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- JPWO2019129221A5 JPWO2019129221A5 JP2020536043A JP2020536043A JPWO2019129221A5 JP WO2019129221 A5 JPWO2019129221 A5 JP WO2019129221A5 JP 2020536043 A JP2020536043 A JP 2020536043A JP 2020536043 A JP2020536043 A JP 2020536043A JP WO2019129221 A5 JPWO2019129221 A5 JP WO2019129221A5
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本出願の別の態様は、上述の単離核酸またはベクターのいずれか１つを含む宿主細胞を培養すること、またはコードされた抗ＴＩＧＩＴ構築物の発現に効果的な条件下で上述の単離宿主細胞のいずれか１つを培養すること；及び発現された抗ＴＩＧＩＴ構築物を前記宿主細胞から得ることを含む、上述の単離抗ＴＩＧＩＴ構築物のいずれか１つの産生方法を提供する。いくつかの実施形態では、方法は、上述の単離核酸またはベクターのいずれか１つを含む宿主細胞を産生することをさらに含む。
本発明は、例えば、以下の項目を提供する。
(項目１)
ＴＩＧＩＴを特異的に認識する単一ドメイン抗体（ｓｄＡｂ）部分を含む単離抗ＴＩＧＩＴ構築物であって、前記ｓｄＡｂ部分が、配列番号３６～４２、５４、５６～５９、６３、６５～６７、６９～７０のいずれか１つのアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０６～１１２、１２４、１２６～１２９、１３３、１３５～１３７、１３９～１４０のいずれか１つのアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７６～１８２、１９４、１９６～１９９、２０３、２０５～２０７、２０９～２１０のいずれか１つのアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体を含む、前記単離抗ＴＩＧＩＴ構築物。
(項目２)
前記ｓｄＡｂ部分が、配列番号３６～４２、５４、５６～５９、６３、６５～６７、６９～７０のいずれか１つのアミノ酸配列を含むＣＤＲ１；配列番号１０６～１１２、１２４、１２６～１２９、１３３、１３５～１３７、１３９～１４０のいずれか１つのアミノ酸配列を含むＣＤＲ２；及び配列番号１７６～１８２、１９４、１９６～１９９、２０３、２０５～２０７、２０９～２１０のいずれか１つのアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体を含む、項目１に記載の単離抗ＴＩＧＩＴ構築物。
(項目３)
前記ｓｄＡｂ部分が、以下：
（１）配列番号３６のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０６のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７６のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（２）配列番号３７のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０７のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７７のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（３）配列番号３８のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０８のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７８のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（４）配列番号３９のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０９のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７９のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（５）配列番号４０のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１１０のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１８０のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（６）配列番号４１のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１１１のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１８１のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（７）配列番号４２のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１１２のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１８２のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（８）配列番号５４のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１２４のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１９４のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（９）配列番号５６のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１２６のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１９６のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１０）配列番号５７のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１２７のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１９７のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１１）配列番号５８のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１２８のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１９８のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１２）配列番号５９のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１２９のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１９９のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１３）配列番号６３のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１３３のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号２０３のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１４）配列番号６５のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１３５のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号２０５のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１５）配列番号６６のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１３６のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号２０６のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１６）配列番号６７のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１３７のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号２０７のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（１７）配列番号６９のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１３９のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号２０９のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；または
（１８）配列番号７０のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１４０のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号２１０のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体
のいずれか１つを含む、項目１または２に記載の単離抗ＴＩＧＩＴ構築物。
(項目４)
前記ｓｄＡｂ部分が、以下：
（１）配列番号３６のアミノ酸配列を含むＣＤＲ１；配列番号１０６のアミノ酸配列を含むＣＤＲ２；及び配列番号１７６のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（２）配列番号３７のアミノ酸配列を含むＣＤＲ１；配列番号１０７のアミノ酸配列を含むＣＤＲ２；及び配列番号１７７のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（３）配列番号３８のアミノ酸配列を含むＣＤＲ１；配列番号１０８のアミノ酸配列を含むＣＤＲ２；及び配列番号１７８のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（４）配列番号３９のアミノ酸配列を含むＣＤＲ１；配列番号１０９のアミノ酸配列を含むＣＤＲ２；及び配列番号１７９のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（５）配列番号４０のアミノ酸配列を含むＣＤＲ１；配列番号１１０のアミノ酸配列を含むＣＤＲ２；及び配列番号１８０のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（６）配列番号４１のアミノ酸配列を含むＣＤＲ１；配列番号１１１のアミノ酸配列を含むＣＤＲ２；及び配列番号１８１のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（７）配列番号４２のアミノ酸配列を含むＣＤＲ１；配列番号１１２のアミノ酸配列を含むＣＤＲ２；及び配列番号１８２のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（８）配列番号５４のアミノ酸配列を含むＣＤＲ１；配列番号１２４のアミノ酸配列を含むＣＤＲ２；及び配列番号１９４のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（９）配列番号５６のアミノ酸配列を含むＣＤＲ１；配列番号１２６のアミノ酸配列を含むＣＤＲ２；及び配列番号１９６のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１０）配列番号５７のアミノ酸配列を含むＣＤＲ１；配列番号１２７のアミノ酸配列を含むＣＤＲ２；及び配列番号１９７のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１１）配列番号５８のアミノ酸配列を含むＣＤＲ１；配列番号１２８のアミノ酸配列を含むＣＤＲ２；及び配列番号１９８のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１２）配列番号５９のアミノ酸配列を含むＣＤＲ１；配列番号１２９のアミノ酸配列を含むＣＤＲ２；及び配列番号１９９のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１３）配列番号６３のアミノ酸配列を含むＣＤＲ１；配列番号１３３のアミノ酸配列を含むＣＤＲ２；及び配列番号２０３のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１４）配列番号６５のアミノ酸配列を含むＣＤＲ１；配列番号１３５のアミノ酸配列を含むＣＤＲ２；及び配列番号２０５のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１５）配列番号６６のアミノ酸配列を含むＣＤＲ１；配列番号１３６のアミノ酸配列を含むＣＤＲ２；及び配列番号２０６のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１６）配列番号６７のアミノ酸配列を含むＣＤＲ１；配列番号１３７のアミノ酸配列を含むＣＤＲ２；及び配列番号２０７のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；
（１７）配列番号６９のアミノ酸配列を含むＣＤＲ１；配列番号１３９のアミノ酸配列を含むＣＤＲ２；及び配列番号２０９のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体；または
（１８）配列番号７０のアミノ酸配列を含むＣＤＲ１；配列番号１４０のアミノ酸配列を含むＣＤＲ２；及び配列番号２１０のアミノ酸配列を含むＣＤＲ３；または前記ＣＤＲ領域において最大で約３つのアミノ酸置換を含むその変異体
のいずれか１つを含む、項目１～３のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目５)
前記ｓｄＡｂ部分が、以下：
ａ－１）３７位のアミノ酸残基が、Ｆ、Ｙ、V、Ｌ、Ａ、Ｈ、Ｓ、Ｉ、Ｗ、Ｃ、Ｎ、Ｇ
、Ｄ、Ｔ、及びＰからなる群から選択され；
ａ－２）４４位のアミノ酸残基が、Ｅ、Ｑ、Ｇ、Ｄ、Ａ、Ｋ、Ｒ、Ｌ、Ｐ、Ｓ、V、Ｈ
、Ｔ、Ｎ、Ｗ、Ｍ、及びＩからなる群から選択され；
ａ－３）４５位のアミノ酸残基が、Ｌ、Ｒ、Ｐ、Ｈ、Ｆ、Ｇ、Ｑ、Ｓ、Ｅ、Ｔ、Ｙ、Ｃ、Ｉ、Ｄ、及びVからなる群から選択され；
ａ－４）１０３位のアミノ酸残基が、Ｗ、Ｒ、Ｇ、Ｓ、Ｋ、Ａ、Ｍ、Ｙ、Ｉ、Ｆ、Ｔ、Ｎ、V、Ｑ、Ｐ、Ｅ、及びＣからなる群から選択され；及び
ａ－５）１０８位のアミノ酸残基が、Ｑ、Ｌ、Ｒ、Ｐ、Ｅ、Ｋ、Ｓ、Ｔ、Ｍ、Ａ、及びＨからなる群から選択され；または
ｂ－１）３７位のアミノ酸残基が、Ｆ、Ｙ、Ｌ、Ｉ、及びVからなる群から選択され；
ｂ－２）４４位のアミノ酸残基が、Ｅ及びＱからなる群から選択され；
ｂ－３）４５位のアミノ酸残基が、Ｒ及びＬからなる群から選択され；
ｂ－４）１０３位のアミノ酸残基が、Ｗ、Ｒ、Ｇ、及びＳからなる群から選択され；及び
ｂ－５）１０８位のアミノ酸残基が、Ｑ及びＬからなる群から選択され；または
ｃ－１）３７位のアミノ酸残基が、Ｆ、Ｙ、Ｌ、Ｉ、及びVからなる群から選択され；
ｃ－２）４４位のアミノ酸残基が、Ａ、Ｇ、Ｅ、Ｄ、Ｑ、Ｒ、Ｓ、及びＬからなる群から選択され；
