JPWO2020172601A5 - - Google Patents
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均等物
当業者は、本明細書に記載される本発明の具体的な実施形態に対する多くの均等物を、単に日常的な実験を用いて認識するか、または確認することができる。このような均等物は、以下の特許請求の範囲に包含されることが意図される。
発明の態様
［態様１］（ｉ）カルレティキュリンタンパク質（例えば、野生型または突然変異体カルレティキュリンタンパク質）に結合する第１の抗原結合性ドメインと、
（ｉｉ）ＴＣＲβＶに結合する第２の抗原結合性ドメイン、例えば、表１Ａ、表２Ａ、表３Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３Ａのうちのいずれか１つに開示される抗ＴＣＲβＶ抗原結合性ドメイン、または
ＮＫｐ３０に結合する第２の抗原結合性ドメイン、例えば、表７～１０もしくは１８に開示される抗ＮＫｐ３０抗原結合性ドメインと
を含む多機能性分子。
［態様２］第２の抗原結合性ドメインがＴＣＲβＶに結合する、請求項１に記載の多機能性分子。
［態様３］第２の抗原結合性ドメインがＴ細胞を活性化するか、または第２の抗原結合性ドメインがＴ細胞を活性化しない、請求項２に記載の多機能性分子。
［態様４］第２の抗原結合性ドメインがＴＣＲβＶ１２またはＴＣＲβＶ６（例えば、配列番号１０４４のアミノ酸配列を含む）に結合する、請求項２または３に記載の多機能性分子。
［態様５］第２の抗原結合性ドメインが、表１Ａ、表２Ａ、表３Ａ、表１０Ａ、表１１Ａ、表１２Ａ、または表１３Ａに列挙される１つまたは複数のアミノ酸配列を含む、請求項２から４のいずれかに記載の多機能性分子。
［態様６］第２の抗原結合性ドメインが、
（ａ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３Ａにおける重鎖相補性決定領域１（ＶＨＣＤＲ１）のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ１、表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３ＡにおけるＶＨＣＤＲ２のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ２、および／または表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３ＡにおけるＶＨＣＤＲ３のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ３を含み、
（ｉｉ）ＶＬが、表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３Ａにおける軽鎖相補性決定領域１（ＶＬＣＤＲ１）のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＣＤＲ１、表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３ＡにおけるＶＬＣＤＲ２のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＣＤＲ２、および／または表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３ＡにおけるＶＬＣＤＲ３のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＣＤＲ３を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；
（ｂ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号３の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号４のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号５のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号６の軽鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号７のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号８のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；
（ｃ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号４５の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号４６のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号４７のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号５１の軽鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号５２のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号５３のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；ならびに／あるいは
（ｄ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号４８の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号４９のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号５０のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号５４の軽鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号５５のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号５６のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）
を含む、請求項２から５のいずれかに記載の多機能性分子。
［態様７］第２の抗原結合性ドメインが、
（ａ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３ＡにおけるＶＨのアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含み、かつ／または
（ｉｉ）ＶＬが、表１Ａ、表２Ａ、表１０Ａ、表１１Ａ、表１２Ａ、もしくは表１３ＡにおけるＶＬのアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含み、
（ｉｉｉ）ＶＨが、配列番号９のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含み、かつ／または
（ｉｖ）ＶＬが、配列番号１０のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；
（ｂ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号９のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号１１のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む、重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；ならびに／あるいは
（ｃ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号１３１２のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号１３１４のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）
を含む、請求項２から５のいずれかに記載の多機能性分子。
［態様８］第２の抗原結合性ドメインが、
（ａ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号１７の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号１８のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号１９のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号２０の軽鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号２１のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号２２のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；
（ｂ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号５７の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号５８のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号５９のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号６３の軽鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号６４のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号６５のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；ならびに／あるいは
（ｃ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号６０の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号６１のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号６２のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号６６の軽鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号６７のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号６８のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）
を含む、請求項２から５のいずれかに記載の多機能性分子。
［態様９］第２の抗原結合性ドメインが、
（ａ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、配列番号１５のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含み、かつ／または
（ｉｉ）ＶＬが、配列番号１６のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）；ならびに／あるいは
（ｂ）重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）であって、
（ｉ）ＶＨが、
配列番号２３のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）、
配列番号２４のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）、または
配列番号２５のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含み；かつ／または
（ｉｉ）ＶＬが、
配列番号２６のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）、
配列番号２７のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）、
配列番号２８のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）、
