JPWO2022036285A5

JPWO2022036285A5 -

Info

Publication number: JPWO2022036285A5
Application number: JP2023510448A
Authority: JP
Publication date: 2024-08-20

Description

これらおよび他の変化は、上記に詳述される説明に照らして実施形態についてなされ得る。一般的に、以下の特許請求の範囲において、使用される用語は、特許請求の範囲を、明細書および特許請求の範囲において開示されている特定の実施形態に限定すると解釈されるべきではなく、むしろ、そのような特許請求の範囲が権利を与える均等物の全範囲に沿った全ての可能な実施形態を含むと解釈されるべきである。したがって、特許請求の範囲は、本開示によって限定されない。
本開示は、例えば、以下に関する。
［項１］
それを必要とする対象においてがんを治療するための方法であって、がんが、乳がん、卵巣がん、結腸直腸がん、卵管がん、腹膜がん、前立腺がん、肺がん、または黒色腫であり、方法は、有効量の、
（ａ）（ｉ）Ｔｉｍ１ＩｇＶドメインまたはＴｉｍ４ＩｇＶドメイン；および
（ｉｉ）Ｔｉｍ１ムチンドメインまたはＴｉｍ４ムチンドメイン
を含む、結合ドメインを含む細胞外ドメインと；
（ｂ）一次細胞内シグナル伝達ドメインおよび適宜の二次細胞内シグナル伝達ドメインを含む細胞内シグナル伝達ドメインと；
（ｃ）細胞外ドメインと細胞内シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインと
を含む単鎖キメラタンパク質を含む、キメラＴ細胞免疫グロブリンおよびムチン（Ｔｉｍ）受容体；ならびに
ポリ（ＡＤＰ－リボース）ポリメラーゼ（ＰＡＲＰ）阻害剤
を対象に投与することを含む方法。
［項２］
乳がんが三種陰性乳がんである、項１に記載の方法。
［項３］
卵巣がんが進行卵巣がんである、項１に記載の方法。
［項４］
前立腺がんが進行前立腺がんである、項１に記載の方法。
［項５］
肺がんが非小細胞肺がんである、項１に記載の方法。
［項６］
がんが乳がん遺伝子（ＢＲＣＡ）変異がんである、項１～５のいずれか一項に記載の方法。
［項７］
がんが、ＢＲＣＡ１変異がん、ＢＲＣＡ２変異がん、またはその両方である、項６に記載の方法。
［項８］
ＰＡＲＰ阻害剤が、タラゾパリブ、ニラパリブ、ルカパリブ、オラパリブ、ベリパリブ、ＣＥＰ９７２２、Ｅ７０１６、ＡＧ０１４６９９、ＭＫ４８２７、ＢＭＮ－６７３、パミパリブ、またはそれらの組合せである、項１～７のいずれか一項に記載の方法。
［項９］
ＰＡＲＰ阻害剤がニラパリブを含む、項１～８のいずれか一項に記載の方法。
［項１０］
ＰＡＲＰ阻害剤がタラゾパリブを含む、項１～８のいずれか一項に記載の方法。
［項１１］
ＰＡＲＰ阻害剤がルカパリブを含む、項１～８のいずれか一項に記載の方法。
［項１２］
ＰＡＲＰ阻害剤がオラパリブを含む、項１～８のいずれか一項に記載の方法。
［項１３］
ＰＡＲＰ阻害剤がベリパリブを含む、項１～８のいずれか一項に記載の方法。
［項１４］
ＰＡＲＰ阻害剤がＣＥＰ９７２２を含む、項１～８のいずれか一項に記載の方法。
［項１５］
ＰＡＲＰ阻害剤がＥ７０１６を含む、項１～８のいずれか一項に記載の方法。
［項１６］
ＰＡＲＰ阻害剤がＡＧ０１４６９９を含む、項１～８のいずれか一項に記載の方法。
［項１７］
ＰＡＲＰ阻害剤がＭＫ４８２７を含む、項１～８のいずれか一項に記載の方法。
［項１８］
ＰＡＲＰ阻害剤がＢＭＮ－６７３を含む、項１～８のいずれか一項に記載の方法。
［項１９］
ＰＡＲＰ阻害剤がパミパリブを含む、項１～８のいずれか一項に記載の方法。
［項２０］
追加の治療剤を投与することをさらに含む、項１～１９のいずれか一項に記載の方法。
［項２１］
追加の治療剤が、放射線照射、細胞免疫療法、抗体、免疫チェックポイント分子阻害剤、化学療法、ホルモン療法、ペプチド、抗生物質、抗ウイルス剤、抗真菌剤、抗炎症剤、ＵＶ光療法、電気パルス療法、高密度焦点式超音波療法、腫瘍溶解性ウイルス療法、小分子療法、またはそれらの組合せを含む、項２０に記載の方法。
［項２２］
細胞免疫療法がキメラ抗原受容体またはＴ細胞受容体である、項２１に記載の方法。
［項２３］
追加の治療剤が、血管新生阻害剤（例えばＶＥＧＦ経路阻害剤）、チロシンキナーゼ阻害剤（例えばＥＧＦ経路阻害剤）、受容体チロシンキナーゼ阻害剤、増殖因子阻害剤、ＧＴＰアーゼ阻害剤、セリン／トレオニンキナーゼ阻害剤、転写因子阻害剤、Ｂ－Ｒａｆ阻害剤、ＲＡＦ阻害剤、ＭＥＫ阻害剤、ｍＴＯＲ阻害剤、ＥＧＦＲ阻害剤、ＡＬＫ阻害剤、ＲＯＳ１阻害剤、ＢＣＬ－２阻害剤、ＰＩ３Ｋ阻害剤、ＶＥＧＦＲ阻害剤、ＢＣＲ－ＡＢＬ阻害剤、ＭＥＴ阻害剤、ＭＹＣ阻害剤、ＡＢＬ阻害剤、ＨＥＲ２阻害剤、ＢＴＫ阻害剤、Ｈ－ＲＡＳ阻害剤、Ｋ－ＲＡＳ阻害剤、ＰＤＧＦＲ阻害剤、ＴＲＫ阻害剤、ｃ－ＫＩＴ阻害剤、ｃ－ＭＥＴ阻害剤、ＣＤＫ４／６阻害剤、ＦＡＫ阻害剤、ＦＧＦＲ阻害剤、ＦＬＴ３阻害剤、ＩＤＨ１阻害剤、ＩＤＨ２阻害剤、ＰＤＧＦＲＡ阻害剤、またはＲＥＴ阻害剤を含む、項２０または２１に記載の方法。
［項２４］
結合ドメインが、Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む、項１～２３のいずれか一項に記載の方法。
［項２５］
結合ドメインが、Ｔｉｍ４ＩｇＶドメインおよびＴｉｍ４ムチンドメインを含む、項１～２３のいずれか一項に記載の方法。
［項２６］
結合ドメインが、Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ４ムチンドメインを含む、項１～２３のいずれか一項に記載の方法。
［項２７］
結合ドメインが、Ｔｉｍ４ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む、項１～２３のいずれか一項に記載の方法。
［項２８］
Ｔｉｍ１ＩｇＶドメインが、配列番号３８に示されるアミノ酸配列を含む、項１～２４または２６のいずれか一項に記載の方法。
［項２９］
Ｔｉｍ１ＩｇＶドメインが、配列番号３８においてＲ６６Ｇ置換を含む改変Ｔｉｍ１ＩｇＶドメインである、項１～２４、２６または２８のいずれか一項に記載の方法。
［項３０］
改変Ｔｉｍ１ＩｇＶドメインが、配列番号４１に示されるアミノ酸配列を含む、項２９に記載の方法。
［項３１］
Ｔｉｍ１ムチンドメインが、配列番号３９に示されるアミノ酸配列を含む、項１～２５、または２７～３０のいずれか一項に記載の方法。
［項３２］
Ｔｉｍ４ＩｇＶドメインが、配列番号３４に示されるアミノ酸配列を含む、項１～２３、２５または２７のいずれか一項に記載の方法。
［項３３］
Ｔｉｍ４ムチンドメインが、配列番号３５に示されるアミノ酸配列を含む、項１～２３、２５または２６のいずれか一項に記載の方法。
［項３４］
膜貫通ドメインが、Ｔｉｍ４膜貫通ドメイン、Ｔｉｍ１膜貫通ドメイン、ＣＤ２８膜貫通ドメイン、４－１ＢＢ膜貫通ドメイン、ＯＸ４０膜貫通ドメイン、ＣＤ２７膜貫通ドメイン、ＩＣＯＳ膜貫通ドメイン、ＣＤ２膜貫通ドメイン、ＬＦＡ－１膜貫通ドメイン、ＣＤ３０膜貫通ドメイン、ＣＤ４０膜貫通ドメイン、ＰＤ－１膜貫通ドメイン、ＣＤ７膜貫通ドメイン、ＬＩＧＨＴ膜貫通ドメイン、ＮＫＧ２Ｃ膜貫通ドメイン、またはＢ７－Ｈ３膜貫通ドメインを含む、項１～３３のいずれか一項に記載の方法。
［項３５］
Ｔｉｍ４膜貫通ドメインが配列番号１４４もしくは２３のアミノ酸配列を含むかまたはからなるか；Ｔｉｍ１膜貫通ドメインが配列番号８のアミノ酸配列を含むかまたはからなるか；ＣＤ２８膜貫通ドメインが配列番号１４５のアミノ酸配列を含むかまたはからなるか；４－１ＢＢ膜貫通ドメインが配列番号１４６のアミノ酸配列を含むかまたはからなるか；ＯＸ４０膜貫通ドメインが配列番号１４７のアミノ酸配列を含むかまたはからなるか；ＣＤ２７膜貫通ドメインが配列番号１４８のアミノ酸配列を含むかまたはからなるか；ＩＣＯＳ膜貫通ドメインが配列番号１４９のアミノ酸配列を含むかまたはからなるか；ＣＤ２膜貫通ドメインが配列番号１５０のアミノ酸配列を含むかまたはからなるか；ＬＦＡ－１膜貫通ドメインが配列番号１５１のアミノ酸配列を含むかまたはからなるか；ＣＤ３０膜貫通ドメインが配列番号１５２のアミノ酸配列を含むかまたはからなるか；ＣＤ４０膜貫通ドメインが配列番号１５３のアミノ酸配列を含むかまたはからなるか；ＰＤ－１膜貫通ドメインが配列番号１５４のアミノ酸配列を含むかまたはからなるか；ＣＤ７膜貫通ドメインが配列番号１５５のアミノ酸配列を含むかまたはからなるか；ＬＩＧＨＴ膜貫通ドメインが配列番号１５６のアミノ酸配列を含むかまたはからなるか；ＮＫＧ２Ｃ膜貫通ドメインが配列番号１５７のアミノ酸配列を含むかまたはからなるか；あるいはＢ７－Ｈ３膜貫通ドメインが配列番号１５８のアミノ酸配列を含むかまたはからなる、項３４に記載の方法。
［項３６］
膜貫通ドメインが、Ｔｉｍ１膜貫通ドメイン、Ｔｉｍ４膜貫通ドメイン、またはＣＤ２８膜貫通ドメインを含む、項１～３４のいずれか一項に記載の方法。
［項３７］
Ｔｉｍ１膜貫通ドメインが配列番号８に示されるアミノ酸配列を含むか；Ｔｉｍ４膜貫通ドメインが配列番号６もしくは２３に示されるアミノ酸配列を含むか、またはＣＤ２８膜貫通ドメインが配列番号７のアミノ酸配列を含む、項４２に記載の方法。
［項３８］
キメラＴｉｍ受容体が、細胞外スペーサードメインをさらに含む、項１～３７のいずれか一項に記載の方法。
［項３９］
細胞外スペーサードメインが、ＩｇＧ４ヒンジ領域またはＣＤ２８ヒンジ領域を含む、項３８に記載の方法。
［項４０］
ＩｇＧ４ヒンジ領域が配列番号３に示されるアミノ酸配列を含むか、またはＣＤ２８ヒンジ領域が配列番号３２に示されるアミノ酸配列を含む、項３９に記載の方法。
［項４１］
一次シグナル伝達ドメインが、ＣＤ２８共刺激性シグナル伝達ドメイン；４－１ＢＢ共刺激性シグナル伝達ドメイン；ＣＤ２７共刺激性シグナル伝達ドメイン；ＩＣＯＳ共刺激性シグナル伝達ドメイン；ＬＦＡ－１共刺激性シグナル伝達ドメイン；ＯＸ４０共刺激性シグナル伝達ドメイン；ＣＤ２共刺激性シグナル伝達ドメイン；またはＩＣＡＭ－１共刺激性シグナル伝達ドメインを含む、項１～４０のいずれか一項に記載の方法。
［項４２］
ＣＤ２８共刺激性シグナル伝達ドメインが配列番号１１８もしくは１１９のアミノ酸配列を含むか；４－１ＢＢ共刺激性シグナル伝達ドメインが配列番号１２２のアミノ酸配列を含むか；ＣＤ２７共刺激性シグナル伝達ドメインが配列番号１６９のアミノ酸配列を含むか；ＩＣＯＳ共刺激性シグナル伝達ドメインが配列番号１７２のアミノ酸配列を含むか；ＬＦＡ－１共刺激性シグナル伝達ドメインが配列番号１７１のアミノ酸配列を含むか；ＯＸ４０共刺激性シグナル伝達ドメインが配列番号１６６のアミノ酸配列を含むか；ＣＤ２共刺激性シグナル伝達ドメインが配列番号１６７のアミノ酸配列を含むか；またはＩＣＡＭ－１共刺激性シグナル伝達が配列番号１７０のアミノ酸配列を含む、項４１に記載の方法。
［項４３］
二次シグナル伝達ドメインが、ＣＤ３ζシグナル伝達ドメインを含む、項１～４２のいずれか一項に記載の方法。
［項４４］
ＣＤ３ζシグナル伝達ドメインが、配列番号５または配列番号２７のアミノ酸配列を含む、項４３に記載の方法。
［項４５］
一次シグナル伝達ドメインが、ＣＤ２８共刺激性シグナル伝達ドメイン；４－１ＢＢ共刺激性シグナル伝達ドメイン；ＣＤ２７共刺激性シグナル伝達ドメイン；ＩＣＯＳ共刺激性シグナル伝達ドメイン；ＬＦＡ－１共刺激性シグナル伝達ドメイン；ＯＸ４０共刺激性シグナル伝達ドメイン；ＣＤ２共刺激性シグナル伝達ドメイン；またはＩＣＡＭ－１共刺激性シグナル伝達ドメインを含む、項１～４０のいずれか一項に記載の方法。
［項４６］
ＣＤ２８共刺激性シグナル伝達ドメインが配列番号１１８もしくは１１９のアミノ酸配列を含むか；４－１ＢＢ共刺激性シグナル伝達ドメインが配列番号１２２のアミノ酸配列を含むか；ＣＤ２７共刺激性シグナル伝達ドメインが配列番号１６９のアミノ酸配列を含むか；ＩＣＯＳ共刺激性シグナル伝達ドメインが配列番号１７２のアミノ酸配列を含むか；ＬＦＡ－１共刺激性シグナル伝達ドメインが配列番号１７１のアミノ酸配列を含むか；ＯＸ４０共刺激性シグナル伝達ドメインが配列番号１６６のアミノ酸配列を含むか；ＣＤ２共刺激性シグナル伝達ドメインが配列番号１６７のアミノ酸配列を含むか；またはＩＣＡＭ－１共刺激性シグナル伝達ドメインが配列番号１７０のアミノ酸配列を含む、項４５に記載の方法。
［項４７］
二次シグナル伝達ドメインが、ＤＡＰ１２シグナル伝達ドメインを含む、項１～４２、４５、または４６のいずれか一項に記載の方法。
［項４８］
ＤＡＰ１２シグナル伝達ドメインが、配列番号１８０のアミノ酸配列を含む、項４７に記載の方法。
［項４９］
一次細胞内シグナル伝達ドメインが、Ｔｉｍ１シグナル伝達ドメイン、Ｔｉｍ４シグナル伝達ドメイン、ＴＲＡＦ２シグナル伝達ドメイン、ＴＲＡＦ６シグナル伝達ドメイン、ＣＤ２８シグナル伝達ドメイン、ＤＡＰ１２シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメイン、ＴＬＲ２シグナル伝達ドメイン、またはＴＬＲ８シグナル伝達ドメインを含む、項１～４０のいずれか一項に記載の方法。
［項５０］
Ｔｉｍ１シグナル伝達ドメインが配列番号４４に示されるアミノ酸配列を含むか、Ｔｉｍ４シグナル伝達ドメインが配列番号４５、２２４もしくは２２５に示されるアミノ酸配列を含むか、ＴＲＡＦ２シグナル伝達ドメインが配列番号４８に示されるアミノ酸配列を含むか、ＴＲＡＦ６シグナル伝達ドメインが配列番号４６に示されるアミノ酸配列を含むか、ＣＤ２８シグナル伝達ドメインが配列番号４もしくは２６に示されるアミノ酸配列を含むか、ＤＡＰ１２シグナル伝達ドメインが配列番号９に示されるアミノ酸配列を含むか、ＣＤ３ζシグナル伝達ドメインが配列番号５に示されるアミノ酸配列を含むか、ＴＬＲ２シグナル伝達ドメインが配列番号２２２に示されるアミノ酸配列を含むか；またはＴＬＲ８シグナル伝達ドメインが配列番号４７に示されるアミノ酸配列を含む、項４９に記載の方法。
［項５１］
二次細胞内シグナル伝達ドメインが、Ｔｉｍ１シグナル伝達ドメイン、Ｔｉｍ４シグナル伝達ドメイン、ＴＲＡＦ２シグナル伝達ドメイン、ＴＲＡＦ６シグナル伝達ドメイン、ＣＤ２８シグナル伝達ドメイン、ＤＡＰ１２シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメイン、ＴＬＲ２シグナル伝達ドメイン、またはＴＬＲ８シグナル伝達ドメインを含む、項１～４２、４９または５０のいずれか一項に記載の方法。
［項５２］
Ｔｉｍ１シグナル伝達ドメインが配列番号４４に示されるアミノ酸配列を含むか、Ｔｉｍ４シグナル伝達ドメインが配列番号４５、２２４もしくは２２５に示されるアミノ酸配列を含むか、ＴＲＡＦ２シグナル伝達ドメインが配列番号４８に示されるアミノ酸配列を含むか、ＴＲＡＦ６シグナル伝達ドメインが配列番号４６に示されるアミノ酸配列を含むか、ＣＤ２８シグナル伝達ドメインが配列番号４もしくは２６に示されるアミノ酸配列を含むか、ＤＡＰ１２シグナル伝達ドメインが配列番号９に示されるアミノ酸配列を含むか、ＣＤ３ζシグナル伝達ドメインが配列番号５に示されるアミノ酸配列を含むか、ＴＬＲ２シグナル伝達ドメインが配列番号２２２に示されるアミノ酸配列を含むか；またはＴＬＲ８シグナル伝達ドメインが配列番号４７に示されるアミノ酸配列を含む、項５１に記載の方法。
［項５３］
（ｉ）結合ドメインがＴｉｍ４ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含み、一次細胞内シグナル伝達ドメインがＴＬＲ８シグナル伝達ドメインを含み、二次細胞内シグナル伝達ドメインがＣＤ３ζシグナル伝達ドメインを含み、かつ膜貫通ドメインがＴｉｍ１膜貫通ドメインを含むか；