ｃ－３）４５位のアミノ酸残基が、Ｌ、Ｒ、及びＣからなる群から選択され；
ｃ－４）１０３位のアミノ酸残基が、Ｐ、Ｒ、及びＳからなる群から選択され；及び
ｃ－５）１０８位のアミノ酸残基が、Ｑ及びＬからなる群から選択され；
のいずれか１つのアミノ酸配列を含むV
H
Ｈドメインを含み、
前記アミノ酸位置が、Ｋａｂａｔ番号付けに従っており、１０８位がＱである場合、１０８位が、Ｌに適宜ヒト化することができる、項目１～４のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目６)
前記ｓｄＡｂ部分が、配列番号２５３～２５９、２７１、２７３～２７６、２８０、２８２～２８４、２８６～２８７のいずれか１つのアミノ酸配列を含むV
H
Ｈドメイン、または配列番号２５３～２５９、２７１、２７３～２７６、２８０、２８２～２８４、２８６～２８７のいずれか１つに対して少なくとも約８０％の配列同一性を有するその変異体を含む、項目１～５のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目７)
前記ｓｄＡｂ部分が、配列番号２５３～２５９、２７１、２７３～２７６、２８０、２８２～２８４、２８６～２８７のいずれか１つのアミノ酸配列を含むV
H
Ｈドメイン、または前記V
H
Ｈドメインにおいて最大で約３つのアミノ酸置換を含むその変異体を含む、項目６に記載の単離抗ＴＩＧＩＴ構築物。
(項目８)
前記ｓｄＡｂ部分と前記ＴＩＧＩＴの間の結合のＫ
ｄ
が、約１０
－５
Ｍ～約１０
－１２
Ｍである、項目１～７のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目９)
前記ｓｄＡｂ部分と前記ＴＩＧＩＴの間の結合のＫ
ｄ
が、約１０
－７
Ｍ～約１０
－１２
Ｍである、項目８に記載の単離抗ＴＩＧＩＴ構築物。
(項目１０)
ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分が、ラクダ、キメラ、ヒト、部分ヒト化、または完全ヒト化である、項目１～９のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目１１)
前記単離抗ＴＩＧＩＴ構築物が、ｓｄＡｂ－Ｆｃ融合タンパク質である、項目１～１０のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目１２)
前記ｓｄＡｂ－Ｆｃ融合タンパク質が、単量体または二量体である、項目１１に記載の単離抗ＴＩＧＩＴ構築物。
(項目１３)
前記Ｆｃ断片が、ヒトＩｇＧ１（ｈＩｇＧ１）Ｆｃ、エフェクターレス（不活性）ｈＩｇＧ１ Ｆｃ、またはｈＩｇＧ４ Ｆｃである、項目１１または１２に記載の単離抗ＴＩＧＩＴ構築物。
(項目１４)
前記ｓｄＡｂ－Ｆｃ融合タンパク質が、配列番号２８８～２９４、３０６、３０８～３１１、３１５、３１７～３１９、３２１～３２２、及び３６５～３６７のいずれか１つのアミノ酸配列を含む、項目１１～１３のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目１５)
前記単離抗ＴＩＧＩＴ構築物が、第２のエピトープを特異的に認識する第２の抗体部分をさらに含む、項目１～１０のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目１６)
前記第２の抗体部分が、完全長抗体、Ｆａｂ、Ｆａｂ’、（Ｆａｂ’）
２
、ＦV、一本
鎖ＦV（ｓｃＦV）、ｓｃＦV－ｓｃＦV、ミニボディ、ダイアボディ、またはｓｄＡｂである、項目１５に記載の単離抗ＴＩＧＩＴ構築物。
(項目１７)
前記抗ＴＩＧＩＴ構築物が、多重特異性である、項目１５または１６に記載の単離抗ＴＩＧＩＴ構築物。
(項目１８)
ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分、及び前記第２の抗体部分が、ペプチドリンカーによって適宜連結される、項目１５～１７のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目１９)
前記ペプチドリンカーが、配列番号３２４及び３７０～３７８のいずれか１つのアミノ酸配列を含む、項目１８に記載の単離抗ＴＩＧＩＴ構築物。
(項目２０)
前記第２の抗体部分が、２つの重鎖及び２つの軽鎖からなる完全長抗体である、項目１５～１９のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目２１)
前記重鎖のＦｃ断片が、ＩｇＧ１ Ｆｃ、エフェクターレスＩｇＧ１ Ｆｃ、ＩｇＧ２
Ｆｃ、またはＩｇＧ４ Ｆｃであり得る、項目２０に記載の単離抗ＴＩＧＩＴ構築物。
(項目２２)
ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分のＮ末端が、前記完全長抗体の少なくとも１つの重鎖のＣ末端に融合される、項目２０または２１に記載の単離抗ＴＩＧＩＴ構築物。
(項目２３)
ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分のＣ末端が、前記完全長抗体の少なくとも１つの重鎖のＮ末端に融合される、項目２０または２１に記載の単離抗ＴＩＧＩＴ構築物。
(項目２４)
ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分のＮ末端が、前記完全長抗体の軽鎖の少なくとも１つのＣ末端に融合される、項目２０または２１に記載の単離抗ＴＩＧＩＴ構築物。
(項目２５)
ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分のＣ末端が、前記完全長抗体の軽鎖の少なくとも１つのＮ末端に融合される、項目２０または２１に記載の単離抗ＴＩＧＩＴ構築物。
(項目２６)
前記完全長抗体が、ＰＤ－１を特異的に認識する、項目２０～２５のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目２７)
前記完全長抗体が、配列番号３８５のアミノ酸配列を含む重鎖可変ドメイン（V
H
）、及び配列番号３８６のアミノ酸配列を含む軽鎖可変ドメイン（V
L
）を含む、項目２６に記載の単離抗ＴＩＧＩＴ構築物。
(項目２８)
前記完全長抗体が、配列番号３８７のアミノ酸配列を含む重鎖可変ドメイン（V
H
）、及び配列番号３８８のアミノ酸配列を含む軽鎖可変ドメイン（V
L
）を含む、項目２６に記載の単離抗ＴＩＧＩＴ構築物。
(項目２９)
前記完全長抗体が、配列番号４０６のアミノ酸配列を含む重鎖可変ドメイン（V
H
）、及び配列番号４０７のアミノ酸配列を含む軽鎖可変ドメイン（V
L
）を含む、項目２６に記載の単離抗ＴＩＧＩＴ構築物。
(項目３０)
前記完全長抗体が、配列番号３９０のアミノ酸配列を含む重鎖、及び配列番号３９１のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の重鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、前記重鎖融合ポリペプチドが、配列番号３９４または３９６のアミノ酸配列を含む、項目２６または２９のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目３１)
前記完全長抗体が、配列番号３９０のアミノ酸配列を含む重鎖、及び配列番号３９１のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の軽鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、前記軽鎖融合ポリペプチドが、配列番号３９９または４０１のアミノ酸配列を含む、項目２６または２９のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目３２)
前記完全長抗体が、ＰＤ－Ｌ１を特異的に認識する、項目２０～２５のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目３３)
前記完全長抗体が、１）配列番号３４９のアミノ酸配列を含む重鎖相補性決定領域（ＨＣ－ＣＤＲ）１、配列番号３５０のアミノ酸配列を含むＨＣ－ＣＤＲ２、及び配列番号３５１のアミノ酸配列を含むＨＣ－ＣＤＲ３を含むＶ
Ｈ
、及び２）配列番号３５２のアミノ酸配列を含む軽鎖相補性決定領域（ＬＣ－ＣＤＲ）１、配列番号３５３のアミノ酸配列を含むＬＣ－ＣＤＲ２、及び配列番号３５４のアミノ酸配列を含むＬＣ－ＣＤＲ３を含むＶ
Ｌ
を含む、項目３２に記載の単離抗ＴＩＧＩＴ構築物。
(項目３４)
前記完全長抗体が、配列番号３３９のアミノ酸配列を含むＶ
Ｈ
、及び配列番号３４０のアミノ酸配列を含むＶ
Ｌ
を含む、項目３３に記載の単離抗ＴＩＧＩＴ構築物。
(項目３５)
前記完全長抗体が、配列番号３２３または３２７のアミノ酸配列を含む重鎖、及び配列番号３２８のアミノ酸配列を含む軽鎖を含む、項目３３または３４に記載の単離抗ＴＩＧＩＴ構築物。
(項目３６)
前記完全長抗体が、配列番号３２９のアミノ酸配列を含む重鎖、及び配列番号３３０のアミノ酸配列を含む軽鎖を含む、項目３３または３４に記載の単離抗ＴＩＧＩＴ構築物。
(項目３７)
前記完全長抗体が、配列番号３７９のアミノ酸配列を含むＶ
Ｈ
、及び配列番号３８０のアミノ酸配列を含むＶ
Ｌ
を含む、項目３２に記載の単離抗ＴＩＧＩＴ構築物。
(項目３８)
前記完全長抗体が、配列番号３８３のアミノ酸配列を含むＶ
Ｈ
、及び配列番号３８４のアミノ酸配列を含むＶ
Ｌ
を含む、項目３２に記載の単離抗ＴＩＧＩＴ構築物。
(項目３９)
前記完全長抗体が、配列番号３８１のアミノ酸配列を含むＶ
Ｈ
、及び配列番号３８２のアミノ酸配列を含むＶ
Ｌ
を含む、項目３２に記載の単離抗ＴＩＧＩＴ構築物。
(項目４０)
前記完全長抗体が、配列番号３３１のアミノ酸配列を含む重鎖、及び配列番号３３２のアミノ酸配列を含む軽鎖を含む、項目３９に記載の単離抗ＴＩＧＩＴ構築物。
(項目４１)
前記完全長抗体が、配列番号３３３のアミノ酸配列を含む重鎖、及び配列番号３３４のアミノ酸配列を含む軽鎖を含む、項目３９に記載の単離抗ＴＩＧＩＴ構築物。
(項目４２)
前記完全長抗体が、配列番号３２７のアミノ酸配列を含む重鎖、及び配列番号３２８のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の重鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３４３のアミノ酸配列を含む、項目３２～３６のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目４３)
前記完全長抗体が、配列番号３２３のアミノ酸配列を含む重鎖、及び配列番号３２８のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の重鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３５７または３５９のアミノ酸配列を含む、項目３２～３６のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目４４)
前記完全長抗体が、配列番号３２９のアミノ酸配列を含む重鎖、及び配列番号３３０のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の重鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３４１または４０２のアミノ酸配列を含む、項目３２～３６のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目４５)
前記完全長抗体が、配列番号３２３のアミノ酸配列を含む重鎖、及び配列番号３２８のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の軽鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、及び前記軽鎖融合ポリペプチドが、配列番号３６２または３６４のアミノ酸配列を含む、項目３２～３６のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目４６)
前記完全長抗体が、配列番号３２９のアミノ酸配列を含む重鎖、及び配列番号３３０のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の軽鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、及び前記軽鎖融合ポリペプチドが、配列番号４０５のアミノ酸配列を含む、項目３２～３６のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目４７)
前記完全長抗体が、配列番号３３１のアミノ酸配列を含む重鎖、及び配列番号３３２のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の重鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３４７のアミノ酸配列を含む、項目３２及び３９～４１のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目４８)
前記完全長抗体が、配列番号３３３のアミノ酸配列を含む重鎖、及び配列番号３３４のアミノ酸配列を含む軽鎖を含み、前記完全長抗体の重鎖の少なくとも１つが、ＴＩＧＩＴを特異的に認識する前記ｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３４５のアミノ酸配列を含む、項目３２及び３９～４１のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物。
(項目４９)
ＴＩＧＩＴを特異的に認識するｓｄＡｂ部分を含む単離抗ＴＩＧＩＴ構築物であって、前記ｓｄＡｂ部分が、配列番号２５３～２５９、２７１、２７３～２７６、２８０、２８２～２８４、２８６～２８７のいずれか１つのＣＤＲ１、ＣＤＲ２、及びＣＤＲ３を含む、前記単離抗ＴＩＧＩＴ構築物。
(項目５０)
項目１～４９のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物と競合的にＴＩＧＩＴに特異的に結合する、単離抗ＴＩＧＩＴ構築物。
(項目５１)
項目１～５０のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物、及び適宜、薬学的に許容可能な担体を含む、医薬組成物。
(項目５２)
ＴＩＧＩＴ関連疾患を有する個体の治療方法であって、前記個体に有効量の項目５１に記載の医薬組成物を投与することを含む、前記方法。
(項目５３)
前記ＴＩＧＩＴ関連疾患が、がんである、項目５２に記載の方法。
(項目５４)
前記がんが、固形腫瘍である、項目５３に記載の方法。
(項目５５)
前記がんが、大腸がんである、項目５４に記載の方法。
(項目５６)
前記個体に追加の療法を投与することをさらに含む、項目５２～５５のいずれか１項に記載の方法。
(項目５７)
前記追加の療法が、外科手術、放射線、化学療法、免疫療法、ホルモン療法、またはそれらの組み合わせである、項目５６に記載の方法。
(項目５８)
前記追加の療法が、免疫療法である、項目５７に記載の方法。
(項目５９)
前記免疫療法が、前記個体に、免疫調節薬を含む第２の医薬組成物の有効量を投与することを含む、項目５８に記載の方法。
(項目６０)
前記免疫調節薬が、免疫チェックポイント阻害薬である、項目５９に記載の方法。
(項目６１)
前記免疫チェックポイント阻害薬が、ＰＤ－１またはＰＤ－Ｌ１を特異的に認識する抗体である、項目６０に記載の方法。
(項目６２)
前記医薬組成物が、全身投与される、項目５２～６１のいずれか１項に記載の方法。
(項目６３)
前記医薬組成物が、局所投与される、項目５２～６１のいずれか１項に記載の方法。
(項目６４)
前記個体が、ヒトである、項目５２～６３のいずれか１項に記載の方法。
(項目６５)