配列番号２９のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）、または
配列番号３０のアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む、
重鎖可変領域（ＶＨ）および／または軽鎖可変領域（ＶＬ）
を含む、請求項２から５のいずれかに記載の多機能性分子。
［態様１０］例えば、Ｎ末端からＣ末端まで、第１のＶＬおよび第１のＣＬを含む第１のポリペプチド、
例えば、Ｎ末端からＣ末端まで、第１のＶＨ、第１のＣＨ１、第１の二量体化ドメイン（例えば、第１のＦｃ）、およびＴＣＲ（例えば、ＴＣＲＶβ）に結合する第１の部分（例えば、ＴＣＲ（例えば、ＴＣＲＶβ）に結合する第１のｓｃＦｖ）を含む第２のポリペプチド、
例えば、Ｎ末端からＣ末端まで、第２のＶＨ、第２のＣＨ１、第２の二量体化ドメイン（例えば、第２のＦｃ）、および任意選択でＴＣＲ（例えば、ＴＣＲＶβ）に結合する第２の部分（例えば、ＴＣＲ（例えば、ＴＣＲＶβ）に結合する第２のｓｃＦｖ）を含む第３のポリペプチド、
例えば、Ｎ末端からＣ末端まで、第２のＶＬおよび第２のＣＬを含む第４のポリペプチド
を含み、
第１のＶＬおよび第１のＶＨが第１のカルレティキュリンタンパク質に結合する第１の抗原結合性ドメインを形成し、第２のＶＬおよび第２のＶＨが第２のカルレティキュリンタンパク質に結合する第３の抗原結合性ドメインを形成し、
任意選択で、第１および第２のカルレティキュリンタンパク質が配列番号６２８５または６２８６のアミノ酸配列を含み、
任意選択で、第１および第２のカルレティキュリン突然変異体タンパク質が、配列番号６３１３のアミノ酸配列を含む分子、または配列番号６３１４のアミノ酸配列を含む分子からそれぞれ独立して選択され、
任意選択で、多機能性分子が図３Ａまたは３Ｂの構成を含む、
請求項２から９のいずれかに記載の多機能性分子。
［態様１１］第２の抗原結合性ドメインがＮＫｐ３０に結合する、請求項１に記載の多機能性分子。
［態様１２］第２の抗原結合性ドメインが、ＮＫｐ３０に結合する（例えば、それを活性化させる）抗体分子、例えば抗原結合性ドメイン、またはリガンドから選択され、例えば、第２の抗原結合性ドメインが、ＮＫｐ３０に結合する（例えば、それを活性化させる）抗体分子またはリガンドである、請求項１１に記載の多機能性分子。
［態様１３］第２の抗原結合性ドメインが、
（ｉ）表７、表９、表１０、もしくは表１８の重鎖相補性決定領域１（ＶＨＣＤＲ１）のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ１、表７、表９、表１０、もしくは表１８のＶＨＣＤＲ２のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ２、および／または表７、表９、表１０、もしくは表１８のＶＨＣＤＲ３のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ３を含む重鎖可変領域（ＶＨ）、ならびに／あるいは
（ｉｉ）表８、表９、表１０、もしくは表１８の軽鎖相補性決定領域１（ＶＬＣＤＲ１）のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＣＤＲ１、表８、表９、表１０、もしくは表１８のＶＬＣＤＲ２のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＣＤＲ２、および／または表８、表９、表１０、もしくは表１８のＶＬＣＤＲ３のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＣＤＲ３を含む軽鎖可変領域（ＶＬ）
を含む、請求項１１または１２に記載の多機能性分子。
［態様１４］第２の抗原結合性ドメインが、
（ｉ）配列番号７３１３の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号６００１のＶＨＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列、および／または配列番号７３１５のＶＨＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列を含む重鎖可変領域（ＶＨ）；ならびに／あるいは
（ｉｉ）配列番号７３２６の軽鎖相補性決定領域１（ＶＬＣＤＲ１）アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、配列番号７３２７のＶＬＣＤＲ２アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）、および／または配列番号７３２９のＶＬＣＤＲ３アミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を含む軽鎖可変領域（ＶＬ）
を含む、請求項１３に記載の多機能性分子。
［態様１５］第２の抗原結合性ドメインが、
（ｉ）配列番号７２９８もしくは７３００～７３０４のいずれかのアミノ酸配列（または配列番号７２９８もしくは７３００～７３０４のいずれかに対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＨ；および／または
（ｉｉ）配列番号７２９９もしくは７３０５～７３０９のいずれかのアミノ酸配列（または配列番号７２９９もしくは７３０５～７３０９のいずれかに対して少なくとも約９３％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＬ
を含む、請求項１３または１４に記載の多機能性分子。
［態様１６］第２の抗原結合性ドメインが、
（ｉ）配列番号７３０２のアミノ酸配列（または７３０２に対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＨ、および配列番号７３０５のアミノ酸配列（または７３０５に対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＬ；または
（ｉｉ）配列番号７３０２のアミノ酸配列（または７３０２に対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＨ、および配列番号７３０９のアミノ酸配列（または７３０９に対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＬ
を含む、請求項１３から１５のいずれかに記載の多機能性分子。
［態様１７］第２の抗原結合性ドメインが、
（ｉ）配列番号７３１０のアミノ酸配列（または７３１０に対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）；または
（ｉｉ）配列番号７３１１のアミノ酸配列（または７３１１に対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）
を含む、請求項１３から１６のいずれかに記載の多機能性分子。
［態様１８］第２の抗原結合性ドメインが、
（ｉ）配列番号６０００の重鎖相補性決定領域１（ＶＨＣＤＲ１）アミノ酸配列、配列番号６００１のＶＨＣＤＲ２アミノ酸配列、および／または配列番号６００２のＶＨＣＤＲ３アミノ酸配列を含む重鎖可変領域（ＶＨ）、ならびに
（ｉｉ）配列番号６０６３の軽鎖相補性決定領域１（ＶＬＣＤＲ１）アミノ酸配列、配列番号６０６４のＶＬＣＤＲ２アミノ酸配列、および／または配列番号７２９３のＶＬＣＤＲ３アミノ酸配列を含む軽鎖可変領域（ＶＬ）
を含む、請求項１１または１２に記載の多機能性分子。
［態様１９］第２の抗原結合性ドメインが、
（１）表７、表９、表１０、もしくは表１８の重鎖フレームワーク領域１（ＶＨＦＷＲ１）のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ１、表７、表９、表１０、もしくは表１８のＶＨＦＷＲ２のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ２、表７、表９、表１０、もしくは表１８のＶＨＦＷＲ３のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ３、または表７、表９、表１０、もしくは表１８のＶＨＦＷＲ４のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ４を含む重鎖可変領域（ＶＨ）、および／あるいは
（２）表８、表９、表１０、もしくは表１８の軽鎖フレームワーク領域１（ＶＬＦＷＲ１）のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ１、表８、表９、表１０、もしくは表１８のＶＬＦＷＲ２のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ２、表８、表９、表１０、もしくは表１８のＶＬＦＷＲ３のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ３、または表８、表９、表１０、もしくは表１８のＶＬＦＷＲ４のアミノ酸配列（またはそれからの１つ、２つ、３つ、４つ、５つ、もしくは６つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ４を含む軽鎖可変領域（ＶＬ）
を含む、請求項１１、１２、または１８のいずれかに記載の多機能性分子。
［態様２０］第２の抗原結合性ドメインが、
（１）配列番号６００３の重鎖フレームワーク領域１（ＶＨＦＷＲ１）アミノ酸配列、配列番号６００４のＶＨＦＷＲ２アミノ酸配列、配列番号６００５のＶＨＦＷＲ３アミノ酸配列、または配列番号６００６のＶＨＦＷＲ４アミノ酸配列を含む重鎖可変領域（ＶＨ）、および
（３）配列番号６０６６の軽鎖フレームワーク領域１（ＶＬＦＷＲ１）アミノ酸配列、配列番号６０６７のＶＬＦＷＲ２アミノ酸配列、配列番号７２９２のＶＬＦＷＲ３アミノ酸配列、または配列番号６０６９のＶＬＦＷＲ４アミノ酸配列を含む軽鎖可変領域（ＶＬ）
を含む、請求項１９に記載の多機能性分子。
［態様２１］第２の抗原結合性ドメインが、
（ｉ）表７、表９、表１０、もしくは表１８のＶＨのアミノ酸配列（またはそれに対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＨ、および／または
（ｉｉ）表８、表９、表１０、もしくは表１８のＶＬのアミノ酸配列（またはそれに対して少なくとも約９３％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＬ
を含む、請求項１１、１２、または１８から２０のいずれか１項に記載の多機能性分子。
［態様２２］第２の抗原結合性ドメインが、表１０の重鎖のアミノ酸配列（またはそれに対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む重鎖を含む、請求項１１、１２、または１８から２１のいずれかに記載の多機能性分子。
［態様２３］第２の抗原結合性ドメインが、表１０の軽鎖のアミノ酸配列（またはそれに対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む軽鎖を含む、請求項１１、１２、または１８から２２のいずれかに記載の多機能性分子。
［態様２４］第２の抗原結合性ドメインが、表１０の重鎖のアミノ酸配列（またはそれに対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む重鎖、および表１０の軽鎖のアミノ酸配列（またはそれに対して少なくとも約７５％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含む軽鎖を含む、請求項１１、１２、または１８から２３のいずれかに記載の多機能性分子。
［態様２５］例えば、Ｎ末端からＣ末端まで、第１のＶＬおよび第１のＣＬを含む第１のポリペプチド、
例えば、Ｎ末端からＣ末端まで、第１のＶＨ、第１のＣＨ１、第１の二量体化ドメイン（例えば、第１のＦｃ）、およびＮＫｐ３０に結合する第１の部分（例えば、ＮＫｐ３０に結合する第１の抗体分子またはリガンド）を含む第２のポリペプチド、
例えば、Ｎ末端からＣ末端まで、第２のＶＨ、第２のＣＨ１、第２の二量体化ドメイン（例えば、第２のＦｃ）、および任意選択でＮＫｐ３０に結合する第２の部分（例えば、ＮＫｐ３０に結合する第２の抗体分子またはリガンド）を含む第３のポリペプチド、
例えば、Ｎ末端からＣ末端まで、第２のＶＬおよび第２のＣＬを含む第４のポリペプチド
を含み、
第１のＶＬおよび第１のＶＨが、第１のカルレティキュリンタンパク質に結合する第１の抗原結合性ドメインを形成し、第２のＶＬおよび第２のＶＨが第２のカルレティキュリンタンパク質に結合する第３の抗原結合性ドメインを形成し、
任意選択で、第１および第２のカルレティキュリンタンパク質が配列番号６２８５または６２８６のアミノ酸配列を含み、