（ｉｉ）結合ドメインがＴｉｍ４ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含み、一次細胞内シグナル伝達ドメインがＣＤ２８シグナル伝達ドメインを含み、二次細胞内シグナル伝達ドメインがＤＡＰ１２シグナル伝達ドメインを含み、かつ膜貫通ドメインがＴｉｍ１膜貫通ドメインを含むか；または
（ｉｉｉ）結合ドメインがＴｉｍ４ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含み、一次細胞内シグナル伝達ドメインがＣＤ２８シグナル伝達ドメインを含み、二次細胞内シグナル伝達ドメインがＤＡＰ１２シグナル伝達ドメインを含み、かつ膜貫通ドメインがＣＤ２８膜貫通ドメインを含む、
項１～５２のいずれか一項に記載の方法。
［項５４］
（ｉ）Ｔｉｍ４ＩｇＶドメインが配列番号３４のアミノ酸配列を含み、Ｔｉｍ１ムチンドメインが配列番号３９のアミノ酸配列を含み、ＴＬＲ８シグナル伝達ドメインが配列番号４７のアミノ酸配列を含み、ＣＤ３ζシグナル伝達ドメインが配列番号５もしくは配列番号２７のアミノ酸配列を含み；かつＴｉｍ１膜貫通ドメインが配列番号８のアミノ酸配列を含むか；
（ｉｉ）Ｔｉｍ４ＩｇＶドメインが配列番号３４のアミノ酸配列を含み、Ｔｉｍ１ムチンドメインが配列番号３９のアミノ酸配列を含み、ＣＤ２８シグナル伝達ドメインが配列番号４のアミノ酸配列を含み、ＤＡＰ１２シグナル伝達ドメインが配列番号９のアミノ酸配列を含み；かつＴｉｍ１膜貫通ドメインが配列番号８のアミノ酸配列を含むか；または
（ｉｉｉ）Ｔｉｍ４ＩｇＶドメインが配列番号３４のアミノ酸配列を含み、Ｔｉｍ１ムチンドメインが配列番号３９のアミノ酸配列を含み、ＣＤ２８シグナル伝達ドメインが配列番号４のアミノ酸配列を含み、ＤＡＰ１２シグナル伝達ドメインが配列番号９のアミノ酸配列を含み；かつＣＤ２８膜貫通ドメインが配列番号７のアミノ酸配列を含む、
項５３に記載の方法。
［項５５］
（ｉ）単鎖キメラタンパク質が配列番号６７のアミノ酸２５～６２８を含むか；
（ｉｉ）単鎖キメラタンパク質が配列番号６８のアミノ酸２５～４１６を含むか；または
（ｉｉｉ）単鎖キメラタンパク質が配列番号６９のアミノ酸２５～４２２を含む、
項５３または５４に記載の方法。
［項５６］
（ｉ）単鎖キメラタンパク質が配列番号６７のアミノ酸配列を含むか；
（ｉｉ）単鎖キメラタンパク質が配列番号６８のアミノ酸配列を含むか；または
（ｉｉｉ）単鎖キメラタンパク質が配列番号６９のアミノ酸配列を含む、
項５３～５５のいずれか一項に記載の方法。
［項５７］
キメラ受容体が、
（ｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；Ｔｉｍ１シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン、およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン；
（ｉｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン、Ｔｉｍ４シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン；およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン；
（ｉｉｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＣＤ２８シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、およびＣＤ２８膜貫通ドメインを含む膜貫通ドメイン；
（ｉｖ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＴＲＡＦ６シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン；
（ｖ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＴＲＡＦ６シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、およびＣＤ２８膜貫通ドメインを含む膜貫通ドメイン；
（ｖｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＴＲＡＦ２シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン；
（ｖｉｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＴＲＡＦ２シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、およびＣＤ２８膜貫通ドメインを含む膜貫通ドメイン；
（ｖｉｉｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＴＬＲ８シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン、およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン；
（ｉｘ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＣＤ２８シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＤＡＰ１２シグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン、およびＣＤ２８膜貫通ドメインを含む膜貫通ドメイン；または
（ｘ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；ＣＤ２８シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＤＡＰ１２シグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン、およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン
を含む、項１～５２のいずれか一項に記載の方法。
［項５８］
キメラＴｉｍ４受容体が、
（ｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４４のアミノ酸配列を含むＴｉｍ１シグナル伝達ドメイン、配列番号４のアミノ酸配列を含むＣＤ３ζシグナル伝達ドメイン、および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン；
（ｉｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４５、２２４もしくは２２５のアミノ酸配列を含むＴｉｍ４シグナル伝達ドメイン、配列番号５もしくは配列番号２７のアミノ酸配列を含むＣＤ３ζシグナル伝達ドメイン；および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン；
（ｉｉｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４のアミノ酸配列を含むＣＤ２８シグナル伝達ドメイン、および配列番号７のアミノ酸配列を含むＣＤ２８膜貫通ドメイン；
（ｉｖ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４６のアミノ酸配列を含むＴＲＡＦ６シグナル伝達ドメイン、および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン；
（ｖ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４６のアミノ酸配列を含むＴＲＡＦ６シグナル伝達ドメイン、および配列番号７のアミノ酸配列を含むＣＤ２８膜貫通ドメイン；
（ｖｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４８のアミノ酸配列を含むＴＲＡＦ２シグナル伝達ドメイン、および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン；
（ｖｉｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４８のアミノ酸配列を含むＴＲＡＦ２シグナル伝達ドメイン、および配列番号７のアミノ酸配列を含むＣＤ２８膜貫通ドメイン；
（ｖｉｉｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４７のアミノ酸配列を含むＴＬＲ８シグナル伝達ドメイン、配列番号５もしくは配列番号２７のアミノ酸配列を含むＣＤ３ζシグナル伝達ドメイン、および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン；
（ｉｘ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４のアミノ酸配列を含むＣＤ２８シグナル伝達ドメイン、ＤＡＰ１２シグナル伝達ドメイン９、および配列番号７のアミノ酸配列を含むＣＤ２８膜貫通ドメイン；または
（ｘ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４のアミノ酸配列を含むＣＤ２８シグナル伝達ドメイン、配列番号９のアミノ酸配列を含むＤＡＰ１２シグナル伝達ドメイン、および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン
を含む、項５７に記載の方法。
［項５９］
キメラＴｉｍ受容体が、
（ｉ）配列番号４９のアミノ酸２１～４５６を含む単鎖キメラタンパク質；
（ｉｉ）配列番号５０のアミノ酸２１～４７１を含む単鎖キメラタンパク質；
（ｉｉｉ）配列番号５１のアミノ酸２１～３６３を含む単鎖キメラタンパク質；
（ｉｖ）配列番号５２のアミノ酸２１～５９０を含む単鎖キメラタンパク質；
（ｖ）配列番号５３のアミノ酸２１～５９６を含む単鎖キメラタンパク質；
（ｖｉ）配列番号５４のアミノ酸２１～６１９を含む単鎖キメラタンパク質；
（ｖｉｉ）配列番号５５のアミノ酸２１～６２５を含む単鎖キメラタンパク質；
（ｖｉｉｉ）配列番号５６のアミノ酸２１～６２１を含む単鎖キメラタンパク質；
（ｉｘ）配列番号５７のアミノ酸２１～４１５を含む単鎖キメラタンパク質；または
（ｘ）配列番号５８のアミノ酸２１～４０９を含む単鎖キメラタンパク質
を含む、項１～５２のいずれか一項に記載の方法。
［項６０］
キメラＴｉｍ受容体が、
（ｉ）配列番号４９のアミノ酸配列を含む単鎖キメラタンパク質；
（ｉｉ）配列番号５０のアミノ酸配列を含む単鎖キメラタンパク質；
（ｉｉｉ）配列番号５１のアミノ酸配列を含む単鎖キメラタンパク質；
（ｉｖ）配列番号５２のアミノ酸配列を含む単鎖キメラタンパク質；
（ｖ）配列番号５３のアミノ酸配列を含む単鎖キメラタンパク質；
（ｖｉ）配列番号５４のアミノ酸配列を含む単鎖キメラタンパク質；
（ｖｉｉ）配列番号５５のアミノ酸配列を含む単鎖キメラタンパク質；
（ｖｉｉｉ）配列番号５６のアミノ酸配列を含む単鎖キメラタンパク質；
（ｉｘ）配列番号５７のアミノ酸配列を含む単鎖キメラタンパク質；または
（ｘ）配列番号５８のアミノ酸配列を含む単鎖キメラタンパク質
を含む、項５９に記載の方法。
［項６１］
キメラＴｉｍ受容体が、
（ｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；Ｔｉｍ１シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン、およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン；
（ｉｉ）Ｔｉｍ１ＩｇＶドメインおよびＴｉｍ１ムチンドメインを含む結合ドメイン；Ｔｉｍ４シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン；およびＴｉｍ１膜貫通ドメインを含む膜貫通ドメイン；
（ｉｉｉ）Ｔｉｍ４ＩｇＶドメインおよびＴｉｍ４ムチンドメインを含む結合ドメイン；Ｔｉｍ４シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン；およびＴｉｍ４膜貫通ドメインを含む膜貫通ドメイン；または
（ｉｖ）Ｔｉｍ４ＩｇＶドメインおよびＴｉｍ４ムチンドメインを含む結合ドメイン；Ｔｉｍ１シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン；およびＴｉｍ４膜貫通ドメインを含む膜貫通ドメイン
を含む、項１～５２のいずれか一項に記載の方法。
［項６２］
キメラＴｉｍ受容体が、
（ｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４４のアミノ酸配列を含むＴｉｍ１シグナル伝達ドメイン、配列番号５もしくは配列番号２７のアミノ酸配列を含むＣＤ３ζシグナル伝達ドメイン、および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン；
（ｉｉ）配列番号３８のアミノ酸配列を含むＴｉｍ１ＩｇＶドメイン、配列番号３９のアミノ酸配列を含むＴｉｍ１ムチンドメイン、配列番号４５、２２４もしくは２２５のアミノ酸配列を含むＴｉｍ４シグナル伝達ドメイン、配列番号５もしくは配列番号２７のアミノ酸配列を含むＣＤ３ζシグナル伝達ドメイン；および配列番号８のアミノ酸配列を含むＴｉｍ１膜貫通ドメイン；
（ｉｉｉ）配列番号３４のアミノ酸配列を含むＴｉｍ４ＩｇＶドメイン、配列番号３５のアミノ酸配列を含むＴｉｍ４ムチンドメイン、配列番号４５、２２４もしくは２２５のアミノ酸配列を含むＴｉｍ４シグナル伝達ドメイン、配列番号５もしくは配列番号２７のアミノ酸配列を含むＣＤ３ζシグナル伝達ドメイン；および配列番号５のアミノ酸配列を含むＴｉｍ４膜貫通ドメイン；または
（ｉｖ）配列番号３４のアミノ酸配列を含むＴｉｍ４ＩｇＶドメイン、配列番号３５のアミノ酸配列を含むＴｉｍ４ムチンドメイン、配列番号４４のアミノ酸配列を含むＴｉｍ１シグナル伝達ドメイン、配列番号５もしくは配列番号２７のアミノ酸配列を含むＣＤ３ζシグナル伝達ドメイン；および配列番号６のアミノ酸配列を含むＴｉｍ４膜貫通ドメイン
を含む、項６１に記載の方法。
［項６３］
キメラＴｉｍ受容体が、
（ｉ）配列番号４９のアミノ酸２１～４５６を含む単鎖キメラタンパク質；
（ｉｉ）配列番号５０のアミノ酸２１～４７１を含む単鎖キメラタンパク質；
（ｉｉｉ）配列番号５９のアミノ酸２５～４９０を含む単鎖キメラタンパク質；または
（ｉｖ）配列番号６０のアミノ酸２５～４９５を含む単鎖キメラタンパク質
を含む、項６１または６２に記載の方法。
［項６４］
キメラＴｉｍ受容体が、
（ｉ）配列番号４９のアミノ酸配列を含む単鎖キメラタンパク質；
（ｉｉ）配列番号５０のアミノ酸配列を含む単鎖キメラタンパク質；
（ｉｉｉ）配列番号５９のアミノ酸配列を含む単鎖キメラタンパク質；または
（ｉｖ）配列番号６０のアミノ酸配列を含む単鎖キメラタンパク質
を含む、項６１～６３のいずれか一項に記載の方法。
［項６５］
キメラＴｉｍ受容体が、
（ｉ）配列番号１９５のアミノ酸配列もしくは配列番号１９５のアミノ酸２５～４７３を含む単鎖キメラタンパク質；