項目１～５０のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物をコードする、単離核酸。
(項目６６)
項目６５に記載の単離核酸を含む、ベクター。
(項目６７)
項目６５に記載の単離核酸、または項目６６に記載のベクターを含む、単離宿主細胞。
(項目６８)
項目１～５０のいずれか１項に記載の単離抗ＴＩＧＩＴ構築物、項目６５に記載の単離核酸、項目６６に記載のベクター、または項目６７に記載の単離宿主細胞を含む、キット。
(項目６９)
抗ＴＩＧＩＴ構築物の生成方法であって、
（ａ）コードされた抗ＴＩＧＩＴ構築物を発現するのに有効な条件下で、項目６５に記載の単離核酸、項目６６に記載のベクター、または項目６７に記載の単離宿主細胞を含む宿主細胞を培養すること；及び（ｂ）前記宿主細胞から、発現された抗ＴＩＧＩＴ構築物を得ることを含む、前記方法。
(項目７０)
工程（ａ）が、項目６５に記載の単離核酸または項目６６に記載のベクターを含む宿主細胞を生成することをさらに含む、項目６９に記載の方法。
Another aspect of the application is the isolated host described above under conditions effective for culturing a host cell containing any one of the isolated nucleic acids or vectors described above, or for expressing the encoded anti-TIGIT construct. Provided is a method for producing any one of the isolated anti-TIGIT constructs described above, comprising culturing any one of the cells; and obtaining the expressed anti-TIGIT construct from the host cell. In some embodiments, the method further comprises producing a host cell comprising any one of the isolated nucleic acids or vectors described above.
The present invention provides, for example, the following items.
(Item 1)
An isolated anti-TIGIT construct comprising a single domain antibody (sdAb) moiety that specifically recognizes TIGIT, wherein the sdAb moiety is SEQ ID NO: 36-42, 54, 56-59, 63, 65-67, 69. CDR1 containing any one amino acid sequence of ~ 70, or a variant thereof containing up to about 3 amino acid substitutions; any of SEQ ID NOs: 106-112, 124, 126-129, 133, 135-137, 139-140. CDR2 containing one amino acid sequence, or a variant thereof containing up to about three amino acid substitutions; and any one of SEQ ID NOs: 176-182, 194, 196-199, 203, 205-207, 209-210. The isolated anti-TIGIT construct comprising CDR3 comprising an amino acid sequence, or a variant thereof comprising up to about 3 amino acid substitutions.
(Item 2)
CDR1 in which the sdAb moiety comprises the amino acid sequence of any one of SEQ ID NOs: 36-42, 54, 56-59, 63, 65-67, 69-70; SEQ ID NOs: 106-112, 124, 126-129, 133. , 135-137, CDR2 comprising any one amino acid sequence of 139-140; and any one amino acid sequence of SEQ ID NOs: 176-182, 194, 196-199, 203, 205-207, 209-210. CDR3; or the isolated anti-TIGIT construct of item 1, comprising a variant thereof comprising up to about 3 amino acid substitutions in the CDR region.
(Item 3)
The sdAb portion is as follows:
(1) CDR1 containing the amino acid sequence of SEQ ID NO: 36, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 106, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 176, or a variant thereof containing up to about 3 amino acid substitutions;
(2) CDR1 containing the amino acid sequence of SEQ ID NO: 37, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 107, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 177, or a variant thereof containing up to about 3 amino acid substitutions;
(3) CDR1 containing the amino acid sequence of SEQ ID NO: 38, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 108, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 178, or a variant thereof containing up to about 3 amino acid substitutions;
(4) CDR1 containing the amino acid sequence of SEQ ID NO: 39, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 109, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 179, or a variant thereof containing up to about 3 amino acid substitutions;
(5) CDR1 containing the amino acid sequence of SEQ ID NO: 40, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 110, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 180, or a variant thereof containing up to about 3 amino acid substitutions;
(6) CDR1 containing the amino acid sequence of SEQ ID NO: 41, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 111, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 181 or a variant thereof containing up to about 3 amino acid substitutions;
(7) CDR1 containing the amino acid sequence of SEQ ID NO: 42, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 112, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 182, or a variant thereof containing up to about 3 amino acid substitutions;
(8) CDR1 containing the amino acid sequence of SEQ ID NO: 54, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 124, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 194, or a variant thereof containing up to about 3 amino acid substitutions;
(9) CDR1 containing the amino acid sequence of SEQ ID NO: 56, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 126, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 196, or a variant thereof containing up to about 3 amino acid substitutions;
(10) CDR1 containing the amino acid sequence of SEQ ID NO: 57, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 127, or a variant thereof containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 197, or a variant thereof containing up to about 3 amino acid substitutions;
(11) CDR1 containing the amino acid sequence of SEQ ID NO: 58, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 128, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 198, or a variant thereof containing up to about 3 amino acid substitutions;
(12) CDR1 containing the amino acid sequence of SEQ ID NO: 59, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 129, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 199, or a variant thereof containing up to about 3 amino acid substitutions;
(13) CDR1 containing the amino acid sequence of SEQ ID NO: 63, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 133, or a variant thereof containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 203, or a variant thereof containing up to about 3 amino acid substitutions;
(14) CDR1 containing the amino acid sequence of SEQ ID NO: 65, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 135, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 205, or a variant thereof containing up to about 3 amino acid substitutions;
(15) CDR1 containing the amino acid sequence of SEQ ID NO: 66, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 136, or a variant thereof containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 206, or a variant thereof containing up to about 3 amino acid substitutions;
(16) CDR1 containing the amino acid sequence of SEQ ID NO: 67, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 137, or a variant thereof containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 207, or a variant thereof containing up to about 3 amino acid substitutions;
(17) CDR1 containing the amino acid sequence of SEQ ID NO: 69, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 139, or a variant thereof containing up to about 3 amino acid substitutions. And a CDR3 containing the amino acid sequence of SEQ ID NO: 209, or a variant thereof containing up to about 3 amino acid substitutions; or
(18) CDR1 containing the amino acid sequence of SEQ ID NO: 70, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 140, or a variant thereof containing up to about 3 amino acid substitutions. ; And CDR3 containing the amino acid sequence of SEQ ID NO: 210, or a variant thereof containing up to about 3 amino acid substitutions.