任意選択で、第１および第２のカルレティキュリン突然変異体タンパク質が、配列番号６３１３のアミノ酸配列を含む分子、または配列番号６３１４のアミノ酸配列を含む分子からそれぞれ独立して選択され、
任意選択で、多機能性分子が図３Ａまたは３Ｂの構成を含む、
請求項１１から２４のいずれかに記載の多機能性分子。
［態様２６］カルレティキュリンタンパク質が配列番号６２８５～６３１２から選択されるアミノ酸配列を含み、任意選択で、カルレティキュリンタンパク質が配列番号６３１３～６３４６から選択されるアミノ酸配列を含む、請求項１～２５のいずれか１項に記載の多機能性分子。
［態様２７］カルレティキュリンタンパク質が配列番号６２８５のアミノ酸配列を含む、請求項１～２６のいずれか１項に記載の多機能性分子。
［態様２８］カルレティキュリンタンパク質が配列番号６２８６のアミノ酸配列を含む、請求項１～２７のいずれか１項に記載の多機能性分子。
［態様２９］第１の抗原結合性ドメインがカルレティキュリンタンパク質のＣ末端内に位置するエピトープに結合し、任意選択で、第１の抗原結合性ドメインが配列番号６２８５または６２８６のアミノ酸配列内に位置するエピトープに結合する、請求項１～２８のいずれか１項に記載の多機能性分子。
［態様３０］第２のカルレティキュリンタンパク質に結合する第３の抗原結合性ドメインであって、例えば、第２のカルレティキュリン突然変異体タンパク質が配列番号６２８５または６２８６のアミノ酸配列を含む、第３の抗原結合性ドメインをさらに含み、任意選択で、
（ｉ）第３の抗原結合性ドメインが第１の抗原結合性ドメインと異なるか、または
（ｉｉ）第３の抗原結合性ドメインが第１の抗原結合性ドメインと同じである、
請求項１～２９のいずれか１項に記載の多機能性分子。
［態様３１］第２のカルレティキュリン分子が第１の抗原結合性ドメインによって結合されるカルレティキュリン分子と同じである、請求項３０に記載の多機能性分子。
［態様３２］第２のカルレティキュリン分子が第１の抗原結合性ドメインによって結合されるカルレティキュリン分子と異なる、請求項３０に記載の多機能性分子。
［態様３３］第２のカルレティキュリンタンパク質が配列番号６２８５～６３１２から選択されるアミノ酸配列を含み、任意選択で、第２のカルレティキュリンタンパク質が配列番号６３１３～６３４６から選択されるアミノ酸配列を含む、請求項３０から３２のいずれかに記載の多機能性分子。
［態様３４］第１の抗原結合性ドメインによって結合されるカルレティキュリンタンパク質が配列番号６２８５のアミノ酸配列を含み、第２のカルレティキュリンタンパク質が配列番号６２８６のアミノ酸配列を含む、請求項３３に記載の多機能性分子。
［態様３５］第３の抗原結合性ドメインが第２のカルレティキュリンタンパク質のＣ末端内に位置するエピトープに結合し、任意選択で、第３の抗原結合性ドメインが配列番号６２８５または６２８６のアミノ酸配列内に位置するエピトープに結合する、請求項３０から３４のいずれかに記載の多機能性分子。
［態様３６］第１の抗原結合性ドメインが、
（ｉ）表４、表７Ａ、もしくは表１７における重鎖相補性決定領域１（ＶＨＣＤＲ１）のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ１、表４、表７Ａ、もしくは表１７におけるＶＨＣＤＲ２のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ２、および／または表４、表７Ａ、もしくは表１７におけるＶＨＣＤＲ３のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ３を含む重鎖可変領域（ＶＨ）；
（ｉｉ）表５、表７Ａ、もしくは表１８における軽鎖相補性決定領域１（ＶＬＣＤＲ１）のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ１、表５、表７Ａ、もしくは表１８におけるＶＬＣＤＲ２のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ２、および／または表５、表７Ａ、もしくは表１８におけるＶＬＣＤＲ３のアミノ酸配列（または１つ、２つ、３つ、もしくは４つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＣＤＲ３を含む軽鎖可変領域（ＶＬ）；
（ｉｉｉ）表７Ａもしくは表１６におけるＶＨのアミノ酸配列（またはそれに対して少なくとも約７７％、８０％、８５％、９０％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＨ；
（ｉｖ）表７Ａもしくは表１６におけるＶＬのアミノ酸配列（またはそれに対して少なくとも約９３％、９５％、もしくは９９％の配列同一性を有するアミノ酸配列）を含むＶＬ；
（ｖ）表４もしくは表６における重鎖フレームワーク領域１（ＶＨＦＷＲ１）のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ１、表４もしくは表６におけるＶＨＦＷＲ２のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ２、表４もしくは表６におけるＶＨＦＷＲ３のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ３、および／または表４もしくは表６におけるＶＨＦＷＲ４のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＨＦＷＲ４を含むＶＨ、ならびに／あるいは
（ｖｉ）表５もしくは表６における軽鎖フレームワーク領域１（ＶＬＦＷＲ１）のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ１、表５もしくは表６におけるＶＬＦＷＲ２のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ２、表５もしくは表６におけるＶＬＦＷＲ３のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ３、および／または表５もしくは表６におけるＶＬＦＷＲ４のアミノ酸配列（または１つ、２つ、３つ、４つ、５つ、６つ、７つ、８つ、もしくは９つ以下の突然変異、例えば、置換、付加、もしくは欠失を有する配列）を有するＶＬＦＷＲ４を含むＶＬ
を含む、請求項１～３５のいずれか１項に記載の多機能性分子。
［態様３７］腫瘍標的化部分をさらに含む、請求項１～３６のいずれか１項に記載の多機能性分子。
［態様３８］腫瘍標的化部分が腫瘍抗原に結合する、請求項３７に記載の多機能性分子。
［態様３９］腫瘍抗原が、Ｇ６Ｂ、ＣＤ３４、ＣＤ４１、Ｐ－セレクチン、Ｃｌｅｃ２、ｃＫＩＴ、ＦＬＴ３、ＭＰＬ、ＩＴＧＢ３、ＩＴＧＢ２、ＧＰ５、ＧＰ６、ＧＰ９、ＧＰ１ＢＡ、ＤＳＣ２、ＦＣＧＲ２Ａ、ＴＮＦＲＳＦ１０Ａ、ＴＮＦＲＳＦ１０Ｂ、またはＴＭ４ＳＦ１から選択される、請求項３８に記載の多機能性分子。
［態様４０］腫瘍標的化部分が、例えば、Ｇ６Ｂ、ＣＤ３４、ＣＤ４１、Ｐ－セレクチン、Ｃｌｅｃ２、ｃＫＩＴ、ＦＬＴ３、ＭＰＬ、ＩＴＧＢ３、ＩＴＧＢ２、ＧＰ５、ＧＰ６、ＧＰ９、ＧＰ１ＢＡ、ＤＳＣ２、ＦＣＧＲ２Ａ、ＴＮＦＲＳＦ１０Ａ、ＴＮＦＲＳＦ１０Ｂ、またはＴＭ４ＳＦ１から選択される腫瘍抗原に結合する抗体分子を含む、請求項３７に記載の多機能性分子。
［態様４１］腫瘍標的化部分が、例えば、表Ａまたは表２０に列挙されるＶＨおよび／またはＶＬ配列を含む、請求項４０に記載の多機能性分子。
［態様４２］非腫瘍細胞よりも骨髄増殖性新生物細胞に優先的に結合し、任意選択で、多機能性分子と骨髄増殖性新生物細胞との結合が、多機能性分子と非腫瘍細胞との結合よりも１０、２０、３０、４０、５０倍を超えて大きい、請求項１～４１のいずれか１項に記載の多機能性分子。
［態様４３］骨髄増殖性新生物細胞が、骨髄線維症細胞、本態性血小板血症細胞、真性赤血球増加症細胞、または慢性骨髄がん細胞から選択され、任意選択で、
骨髄増殖性新生物細胞がＪＡＫ２ Ｖ６１７Ｆ突然変異を含まないか、または
骨髄増殖性新生物細胞がＭＰＬ突然変異を含まない、
請求項４２に記載の多機能性分子。
［態様４４］リンカー、例えば、第１の抗原結合性ドメインと第２の抗原結合性ドメインとの間のリンカーをさらに含む、請求項１～４３のいずれか１項に記載の多機能性分子。
［態様４５］リンカーが、切断性リンカー、非切断性リンカー、ペプチドリンカー、可撓性リンカー、剛性リンカー、ヘリックスリンカー、または非ヘリックスリンカーから選択される、請求項４４に記載の多機能性分子。
［態様４６］リンカーがペプチドリンカーである、請求項４４または４５に記載の多機能性分子。
［態様４７］ペプチドリンカーがＧｌｙおよびＳｅｒを含む、請求項４６に記載の多機能性分子。
［態様４８］ペプチドリンカーが、配列番号６２１４～６２１７、または６２２０～６２２１および７７～７８から選択されるアミノ酸配列を含む、請求項４６に記載の多機能性分子。
［態様４９］請求項１～４８のいずれか１項に記載の多機能性分子をコードする核酸分子。
［態様５０］請求項４９に記載の核酸分子を含むベクター、例えば、発現ベクター。
［態様５１］請求項４９に記載の核酸分子または請求項５０に記載のベクターを含む細胞。
［態様５２］請求項１から４８のいずれか１項に記載の多機能性分子を作製する、例えば、産生する方法であって、適切な条件、例えば、遺伝子発現および／またはホモもしくはヘテロ二量体化に適した条件下で、請求項５１に記載の細胞を培養するステップを含む、方法。
［態様５３］請求項１から４８のいずれか１項に記載の多機能性分子と、薬学的に許容される担体、賦形剤または安定化剤とを含む医薬組成物。
［態様５４］がんを処置する方法であって、それを必要とする対象に、請求項１から４８のいずれか１項に記載の多機能性分子を投与するステップを含み、多機能性分子ががんを処置するのに有効な量で投与される、方法。
［態様５５］がんを処置するための医薬の製造のための、請求項１から４８のいずれか１項に記載の多機能性分子の使用。
［態様５６］対象が第１および／または第２のカルレティキュリンタンパク質を発現するがん細胞を有する、請求項５４に記載の方法または請求項５５に記載の使用。
［態様５７］対象がＪＡＫ２ Ｖ６１７Ｆ突然変異を有する、請求項５４もしくは５６に記載の方法または請求項５５もしくは５６に記載の使用。
［態様５８］対象がＪＡＫ２ Ｖ６１７Ｆ突然変異を有しない、請求項５４もしくは５６に記載の方法または請求項５５もしくは５６に記載の使用。
［態様５９］対象がＭＰＬ突然変異を有する、請求項５４もしくは５６から５８のいずれか１項に記載の方法または請求項５５から５８のいずれか１項に記載の使用。
［態様６０］対象がＭＰＬ突然変異を有しない、請求項５４もしくは５６から５８のいずれか１項に記載の方法または請求項５５から５８のいずれか１項に記載の使用。
［態様６１］がんが血液がんであり、任意選択で、がんが、骨髄増殖性新生物、例えば、原発性もしくは特発性骨髄線維症（ＭＦ）、本態性血小板増加症（ＥＴ）、真性赤血球増加症（ＰＶ）、または慢性骨髄性白血病（ＣＭＬ）であり、任意選択で、がんが骨髄線維症である、請求項５４もしくは５６から６０のいずれか１項に記載の方法または請求項５５から６０のいずれか１項に記載の使用。
［態様６２］がんが固形腫瘍がんである、請求項５４もしくは５６から６０のいずれか１項に記載の方法または請求項５５から６０のいずれか１項に記載の使用。
［態様６３］第２の治療処置を施すステップをさらに含む、請求項５４もしくは５６から６２のいずれかに記載の方法または請求項５５から６２のいずれか１項に記載の使用。
［態様６４］第２の治療処置が、治療剤（例えば、化学療法剤、生物剤、ホルモン療法）、放射線、または外科手術を含む、請求項６３に記載の方法または請求項６３に記載の使用。
［態様６５］治療剤が化学療法剤または生物剤から選択される、請求項６４に記載の方法または請求項６４に記載の使用。
EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
Aspects of the Invention [Aspect 1] (i) a first antigen-binding domain that binds to a calreticulin protein (e.g., a wild-type or mutant calreticulin protein);
(ii) a second antigen binding domain that binds to TCRβV, e.g. A multifunctional molecule comprising a TCRβV antigen-binding domain, or a second antigen-binding domain that binds NKp30, eg, an anti-NKp30 antigen-binding domain disclosed in Tables 7-10 or 18.