（ｉｉ）配列番号１９６のアミノ酸配列もしくは配列番号１９６のアミノ酸２５～４４６を含む単鎖キメラタンパク質；
（ｉｉｉ）配列番号１９７のアミノ酸配列もしくは配列番号１９７のアミノ酸２５～４３４を含む単鎖キメラタンパク質；または
（ｉｖ）配列番号１９８のアミノ酸配列もしくは配列番号１９８のアミノ酸２５～４２８を含む単鎖キメラタンパク質
を含む、項１～５２のいずれか一項に記載の方法。
［項６６］
キメラＴｉｍ受容体が、
（ａ）（ｉ）Ｔｉｍ４ＩｇＶドメインおよびＴｉｍ４ムチンドメインを含む結合ドメインを含む細胞外ドメインと；
（ｂ）ＣＤ２８シグナル伝達ドメイン、ＣＤ３ζシグナル伝達ドメイン、および４－１ＢＢシグナル伝達ドメインから選択される一次細胞内シグナル伝達ドメイン、およびＴＬＲ２シグナル伝達ドメインまたはＴＬＲ８シグナル伝達ドメインから選択される二次細胞内シグナル伝達ドメインを含む細胞内シグナル伝達ドメインと；
（ｃ）細胞外ドメインと細胞内シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインと
を含む、項１～５２のいずれか一項に記載の方法。
［項６７］
Ｔｉｍ４ＩｇＶドメインが配列番号３４に示されるアミノ酸配列を含むか、Ｔｉｍ４ムチンドメインが配列番号３５に示されるアミノ酸配列を含むか、またはその両方である、項６６に記載の方法。
［項６８］
結合ドメインが配列番号２または４２のアミノ酸配列を含む、項６７に記載の方法。
［項６９］
キメラＴｉｍ受容体が細胞外スペーサードメインをさらに含む、項６６～６８のいずれか一項に記載の方法。
［項７０］
細胞外スペーサードメインがＩｇＧ４ヒンジ領域またはＣＤ２８ヒンジ領域を含む、項６９に記載の方法。
［項７１］
ＩｇＧ４ヒンジ領域が配列番号３に示されるアミノ酸配列を含むか、またはＣＤ２８ヒンジ領域が配列番号３２に示されるアミノ酸配列を含む、項７０に記載の方法。
［項７２］
膜貫通ドメインが、Ｔｉｍ１膜貫通ドメイン、Ｔｉｍ４膜貫通ドメイン、またはＣＤ２８膜貫通ドメインを含む、項６６～７１のいずれか一項に記載の方法。
［項７３］
Ｔｉｍ１膜貫通ドメインが配列番号８に示されるアミノ酸配列を含むか、Ｔｉｍ４膜貫通ドメインが配列番号６もしくは２３に示されるアミノ酸配列を含むか、またはＣＤ２８膜貫通ドメインが配列番号７のアミノ酸配列を含む、項７２に記載の方法。
［項７４］
ＣＤ２８シグナル伝達ドメインが配列番号４もしくは配列番号２６に示されるアミノ酸配列を含むか、ＣＤ３ζシグナル伝達ドメインが配列番号５もしくは配列番号２７に示されるアミノ酸配列を含むか、または４－１ＢＢシグナル伝達ドメインが配列番号１００に示されるアミノ酸配列を含む、項６６～７３のいずれか一項に記載の方法。
［項７５］
ＴＬＲ２シグナル伝達ドメインが配列番号２２２に示されるアミノ酸配列を含むか、またはＴＬＲ８シグナル伝達ドメインが配列番号４７に示されるアミノ酸配列を含む、項６６～７４のいずれか一項に記載の方法。
［項７６］
キメラＴｉｍ受容体が、
（ａ）（ｉ）Ｔｉｍ４ＩｇＶドメインおよびＴｉｍ４ムチンドメインを含む結合ドメインを含む細胞外ドメインと；
（ｂ）免疫受容体チロシンベース活性化モチーフ（ＩＴＡＭ）含有シグナル伝達ドメインを含む一次細胞内シグナル伝達ドメイン；共刺激性シグナル伝達ドメイン、Ｔｉｍ１シグナル伝達ドメイン、またはＴｉｍ４シグナル伝達ドメインを含む二次細胞内シグナル伝達ドメイン；およびＴＬＲシグナル伝達ドメインを含む三次細胞内シグナル伝達ドメインを含む細胞内シグナル伝達ドメインと；
（ｃ）細胞外ドメインと細胞内シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインと
を含む、項１～５２のいずれか一項に記載の方法。
［項７７］
ＩＴＡＭ含有シグナル伝達ドメインが、ＣＤ３ζシグナル伝達ドメインまたはＤＡＰ１２シグナル伝達ドメインである、項７６に記載のキメラＴｉｍ受容体。
［項７８］
共刺激性シグナル伝達ドメインが、４－１ＢＢシグナル伝達ドメインまたはＣＤ２８シグナル伝達ドメインである、項７６または７７に記載のキメラＴｉｍ受容体。
［項７９］
ＴＬＲシグナル伝達ドメインが、ＴＬＲ２シグナル伝達ドメインまたはＴＬＲ８シグナル伝達ドメインである、項７６～７８のいずれか一項に記載のキメラＴｉｍ受容体。
［項８０］
単鎖タンパク質が、表１、２または４～１０のいずれかに示されるアミノ酸配列を含む、項１～７９のいずれか一項に記載の方法。
［項８１］
キメラＴｉｍ受容体が、単鎖タンパク質をコードするポリヌクレオチドとして投与される、項１～８０のいずれか一項に記載の方法。
［項８２］
キメラＴｉｍ受容体が、ポリヌクレオチドを含むベクターとして投与される、項８１に記載の方法。
［項８３］
キメラＴｉｍ受容体が、キメラＴｉｍ受容体、ポリヌクレオチド、またはベクターを含む操作された細胞として投与される、項８２に記載の方法。
［項８４］
細胞が免疫細胞である、項８３に記載の方法。
［項８５］
細胞がＴ細胞である、項８３または８４に記載の方法。
［項８６］
細胞が、ＣＤ４＋Ｔ細胞、ＣＤ８＋Ｔ細胞、またはＣＤ４＋／ＣＤ８＋Ｔ細胞である、項８３～８５のいずれか一項に記載の方法。
［項８７］
細胞がヒト細胞である、項８３～８５のいずれか一項に記載の方法。
［項８８］
キメラＴｉｍ受容体が、キメラＴｉｍ受容体、ポリヌクレオチド、ベクター、または操作された細胞、および薬学的に許容される賦形剤を含む組成物として投与される、項１～８７のいずれか一項に記載の方法。
These and other changes can be made to the embodiments in light of the description detailed above. Generally, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but rather to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure.
The present disclosure relates, for example, to the following:
[Item 1]
A method for treating cancer in a subject in need thereof, wherein the cancer is breast cancer, ovarian cancer, colorectal cancer, fallopian tube cancer, peritoneal cancer, prostate cancer, lung cancer, or melanoma, the method comprising administering to a subject an effective amount of
(a) (i) a Tim1 IgV domain or a Tim4 IgV domain; and
(ii) a Tim1 mucin domain or a Tim4 mucin domain
an extracellular domain comprising a binding domain comprising:
(b) an intracellular signaling domain comprising a primary intracellular signaling domain and an optional secondary intracellular signaling domain;
(c) a transmembrane domain located between and connecting the extracellular domain and the intracellular signaling domain;
a chimeric T cell immunoglobulin and mucin (Tim) receptor, comprising a single chain chimeric protein comprising:
Poly(ADP-ribose) polymerase (PARP) inhibitors
The method comprises administering to a subject.
[Item 2]
Item 2. The method according to item 1, wherein the breast cancer is triple-negative breast cancer.
[Item 3]
Item 2. The method according to item 1, wherein the ovarian cancer is advanced ovarian cancer.
[Item 4]
Item 2. The method according to item 1, wherein the prostate cancer is advanced prostate cancer.
[Item 5]
Item 2. The method according to item 1, wherein the lung cancer is non-small cell lung cancer.
[Item 6]
Item 6. The method according to any one of items 1 to 5, wherein the cancer is a breast cancer gene (BRCA) mutated cancer.
[Item 7]
7. The method of claim 6, wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, or both.
[Item 8]
8. The method of any one of paragraphs 1 to 7, wherein the PARP inhibitor is talazoparib, niraparib, rucaparib, olaparib, veliparib, CEP9722, E7016, AG014699, MK4827, BMN-673, pamiparib, or a combination thereof.
[Item 9]
9. The method according to any one of paragraphs 1 to 8, wherein the PARP inhibitor comprises niraparib.
[Item 10]
9. The method of any one of paragraphs 1 to 8, wherein the PARP inhibitor comprises talazoparib.
[Item 11]
Item 9. The method of any one of items 1 to 8, wherein the PARP inhibitor comprises rucaparib.
[Item 12]
Item 9. The method of any one of items 1 to 8, wherein the PARP inhibitor comprises olaparib.
[Item 13]
9. The method of any one of paragraphs 1 to 8, wherein the PARP inhibitor comprises veliparib.
[Item 14]
9. The method of any one of paragraphs 1 to 8, wherein the PARP inhibitor comprises CEP9722.
[Item 15]
9. The method of any one of paragraphs 1 to 8, wherein the PARP inhibitor comprises E7016.
[Item 16]
9. The method of any one of paragraphs 1 to 8, wherein the PARP inhibitor comprises AG014699.
[Item 17]
Item 9. The method according to any one of items 1 to 8, wherein the PARP inhibitor comprises MK4827.
[Item 18]
9. The method of any one of paragraphs 1 to 8, wherein the PARP inhibitor comprises BMN-673.
[Item 19]
Item 9. The method of any one of items 1 to 8, wherein the PARP inhibitor comprises pamiparib.
[Item 20]
20. The method of any one of paragraphs 1 to 19, further comprising administering an additional therapeutic agent.
[Item 21]
21. The method of claim 20, wherein the additional therapeutic agent comprises radiation, cellular immunotherapy, an antibody, an immune checkpoint molecule inhibitor, chemotherapy, hormone therapy, a peptide, an antibiotic, an antiviral agent, an antifungal agent, an anti-inflammatory agent, UV light therapy, electrical pulse therapy, high intensity focused ultrasound therapy, oncolytic virus therapy, small molecule therapy, or a combination thereof.
[Item 22]
22. The method of claim 21, wherein the cellular immunotherapy is a chimeric antigen receptor or a T cell receptor.
[Item 23]
22. The method of paragraph 20 or 21, wherein the additional therapeutic agent comprises an angiogenesis inhibitor (e.g., a VEGF pathway inhibitor), a tyrosine kinase inhibitor (e.g., an EGF pathway inhibitor), a receptor tyrosine kinase inhibitor, a growth factor inhibitor, a GTPase inhibitor, a serine/threonine kinase inhibitor, a transcription factor inhibitor, a B-Raf inhibitor, a RAF inhibitor, a MEK inhibitor, an mTOR inhibitor, an EGFR inhibitor, an ALK inhibitor, a ROS1 inhibitor, a BCL-2 inhibitor, a PI3K inhibitor, a VEGFR inhibitor, a BCR-ABL inhibitor, a MET inhibitor, a MYC inhibitor, an ABL inhibitor, a HER2 inhibitor, a BTK inhibitor, an H-RAS inhibitor, a K-RAS inhibitor, a PDGFR inhibitor, a TRK inhibitor, a c-KIT inhibitor, a c-MET inhibitor, a CDK4/6 inhibitor, a FAK inhibitor, a FGFR inhibitor, a FLT3 inhibitor, an IDH1 inhibitor, an IDH2 inhibitor, a PDGFRA inhibitor, or a RET inhibitor.