The isolated anti-TIGIT construct according to item 1 or 2, comprising any one of.
(Item 4)
The sdAb portion is as follows:
(1) CDR1 comprising the amino acid sequence of SEQ ID NO: 36; CDR2 comprising the amino acid sequence of SEQ ID NO: 106; and CDR3 comprising the amino acid sequence of SEQ ID NO: 176; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(2) CDR1 comprising the amino acid sequence of SEQ ID NO: 37; CDR2 comprising the amino acid sequence of SEQ ID NO: 107; and CDR3 comprising the amino acid sequence of SEQ ID NO: 177; or its mutation comprising up to about 3 amino acid substitutions in the CDR region. body;
(3) CDR1 comprising the amino acid sequence of SEQ ID NO: 38; CDR2 comprising the amino acid sequence of SEQ ID NO: 108; and CDR3 comprising the amino acid sequence of SEQ ID NO: 178; or its mutation comprising up to about 3 amino acid substitutions in the CDR region. body;
(4) CDR1 comprising the amino acid sequence of SEQ ID NO: 39; CDR2 comprising the amino acid sequence of SEQ ID NO: 109; and CDR3 comprising the amino acid sequence of SEQ ID NO: 179; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(5) CDR1 comprising the amino acid sequence of SEQ ID NO: 40; CDR2 comprising the amino acid sequence of SEQ ID NO: 110; and CDR3 comprising the amino acid sequence of SEQ ID NO: 180; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(6) CDR1 comprising the amino acid sequence of SEQ ID NO: 41; CDR2 comprising the amino acid sequence of SEQ ID NO: 111; and CDR3 comprising the amino acid sequence of SEQ ID NO: 181; or its mutation comprising up to about 3 amino acid substitutions in the CDR region. body;
(7) CDR1 comprising the amino acid sequence of SEQ ID NO: 42; CDR2 comprising the amino acid sequence of SEQ ID NO: 112; and CDR3 comprising the amino acid sequence of SEQ ID NO: 182; or its mutation comprising up to about 3 amino acid substitutions in the CDR region. body;
(8) CDR1 comprising the amino acid sequence of SEQ ID NO: 54; CDR2 comprising the amino acid sequence of SEQ ID NO: 124; and CDR3 comprising the amino acid sequence of SEQ ID NO: 194; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(9) CDR1 comprising the amino acid sequence of SEQ ID NO: 56; CDR2 comprising the amino acid sequence of SEQ ID NO: 126; and CDR3 comprising the amino acid sequence of SEQ ID NO: 196; or its mutation comprising up to about 3 amino acid substitutions in the CDR region. body;
(10) CDR1 comprising the amino acid sequence of SEQ ID NO: 57; CDR2 comprising the amino acid sequence of SEQ ID NO: 127; and CDR3 comprising the amino acid sequence of SEQ ID NO: 197; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(11) CDR1 comprising the amino acid sequence of SEQ ID NO: 58; CDR2 comprising the amino acid sequence of SEQ ID NO: 128; and CDR3 comprising the amino acid sequence of SEQ ID NO: 198; or its mutation comprising up to about 3 amino acid substitutions in the CDR region. body;
(12) CDR1 comprising the amino acid sequence of SEQ ID NO: 59; CDR2 comprising the amino acid sequence of SEQ ID NO: 129; and CDR3 comprising the amino acid sequence of SEQ ID NO: 199; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(13) CDR1 comprising the amino acid sequence of SEQ ID NO: 63; CDR2 comprising the amino acid sequence of SEQ ID NO: 133; and CDR3 comprising the amino acid sequence of SEQ ID NO: 203; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(14) CDR1 comprising the amino acid sequence of SEQ ID NO: 65; CDR2 comprising the amino acid sequence of SEQ ID NO: 135; and CDR3 comprising the amino acid sequence of SEQ ID NO: 205; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(15) CDR1 comprising the amino acid sequence of SEQ ID NO: 66; CDR2 comprising the amino acid sequence of SEQ ID NO: 136; and CDR3 comprising the amino acid sequence of SEQ ID NO: 206; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(16) CDR1 comprising the amino acid sequence of SEQ ID NO: 67; CDR2 comprising the amino acid sequence of SEQ ID NO: 137; and CDR3 comprising the amino acid sequence of SEQ ID NO: 207; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body;
(17) CDR1 comprising the amino acid sequence of SEQ ID NO: 69; CDR2 comprising the amino acid sequence of SEQ ID NO: 139; and CDR3 comprising the amino acid sequence of SEQ ID NO: 209; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. Body; or
(18) CDR1 comprising the amino acid sequence of SEQ ID NO: 70; CDR2 comprising the amino acid sequence of SEQ ID NO: 140; and CDR3 comprising the amino acid sequence of SEQ ID NO: 210; or a variation thereof comprising up to about 3 amino acid substitutions in the CDR region. body
The isolated anti-TIGIT construct according to any one of items 1 to 3, which comprises any one of the above.
(Item 5)
The sdAb portion is as follows:
a-1) The amino acid residue at position 37 is F, Y, V, L, A, H, S, I, W, C, N, G.
, D, T, and P;
a-2) The amino acid residue at position 44 is E, Q, G, D, A, K, R, L, P, S, V, H.
, T, N, W, M, and I;
a-3) The amino acid residue at position 45 is selected from the group consisting of L, R, P, H, F, G, Q, S, E, T, Y, C, I, D, and V;
a-4) Amino acid residue at position 103 consists of W, R, G, S, K, A, M, Y, I, F, T, N, V, Q, P, E, and C. Selected; and
a-5) The amino acid residue at position 108 is selected from the group consisting of Q, L, R, P, E, K, S, T, M, A, and H; or
b-1) The amino acid residue at position 37 is selected from the group consisting of F, Y, L, I, and V;
b-2) The amino acid residue at position 44 is selected from the group consisting of E and Q;
b-3) The amino acid residue at position 45 is selected from the group consisting of R and L;
b-4) The amino acid residue at position 103 is selected from the group consisting of W, R, G, and S; and
b-5) The amino acid residue at position 108 is selected from the group consisting of Q and L; or
c-1) The amino acid residue at position 37 is selected from the group consisting of F, Y, L, I, and V;
c-2) The amino acid residue at position 44 is selected from the group consisting of A, G, E, D, Q, R, S, and L;
c-3) The amino acid residue at position 45 is selected from the group consisting of L, R, and C;
c-4) The amino acid residue at position 103 is selected from the group consisting of P, R, and S; and
c-5) The amino acid residue at position 108 is selected from the group consisting of Q and L;
Contains a VH H domain containing any one of the amino acid sequences of
The isolated anti-TIGIT construct according to any one of items 1 to 4, wherein the amino acid position follows Kabat numbering and the 108th position is Q, where the 108th position can be appropriately humanized to L. ..
(Item 6)
The sdAb moiety is a VH H domain containing the amino acid sequence of any one of SEQ ID NOs: 253 to 259, 271, 273 to 276, 280, 282 to 284, 286 to 287 , or SEQ ID NOs: 253 to 259, 271, 273. 276, 280, 282-284, 286-287. The isolation according to any one of items 1-5, comprising a variant thereof having at least about 80% sequence identity to any one. Anti-TIGIT construct.
(Item 7)
The sdAb moiety comprises a VH H domain comprising any one amino acid sequence of SEQ ID NOs: 253 to 259, 271, 273 to 276, 280, 282 to 284, 286 to 287 , or up to about about the VH H domain . The isolated anti-TIGIT construct according to item 6, comprising a variant thereof comprising three amino acid substitutions.
(Item 8)
The isolated anti-TIGIT construct according to any one of items 1 to 7, wherein the Kd of the bond between the sdAb moiety and the TIGIT is from about 10-5 M to about 10-12 M.
(Item 9)
The isolated anti-TIGIT construct according to item 8, wherein the Kd of the bond between the sdAb moiety and the TIGIT is from about 10-7 M to about 10-12 M.
(Item 10)
The isolated anti-TIGIT construct according to any one of items 1 to 9, wherein the sdAb moiety that specifically recognizes TIGIT is a camel, chimera, human, partially humanized, or fully humanized.
(Item 11)
The isolated anti-TIGIT construct according to any one of items 1 to 10, wherein the isolated anti-TIGIT construct is an sdAb-Fc fusion protein.
(Item 12)
11. The isolated anti-TIGIT construct according to item 11, wherein the sdAb-Fc fusion protein is a monomer or a dimer.
(Item 13)
The isolated anti-TIGIT construct according to item 11 or 12, wherein the Fc fragment is a human IgG1 (hIgG1) Fc, an effectorless (inactive) hIgG1 Fc, or a hIgG4 Fc.