[Aspect 2] The multifunctional molecule according to aspect 1, wherein the second antigen-binding domain binds to TCRβV.
[Aspect 3] The multifunctional molecule according to aspect 2, wherein the second antigen-binding domain activates T cells or the second antigen-binding domain does not activate T cells.
[Aspect 4] The multifunctional molecule according to aspect 2 or 3, wherein the second antigen-binding domain binds to TCRβV12 or TCRβV6 (eg, comprising the amino acid sequence of SEQ ID NO: 1044).
[Aspect 5] The claim, wherein the second antigen-binding domain comprises one or more amino acid sequences listed in Table 1A, Table 2A, Table 3A, Table 10A, Table 11A, Table 12A, or Table 13A. 5. The multifunctional molecule according to any one of 2-4.
[Aspect 6] The second antigen-binding domain is
(a) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH is the amino acid sequence (or one, two, three, or The amino acid sequence of VHCDR1, VHCDR2 in Table 1A, Table 2A, Table 10A, Table 11A, Table 12A, or Table 13A (or 1 VHCDR2 having 1, 2, 3, or 4 or fewer mutations, e.g., sequences having substitutions, additions, or deletions, and/or Tables 1A, 2A, 10A, 11A, 12A or a VHCDR3 having the amino acid sequence of VHCDR3 in Table 13A (or a sequence having no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions),
(ii) VL is the amino acid sequence of light chain complementarity determining region 1 (VLCDR1) (or one, two, three, or The amino acid sequence of VLCDR1, VLCDR2 in Table 1A, Table 2A, Table 10A, Table 11A, Table 12A, or Table 13A (or 1 VLCDR2 having no more than 1, 2, 3, or 4 mutations, e.g. or a VLCDR3 having the amino acid sequence of VLCDR3 in Table 13A (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions),
heavy chain variable region (VH) and/or light chain variable region (VL);
(b) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH has the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 3 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) ), the VHCDR2 amino acid sequence of SEQ ID NO: 4 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or SEQ ID NO: 5 VHCDR3 amino acid sequences (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions), and/or (ii) VL is the sequence light chain complementarity determining region 1 (VHCDR1) amino acid sequence of number 6 (or a sequence with 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions, or deletions), SEQ ID NO: 7 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or the VHCDR3 amino acid sequence of SEQ ID NO: 8 (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions);
heavy chain variable region (VH) and/or light chain variable region (VL);
(c) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH has the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 45 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) ), the VHCDR2 amino acid sequence of SEQ ID NO: 46 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or SEQ ID NO: 47 VHCDR3 amino acid sequences (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions), and/or (ii) VL is the sequence Light Chain Complementarity Determining Region 1 (VHCDR1) amino acid sequence of number 51 (or a sequence with 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions, or deletions), SEQ ID NO: 52 VHCDR2 amino acid sequences (or sequences with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or the VHCDR3 amino acid sequence of SEQ ID NO: 53 (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions);
a heavy chain variable region (VH) and/or a light chain variable region (VL); and/or (d) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH has the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 48 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) ), the VHCDR2 amino acid sequence of SEQ ID NO: 49 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or SEQ ID NO: 50 VHCDR3 amino acid sequences (or sequences with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or (ii) VL is the sequence light chain complementarity determining region 1 (VHCDR1) amino acid sequence of number 54 (or a sequence with 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions, or deletions), SEQ ID NO: 55 VHCDR2 amino acid sequences (or sequences with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or the VHCDR3 amino acid sequence of SEQ ID NO: 56 (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions);
heavy chain variable region (VH) and/or light chain variable region (VL)
6. The multifunctional molecule of any one of claims 2-5, comprising:
[Aspect 7] The second antigen-binding domain is
(a) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH is the amino acid sequence of VH in Table 1A, Table 2A, Table 10A, Table 11A, Table 12A, or Table 13A (or at least about 77%, 80%, 85%, 90%, 95% thereof) , or an amino acid sequence having 99% sequence identity), and/or (ii) VL has the amino acid sequence of VL in Table 1A, Table 2A, Table 10A, Table 11A, Table 12A, or Table 13A (or amino acid sequences having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto);
(iii) the VH comprises the amino acid sequence of SEQ ID NO:9 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto); and /or (iv) VL comprises the amino acid sequence of SEQ ID NO: 10 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) ,
heavy chain variable region (VH) and/or light chain variable region (VL);
(b) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) the VH comprises the amino acid sequence of SEQ ID NO:9 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto); and /or (ii) VL comprises the amino acid sequence of SEQ ID NO: 11 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) , a heavy chain variable region (VH) and/or a light chain variable region (VL); and/or (c) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) the VH comprises the amino acid sequence of SEQ ID NO: 1312 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto); and /or (ii) VL comprises the amino acid sequence of SEQ ID NO: 1314 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) ,
heavy chain variable region (VH) and/or light chain variable region (VL)
6. The multifunctional molecule of any one of claims 2-5, comprising:
[Aspect 8] The second antigen-binding domain is
(a) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH has the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 17 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) ), the VHCDR2 amino acid sequence of SEQ ID NO: 18 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or SEQ ID NO: 19 VHCDR3 amino acid sequences (or sequences with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or (ii) VL is the sequence light chain complementarity determining region 1 (VHCDR1) amino acid sequence of number 20 (or a sequence with 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions, or deletions), SEQ ID NO: 21 VHCDR2 amino acid sequences (or sequences with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or the VHCDR3 amino acid sequence of SEQ ID NO: 22 (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions);
heavy chain variable region (VH) and/or light chain variable region (VL);
(b) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH has the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 57 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) ), the VHCDR2 amino acid sequence of SEQ ID NO: 58 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or SEQ ID NO: 59 VHCDR3 amino acid sequences (or sequences with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or (ii) VL is the sequence light chain complementarity determining region 1 (VHCDR1) amino acid sequence of number 63 (or a sequence with 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions, or deletions), SEQ ID NO: 64 VHCDR2 amino acid sequence (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or the VHCDR3 amino acid sequence of SEQ ID NO: 65 (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions);
a heavy chain variable region (VH) and/or a light chain variable region (VL); and/or (c) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH has the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 60 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) ), the VHCDR2 amino acid sequence of SEQ ID NO: 61 (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or SEQ ID NO: 62 VHCDR3 amino acid sequences (or sequences with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or (ii) VL is the sequence light chain complementarity determining region 1 (VHCDR1) amino acid sequence of number 66 (or a sequence with 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions, or deletions), SEQ ID NO: 67 VHCDR2 amino acid sequence (or a sequence with no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or the VHCDR3 amino acid sequence of SEQ ID NO: 68 (or sequences with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions);
heavy chain variable region (VH) and/or light chain variable region (VL)
6. The multifunctional molecule of any one of claims 2-5, comprising:
[Aspect 9] The second antigen-binding domain is
(a) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) the VH comprises the amino acid sequence of SEQ ID NO: 15 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto); and /or (ii) VL comprises the amino acid sequence of SEQ ID NO: 16 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) ,
a heavy chain variable region (VH) and/or a light chain variable region (VL); and/or (b) a heavy chain variable region (VH) and/or a light chain variable region (VL),
(i) VH is
the amino acid sequence of SEQ ID NO: 23 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto);
The amino acid sequence of SEQ ID NO:24 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto), or the amino acid sequence of SEQ ID NO:25 (or amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity to it);
the amino acid sequence of SEQ ID NO: 26 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto);
the amino acid sequence of SEQ ID NO: 27 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto);
the amino acid sequence of SEQ ID NO: 28 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto);
The amino acid sequence of SEQ ID NO:29 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto), or the amino acid sequence of SEQ ID NO:30 (or amino acid sequences having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto);
heavy chain variable region (VH) and/or light chain variable region (VL)
6. The multifunctional molecule of any one of claims 2-5, comprising:
[Aspect 10] For example, a first polypeptide comprising a first VL and a first CL from the N-terminus to the C-terminus,
For example, from N-terminus to C-terminus, a first VH, a first CH1, a first dimerization domain (e.g., a first Fc), and a first portion that binds a TCR (e.g., TCRVβ) a second polypeptide comprising (e.g., a first scFv that binds to a TCR (e.g., TCRVβ));
For example, from N-terminus to C-terminus, a second VH, a second CH1, a second dimerization domain (e.g., a second Fc), and optionally a second that binds a TCR (e.g., TCRVβ). a third polypeptide comprising a portion of 2 (e.g., a second scFv that binds a TCR (e.g., TCRVβ));
For example, comprising, from N-terminus to C-terminus, a fourth polypeptide comprising a second VL and a second CL,
the first VL and the first VH form a first antigen-binding domain that binds to the first calreticulin protein and the second VL and the second VH form the second calreticulin protein forming a third antigen-binding domain that binds to
optionally, the first and second calreticulin proteins comprise the amino acid sequence of SEQ ID NO: 6285 or 6286;
optionally, the first and second calreticulin mutant proteins are each independently selected from a molecule comprising the amino acid sequence of SEQ ID NO: 6313 or a molecule comprising the amino acid sequence of SEQ ID NO: 6314;
optionally, the multifunctional molecule comprises the configuration of Figure 3A or 3B;
10. A multifunctional molecule according to any one of claims 2-9.
[Aspect 11] The multifunctional molecule according to aspect 1, wherein the second antigen-binding domain binds to NKp30.