[Item 24]
24. The method of any one of paragraphs 1 to 23, wherein the binding domain comprises a Tim1 IgV domain and a Tim1 mucin domain.
[Item 25]
24. The method of any one of paragraphs 1 to 23, wherein the binding domain comprises a Tim4 IgV domain and a Tim4 mucin domain.
[Item 26]
24. The method of any one of paragraphs 1 to 23, wherein the binding domain comprises a Tim1 IgV domain and a Tim4 mucin domain.
[Item 27]
24. The method of any one of paragraphs 1 to 23, wherein the binding domain comprises the Tim4 IgV domain and the Tim1 mucin domain.
[Item 28]
27. The method of any one of paragraphs 1 to 24 or 26, wherein the Tim1 IgV domain comprises the amino acid sequence set forth in SEQ ID NO:38.
[Item 29]
29. The method of any one of paragraphs 1 to 24, 26 or 28, wherein the Tim1 IgV domain is a modified Tim1 IgV domain that comprises an R66G substitution in SEQ ID NO:38.
[Item 30]
30. The method of claim 29, wherein the modified Tim1 IgV domain comprises the amino acid sequence set forth in SEQ ID NO:41.
[Item 31]
The method of any one of paragraphs 1 to 25, or 27 to 30, wherein the Tim1 mucin domain comprises the amino acid sequence set forth in SEQ ID NO:39.
[Item 32]
28. The method of any one of paragraphs 1 to 23, 25 or 27, wherein the Tim4 IgV domain comprises the amino acid sequence set forth in SEQ ID NO:34.
[Item 33]
27. The method of any one of paragraphs 1 to 23, 25 or 26, wherein the Tim4 mucin domain comprises the amino acid sequence set forth in SEQ ID NO:35.
[Item 34]
34. The method of any one of paragraphs 1 to 33, wherein the transmembrane domain comprises a Tim4 transmembrane domain, a Tim1 transmembrane domain, a CD28 transmembrane domain, a 4-1BB transmembrane domain, an OX40 transmembrane domain, a CD27 transmembrane domain, an ICOS transmembrane domain, a CD2 transmembrane domain, an LFA-1 transmembrane domain, a CD30 transmembrane domain, a CD40 transmembrane domain, a PD-1 transmembrane domain, a CD7 transmembrane domain, a LIGHT transmembrane domain, an NKG2C transmembrane domain, or a B7-H3 transmembrane domain.
[Item 35]
the Tim4 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 144 or 23; the Tim1 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 8; the CD28 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 145; the 4-1BB transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 146; the OX40 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 147; the CD27 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 148; the ICOS transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 149; the CD2 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 150; the LFA-1 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 151; The method of claim 34, wherein the transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 151; the CD30 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 152; the CD40 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 153; the PD-1 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 154; the CD7 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 155; the LIGHT transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 156; the NKG2C transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 157; or the B7-H3 transmembrane domain comprises or consists of the amino acid sequence of SEQ ID NO: 158.
[Item 36]
35. The method of any one of paragraphs 1 to 34, wherein the transmembrane domain comprises a Tim1 transmembrane domain, a Tim4 transmembrane domain, or a CD28 transmembrane domain.
[Item 37]
The method of claim 42, wherein the Tim1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 8; the Tim4 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 6 or 23, or the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 7.
[Item 38]
38. The method of any one of paragraphs 1 to 37, wherein the chimeric Tim receptor further comprises an extracellular spacer domain.
[Item 39]
39. The method of claim 38, wherein the extracellular spacer domain comprises an IgG4 hinge region or a CD28 hinge region.
[Item 40]
40. The method of claim 39, wherein the IgG4 hinge region comprises the amino acid sequence set forth in SEQ ID NO:3, or the CD28 hinge region comprises the amino acid sequence set forth in SEQ ID NO:32.
[Item 41]
41. The method of any one of paragraphs 1 to 40, wherein the primary signaling domain comprises a CD28 costimulatory signaling domain; a 4-1BB costimulatory signaling domain; a CD27 costimulatory signaling domain; an ICOS costimulatory signaling domain; an LFA-1 costimulatory signaling domain; an OX40 costimulatory signaling domain; a CD2 costimulatory signaling domain; or an ICAM-1 costimulatory signaling domain.
[Item 42]
The method of claim 41, wherein the CD28 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 118 or 119; the 4-1BB costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 122; the CD27 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 169; the ICOS costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 172; the LFA-1 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 171; the OX40 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 166; the CD2 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 167; or the ICAM-1 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 170.
[Item 43]
43. The method of any one of paragraphs 1 to 42, wherein the secondary signaling domain comprises a CD3 zeta signaling domain.
[Item 44]
The method of claim 43, wherein the CD3ζ signaling domain comprises the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27.
[Item 45]
41. The method of any one of paragraphs 1 to 40, wherein the primary signaling domain comprises a CD28 costimulatory signaling domain; a 4-1BB costimulatory signaling domain; a CD27 costimulatory signaling domain; an ICOS costimulatory signaling domain; an LFA-1 costimulatory signaling domain; an OX40 costimulatory signaling domain; a CD2 costimulatory signaling domain; or an ICAM-1 costimulatory signaling domain.
[Item 46]
The method of paragraph 45, wherein the CD28 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 118 or 119; the 4-1BB costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 122; the CD27 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 169; the ICOS costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 172; the LFA-1 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 171; the OX40 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 166; the CD2 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 167; or the ICAM-1 costimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 170.
