti-CD38 antibody is of the IgG1 isotype;
ｈ）前記抗ＣＤ３８抗体が、約８ｍｇ／ｋｇ～約１６ｍｇ／ｋｇの用量で投与されるものであり、 h) said anti-CD38 antibody is administered at a dose of about 8 mg/kg to about 16 mg/kg;
ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬及び前記抗ＣＤ３８抗体が、静脈内注射によって投与されるものである、 wherein the T-cell redirecting therapeutic that binds to CD19 and the anti-CD38 antibody are administered by intravenous injection;
ｉ）ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、静脈内注射によって投与され、前記抗ＣＤ３８抗体が、皮下注射によって投与されるものである、 i) said T cell redirecting therapeutic that binds to CD19 is administered by intravenous injection and said anti-CD38 antibody is administered by subcutaneous injection;
ｊ）前記対象が、ヒトである、 j) said subject is a human;
ｋ）ＣＤ１９に結合する前記Ｔ細胞リダイレクト治療薬が、ＣＤ１９×ＣＤ３二重特異性抗体である、及び／又は k) said T cell redirecting therapeutic that binds to CD19 is a CD19xCD3 bispecific antibody, and/or
ｌ）前記対象に１つ又は２つ以上の抗癌剤療法を投与することと組み合わせて用いるものであり、 l) in combination with administering to said subject one or more anti-cancer drug therapies,
場合により、前記１つ又は２つ以上の抗癌剤療法が、自家幹細胞移植（ＡＳＣＴ）、放射線、手術、化学療法剤、免疫調節剤、及び標的化癌療法からなる群から選択される、 optionally, the one or more anticancer drug therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies;
請求項２５～２９のいずれか一項に記載の組成物。A composition according to any one of claims 25-29.
ａ）場合により、前記抗ＣＤ３８抗体が、配列番号１２のＨＣ及び配列番号１３のＬＣを含む、及び／又は a) optionally, said anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13, and/or
前記組み合わせ医薬が、非固定組み合わせである、 wherein the combination pharmaceutical is a non-fixed combination;
ｂ）前記組み合わせ医薬が、 b) said combination medicament is
ｉ）約２５ｍＭの酢酸、約６０ｍＭの塩化ナトリウム、約１４０マンニトール、及び約０．０４％ｗ／ｖのポリソルベート－２０（ＰＳ－２０）中の約２０ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体を含み、ｐＨ約５．５である、又は i) about 20 mg/mL to about 120 mg/mL of said anti-CD38 in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w/v polysorbate-20 (PS-20); comprising an antibody and having a pH of about 5.5, or
約１，８００ｍｇの前記抗ＣＤ３８抗体及び約３０，０００ＵのｒＨｕＰＨ２０を含み、 about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20;
場合により、約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体及び約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０を含み、 optionally about 120 mg/mL of said anti-CD38 antibody and about 2,000 U/mL of rHuPH20;
例えば、前記組み合わせ医薬が、１つ又は２つ以上の賦形剤を更に含み、 For example, said combination medicament further comprises one or more excipients,
場合により、前記１つ又は２つ以上の賦形剤が、ヒスチジン、メチオニン、ソルビトール、若しくはポリソルベート－２０（ＰＳ－２０）、又はこれらの任意の組み合わせである、 optionally, said one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof;
ｉｉ）例えば、前記組み合わせ医薬が、 ii) for example, said combination medicament is
Ｉ．約１００ｍｇ／ｍＬ～約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 I. about 100 mg/mL to about 120 mg/mL of said anti-CD38 antibody;
ＩＩ．約５ｍＭ～約１５ｍＭのヒスチジンと、 II. about 5 mM to about 15 mM histidine;
ＩＩＩ．約１００ｍＭ～約３００ｍＭのソルビトールと、 III. about 100 mM to about 300 mM sorbitol;
ＩＶ．約０．０１％ｗ／ｖ～約０．０４％ｗ／ｖのＰＳ－２０と、 IV. PS-20 from about 0.01% w/v to about 0.04% w/v;
Ｖ．約１ｍｇ／ｍＬ～約２ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．５～５．６であり、 V. from about 1 mg/mL to about 2 mg/mL methionine and having a pH of about 5.5-5.6;
場合により、前記組み合わせ医薬が、 Optionally, said combination pharmaceutical is
Ａ．約１０ｍＭのヒスチジンを含む、 A. containing about 10 mM histidine;
Ｂ．約３００ｍＭのソルビトールを含む、 B. containing about 300 mM sorbitol;
Ｃ．約０．０４％（ｗ／ｖ）のＰＳ－２０を含む、 C. containing about 0.04% (w/v) PS-20;
Ｄ．約１ｍｇ／ｍＬのメチオニンを含む、 D. containing about 1 mg/mL methionine;
Ｅ．下記： E. the below described:
ａ．約１，８００ｍｇの前記抗ＣＤ３８抗体と、 a. about 1,800 mg of said anti-CD38 antibody;
ｂ．約３０，０００ＵのｒＨｕＰＨ２０と、 b. about 30,000 U of rHuPH20;
ｃ．約１０ｍＭのヒスチジンと、 c. about 10 mM histidine;
ｄ．約３００ｍＭのソルビトールと、 d. about 300 mM sorbitol; and
ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 e. about 0.04% (w/v) PS-20;
ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、及び／又は f. about 1 mg/mL methionine and a pH of about 5.6; and/or
Ｆ．下記： F. the below described:
ａ．約１２０ｍｇ／ｍＬの前記抗ＣＤ３８抗体と、 a. about 120 mg/mL of said anti-CD38 antibody;
ｂ．約２，０００Ｕ／ｍＬのｒＨｕＰＨ２０と、 b. rHuPH20 at about 2,000 U/mL;
ｃ．約１０ｍＭのヒスチジンと、 c. about 10 mM histidine;
ｄ．約３００ｍＭのソルビトールと、 d. about 300 mM sorbitol; and
ｅ．約０．０４％（ｗ／ｖ）のＰＳ－２０と、 e. about 0.04% (w/v) PS-20;
ｆ．約１ｍｇ／ｍＬのメチオニンとを含み、ｐＨ約５．６である、 f. about 1 mg/mL methionine and a pH of about 5.6;
請求項３１に記載の組み合わせ医薬。32. A pharmaceutical combination according to claim 31.
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