[Aspect 12] The second antigen-binding domain is selected from an antibody molecule that binds to (e.g., activates) NKp30, e.g., an antigen-binding domain, or a ligand, e.g., the second antigen-binding domain is an antibody molecule or ligand that binds to (eg activates) NKp30.
[Aspect 13] The second antigen-binding domain is
(i) the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of Table 7, Table 9, Table 10, or Table 18 (or no more than 1, 2, 3, or 4 mutations, e.g., the amino acid sequence of VHCDR1, VHCDR2 of Table 7, Table 9, Table 10, or Table 18 (or sequences with substitutions, additions, or deletions) (or no more than 1, 2, 3, or 4 mutations) , e.g., sequences with substitutions, additions, or deletions), and/or the amino acid sequences of VHCDR3 of Table 7, Table 9, Table 10, or Table 18 (or one, two, three, or a heavy chain variable region (VH) comprising a VHCDR3 having 4 or fewer mutations, e.g., sequences having substitutions, additions, or deletions, and/or VLCDR1 having the 18 light chain complementarity determining region 1 (VLCDR1) amino acid sequence (or a sequence having no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) , Table 8, Table 9, Table 10, or Table 18 (or a sequence having no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions) and/or the amino acid sequence of VLCDR3 of Table 8, Table 9, Table 10, or Table 18 (or up to 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or light chain variable region (VL) comprising VLCDR3 with a sequence having a deletion)
13. The multifunctional molecule of claim 11 or 12, comprising
[Aspect 14] The second antigen-binding domain is
(i) the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 7313 (or a sequence with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions) ), the VHCDR2 amino acid sequence of SEQ ID NO: 6001 (or a sequence with 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions, or deletions, and/or the VHCDR3 amino acid sequence of SEQ ID NO: 7315 a heavy chain variable region (VH) comprising a sequence (or a sequence having no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions; and/or (ii) a SEQ ID NO: 7326 light chain complementarity determining region 1 (VLCDR1) amino acid sequence (or a sequence with 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or deletions), SEQ ID NO: 7327 (or a sequence having no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions, or deletions), and/or the VLCDR3 amino acid sequence of SEQ ID NO: 7329 (or 1 light chain variable region (VL) comprising 1, 2, 3, or 4 or fewer mutations, e.g., sequences having substitutions, additions, or deletions)
14. The multifunctional molecule of claim 13, comprising
[Aspect 15] The second antigen-binding domain is
(i) the amino acid sequence of any of SEQ ID NOs: 7298 or 7300-7304 (or at least about 75%, 80%, 85%, 90%, 95%, or 99% of any of SEQ ID NOs: 7298 or 7300-7304); and/or (ii) the amino acid sequence of any of SEQ ID NOS: 7299 or 7305-7309 (or at least about amino acid sequences with 93%, 95%, or 99% sequence identity)
15. The multifunctional molecule of claim 13 or 14, comprising
[Aspect 16] The second antigen-binding domain is
(i) a VH comprising the amino acid sequence of SEQ ID NO: 7302 (or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity to 7302), and a sequence a VL comprising the amino acid sequence of number 7305 (or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity to 7305); or (ii) a SEQ ID NO: a VH comprising the amino acid sequence of 7302 (or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity to 7302) and the amino acid sequence of SEQ ID NO:7309 (or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity to 7309)
16. The multifunctional molecule of any of claims 13-15, comprising:
[Aspect 17] The second antigen-binding domain is
(i) the amino acid sequence of SEQ ID NO: 7310 (or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity to 7310); or (ii) a sequence the amino acid sequence of number 7311 (or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity to 7311)
17. The multifunctional molecule of any of claims 13-16, comprising
[Aspect 18] The second antigen-binding domain is
(i) a heavy chain variable region (VH) comprising the heavy chain complementarity determining region 1 (VHCDR1) amino acid sequence of SEQ ID NO: 6000, the VHCDR2 amino acid sequence of SEQ ID NO: 6001, and/or the VHCDR3 amino acid sequence of SEQ ID NO: 6002; ii) a light chain variable region (VL) comprising the light chain complementarity determining region 1 (VLCDR1) amino acid sequence of SEQ ID NO:6063, the VLCDR2 amino acid sequence of SEQ ID NO:6064, and/or the VLCDR3 amino acid sequence of SEQ ID NO:7293
13. The multifunctional molecule of claim 11 or 12, comprising
[Aspect 19] The second antigen-binding domain is
(1) the amino acid sequence of heavy chain framework region 1 (VHFWR1) of Table 7, Table 9, Table 10, or Table 18 (or 1, 2, 3, 4, 5, or 6 therefrom) The amino acid sequence of VHFWR1, VHFWR2 of Table 7, Table 9, Table 10, or Table 18 (or one, two, three therefrom) having the following mutations, e.g., sequences having substitutions, additions, or deletions: Amino acid sequences of VHFWR2, VHFWR3 of Table 7, Table 9, Table 10, or Table 18 having no more than 1, 4, 5, or 6 mutations, e.g., substitutions, additions, or deletions. (or a sequence having no more than 1, 2, 3, 4, 5, or 6 mutations, e.g., substitutions, additions, or deletions therefrom), or Tables 7, 9 , Table 10, or VHFWR4 amino acid sequence of Table 18 (or having no more than 1, 2, 3, 4, 5, or 6 mutations, e.g., substitutions, additions, or deletions therefrom) and/or (2) the amino acid sequence of light chain framework region 1 (VLFWR1) of Table 8, Table 9, Table 10, or Table 18 (or derived from 1, 2, 3, 4, 5, or 6 mutations, e.g., sequences with substitutions, additions, or deletions), Table 8, Table 9, Table 10, or VLFWR2 having the amino acid sequence of VLFWR2 of Table 18 (or a sequence having no more than 1, 2, 3, 4, 5, or 6 mutations, e.g., substitutions, additions, or deletions therefrom) , the amino acid sequence of VLFWR3 of Table 8, Table 9, Table 10, or Table 18 (or no more than 1, 2, 3, 4, 5, or 6 mutations, e.g., substitutions, additions therefrom) , or sequences with deletions), or VLFWR4 amino acid sequences of Table 8, Table 9, Table 10, or Table 18 (or one, two, three, four, five, or A light chain variable region (VL) comprising VLFWR4 having no more than 6 mutations, e.g., sequences with substitutions, additions, or deletions
19. The multifunctional molecule of any of claims 11, 12, or 18, comprising
[Aspect 20] The second antigen-binding domain is
(1) a heavy chain variable region comprising the heavy chain framework region 1 (VHFWR1) amino acid sequence of SEQ ID NO: 6003, the VHFWR2 amino acid sequence of SEQ ID NO: 6004, the VHFWR3 amino acid sequence of SEQ ID NO: 6005, or the VHFWR4 amino acid sequence of SEQ ID NO: 6006 ( VH), and (3) a light chain framework region 1 (VLFWR1) amino acid sequence of SEQ ID NO:6066, the VLFWR2 amino acid sequence of SEQ ID NO:6067, the VLFWR3 amino acid sequence of SEQ ID NO:7292, or the VLFWR4 amino acid sequence of SEQ ID NO:6069. chain variable region (VL)
20. The multifunctional molecule of claim 19, comprising
[Aspect 21] The second antigen-binding domain is
(i) the amino acid sequence of a VH of Table 7, Table 9, Table 10, or Table 18 (or having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto); and/or (ii) the amino acid sequence of the VL of Table 8, Table 9, Table 10, or Table 18 (or at least about 93%, 95%, or 99% sequence identity thereto) VL containing a unique amino acid sequence)
21. The multifunctional molecule of any one of claims 11, 12, or 18-20, comprising:
[Aspect 22] The second antigen-binding domain has a heavy chain amino acid sequence of Table 10 (or at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) 22. The multifunctional molecule of any of claims 11, 12, or 18-21, comprising a heavy chain comprising an amino acid sequence having
[Aspect 23] The second antigen-binding domain has a light chain amino acid sequence of Table 10 (or at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) 23. The multifunctional molecule of any of claims 11, 12, or 18-22, comprising a light chain comprising an amino acid sequence having
[Aspect 24] The second antigen-binding domain has a heavy chain amino acid sequence of Table 10 (or at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) (or having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity to the heavy chain and light chain amino acid sequences of Table 10) 24. The multifunctional molecule of any of claims 11, 12, or 18-23, comprising a light chain comprising the amino acid sequence).
[Aspect 25] For example, a first polypeptide comprising a first VL and a first CL from the N-terminus to the C-terminus,
For example, from N-terminus to C-terminus, a first VH, a first CH1, a first dimerization domain (e.g., a first Fc), and a first portion that binds NKp30 (e.g., a second polypeptide that binds the first antibody molecule or ligand);
For example, from N-terminus to C-terminus, a second VH, a second CH1, a second dimerization domain (e.g., a second Fc), and optionally a second portion that binds NKp30 (e.g., , a second antibody molecule or ligand that binds to NKp30);
For example, comprising, from N-terminus to C-terminus, a fourth polypeptide comprising a second VL and a second CL,
The first VL and the first VH form a first antigen binding domain that binds to the first calreticulin protein, and the second VL and the second VH are the second calreticulin forming a third antigen-binding domain that binds to the protein;
optionally, the first and second calreticulin proteins comprise the amino acid sequence of SEQ ID NO: 6285 or 6286;
optionally, the first and second calreticulin mutant proteins are each independently selected from a molecule comprising the amino acid sequence of SEQ ID NO: 6313 or a molecule comprising the amino acid sequence of SEQ ID NO: 6314;
optionally, the multifunctional molecule comprises the configuration of Figure 3A or 3B;
25. A multifunctional molecule according to any of claims 11-24.
[Aspect 26] The claim wherein the calreticulin protein comprises an amino acid sequence selected from SEQ ID NOS:6285-6312, and optionally the calreticulin protein comprises an amino acid sequence selected from SEQ ID NOS:6313-6346. 26. The multifunctional molecule according to any one of 1-25.