[Item 47]
47. The method of any one of paragraphs 1-42, 45, or 46, wherein the secondary signaling domain comprises a DAP12 signaling domain.
[Item 48]
48. The method of claim 47, wherein the DAP12 signaling domain comprises the amino acid sequence of SEQ ID NO:180.
[Item 49]
41. The method of any one of paragraphs 1 to 40, wherein the primary intracellular signaling domain comprises a Tim1 signaling domain, a Tim4 signaling domain, a TRAF2 signaling domain, a TRAF6 signaling domain, a CD28 signaling domain, a DAP12 signaling domain, a CD3ζ signaling domain, a TLR2 signaling domain, or a TLR8 signaling domain.
[Item 50]
The method of claim 49, wherein the Tim1 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 44, the Tim4 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 45, 224 or 225, the TRAF2 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 48, the TRAF6 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 46, the CD28 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 4 or 26, the DAP12 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 9, the CD3ζ signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 5, the TLR2 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 222; or the TLR8 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 47.
[Item 51]
51. The method of any one of paragraphs 1-42, 49 or 50, wherein the secondary intracellular signaling domain comprises a Tim1 signaling domain, a Tim4 signaling domain, a TRAF2 signaling domain, a TRAF6 signaling domain, a CD28 signaling domain, a DAP12 signaling domain, a CD3ζ signaling domain, a TLR2 signaling domain, or a TLR8 signaling domain.
[Item 52]
The method of claim 51, wherein the Tim1 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 44, the Tim4 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 45, 224 or 225, the TRAF2 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 48, the TRAF6 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 46, the CD28 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 4 or 26, the DAP12 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 9, the CD3ζ signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 5, the TLR2 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 222; or the TLR8 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 47.
[Item 53]
(i) the binding domain comprises a Tim4 IgV domain and a Tim1 mucin domain, the primary intracellular signaling domain comprises a TLR8 signaling domain, the secondary intracellular signaling domain comprises a CD3ζ signaling domain, and the transmembrane domain comprises a Tim1 transmembrane domain;
(ii) the binding domain comprises a Tim4 IgV domain and a Tim1 mucin domain, the first intracellular signaling domain comprises a CD28 signaling domain, the second intracellular signaling domain comprises a DAP12 signaling domain, and the transmembrane domain comprises a Tim1 transmembrane domain; or
(iii) the binding domain comprises a Tim4 IgV domain and a Tim1 mucin domain, the first intracellular signaling domain comprises a CD28 signaling domain, the second intracellular signaling domain comprises a DAP12 signaling domain, and the transmembrane domain comprises a CD28 transmembrane domain;
Item 53. The method according to any one of items 1 to 52.
[Item 54]
(i) the Tim4 IgV domain comprises the amino acid sequence of SEQ ID NO:34, the Tim1 mucin domain comprises the amino acid sequence of SEQ ID NO:39, the TLR8 signaling domain comprises the amino acid sequence of SEQ ID NO:47, the CD3ζ signaling domain comprises the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27; and the Tim1 transmembrane domain comprises the amino acid sequence of SEQ ID NO:8;
(ii) the Tim4 IgV domain comprises the amino acid sequence of SEQ ID NO:34, the Tim1 mucin domain comprises the amino acid sequence of SEQ ID NO:39, the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO:4, the DAP12 signaling domain comprises the amino acid sequence of SEQ ID NO:9; and the Tim1 transmembrane domain comprises the amino acid sequence of SEQ ID NO:8; or
(iii) the Tim4 IgV domain comprises the amino acid sequence of SEQ ID NO:34, the Tim1 mucin domain comprises the amino acid sequence of SEQ ID NO:39, the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO:4, the DAP12 signaling domain comprises the amino acid sequence of SEQ ID NO:9; and the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO:7.
54. The method according to claim 53.
[Item 55]
(i) the single-chain chimeric protein comprises amino acids 25 to 628 of SEQ ID NO:67;
(ii) the single-chain chimeric protein comprises amino acids 25 to 416 of SEQ ID NO:68; or
(iii) the single-chain chimeric protein comprises amino acids 25-422 of SEQ ID NO:69;
55. The method according to item 53 or 54.
[Item 56]
(i) the single-chain chimeric protein comprises the amino acid sequence of SEQ ID NO:67;
(ii) the single-chain chimeric protein comprises the amino acid sequence of SEQ ID NO:68; or
(iii) the single-chain chimeric protein comprises the amino acid sequence of SEQ ID NO: 69;
56. The method according to any one of items 53 to 55.
[Item 57]
The chimeric receptor is
(i) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the Tim1 signaling domain, a secondary intracellular signaling domain comprising the CD3ζ signaling domain, and a transmembrane domain comprising the Tim1 transmembrane domain;
(ii) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain, a primary intracellular signaling domain comprising the Tim4 signaling domain, a secondary intracellular signaling domain comprising the CD3ζ signaling domain; and a transmembrane domain comprising the Tim1 transmembrane domain;
(iii) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the CD28 signaling domain, and a transmembrane domain comprising the CD28 transmembrane domain;
(iv) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the TRAF6 signaling domain, and a transmembrane domain comprising the Tim1 transmembrane domain;
(v) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the TRAF6 signaling domain, and a transmembrane domain comprising the CD28 transmembrane domain;
(vi) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the TRAF2 signaling domain, and a transmembrane domain comprising the Tim1 transmembrane domain;
(vii) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the TRAF2 signaling domain, and a transmembrane domain comprising the CD28 transmembrane domain;
(viii) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising a TLR8 signaling domain, a secondary intracellular signaling domain comprising a CD3ζ signaling domain, and a transmembrane domain comprising the Tim1 transmembrane domain;