(Item 14)
Any of items 11-13, wherein the sdAb-Fc fusion protein comprises the amino acid sequence of any one of SEQ ID NOs: 288-294, 306, 308-311, 315, 317-319, 321-322, and 365-367. The isolated anti-TIGIT construct according to item 1.
(Item 15)
The isolated anti-TIGIT construct according to any one of items 1 to 10, wherein the isolated anti-TIGIT construct further comprises a second antibody moiety that specifically recognizes the second epitope.
(Item 16)
The second antibody portion is a full-length antibody, Fab, Fab', (Fab') 2 , FV, one.
The isolated anti-TIGIT construct according to item 15, which is a chain FV (scFV), scFV-scFV, minibody, Diabody, or sdAb.
(Item 17)
The isolated anti-TIGIT construct according to item 15 or 16, wherein the anti-TIGIT construct is multispecific.
(Item 18)
The isolated anti-TIGIT construct according to any one of items 15 to 17, wherein the sdAb moiety that specifically recognizes TIGIT and the second antibody moiety are appropriately linked by a peptide linker.
(Item 19)
The isolated anti-TIGIT construct of item 18, wherein the peptide linker comprises the amino acid sequence of any one of SEQ ID NOs: 324 and 370-378.
(Item 20)
The isolated anti-TIGIT construct according to any one of items 15 to 19, wherein the second antibody moiety is a full-length antibody consisting of two heavy chains and two light chains.
(Item 21)
The Fc fragment of the heavy chain is IgG1 Fc, effectorless IgG1 Fc, IgG2.
20. The isolated anti-TIGIT construct according to item 20, which may be Fc, or IgG4 Fc.
(Item 22)
The isolated anti-TIGIT construct according to item 20 or 21, wherein the N-terminus of the sdAb moiety that specifically recognizes TIGIT is fused to the C-terminus of at least one heavy chain of the full-length antibody.
(Item 23)
The isolated anti-TIGIT construct according to item 20 or 21, wherein the C-terminus of the sdAb moiety that specifically recognizes TIGIT is fused to the N-terminus of at least one heavy chain of the full-length antibody.
(Item 24)
The isolated anti-TIGIT construct according to item 20 or 21, wherein the N-terminus of the sdAb moiety that specifically recognizes TIGIT is fused to at least one C-terminus of the light chain of the full-length antibody.
(Item 25)
The isolated anti-TIGIT construct according to item 20 or 21, wherein the C-terminus of the sdAb moiety that specifically recognizes TIGIT is fused to at least one N-terminus of the light chain of the full-length antibody.
(Item 26)
The isolated anti-TIGIT construct according to any one of items 20 to 25, wherein the full-length antibody specifically recognizes PD-1.
(Item 27)
26. The isolation according to item 26, wherein the full-length antibody comprises a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO: 385 and a light chain variable domain (V L ) comprising the amino acid sequence of SEQ ID NO: 386. Anti-TIGIT construct.
(Item 28)
26. The isolation according to item 26, wherein the full-length antibody comprises a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO: 387 and a light chain variable domain (V L ) comprising the amino acid sequence of SEQ ID NO: 388. Anti-TIGIT construct.
(Item 29)
26. The isolation according to item 26, wherein the full-length antibody comprises a heavy chain variable domain (V H ) comprising the amino acid sequence of SEQ ID NO: 406 and a light chain variable domain (V L ) comprising the amino acid sequence of SEQ ID NO: 407. Anti-TIGIT construct.
(Item 30)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 390 and a light chain comprising the amino acid sequence of SEQ ID NO: 391, and at least one of the heavy chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of items 26 or 29, wherein the heavy chain fusion polypeptide is fused to the sdAb moiety and comprises the amino acid sequence of SEQ ID NO: 394 or 396.
(Item 31)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 390 and a light chain comprising the amino acid sequence of SEQ ID NO: 391, and at least one of the light chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of items 26 or 29, wherein the light chain fusion polypeptide is fused to the sdAb moiety and comprises the amino acid sequence of SEQ ID NO: 399 or 401.
(Item 32)
The isolated anti-TIGIT construct according to any one of items 20 to 25, wherein the full-length antibody specifically recognizes PD-L1.
(Item 33)
The full-length antibody comprises 1) heavy chain complementarity determining regions (HC-CDRs) containing the amino acid sequence of SEQ ID NO: 349, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 350, and the amino acid sequence of SEQ ID NO: 351. VH containing HC-CDR3 and 2) light chain complementarity determining regions (LC-CDR) 1 containing the amino acid sequence of SEQ ID NO: 352, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 353, and the amino acid of SEQ ID NO: 354. 32. The isolated anti-TIGIT construct according to item 32, comprising VL comprising LC-CDR3 comprising a sequence .
(Item 34)
33. The isolated anti-TIGIT construct according to item 33, wherein the full-length antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 339 and a VL comprising the amino acid sequence of SEQ ID NO: 340 .
(Item 35)
33 or 34. The isolated anti-TIGIT construct according to item 33 or 34, wherein the full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 323 or 327 and a light chain comprising the amino acid sequence of SEQ ID NO: 328.
(Item 36)
33 or 34. The isolated anti-TIGIT construct according to item 33 or 34, wherein the full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 329 and a light chain comprising the amino acid sequence of SEQ ID NO: 330.
(Item 37)
32. The isolated anti- TIGIT construct of item 32, wherein the full-length antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 379 and a VL comprising the amino acid sequence of SEQ ID NO: 380 .
(Item 38)
32. The isolated anti- TIGIT construct of item 32, wherein the full-length antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 383 and a VL comprising the amino acid sequence of SEQ ID NO: 384 .
(Item 39)
32. The isolated anti- TIGIT construct of item 32, wherein the full-length antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 381 and a VL comprising the amino acid sequence of SEQ ID NO: 382 .
(Item 40)
39. The isolated anti-TIGIT construct according to item 39, wherein the full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 331 and a light chain comprising the amino acid sequence of SEQ ID NO: 332.
(Item 41)
39. The isolated anti-TIGIT construct of item 39, wherein the full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 333 and a light chain comprising the amino acid sequence of SEQ ID NO: 334.
(Item 42)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 327 and a light chain comprising the amino acid sequence of SEQ ID NO: 328, and at least one of the heavy chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of items 32 to 36, wherein the sdAb moiety is fused and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 343.
(Item 43)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 323 and a light chain comprising the amino acid sequence of SEQ ID NO: 328, and at least one of the heavy chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of items 32-36, wherein the sdAb moiety is fused and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 357 or 359.
(Item 44)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 329 and a light chain comprising the amino acid sequence of SEQ ID NO: 330, and at least one of the heavy chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of items 32-36, wherein the sdAb moiety is fused and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 341 or 402.
(Item 45)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 323 and a light chain comprising the amino acid sequence of SEQ ID NO: 328, and at least one of the light chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of items 32-36, wherein the sdAb moiety is fused and the light chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 362 or 364.
(Item 46)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 329 and a light chain comprising the amino acid sequence of SEQ ID NO: 330, and at least one of the light chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of items 32-36, wherein the sdAb moiety is fused and the light chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 405.
(Item 47)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 331 and a light chain comprising the amino acid sequence of SEQ ID NO: 332, and at least one of the heavy chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of Items 32 and 39-41, wherein the sdAb moiety is fused and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 347.
(Item 48)
The full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 333 and a light chain comprising the amino acid sequence of SEQ ID NO: 334, and at least one of the heavy chains of the full-length antibody specifically recognizes TIGIT. The isolated anti-TIGIT construct according to any one of Items 32 and 39-41, wherein the sdAb moiety is fused and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 345.
(Item 49)
An isolated anti-TIGIT construct comprising an sdAb moiety that specifically recognizes TIGIT, wherein the sdAb moiety is any one of SEQ ID NOs: 253 to 259, 271, 273 to 276, 280, 282 to 284, 286 to 287. The isolated anti-TIGIT construct comprising two CDR1, CDR2, and CDR3.
(Item 50)
An isolated anti-TIGIT construct that specifically binds to TIGIT in a competitive manner with the isolated anti-TIGIT construct according to any one of items 1-49.
(Item 51)
A pharmaceutical composition comprising the isolated anti-TIGIT construct according to any one of items 1 to 50 and, as appropriate, a pharmaceutically acceptable carrier.
(Item 52)
A method for treating an individual having a TIGIT-related disease, which comprises administering an effective amount of the pharmaceutical composition according to item 51 to the individual.
(Item 53)
52. The method of item 52, wherein the TIGIT-related disease is cancer.
(Item 54)
53. The method of item 53, wherein the cancer is a solid tumor.
(Item 55)
54. The method of item 54, wherein the cancer is colorectal cancer.
(Item 56)
The method of any one of items 52-55, further comprising administering additional therapy to the individual.
(Item 57)
56. The method of item 56, wherein the additional therapy is surgery, radiation, chemotherapy, immunotherapy, hormone therapy, or a combination thereof.
(Item 58)
58. The method of item 57, wherein the additional therapy is immunotherapy.
(Item 59)
58. The method of item 58, wherein the immunotherapy comprises administering to the individual an effective amount of a second pharmaceutical composition comprising an immunomodulator.
(Item 60)
59. The method of item 59, wherein the immunomodulator is an immune checkpoint inhibitor.
(Item 61)
60. The method of item 60, wherein the immune checkpoint inhibitor is an antibody that specifically recognizes PD-1 or PD-L1.