[Aspect 27] The multifunctional molecule according to any one of aspects 1 to 26, wherein the calreticulin protein comprises the amino acid sequence of SEQ ID NO:6285.
[Aspect 28] The multifunctional molecule according to any one of aspects 1 to 27, wherein the calreticulin protein comprises the amino acid sequence of SEQ ID NO:6286.
[Aspect 29] The first antigen-binding domain binds to an epitope located within the C-terminus of the calreticulin protein, and optionally the first antigen-binding domain is within the amino acid sequence of SEQ ID NO: 6285 or 6286 29. A multifunctional molecule according to any one of claims 1 to 28, which binds to an epitope located at .
[Aspect 30] A third antigen-binding domain that binds to a second calreticulin protein, wherein, for example, the second calreticulin mutant protein comprises the amino acid sequence of SEQ ID NO: 6285 or 6286 , further comprising a third antigen-binding domain, optionally
(i) the third antigen-binding domain is different from the first antigen-binding domain, or (ii) the third antigen-binding domain is the same as the first antigen-binding domain,
A multifunctional molecule according to any one of claims 1-29.
[Aspect 31] The multifunctional molecule according to aspect 30, wherein the second calreticulin molecule is the same as the calreticulin molecule bound by the first antigen-binding domain.
[Aspect 32] A multifunctional molecule according to aspect 30, wherein the second calreticulin molecule is different from the calreticulin molecule bound by the first antigen-binding domain.
[Aspect 33] The second calreticulin protein comprises an amino acid sequence selected from SEQ ID NOs: 6285-6312, optionally the second calreticulin protein comprises amino acids selected from SEQ ID NOs: 6313-6346 33. The multifunctional molecule of any of claims 30-32, comprising a sequence.
[Aspect 34] The claim, wherein the calreticulin protein bound by the first antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 6285, and the second calreticulin protein comprises the amino acid sequence of SEQ ID NO: 6286. 33. The multifunctional molecule according to 33.
[Aspect 35] The third antigen-binding domain binds to an epitope located within the C-terminus of the second calreticulin protein, and optionally the third antigen-binding domain is of SEQ ID NO: 6285 or 6286. 35. The multifunctional molecule of any of claims 30-34, which binds to an epitope located within the amino acid sequence.
[Aspect 36] The first antigen-binding domain is
(i) the amino acid sequence of heavy chain complementarity determining region 1 (VHCDR1) in Table 4, Table 7A, or Table 17 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions) , or sequences with deletions), VHCDR2 in Table 4, Table 7A, or Table 17 (or 1, 2, 3, or 4 or fewer mutations, e.g., substitutions, additions, or a sequence with a deletion) and/or the amino acid sequence of VHCDR3 in Table 4, Table 7A, or Table 17 (or no more than 1, 2, 3, or 4 mutations, e.g., a heavy chain variable region (VH) comprising a VHCDR3 with a sequence having a substitution, addition, or deletion);
(ii) the amino acid sequence of light chain complementarity determining region 1 (VLCDR1) in Table 5, Table 7A, or Table 18 (or no more than 1, 2, 3, or 4 mutations, e.g., substitutions, additions) , or a sequence with a deletion), VLCDR2 in Table 5, Table 7A, or Table 18 (or 1, 2, 3, or no more than 4 mutations, e.g., substitutions, additions , or a sequence with a deletion), and/or the amino acid sequence of VLCDR3 in Table 5, Table 7A, or Table 18 (or no more than 1, 2, 3, or 4 mutations, e.g., a light chain variable region (VL) comprising VHCDR3 with a sequence having a substitution, addition, or deletion);
(iii) a VH comprising the amino acid sequence of a VH in Table 7A or Table 16 (or an amino acid sequence having at least about 77%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto) ;
(iv) a VL comprising the amino acid sequence of a VL in Table 7A or Table 16 (or an amino acid sequence having at least about 93%, 95%, or 99% sequence identity thereto);
(v) the amino acid sequence of heavy chain framework region 1 (VHFWR1) in Table 4 or Table 6 (or 1, 2, 3, 4, 5, 6, 7, 8, or 9 Amino acid sequences of VHFWR1, VHFWR2 in Table 4 or Table 6 (or 1, 2, 3, 4, 5, 6) having the following mutations, e.g., sequences with substitutions, additions, or deletions: VHFWR2 having no more than 1, 7, 8, or 9 mutations, e.g., sequences having substitutions, additions, or deletions); , 3, 4, 5, 6, 7, 8, or 9 mutations, e.g., sequences having substitutions, additions, or deletions), and/or Table 4 or The amino acid sequence of VHFWR4 in Table 6 (or no more than 1, 2, 3, 4, 5, 6, 7, 8, or 9 mutations, e.g., substitutions, additions, or deletions) and/or (vi) the amino acid sequence of light chain framework region 1 (VLFWR1) in Table 5 or Table 6 (or 1, 2, 3, 4, 5 VLFWR1 having no more than 1, 6, 7, 8, or 9 mutations, e.g., sequences having substitutions, additions, or deletions); , 2, 3, 4, 5, 6, 7, 8, or 9 mutations, e.g., sequences having substitutions, additions, or deletions), Table 5 or The amino acid sequence of VLFWR3 in Table 6 (or no more than 1, 2, 3, 4, 5, 6, 7, 8, or 9 mutations, e.g., substitutions, additions, or deletions) and/or the amino acid sequence of VLFWR4 in Table 5 or Table 6 (or 1, 2, 3, 4, 5, 6, 7, 8, or 9 VL comprising VLFWR4 with the following mutations, e.g., sequences with substitutions, additions, or deletions:
The multifunctional molecule of any one of claims 1-35, comprising a
[Aspect 37] A multifunctional molecule according to any one of aspects 1 to 36, further comprising a tumor targeting moiety.
[Aspect 38] The multifunctional molecule of Aspect 37, wherein the tumor targeting moiety binds to a tumor antigen.
[Aspect 39] The tumor antigen is selected from G6B, CD34, CD41, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1 39. The multifunctional molecule of claim 38, wherein
[Aspect 40] The tumor targeting moiety is, for example, 38. The multifunctional molecule of claim 37, comprising an antibody molecule that binds to a tumor antigen selected from or TM4SF1.
[Aspect 41] A multifunctional molecule according to aspect 40, wherein the tumor targeting moiety comprises the VH and/or VL sequences listed in Table A or Table 20, for example.
[Aspect 42] Binds preferentially to myeloproliferative neoplastic cells over non-tumor cells, and optionally binding of the multifunctional molecule to the myeloproliferative neoplastic cells 42. The multifunctional molecule of any one of claims 1-41, which is more than 10, 20, 30, 40, 50 times greater than binding to.
[Aspect 43] The myeloproliferative neoplastic cells are selected from myelofibrosis cells, essential thrombocythemia cells, polycythemia vera cells, or chronic myeloid cancer cells, optionally
the myeloproliferative neoplastic cells do not contain the JAK2 V617F mutation or the myeloproliferative neoplastic cells do not contain the MPL mutation;
43. The multifunctional molecule of claim 42.
[Aspect 44] The multifunctional molecule according to any one of aspects 1 to 43, further comprising a linker, eg, a linker between the first antigen-binding domain and the second antigen-binding domain.
[Aspect 45] The multifunctional molecule of aspect 44, wherein the linker is selected from cleavable linkers, non-cleavable linkers, peptide linkers, flexible linkers, rigid linkers, helical linkers, or non-helical linkers.
[Aspect 46] The multifunctional molecule according to aspect 44 or 45, wherein the linker is a peptide linker.
[Aspect 47] The multifunctional molecule according to aspect 46, wherein the peptide linker comprises Gly and Ser.
[Aspect 48] The multifunctional molecule according to aspect 46, wherein the peptide linker comprises an amino acid sequence selected from SEQ ID NOs: 6214-6217, or 6220-6221 and 77-78.
[Aspect 49] A nucleic acid molecule encoding the multifunctional molecule according to any one of aspects 1-48.
[Aspect 50] A vector, such as an expression vector, comprising the nucleic acid molecule of aspect 49.
[Aspect 51] A cell containing the nucleic acid molecule according to item 49 or the vector according to item 50.
[Aspect 52] A method of making, e.g. producing, a multifunctional molecule according to any one of claims 1 to 48, wherein suitable conditions e.g. gene expression and/or homo- or heterodimerization 52. A method comprising culturing the cells of claim 51 under conditions suitable for somatization.
[Aspect 53] A pharmaceutical composition comprising the multifunctional molecule according to any one of aspects 1 to 48 and a pharmaceutically acceptable carrier, excipient or stabilizer.