(ix) a binding domain comprising a Tim1 IgV domain and a Tim1 mucin domain; a primary intracellular signaling domain comprising a CD28 signaling domain, a secondary intracellular signaling domain comprising a DAP12 signaling domain, and a transmembrane domain comprising a CD28 transmembrane domain; or
(x) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the CD28 signaling domain, a secondary intracellular signaling domain comprising the DAP12 signaling domain, and a transmembrane domain comprising the Tim1 transmembrane domain.
Item 53. The method according to any one of items 1 to 52, comprising:
[Item 58]
The chimeric Tim4 receptor
(i) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a Tim1 signaling domain comprising the amino acid sequence of SEQ ID NO:44, a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO:4, and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO:8;
(ii) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a Tim4 signaling domain comprising the amino acid sequence of SEQ ID NO:45, 224 or 225, a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27; and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO:8;
(iii) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a CD28 signaling domain comprising the amino acid sequence of SEQ ID NO:4, and a CD28 transmembrane domain comprising the amino acid sequence of SEQ ID NO:7;
(iv) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a TRAF6 signaling domain comprising the amino acid sequence of SEQ ID NO:46, and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO:8;
(v) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a TRAF6 signaling domain comprising the amino acid sequence of SEQ ID NO:46, and a CD28 transmembrane domain comprising the amino acid sequence of SEQ ID NO:7;
(vi) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a TRAF2 signaling domain comprising the amino acid sequence of SEQ ID NO:48, and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO:8;
(vii) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a TRAF2 signaling domain comprising the amino acid sequence of SEQ ID NO:48, and a CD28 transmembrane domain comprising the amino acid sequence of SEQ ID NO:7;
(viii) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a TLR8 signaling domain comprising the amino acid sequence of SEQ ID NO:47, a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27, and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO:8;
(ix) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a CD28 signaling domain comprising the amino acid sequence of SEQ ID NO:4, a DAP12 signaling domain 9, and a CD28 transmembrane domain comprising the amino acid sequence of SEQ ID NO:7; or
(x) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO: 38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO: 39, a CD28 signaling domain comprising the amino acid sequence of SEQ ID NO: 4, a DAP12 signaling domain comprising the amino acid sequence of SEQ ID NO: 9, and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 8.
58. The method of claim 57, comprising:
[Item 59]
The chimeric Tim receptor is
(i) a single-chain chimeric protein comprising amino acids 21 to 456 of SEQ ID NO:49;
(ii) a single-chain chimeric protein comprising amino acids 21-471 of SEQ ID NO:50;
(iii) a single-chain chimeric protein comprising amino acids 21 to 363 of SEQ ID NO:51;
(iv) a single-chain chimeric protein comprising amino acids 21-590 of SEQ ID NO:52;
(v) a single-chain chimeric protein comprising amino acids 21 to 596 of SEQ ID NO:53;
(vi) a single-chain chimeric protein comprising amino acids 21 to 619 of SEQ ID NO:54;
(vii) a single-chain chimeric protein comprising amino acids 21 to 625 of SEQ ID NO:55;
(viii) a single-chain chimeric protein comprising amino acids 21 to 621 of SEQ ID NO:56;
(ix) a single-chain chimeric protein comprising amino acids 21 to 415 of SEQ ID NO: 57; or
(x) a single-chain chimeric protein comprising amino acids 21 to 409 of SEQ ID NO:58
Item 53. The method according to any one of items 1 to 52, comprising:
[Item 60]
The chimeric Tim receptor is
(i) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 49;
(ii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:50;
(iii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:51;
(iv) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:52;
(v) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:53;
(vi) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:54;
(vii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:55;
(viii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:56;
(ix) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 57; or
(x) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:58
60. The method of claim 59, comprising:
[Item 61]
The chimeric Tim receptor is
(i) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the Tim1 signaling domain, a secondary intracellular signaling domain comprising the CD3ζ signaling domain, and a transmembrane domain comprising the Tim1 transmembrane domain;
(ii) a binding domain comprising the Tim1 IgV domain and the Tim1 mucin domain; a primary intracellular signaling domain comprising the Tim4 signaling domain, a secondary intracellular signaling domain comprising the CD3ζ signaling domain; and a transmembrane domain comprising the Tim1 transmembrane domain;
(iii) a binding domain comprising the Tim4 IgV domain and the Tim4 mucin domain; a primary intracellular signaling domain comprising the Tim4 signaling domain, a secondary intracellular signaling domain comprising the CD3ζ signaling domain; and a transmembrane domain comprising the Tim4 transmembrane domain; or
(iv) a binding domain comprising the Tim4 IgV domain and the Tim4 mucin domain; a primary intracellular signaling domain comprising the Tim1 signaling domain, a secondary intracellular signaling domain comprising the CD3ζ signaling domain; and a transmembrane domain comprising the Tim4 transmembrane domain.
Item 53. The method according to any one of items 1 to 52, comprising:
[Item 62]
The chimeric Tim receptor is
(i) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a Tim1 signaling domain comprising the amino acid sequence of SEQ ID NO:44, a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27, and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO:8;
(ii) a Tim1 IgV domain comprising the amino acid sequence of SEQ ID NO:38, a Tim1 mucin domain comprising the amino acid sequence of SEQ ID NO:39, a Tim4 signaling domain comprising the amino acid sequence of SEQ ID NO:45, 224 or 225, a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27; and a Tim1 transmembrane domain comprising the amino acid sequence of SEQ ID NO:8;
(iii) a Tim4 IgV domain comprising the amino acid sequence of SEQ ID NO: 34, a Tim4 mucin domain comprising the amino acid sequence of SEQ ID NO: 35, a Tim4 signaling domain comprising the amino acid sequence of SEQ ID NO: 45, 224 or 225, a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 27; and a Tim4 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 5; or