(Item 62)
The method according to any one of items 52 to 61, wherein the pharmaceutical composition is systemically administered.
(Item 63)
The method according to any one of items 52 to 61, wherein the pharmaceutical composition is locally administered.
(Item 64)
The method according to any one of items 52 to 63, wherein the individual is a human.
(Item 65)
An isolated nucleic acid encoding the isolated anti-TIGIT construct according to any one of items 1-50.
(Item 66)
A vector comprising the isolated nucleic acid of item 65.
(Item 67)
An isolated host cell comprising the isolated nucleic acid of item 65 or the vector of item 66.
(Item 68)
A kit comprising the isolated anti-TIGIT construct according to any one of items 1-50, the isolated nucleic acid according to item 65, the vector according to item 66, or the isolated host cell according to item 67.
(Item 69)
A method of generating anti-TIGIT constructs
(A) A host cell comprising the isolated nucleic acid of item 65, the vector of item 66, or the isolated host cell of item 67, under conditions effective to express the encoded anti-TIGIT construct. The method comprising culturing; and (b) obtaining the expressed anti-TIGIT construct from the host cell.
(Item 70)
69. The method of item 69, wherein step (a) further comprises producing a host cell comprising the isolated nucleic acid of item 65 or the vector of item 66.
Claims (29)
（１）配列番号３６のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０６のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７６のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（２）配列番号６３のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１３３のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号２０３のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（３）配列番号３９のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０９のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７９のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（４）配列番号４２のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１１２のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１８２のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（５）配列番号３７のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０７のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７７のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（６）配列番号３８のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１０８のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１７８のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（７）配列番号４０のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１１０のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１８０のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
（８）配列番号４１のアミノ酸配列を含むＣＤＲ１、または最大で約３つのアミノ酸置換を含むその変異体；配列番号１１１のアミノ酸配列を含むＣＤＲ２、または最大で約３つのアミノ酸置換を含むその変異体；及び配列番号１８１のアミノ酸配列を含むＣＤＲ３、または最大で約３つのアミノ酸置換を含むその変異体；
のいずれか１つを含む、請求項１または２に記載の単離抗ＴＩＧＩＴ構築物。 An isolated anti-TIGIT construct comprising a single domain antibody (sdAb) moiety (anti-TIGIT sdAb moiety) that specifically recognizes TIGIT, wherein the anti-TIGIT sdAb moiety is:
(1) CDR1 containing the amino acid sequence of SEQ ID NO: 36, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 106, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 176, or a variant thereof containing up to about 3 amino acid substitutions;
(2) CDR1 containing the amino acid sequence of SEQ ID NO: 63, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 133, or a variant thereof containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 203, or a variant thereof containing up to about 3 amino acid substitutions;
(3) CDR1 containing the amino acid sequence of SEQ ID NO: 39, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 109, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 179, or a variant thereof containing up to about 3 amino acid substitutions;
(4) CDR1 containing the amino acid sequence of SEQ ID NO: 42, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 112, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 182, or a variant thereof containing up to about 3 amino acid substitutions;
( 5 ) CDR1 containing the amino acid sequence of SEQ ID NO: 37, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 107, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 177, or a variant thereof containing up to about 3 amino acid substitutions;
( 6 ) CDR1 containing the amino acid sequence of SEQ ID NO: 38, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 108, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 178, or a variant thereof containing up to about 3 amino acid substitutions;
( 7 ) CDR1 containing the amino acid sequence of SEQ ID NO: 40, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 110, or its variant containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 180, or a variant thereof containing up to about 3 amino acid substitutions;
( 8 ) CDR1 containing the amino acid sequence of SEQ ID NO: 41, or a variant thereof containing up to about 3 amino acid substitutions; CDR2 containing the amino acid sequence of SEQ ID NO: 111, or a variant thereof containing up to about 3 amino acid substitutions. And CDR3 containing the amino acid sequence of SEQ ID NO: 181 or a variant thereof containing up to about 3 amino acid substitutions;
The isolated anti-TIGIT construct according to claim 1 or 2, comprising any one of the above.
（Ｉ）ａ－１）３７位のアミノ酸残基が、Ｆ、Ｙ、V、Ｌ、Ａ、Ｈ、Ｓ、Ｉ、Ｗ、Ｃ、Ｎ、Ｇ、Ｄ、Ｔ、及びＰからなる群から選択され；
ａ－２）４４位のアミノ酸残基が、Ｅ、Ｑ、Ｇ、Ｄ、Ａ、Ｋ、Ｒ、Ｌ、Ｐ、Ｓ、V、Ｈ
、Ｔ、Ｎ、Ｗ、Ｍ、及びＩからなる群から選択され；
ａ－３）４５位のアミノ酸残基が、Ｌ、Ｒ、Ｐ、Ｈ、Ｆ、Ｇ、Ｑ、Ｓ、Ｅ、Ｔ、Ｙ、Ｃ、Ｉ、Ｄ、及びVからなる群から選択され；
ａ－４）１０３位のアミノ酸残基が、Ｗ、Ｒ、Ｇ、Ｓ、Ｋ、Ａ、Ｍ、Ｙ、Ｉ、Ｆ、Ｔ、Ｎ、V、Ｑ、Ｐ、Ｅ、及びＣからなる群から選択され；及び
ａ－５）１０８位のアミノ酸残基が、Ｑ、Ｌ、Ｒ、Ｐ、Ｅ、Ｋ、Ｓ、Ｔ、Ｍ、Ａ、及びＨからなる群から選択され；または
（ＩＩ）ｂ－１）３７位のアミノ酸残基が、Ｆ、Ｙ、Ｌ、Ｉ、及びVからなる群から選択され；
ｂ－２）４４位のアミノ酸残基が、Ｅ及びＱからなる群から選択され；
ｂ－３）４５位のアミノ酸残基が、Ｒ及びＬからなる群から選択され；
ｂ－４）１０３位のアミノ酸残基が、Ｗ、Ｒ、Ｇ、及びＳからなる群から選択され；及び
ｂ－５）１０８位のアミノ酸残基が、Ｑ及びＬからなる群から選択され；または
（ＩＩＩ）ｃ－１）３７位のアミノ酸残基が、Ｆ、Ｙ、Ｌ、Ｉ、及びVからなる群から選択され；
ｃ－２）４４位のアミノ酸残基が、Ａ、Ｇ、Ｅ、Ｄ、Ｑ、Ｒ、Ｓ、及びＬからなる群から選択され；
ｃ－３）４５位のアミノ酸残基が、Ｌ、Ｒ、及びＣからなる群から選択され；
ｃ－４）１０３位のアミノ酸残基が、Ｐ、Ｒ、及びＳからなる群から選択され；及び
ｃ－５）１０８位のアミノ酸残基が、Ｑ及びＬからなる群から選択され；
のいずれか１つのアミノ酸配列を含むVHＨドメインを含み、
前記アミノ酸位置が、Ｋａｂａｔ番号付けに従っており、１０８位がＱである場合、１０８位が、Ｌに適宜ヒト化することができる、請求項１に記載の単離抗ＴＩＧＩＴ構築物。 The anti-TIGIT sdAb portion is as follows:
(I) a-1) The amino acid residue at position 37 is selected from the group consisting of F, Y, V, L, A, H, S, I, W, C, N, G, D, T, and P. Beed;
a-2) The amino acid residue at position 44 is E, Q, G, D, A, K, R, L, P, S, V, H.
, T, N, W, M, and I;
a-3) The amino acid residue at position 45 is selected from the group consisting of L, R, P, H, F, G, Q, S, E, T, Y, C, I, D, and V;
a-4) Amino acid residue at position 103 consists of W, R, G, S, K, A, M, Y, I, F, T, N, V, Q, P, E, and C. Selected; and a-5) the amino acid residue at position 108 is selected from the group consisting of Q, L, R, P, E, K, S, T, M, A, and H; or
(II) b-1) The amino acid residue at position 37 is selected from the group consisting of F, Y, L, I, and V;
b-2) The amino acid residue at position 44 is selected from the group consisting of E and Q;
b-3) The amino acid residue at position 45 is selected from the group consisting of R and L;
b-4) The amino acid residue at position 103 is selected from the group consisting of W, R, G, and S; and b-5) the amino acid residue at position 108 is selected from the group consisting of Q and L; or
(III) c-1) The amino acid residue at position 37 is selected from the group consisting of F, Y, L, I, and V;
c-2) The amino acid residue at position 44 is selected from the group consisting of A, G, E, D, Q, R, S, and L;
c-3) The amino acid residue at position 45 is selected from the group consisting of L, R, and C;
c-4) The amino acid residue at position 103 is selected from the group consisting of P, R, and S; and c-5) the amino acid residue at position 108 is selected from the group consisting of Q and L;
Contains a VH H domain containing any one of the amino acid sequences of
The isolated anti-TIGIT construct according to claim 1 , wherein if the amino acid position follows Kabat numbering and position 108 is Q, position 108 can be appropriately humanized to L.
（ｉｉ）前記Ｆｃ断片が、ヒトＩｇＧ１（ｈＩｇＧ１）Ｆｃ、エフェクターレス（不活性）ｈＩｇＧ１ Ｆｃ、もしくはｈＩｇＧ４ Ｆｃである、請求項５に記載の単離抗ＴＩＧＩＴ構築物。 (I) The anti-TIGITsdAb-Fc fusion protein is a dimer and / or
(Ii) The isolated anti-TIGIT construct according to claim 5 , wherein the Fc fragment is a human IgG1 (hIgG1) Fc, an effectorless (inactive) hIgG1 Fc, or a hIgG4 Fc.