[Aspect 54] A method of treating cancer, comprising administering a multifunctional molecule according to any one of claims 1 to 48 to a subject in need thereof, wherein is administered in an effective amount to treat cancer.
[Aspect 55] Use of the multifunctional molecule according to any one of claims 1 to 48 for the manufacture of a medicament for treating cancer.
[Aspect 56] A method according to aspect 54 or a use according to aspect 55, wherein the subject has cancer cells expressing the first and/or the second calreticulin protein.
[Aspect 57] A method according to aspect 54 or 56 or a use according to aspect 55 or 56, wherein the subject has the JAK2 V617F mutation.
[Aspect 58] A method according to aspect 54 or 56 or a use according to aspect 55 or 56, wherein the subject does not have the JAK2 V617F mutation.
[Aspect 59] A method according to any one of aspects 54 or 56-58 or a use according to any one of aspects 55-58, wherein the subject has an MPL mutation.
[Aspect 60] A method according to any one of aspects 54 or 56-58 or a use according to any one of aspects 55-58, wherein the subject does not have an MPL mutation.
[Aspect 61] The cancer is a blood cancer, and optionally, the cancer is a myeloproliferative neoplasm, e.g., primary or idiopathic myelofibrosis (MF), essential thrombocytosis (ET), true 61. The method of any one of claims 54 or 56-60 or claim wherein polycythemia (PV) or chronic myelogenous leukemia (CML) and optionally the cancer is myelofibrosis Use according to any one of 55-60.
[Aspect 62] A method according to any one of aspects 54 or 56 to 60 or a use according to any one of aspects 55 to 60, wherein the cancer is solid tumor cancer.
[Aspect 63] The method of any one of claims 54 or 56-62 or the use of any one of claims 55-62, further comprising administering a second therapeutic treatment.
[Aspect 64] The method of claim 63 or the use of claim 63, wherein the second therapeutic treatment comprises a therapeutic agent (e.g., chemotherapeutic agent, biological agent, hormonal therapy), radiation, or surgery. .
[Aspect 65] A method according to aspect 64 or a use according to aspect 64, wherein the therapeutic agent is selected from a chemotherapeutic agent or a biological agent.
Claims (15)
（ｉｉ）免疫細胞エンゲージャー、サイトカイン、間質改変部分、またはそれらの任意の組み合わせと
を含む多機能性分子であって、
該多機能性分子は、第１のポリペプチドおよび第２のポリペプチドを含み、第１のポリペプチドおよび第２のポリペプチドは、非連続的であり、第１のポリペプチドは、二量体化モジュールの第１のメンバーを含み、第２のポリペプチドは、二量体化モジュールの第２のメンバーを含み；
カルレティキュリンタンパク質に結合する抗原結合性ドメインは、第１のメンバーと連結されており；
カルレティキュリンタンパク質に結合する抗原結合性ドメインは、
（ａ）それぞれ、配列番号６３５８、配列番号６３６０、および配列番号２２７；
（ｂ）それぞれ、配列番号６３５８、配列番号６３６０、および配列番号２２７；
（ｃ）それぞれ、配列番号６２５３、配列番号６２５４、および配列番号６２５５；
（ｄ）それぞれ、配列番号６２５３、配列番号２４３、および配列番号６２５５；
（ｅ）それぞれ、配列番号６３５６、配列番号６３６０、および配列番号２２７；
（ｆ）それぞれ、配列番号６２５６、配列番号６２５７、および配列番号６２５８；または
（ｇ）それぞれ、配列番号６２５６、配列番号６２５７、および配列番号６２６２
の、重鎖相補性決定領域１（ＶＨＣＤＲ１）、重鎖相補性決定領域２（ＶＨＣＤＲ２）、および重鎖相補性決定領域３（ＶＨＣＤＲ３）を含む重鎖可変領域（ＶＨ）を含む、多機能性分子。 (i) an antigen- binding domain that binds to a calreticulin protein;
(ii) immune cell engagers, cytokines, stromal modifying moieties, or any combination thereof;
A multifunctional molecule comprising
The multifunctional molecule comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide are discontinuous and the first polypeptide is a dimeric comprising a first member of the dimerization module, the second polypeptide comprising a second member of the dimerization module;
an antigen-binding domain that binds a calreticulin protein is linked to the first member;
The antigen-binding domain that binds to the calreticulin protein is
(a) SEQ ID NO: 6358, SEQ ID NO: 6360, and SEQ ID NO: 227, respectively;
(b) SEQ ID NO: 6358, SEQ ID NO: 6360, and SEQ ID NO: 227, respectively;
(c) SEQ ID NO: 6253, SEQ ID NO: 6254, and SEQ ID NO: 6255, respectively;
(d) SEQ ID NO: 6253, SEQ ID NO: 243, and SEQ ID NO: 6255, respectively;
(e) SEQ ID NO: 6356, SEQ ID NO: 6360, and SEQ ID NO: 227, respectively;
(f) SEQ ID NO: 6256, SEQ ID NO: 6257, and SEQ ID NO: 6258, respectively; or
(g) SEQ ID NO: 6256, SEQ ID NO: 6257, and SEQ ID NO: 6262, respectively
heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (VHCDR1), heavy chain complementarity determining region 2 (VHCDR2), and heavy chain complementarity determining region 3 (VHCDR3) of molecule .
（ａ）それぞれ、配列番号２５１、配列番号２４６、および配列番号２４８；(a) SEQ ID NO: 251, SEQ ID NO: 246, and SEQ ID NO: 248, respectively;
（ｂ）それぞれ、配列番号２５１、配列番号２５３、および配列番号２５５；(b) SEQ ID NO: 251, SEQ ID NO: 253, and SEQ ID NO: 255, respectively;
（ｃ）それぞれ、配列番号２５８、配列番号２６０、および配列番号２６２；(c) SEQ ID NO: 258, SEQ ID NO: 260, and SEQ ID NO: 262, respectively;
（ｄ）それぞれ、配列番号２６５、配列番号２６７、および配列番号２６９；(d) SEQ ID NO: 265, SEQ ID NO: 267, and SEQ ID NO: 269, respectively;
（ｅ）それぞれ、配列番号２７２、配列番号２７４、および配列番号２７６；(e) SEQ ID NO: 272, SEQ ID NO: 274, and SEQ ID NO: 276, respectively;
（ｆ）それぞれ、配列番号２７９、配列番号２８１、および配列番号２８３；(f) SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 283, respectively;
（ｇ）それぞれ、配列番号１１３、配列番号６２６０、および配列番号６２６１；(g) SEQ ID NO: 113, SEQ ID NO: 6260, and SEQ ID NO: 6261, respectively;
（ｈ）それぞれ、配列番号６２５９、配列番号６２６０、および配列番号６２６１；または(h) SEQ ID NO: 6259, SEQ ID NO: 6260, and SEQ ID NO: 6261, respectively; or
（ｉ）それぞれ、配列番号２７９、配列番号２８１、および配列番号２８３(i) SEQ ID NO: 279, SEQ ID NO: 281, and SEQ ID NO: 283, respectively
の、軽鎖相補性決定領域１（ＶＬＣＤＲ１）、軽鎖相補性決定領域２（ＶＬＣＤＲ２）、および軽鎖相補性決定領域３（ＶＬＣＤＲ３）を含む軽鎖可変領域（ＶＬ）を含む、請求項１に記載の多機能性分子。light chain variable region (VL) comprising light chain complementarity determining region 1 (VLCDR1), light chain complementarity determining region 2 (VLCDR2), and light chain complementarity determining region 3 (VLCDR3) of A multifunctional molecule as described in .