(iv) a Tim4 IgV domain comprising the amino acid sequence of SEQ ID NO:34, a Tim4 mucin domain comprising the amino acid sequence of SEQ ID NO:35, a Tim1 signaling domain comprising the amino acid sequence of SEQ ID NO:44, a CD3ζ signaling domain comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27; and a Tim4 transmembrane domain comprising the amino acid sequence of SEQ ID NO:6.
62. The method of claim 61, comprising:
[Item 63]
The chimeric Tim receptor is
(i) a single-chain chimeric protein comprising amino acids 21 to 456 of SEQ ID NO:49;
(ii) a single-chain chimeric protein comprising amino acids 21-471 of SEQ ID NO:50;
(iii) a single-chain chimeric protein comprising amino acids 25 to 490 of SEQ ID NO:59; or
(iv) a single-chain chimeric protein comprising amino acids 25 to 495 of SEQ ID NO: 60.
63. The method of claim 61 or 62, comprising:
[Item 64]
The chimeric Tim receptor is
(i) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 49;
(ii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:50;
(iii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO:59; or
(iv) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 60
Item 64. The method according to any one of items 61 to 63, comprising:
[Item 65]
The chimeric Tim receptor is
(i) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 195 or amino acids 25 to 473 of SEQ ID NO: 195;
(ii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 196 or amino acids 25 to 446 of SEQ ID NO: 196;
(iii) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 197 or amino acids 25 to 434 of SEQ ID NO: 197; or
(iv) a single-chain chimeric protein comprising the amino acid sequence of SEQ ID NO: 198 or amino acids 25 to 428 of SEQ ID NO: 198.
Item 53. The method according to any one of items 1 to 52, comprising:
[Item 66]
The chimeric Tim receptor is
(a) (i) an extracellular domain comprising a binding domain comprising a Tim4 IgV domain and a Tim4 mucin domain;
(b) an intracellular signaling domain comprising a first intracellular signaling domain selected from a CD28 signaling domain, a CD3ζ signaling domain, and a 4-1BB signaling domain, and a second intracellular signaling domain selected from a TLR2 signaling domain or a TLR8 signaling domain;
(c) a transmembrane domain located between and connecting the extracellular domain and the intracellular signaling domain;
Item 53. The method according to any one of items 1 to 52, comprising:
[Item 67]
67. The method of claim 66, wherein the Tim4 IgV domain comprises the amino acid sequence set forth in SEQ ID NO: 34, the Tim4 mucin domain comprises the amino acid sequence set forth in SEQ ID NO: 35, or both.
[Item 68]
68. The method of claim 67, wherein the binding domain comprises the amino acid sequence of SEQ ID NO: 2 or 42.
[Item 69]
69. The method of any one of paragraphs 66 to 68, wherein the chimeric Tim receptor further comprises an extracellular spacer domain.
[Item 70]
70. The method of claim 69, wherein the extracellular spacer domain comprises an IgG4 hinge region or a CD28 hinge region.
[Item 71]
71. The method of claim 70, wherein the IgG4 hinge region comprises the amino acid sequence set forth in SEQ ID NO:3, or the CD28 hinge region comprises the amino acid sequence set forth in SEQ ID NO:32.
[Item 72]
72. The method of any one of paragraphs 66 to 71, wherein the transmembrane domain comprises a Tim1 transmembrane domain, a Tim4 transmembrane domain, or a CD28 transmembrane domain.
[Item 73]
The method of claim 72, wherein the Tim1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 8, the Tim4 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 6 or 23, or the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 7.
[Item 74]
74. The method of any one of paragraphs 66-73, wherein the CD28 signaling domain comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:26, the CD3ζ signaling domain comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:27, or the 4-1BB signaling domain comprises the amino acid sequence set forth in SEQ ID NO:100.
[Item 75]
75. The method of any one of paragraphs 66-74, wherein the TLR2 signaling domain comprises the amino acid sequence set forth in SEQ ID NO:222 or the TLR8 signaling domain comprises the amino acid sequence set forth in SEQ ID NO:47.
[Item 76]
The chimeric Tim receptor is
(a) (i) an extracellular domain comprising a binding domain comprising a Tim4 IgV domain and a Tim4 mucin domain;
(b) an intracellular signaling domain comprising a primary intracellular signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling domain; a secondary intracellular signaling domain comprising a costimulatory signaling domain, a Tim1 signaling domain, or a Tim4 signaling domain; and a tertiary intracellular signaling domain comprising a TLR signaling domain;
(c) a transmembrane domain located between and connecting the extracellular domain and the intracellular signaling domain;
Item 53. The method according to any one of items 1 to 52, comprising:
[Item 77]
77. The chimeric Tim receptor of paragraph 76, wherein the ITAM-containing signaling domain is a CD3ζ signaling domain or a DAP12 signaling domain.
[Item 78]
78. The chimeric Tim receptor of paragraph 76 or 77, wherein the costimulatory signaling domain is a 4-1BB signaling domain or a CD28 signaling domain.
[Item 79]
79. The chimeric Tim receptor of any one of paragraphs 76-78, wherein the TLR signaling domain is a TLR2 signaling domain or a TLR8 signaling domain.
[Item 80]
80. The method of any one of paragraphs 1 to 79, wherein the single-chain protein comprises an amino acid sequence shown in any of Tables 1, 2 or 4-10.
[Item 81]
81. The method of any one of paragraphs 1 to 80, wherein the chimeric Tim receptor is administered as a polynucleotide encoding a single chain protein.
[Item 82]
82. The method of paragraph 81, wherein the chimeric Tim receptor is administered as a vector containing the polynucleotide.
[Item 83]
83. The method of paragraph 82, wherein the chimeric Tim receptor is administered as an engineered cell containing the chimeric Tim receptor, polynucleotide, or vector.
[Item 84]
84. The method of claim 83, wherein the cell is an immune cell.
[Item 85]
85. The method of paragraph 83 or 84, wherein the cell is a T cell.
[Item 86]
86. The method of any one of paragraphs 83-85, wherein the cell is a CD4+ T cell, a CD8+ T cell, or a CD4+/CD8+ T cell.
[Item 87]
86. The method of any one of paragraphs 83 to 85, wherein the cell is a human cell.
[Item 88]
88. The method of any one of paragraphs 1-87, wherein the chimeric Tim receptor is administered as a composition comprising the chimeric Tim receptor, a polynucleotide, a vector, or an engineered cell, and a pharma- ceutically acceptable excipient.