鎖ＦV（ｓｃＦV）、ｓｃＦV－ｓｃＦV、ミニボディ、ダイアボディ、またはｓｄＡｂである、請求項８に記載の単離抗ＴＩＧＩＴ構築物。 Claim that the second antibody moiety is a full length antibody, Fab, Fab', (Fab') 2 , FV, single chain FV (scFV), scFV-scFV, minibody, diabody, or sdAb. 8. The isolated anti-TIGIT construct according to 8.
Ｆｃ、またはＩｇＧ４ Ｆｃである、請求項１２に記載の単離抗ＴＩＧＩＴ構築物。 The Fc fragment of the heavy chain is IgG1 Fc, effectorless IgG1 Fc, IgG2.
The isolated anti-TIGIT construct according to claim 12 , which is Fc, or IgG4 Fc.
（ｉ）前記抗ＴＩＧＩＴｓｄＡｂ部分のＮ末端が、前記完全長抗体の少なくとも１つの重鎖のＣ末端に融合される、
（ｉｉ）前記抗ＴＩＧＩＴｓｄＡｂ部分のＣ末端が、前記完全長抗体の少なくとも１つの重鎖のＮ末端に融合される、
（ｉｉｉ）前記抗ＴＩＧＩＴｓｄＡｂ部分のＮ末端が、前記完全長抗体の少なくとも１つの軽鎖のＣ末端に融合される、
（ｉｖ）前記抗ＴＩＧＩＴｓｄＡｂ部分のＣ末端が、前記完全長抗体の少なくとも１つの軽鎖のＮ末端に融合される、
（ｖ）前記単離抗ＴＩＧＩＴ構築物が４つの抗ＴＩＧＩＴｓｄＡｂ部分を含み、各々の抗ＴＩＧＩＴｓｄＡｂ部分のＣ末端が、前記完全長抗体の各々の鎖のＮ末端に融合される、および
（ｖｉ）前記単離抗ＴＩＧＩＴ構築物が４つの抗ＴＩＧＩＴｓｄＡｂ部分を含み、前記４つの抗ＴＩＧＩＴｓｄＡｂ部分のうちの２つがたがいに融合されており、前記完全長抗体の各々の重鎖のＮ末端にさらに融合される、
からなる群から選択される構成を含む、請求項１２または１３に記載の単離抗ＴＩＧＩＴ構築物。 The isolated anti-TIGIT construct is described below.
(I) The N-terminus of the anti-TIGIT sdAb moiety is fused to the C-terminus of at least one heavy chain of the full-length antibody.
(Ii) The C-terminus of the anti-TIGITsdAb moiety is fused to the N-terminus of at least one heavy chain of the full-length antibody.
(Iii) The N-terminus of the anti-TIGITSdAb moiety is fused to the C-terminus of at least one light chain of the full-length antibody.
(Iv) The C-terminus of the anti-TIGITsdAb moiety is fused to the N-terminus of at least one light chain of the full-length antibody.
(V) The isolated anti-TIGIT construct comprises four anti-TIGITsdAb moieties, the C-terminus of each anti-TIGITsdAb moiety is fused to the N-terminus of each chain of the full-length antibody, and.
(Vi) The isolated anti-TIGIT construct comprises four anti-TIGITsdAb moieties, two of the four anti-TIGITsdAb moieties fused to each other and further to the N-terminus of each heavy chain of the full-length antibody. Fused,
The isolated anti-TIGIT construct according to claim 12 or 13 , comprising a configuration selected from the group consisting of.
（ｉ）配列番号３８５のアミノ酸配列を含む重鎖可変ドメイン（VH）、及び配列番号３８６のアミノ酸配列を含む軽鎖可変ドメイン（VL）、
（ｉｉ）配列番号３８７のアミノ酸配列を含む重鎖可変ドメイン（V H ）、及び配列番号３８８のアミノ酸配列を含む軽鎖可変ドメイン（V L ）、または
（ｉｉｉ）配列番号４０６のアミノ酸配列を含む重鎖可変ドメイン（V H ）、及び配列番号４０７のアミノ酸配列を含む軽鎖可変ドメイン（V L ）
の重鎖相補性決定領域（ＨＣ－ＣＤＲ）および軽鎖相補性決定領域（ＬＣ－ＣＤＲ）を含む、請求項１５に記載の単離抗ＴＩＧＩＴ構築物。 The anti-PD-1 full-length antibody
(I) Heavy chain variable domain (V H ) containing the amino acid sequence of SEQ ID NO: 385, and light chain variable domain (V L ) containing the amino acid sequence of SEQ ID NO: 386.
(Ii) A heavy chain variable domain (V H ) containing the amino acid sequence of SEQ ID NO: 387, and a light chain variable domain (V L ) containing the amino acid sequence of SEQ ID NO: 388 , or.
(Iii) Heavy chain variable domain (V H ) containing the amino acid sequence of SEQ ID NO: 406, and light chain variable domain (V L ) containing the amino acid sequence of SEQ ID NO: 407.
The isolated anti-TIGIT construct according to claim 15 , which comprises the heavy chain complementarity determining regions (HC-CDRs) and the light chain complementarity determining regions (LC-CDRs) .
（ｉ）配列番号３４９のアミノ酸配列を含むＨＣ－ＣＤＲ１、配列番号３５０のアミノ酸配列を含むＨＣ－ＣＤＲ２、及び配列番号３５１のアミノ酸配列を含むＨＣ－ＣＤＲ３、配列番号３５２のアミノ酸配列を含むＬＣ－ＣＤＲ１、配列番号３５３のアミノ酸配列を含むＬＣ－ＣＤＲ２、及び配列番号３５４のアミノ酸配列を含むＬＣ－ＣＤＲ３、
（ｉｉ）配列番号３３９のアミノ酸配列を含むＶ Ｈ 、及び配列番号３４０のアミノ酸配列を含むＶ Ｌ 、
（ｉｉｉ）配列番号３２３もしくは３２７のアミノ酸配列を含む重鎖、及び配列番号３２８のアミノ酸配列を含む軽鎖、
（ｉｖ）配列番号３２９のアミノ酸配列を含む重鎖、及び配列番号３３０のアミノ酸配列を含む軽鎖、
（ｖ）配列番号３７９のアミノ酸配列を含むＶ Ｈ のＨＣ－ＣＤＲ、及び配列番号３８０のアミノ酸配列を含むＶ Ｌ のＬＣ－ＣＤＲ、
（ｖｉ）配列番号３８３のアミノ酸配列を含むＶ Ｈ のＨＣ－ＣＤＲ、及び配列番号３８４のアミノ酸配列を含むＶ Ｌ のＬＣ－ＣＤＲ、
（ｖｉｉ）配列番号３８１のアミノ酸配列を含むＶ Ｈ のＨＣ－ＣＤＲ、及び配列番号３８２のアミノ酸配列を含むＶ Ｌ のＬＣ－ＣＤＲ、
（ｖｉｉｉ）配列番号３３１のアミノ酸配列を含む重鎖、及び配列番号３３２のアミノ酸配列を含む軽鎖、または
（ｉｘ）配列番号３３３のアミノ酸配列を含む重鎖、及び配列番号３３４のアミノ酸配列を含む軽鎖
を含む、請求項１８に記載の単離抗ＴＩＧＩＴ構築物。 The anti-PD-L1 full-length antibody
(I ) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 349, HC - CDR2 containing the amino acid sequence of SEQ ID NO: 350, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 351 and the amino acid sequence of SEQ ID NO: 352. LC- CDR1 containing , LC-CDR2 containing the amino acid sequence of SEQ ID NO: 353, and LC-CDR 3 containing the amino acid sequence of SEQ ID NO: 354,
(Ii) VH containing the amino acid sequence of SEQ ID NO: 339 , and VL containing the amino acid sequence of SEQ ID NO: 340 .
(Iii) A heavy chain comprising the amino acid sequence of SEQ ID NO: 323 or 327, and a light chain comprising the amino acid sequence of SEQ ID NO: 328.
(Iv) A heavy chain comprising the amino acid sequence of SEQ ID NO: 329 and a light chain comprising the amino acid sequence of SEQ ID NO: 330.
(V) HC-CDR of VH containing the amino acid sequence of SEQ ID NO: 379, and LC-CDR of VL containing the amino acid sequence of SEQ ID NO: 380 .
(Vi) HC-CDR of VH containing the amino acid sequence of SEQ ID NO: 383 , and LC-CDR of VL containing the amino acid sequence of SEQ ID NO: 384 .
(Vii) HC-CDR of VH containing the amino acid sequence of SEQ ID NO: 381 , and LC-CDR of VL containing the amino acid sequence of SEQ ID NO: 382 .
(Viii) A heavy chain comprising the amino acid sequence of SEQ ID NO: 331, and a light chain comprising the amino acid sequence of SEQ ID NO: 332, or
(Ix) A heavy chain containing the amino acid sequence of SEQ ID NO: 333 and a light chain containing the amino acid sequence of SEQ ID NO: 334.