（ｉ）(i)
（ａ）それぞれ、配列番号６２３２、配列番号６２３４、配列番号６２３６、および配列番号６２３０；(a) SEQ ID NO: 6232, SEQ ID NO: 6234, SEQ ID NO: 6236, and SEQ ID NO: 6230, respectively;
（ｂ）それぞれ、配列番号６３６３、配列番号６３６３、配列番号２２６、および配列番号２２８；(b) SEQ ID NO: 6363, SEQ ID NO: 6363, SEQ ID NO: 226, and SEQ ID NO: 228, respectively;
（ｃ）それぞれ、配列番号２２９、配列番号６３６９、配列番号６３７１、および配列番号２２８；(c) SEQ ID NO: 229, SEQ ID NO: 6369, SEQ ID NO: 6371, and SEQ ID NO: 228, respectively;
（ｄ）それぞれ、配列番号６３７３、配列番号６３６９、配列番号６３７１、および配列番号２２８；(d) SEQ ID NO: 6373, SEQ ID NO: 6369, SEQ ID NO: 6371, and SEQ ID NO: 228, respectively;
（ｅ）それぞれ、配列番号６２６３、配列番号６２６４、配列番号６２６５、および配列番号２２８；(e) SEQ ID NO: 6263, SEQ ID NO: 6264, SEQ ID NO: 6265, and SEQ ID NO: 228, respectively;
（ｆ）それぞれ、配列番号６３５７、配列番号６３５９、配列番号６３６１、および配列番号６２７３；(f) SEQ ID NO: 6357, SEQ ID NO: 6359, SEQ ID NO: 6361, and SEQ ID NO: 6273, respectively;
（ｇ）それぞれ、配列番号６２６６、配列番号６２６７、配列番号６２６８、および配列番号６２６９；(g) SEQ ID NO: 6266, SEQ ID NO: 6267, SEQ ID NO: 6268, and SEQ ID NO: 6269, respectively;
（ｈ）それぞれ、配列番号６２７０、配列番号６２７１、配列番号６２７２、および配列番号６２７３；(h) SEQ ID NO: 6270, SEQ ID NO: 6271, SEQ ID NO: 6272, and SEQ ID NO: 6273, respectively;
（ｉ）それぞれ、配列番号６２７４、配列番号６２７５、配列番号６２７６、および配列番号６２７３；または(i) SEQ ID NO: 6274, SEQ ID NO: 6275, SEQ ID NO: 6276, and SEQ ID NO: 6273, respectively; or
（ｊ）それぞれ、配列番号６３６２、配列番号６３６３、配列番号２２６、および配列番号２２８(j) SEQ ID NO: 6362, SEQ ID NO: 6363, SEQ ID NO: 226, and SEQ ID NO: 228, respectively
の、重鎖フレームワーク領域１（ＶＨＦＷＲ１）、重鎖フレームワーク領域２（ＶＨＦＷＲ２）、重鎖フレームワーク領域３（ＶＨＦＷＲ３）、および重鎖フレームワーク領域４（ＶＨＦＷＲ４）を含むＶＨVH comprising heavy chain framework region 1 (VHFWR1), heavy chain framework region 2 (VHFWR2), heavy chain framework region 3 (VHFWR3), and heavy chain framework region 4 (VHFWR4) of
および／またはand/or
（ｉｉ）(ii)
（ａ）それぞれ、配列番号６２３８、配列番号６２４０、配列番号６２４２、および配列番号６２４４；(a) SEQ ID NO: 6238, SEQ ID NO: 6240, SEQ ID NO: 6242, and SEQ ID NO: 6244, respectively;
（ｂ）それぞれ、配列番号２５０、配列番号２５２、配列番号２５４、および配列番号２５６；(b) SEQ ID NO:250, SEQ ID NO:252, SEQ ID NO:254, and SEQ ID NO:256, respectively;
（ｃ）それぞれ、配列番号２５７、配列番号２５９、配列番号２６１、および配列番号２６３；(c) SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261, and SEQ ID NO:263, respectively;
（ｄ）それぞれ、配列番号２６４、配列番号２６６、配列番号２６８、および配列番号２７０；(d) SEQ ID NO:264, SEQ ID NO:266, SEQ ID NO:268, and SEQ ID NO:270, respectively;
（ｅ）それぞれ、配列番号２７１、配列番号２７３、配列番号２７５、および配列番号２７７；(e) SEQ ID NO: 271, SEQ ID NO: 273, SEQ ID NO: 275, and SEQ ID NO: 277, respectively;
（ｆ）それぞれ、配列番号２７８、配列番号２８０、配列番号２８２、および配列番号２８４；(f) SEQ ID NO:278, SEQ ID NO:280, SEQ ID NO:282, and SEQ ID NO:284, respectively;
（ｇ）それぞれ、配列番号６２７７、配列番号６２７８、配列番号６２７９、および配列番号６２８０；(g) SEQ ID NO: 6277, SEQ ID NO: 6278, SEQ ID NO: 6279, and SEQ ID NO: 6280, respectively;
（ｈ）それぞれ、配列番号６３７４、配列番号６３７５、配列番号２４７、および配列番号２４９；または(h) SEQ ID NO: 6374, SEQ ID NO: 6375, SEQ ID NO: 247, and SEQ ID NO: 249, respectively; or
（ｉ）それぞれ、配列番号６２８１、配列番号６２８２、配列番号６２８３、および配列番号６２８４(i) SEQ ID NO: 6281, SEQ ID NO: 6282, SEQ ID NO: 6283, and SEQ ID NO: 6284, respectively
の、軽鎖フレームワーク領域１（ＶＬＦＷＲ１）、軽鎖フレームワーク領域２（ＶＬＦＷＲ２）、軽鎖フレームワーク領域３（ＶＬＦＷＲ３）、および軽鎖フレームワーク領域４（ＶＬＦＷＲ４）を含む軽鎖可変領域（ＶＬ）light chain variable region (VL )
を含む、請求項１または２に記載の多機能性分子。3. The multifunctional molecule of claim 1 or 2, comprising
ＮＫ細胞エンゲージャーは、ＮＫｐ３０またはＮＫｐ４６に結合する抗原結合性ドメインを含んでもよく、かつThe NK cell engager may comprise an antigen binding domain that binds NKp30 or NKp46, and
Ｔ細胞エンゲージャーは、抗ＴＣＲβＶ抗体分子を含んでもよい、the T cell engager may comprise an anti-TCRβV antibody molecule;
請求項１～５のいずれか一項に記載の多機能性分子。A multifunctional molecule according to any one of claims 1-5.
ＴＣＲβＶ１２に結合する抗ＴＣＲβＶ抗体分子は、配列番号１７のＶＨＣＤＲ１、配列番号１８のＶＨＣＤＲ２、および配列番号１９のＶＨＣＤＲ３を含むＶＨ、ならびに配列番号２０のＶＬＣＤＲ１、配列番号２１のＶＬＣＤＲ２、および配列番号２２のＶＬＣＤＲ３Anti-TCRβV antibody molecules that bind to TCRβV12 are VHs comprising VHCDR1 of SEQ ID NO: 17, VHCDR2 of SEQ ID NO: 18, and VHCDR3 of SEQ ID NO: 19, and VLCDR1 of SEQ ID NO: 20, VLCDR2 of SEQ ID NO: 21, and VLCDR2 of SEQ ID NO: 22. VLCDR3
を含むＶＬを含んでもよく；may comprise a VL comprising;
ＴＣＲβＶ６に結合する抗ＴＣＲβＶ抗体分子は、配列番号３のＶＨＣＤＲ１、配列番号４のＶＨＣＤＲ２、および配列番号５のＶＨＣＤＲ３を含むＶＨ、ならびに配列番号６のＶＬＣＤＲ１、配列番号７のＶＬＣＤＲ２、および配列番号８のＶＬＣＤＲ３を含むＶＬを含んでもよく；かつAnti-TCRβV antibody molecules that bind to TCRβV6 include VH comprising VHCDR1 of SEQ ID NO:3, VHCDR2 of SEQ ID NO:4, and VHCDR3 of SEQ ID NO:5, and VLCDR1 of SEQ ID NO:6, VLCDR2 of SEQ ID NO:7, and may comprise a VL comprising VLCDR3; and
ＴＣＲβＶ５に結合する抗ＴＣＲβＶ抗体分子は、（ｉ）配列番号１３１５のＶＨＣＤＲ１、配列番号１３１６のＶＨＣＤＲ２、および配列番号１３１７のＶＨＣＤＲ３を含むＶＨ、ならびに配列番号１３２１のＶＬＣＤＲ１、配列番号１３２２のＶＬＣＤＲ２、および配列番号１３２３のＶＬＣＤＲ３を含むＶＬ；または（ｉｉ）配列番号１２９８のＶＨＣＤＲ１、配列番号１２９９のＶＨＣＤＲ２、および配列番号１３００のＶＨＣＤＲ３を含むＶＨ、ならびに配列番号１３０５のＶＬＣＤＲ１、配列番号１３０６のＶＬＣＤＲ２、および配列番号１３０７のＶＬＣＤＲ３を含むＶＬを含んでもよい、An anti-TCRβV antibody molecule that binds to TCRβV5 has (i) a VH comprising VHCDR1 of SEQ ID NO: 1315, VHCDR2 of SEQ ID NO: 1316, and VHCDR3 of SEQ ID NO: 1317, and VLCDR1 of SEQ ID NO: 1321, VLCDR2 of SEQ ID NO: 1322, and the sequence or (ii) a VH comprising VHCDR1 of SEQ ID NO: 1298, VHCDR2 of SEQ ID NO: 1299, and VHCDR3 of SEQ ID NO: 1300, and VLCDR1 of SEQ ID NO: 1305, VLCDR2 of SEQ ID NO: 1306, and SEQ ID NO: VL including VLCDR3 of 1307,
請求項６に記載の多機能性分子。7. A multifunctional molecule according to claim 6.
抗原結合性ドメインは、配列番号６２８５または６２８６のアミノ酸配列内に位置するエピトーブに結合してもよい、請求項１～１０のいずれか一項に記載の多機能性分子。11. The multifunctional molecule of any one of claims 1-10, wherein the antigen binding domain may bind to an epitope located within the amino acid sequence of SEQ ID NO:6285 or 6286.
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2020
- 2020-02-21 CN CN202080030475.9A patent/CN114127113A/en active Pending
- 2020-02-21 AU AU2020224154A patent/AU2020224154A1/en active Pending
- 2020-02-21 CA CA3131016A patent/CA3131016A1/en active Pending
- 2020-02-21 EP EP20714052.6A patent/EP3927746A1/en active Pending
- 2020-02-21 GB GB2112797.2A patent/GB2599229B/en active Active
- 2020-02-21 SG SG11202109056TA patent/SG11202109056TA/en unknown
- 2020-02-21 WO PCT/US2020/019324 patent/WO2020172601A1/en unknown
- 2020-02-21 JP JP2021549486A patent/JP2022521750A/en active Pending
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2021
- 2021-08-13 US US17/402,329 patent/US20210380670A1/en active Pending
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