Claims

1. A pharmaceutical composition for use in treating cancer, wherein the cancer is breast cancer, ovarian cancer, colorectal cancer, fallopian tube cancer, peritoneal cancer, prostate cancer, lung cancer, or melanoma, and the pharmaceutical composition comprises:
(a) (i ) the Tim4 IgV domain; and
(ii ) an extracellular domain comprising a binding domain, the extracellular domain comprising a Tim4 mucin domain;
(b) (i) a primary intracellular signaling domain comprising a CD28 signaling domain and/or a TLR2 signaling domain ; and
(ii) an intracellular signaling domain comprising a CD3ζ signaling domain or a second intracellular signaling domain comprising a DAP12 signaling domain ;
(c) a chimeric phagocytosis receptor comprising a single-chain chimeric protein comprising an extracellular domain and a transmembrane domain located between and connecting the extracellular domain and the intracellular signaling domain; and a poly(ADP-ribose) polymerase (PARP) inhibitor.
20. A pharmaceutical composition comprising an engineered T cell comprising:

(a) the breast cancer is triple-negative breast cancer ;
(b) the ovarian cancer is advanced ovarian cancer ;
(c) the prostate cancer is advanced prostate cancer ; or
(d) the lung cancer is non-small cell lung cancer;
The pharmaceutical composition of claim 1.

3. The pharmaceutical composition of claim 1 or 2, wherein the cancer is a breast cancer gene (BRCA) mutated cancer, optionally the cancer is a BRCA1 mutated cancer, a BRCA2 mutated cancer, or both.

The pharmaceutical composition according to any one of claims 1 to 3 , wherein the PARP inhibitor is talazoparib, niraparib, rucaparib, olaparib, veliparib, CEP9722, E7016, AG014699, MK4827, BMN-673, pamiparib, or a combination thereof .

The pharmaceutical composition of any one of claims 1 to 4 , further comprising administering an additional therapeutic agent.

6. The pharmaceutical composition of claim 5, wherein the additional therapeutic agent comprises radiation, cellular immunotherapy, an antibody, an immune checkpoint molecule inhibitor, chemotherapy, hormone therapy, a peptide, an antibiotic, an antiviral agent, an antifungal agent, an anti-inflammatory agent , UV light therapy, electrical pulse therapy, high intensity focused ultrasound therapy, oncolytic virus therapy, small molecule therapy, or a combination thereof.

7. The pharmaceutical composition of claim 6 , wherein the cellular immunotherapy is a chimeric antigen receptor or a T cell receptor.

7. The pharmaceutical composition of claim 5 or 6, wherein the additional therapeutic agent comprises an angiogenesis inhibitor (e.g., a VEGF pathway inhibitor), a tyrosine kinase inhibitor (e.g., an EGF pathway inhibitor), a receptor tyrosine kinase inhibitor, a growth factor inhibitor, a GTPase inhibitor, a serine/threonine kinase inhibitor, a transcription factor inhibitor, a B-Raf inhibitor, a RAF inhibitor, a MEK inhibitor, an mTOR inhibitor, an EGFR inhibitor, an ALK inhibitor, a ROS1 inhibitor, a BCL-2 inhibitor, a PI3K inhibitor, a VEGFR inhibitor, a BCR-ABL inhibitor, a MET inhibitor, a MYC inhibitor, an ABL inhibitor, a HER2 inhibitor, a BTK inhibitor, an H-RAS inhibitor, a K-RAS inhibitor, a PDGFR inhibitor, a TRK inhibitor, a c-KIT inhibitor, a c-MET inhibitor, a CDK4/ 6 inhibitor, a FAK inhibitor, a FGFR inhibitor, a FLT3 inhibitor, an IDH1 inhibitor, an IDH2 inhibitor, a PDGFRA inhibitor, or a RET inhibitor .

A pharmaceutical composition according to any one of claims 1 to 8 , wherein the Tim4 IgV domain comprises the amino acid sequence shown in SEQ ID NO: 34 and/or the Tim4 mucin domain comprises the amino acid sequence shown in SEQ ID NO: 35.

The pharmaceutical composition according to any one of claims 1 to 9 , wherein the transmembrane domain comprises the Tim4 transmembrane domain or the CD28 transmembrane domain.

The pharmaceutical composition of claim 10 , wherein the Tim4 transmembrane domain comprises the amino acid sequence shown in SEQ ID NO: 6 or 23, or the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO: 7.

The pharmaceutical composition of any one of claims 1 to 11, wherein the CD28 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 4 or 26, or the TLR2 signaling domain comprises the amino acid sequence set forth in SEQ ID NO: 222.

The pharmaceutical composition of any one of claims 1 to 12, wherein the DAP12 signaling domain comprises the amino acid sequence set forth in SEQ ID NO:9, or the CD3ζ signaling domain comprises the amino acid sequence set forth in SEQ ID NO:5.

A chimeric phagocytosis receptor
(i) the amino acid sequence of SEQ ID NO: 195 or amino acids 25 to 47 3 of SEQ ID NO: 195;
(ii) the amino acid sequence of SEQ ID NO:196 or amino acids 25 to 446 of SEQ ID NO:196 ;
(iii) the amino acid sequence of SEQ ID NO:197 or amino acids 25 to 43 of SEQ ID NO:197 ; or (iv) the amino acid sequence of SEQ ID NO:198 or amino acids 25 to 42 of SEQ ID NO:198.
The pharmaceutical composition according to any one of claims 1 to 13 , comprising:

A chimeric phagocytosis receptor
(a) (i) an extracellular domain comprising a binding domain comprising a Tim4 IgV domain and a Tim4 mucin domain;
(b) an intracellular signaling domain comprising a primary intracellular signaling domain comprising a CD28 signaling domain; a secondary intracellular signaling domain comprising a CD3ζ signaling domain ; and a tertiary intracellular signaling domain comprising a TLR 2 signaling domain;
(c) a transmembrane domain located between and connecting the extracellular domain and the intracellular signaling domain .

The pharmaceutical composition of any one of claims 1 to 15 , wherein the single-chain protein comprises the amino acid sequence of any one of SEQ ID NOs: 162, 195-198, 71, 227-229, 232, 233, 238-240, 243, and 244.

The pharmaceutical composition of any one of claims 1 to 16, wherein the T cells are CD4+ T cells, CD8+ T cells, or CD4+/CD8+ T cells, and/or the T cells are human T cells.