18. The isolated anti-TIGIT construct according to claim 18 .
（ｉｉ）前記抗ＰＤ－Ｌ１完全長抗体が、配列番号３２３のアミノ酸配列を含む重鎖、及び配列番号３２８のアミノ酸配列を含む軽鎖を含み、前記抗ＰＤ－Ｌ１完全長抗体の重鎖の少なくとも１つが、前記抗ＴＩＧＩＴｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３５７または３５９のアミノ酸配列を含むか、
（ｉｉｉ）前記抗ＰＤ－Ｌ１完全長抗体が、配列番号３２９のアミノ酸配列を含む重鎖、及び配列番号３３０のアミノ酸配列を含む軽鎖を含み、前記抗ＰＤ－Ｌ１完全長抗体の重鎖の少なくとも１つが、前記抗ＴＩＧＩＴｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３４１または４０２のアミノ酸配列を含むか、
（ｉｖ）前記抗ＰＤ－Ｌ１完全長抗体が、配列番号３２３のアミノ酸配列を含む重鎖、及び配列番号３２８のアミノ酸配列を含む軽鎖を含み、前記抗ＰＤ－Ｌ１完全長抗体の軽鎖の少なくとも１つが、前記抗ＴＩＧＩＴｓｄＡｂ部分に融合され、及び前記軽鎖融合ポリペプチドが、配列番号３６２または３６４のアミノ酸配列を含むか、
（ｖ）前記抗ＰＤ－Ｌ１完全長抗体が、配列番号３２９のアミノ酸配列を含む重鎖、及び配列番号３３０のアミノ酸配列を含む軽鎖を含み、前記抗ＰＤ－Ｌ１完全長抗体の軽鎖の少なくとも１つが、前記抗ＴＩＧＩＴｓｄＡｂ部分に融合され、及び前記軽鎖融合ポリペプチドが、配列番号４０５のアミノ酸配列を含むか、
（ｖｉ）前記抗ＰＤ－Ｌ１完全長抗体が、配列番号３３１のアミノ酸配列を含む重鎖、及び配列番号３３２のアミノ酸配列を含む軽鎖を含み、前記抗ＰＤ－Ｌ１完全長抗体の重鎖の少なくとも１つが、前記抗ＴＩＧＩＴｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３４７のアミノ酸配列を含むか、または
（ｖｉｉ）前記抗ＰＤ－Ｌ１完全長抗体が、配列番号３３３のアミノ酸配列を含む重鎖、及び配列番号３３４のアミノ酸配列を含む軽鎖を含み、前記抗ＰＤ－Ｌ１完全長抗体の重鎖の少なくとも１つが、前記抗ＴＩＧＩＴｓｄＡｂ部分に融合され、及び前記重鎖融合ポリペプチドが、配列番号３４５のアミノ酸配列を含む、
請求項１８または１９に記載の単離抗ＴＩＧＩＴ構築物。 (I) The anti-PD-L1 full-length antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 327 and a light chain containing the amino acid sequence of SEQ ID NO: 328, and the heavy chain of the anti-PD-L1 full-length antibody. At least one is fused to the anti-TIGIT sdAb moiety and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 343 .
(Ii) The anti-PD-L1 full-length antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 323 and a light chain containing the amino acid sequence of SEQ ID NO: 328, and the heavy chain of the anti-PD-L1 full-length antibody. At least one is fused to the anti-TIGITsdAb moiety, and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 357 or 359.
(Iii) The anti-PD-L1 full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 329 and a light chain comprising the amino acid sequence of SEQ ID NO: 330, which is the heavy chain of the anti-PD-L1 full-length antibody. At least one is fused to the anti-TIGITsdAb moiety, and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 341 or 402.
(Iv) The anti-PD-L1 full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 323 and a light chain comprising the amino acid sequence of SEQ ID NO: 328, and the light chain of the anti-PD-L1 full-length antibody. At least one is fused to the anti-TIGITsdAb moiety, and the light chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 362 or 364.
(V) The anti-PD-L1 full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 329 and a light chain comprising the amino acid sequence of SEQ ID NO: 330, and the light chain of the anti-PD-L1 full-length antibody. At least one is fused to the anti-TIGITsdAb moiety, and the light chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 405.
(Vi) The anti-PD-L1 full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 331 and a light chain comprising the amino acid sequence of SEQ ID NO: 332, which is the heavy chain of the anti-PD-L1 full-length antibody. At least one is fused to the anti-TIGITsdAb moiety, and the heavy chain fusion polypeptide comprises or contains the amino acid sequence of SEQ ID NO: 347.
(Vii) The anti-PD-L1 full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 333 and a light chain comprising the amino acid sequence of SEQ ID NO: 334, which is the heavy chain of the anti-PD-L1 full-length antibody. At least one is fused to the anti-TIGITsdAb moiety, and the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 345.
The isolated anti-TIGIT construct according to claim 18 or 19 .
（ｂ）前記単離抗ＴＩＧＩＴ構築物がＮ末端からＣ末端に２つのポリペプチド：（ｉ）第２のエピトープを特異的に認識する第１のｓｃＦｖ－必要に応じてペプチドリンカー－第１の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ (B) The isolated anti-TIGIT construct has two polypeptides from N-terminus to C-terminus: (i) a first scFv that specifically recognizes a second epitope-a peptide linker as needed-a first anti. TIGITSdAb part-C ＨH ２－Ｃ2-C ＨH ３、および（ｉｉ）第３のエピトープを特異的に認識する第２のｓｃＦｖ－必要に応じてペプチドリンカー－第２の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ3, and (ii) a second scFv that specifically recognizes the third epitope-a peptide linker as needed-a second anti-TIGITSdAb moiety-C ＨH ２－Ｃ2-C ＨH ３、3,
（ｃ）前記単離抗ＴＩＧＩＴ構築物がＮ末端からＣ末端に４つのポリペプチド：（ｉ）Ｖ (C) The isolated anti-TIGIT construct has four polypeptides from the N-terminus to the C-terminus: (i) V. ＬL －Ｃ-C ＬL －必要に応じてペプチドリンカー－第１の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ-Peptide linker as needed-First anti-TIGITsdAb portion-C ＬL 、（ｉｉ）Ｖ, (Ii) V ＨH －Ｃ-C ＨH １－必要に応じてペプチドリンカー－第２の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ1-Peptide linker as needed-Second anti-TIGITsdAb portion-C ＨH １－Ｃ1-C ＨH ２－Ｃ2-C ＨH ３、（ｉｉｉ）Ｖ3, (iii) V ＨH －Ｃ-C ＨH １－必要に応じてペプチドリンカー－第３の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ1-Peptide linker as needed-Third anti-TIGITsdAb portion-C ＨH １－Ｃ1-C ＨH ２－Ｃ2-C ＨH ３、および（ｉｖ）Ｖ3, and (iv) V ＬL －Ｃ-C ＬL －必要に応じてペプチドリンカー－第４の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ-Peptide linker as needed-Fourth anti-TIGITsdAb portion-C ＬL を含み、ポリペプチド（ｉ）のＶContaining, V of polypeptide (i) ＬL －Ｃ-C ＬL およびポリペプチド（ｉｉ）ＶAnd polypeptide (ii) V ＨH －Ｃ-C ＨH １が、第２のエピトープを特異的に認識する第２の抗体部分を形成し、ポリペプチド（ｉｖ）のＶ1 forms a second antibody moiety that specifically recognizes the second epitope, V of the polypeptide (iv). ＬL －Ｃ-C ＬL およびポリペプチド（ｉｉｉ）のＶAnd V of polypeptide (iii) ＨH －Ｃ-C ＨH １が、第３のエピトープを特異的に認識する第３の抗体部分を形成する、1 forms a third antibody moiety that specifically recognizes the third epitope.
（ｄ）前記単離抗ＴＩＧＩＴ構築物がＮ末端からＣ末端に４つのポリペプチド：（ｉ）第１の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ (D) The isolated anti-TIGIT construct has four polypeptides from N-terminus to C-terminus: (i) First anti-TIGTsdAb moiety-C. ＬL 、（ｉｉ）第２のエピトープを特異的に認識する第１のｓｃＦｖ－必要に応じてペプチドリンカー－第２の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ, (Ii) First scFv that specifically recognizes the second epitope-Peptide linker as needed-Second anti-TIGITSdAb portion-C ＨH １－Ｃ1-C ＨH ２－Ｃ2-C ＨH ３、（ｉｉｉ）第３のエピトープを特異的に認識する第２のｓｃＦｖ－必要に応じてペプチドリンカー－第３の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ3. (iii) Second scFv that specifically recognizes the third epitope-Peptide linker if necessary-Third anti-TIGITsdAb portion-C ＨH １－Ｃ1-C ＨH ２－Ｃ2-C ＨH ３、および（ｉｖ）第４の抗ＴＩＧＩＴｓｄＡｂ部分－Ｃ3 and (iv) 4th anti-TIGITsdAb portion-C ＬL
からなる群から選択される構成を含む、請求項８～１１のいずれか一項に記載の単離抗ＴＩＧＩＴ構築物。The isolated anti-TIGIT construct according to any one of claims 8 to 11, comprising a configuration selected from the group consisting of.
（ｉｉ）前記病原性感染が、ウイルス肝炎であるか、または
（ｉｉｉ）前記免疫関連疾患が、Ｔ細胞機能不全障害と関連する、
請求項２４に記載の医薬。 (I) Whether the cancer is a solid tumor
(Ii) The pathogenic infection is viral hepatitis or
(Iii) The immune-related disease is associated with T cell dysfunction.
The medicine according to claim 24 .
（ｉｉ）前記Ｔ細胞機能不全障害がＴ細胞消耗によって特徴付けられる、
請求項２５に記載の医薬。 (I) The solid tumor is colon cancer or
(Ii) The T cell dysfunction disorder is characterized by T cell depletion,
The medicine according to claim 25 .
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