JP2022023132A - グリカン依存性免疫療法分子 - Google Patents
グリカン依存性免疫療法分子 Download PDFInfo
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Abstract
Description
本出願は、2015年5月1日出願の米国仮特許出願第62/155,761号に対する優先権を主張するものであり、その内容全体が参照により本明細書に組み込まれる。
別段の定義がない限り、本明細書で使用される技術用語及び科学用語はすべて、本発明が属する技術分野の当業者に共通して理解されているものと同じ意味を有する。本明細書に記載するものと同様または同等であるいかなる方法及び材料をも本発明の実施または試験に使用することができるが、好ましい方法及び材料について記載する。
本発明は、癌ならびに他の疾患を治療するための組成物及び方法を提供する。癌は、血液悪性腫瘍、固形腫瘍、原発腫瘍、または転移腫瘍であり得る。本発明の組成物には、TACA結合ドメインを含むペプチド、TACA結合ドメインを含むペプチドをコードする核酸分子、TACA結合ドメインを含むペプチドを発現するように改変された細胞、及びペプチド、核酸、細胞、またはそれらの組み合わせを含む基材を含む。
一実施形態では、本発明は、TACA結合ドメインを含む融合ペプチドを含む組成物を提供する。TACA結合ドメインには、TACAに特異的に結合することができる、いずれのペプチド、タンパク質、レクチン、レクチン断片、抗体、抗体断片、小分子、核酸などをも含み得る。例示的なTACA及びその結合パートナーを表1に列挙する。
(配列番号2)。
(配列番号3)。
(配列番号4)。
(配列番号5)。
(配列番号6)。
(配列番号7)。
(配列番号8)。
一実施形態では、本発明は、本明細書の他の箇所に記載するTACA結合ドメインを含むペプチドをコードする単離された核酸を含む組成物を提供する。
本発明は、キメラ抗原受容体(CAR)またはCARをコードする核酸分子を含み、当該CARがTACA結合ドメインを含む組成物を提供する。一実施形態では、CARは細胞外及び細胞内ドメインを含む。細胞外ドメインは、別の用語では抗原結合ドメインとも称される標的特異的結合エレメントを含む。細胞内ドメイン、または別の用語で細胞質ドメインは、共刺激シグナル伝達領域及びゼータ鎖部分を含む。共刺激シグナル伝達領域とは、共刺激分子の細胞内ドメインを含むCARの一部分を指す。共刺激分子とは、抗原に対するリンパ球の効率的な応答に必要とされる抗原受容体またはそのリガンド以外の細胞表面分子である。
一実施形態では、本発明のCARは、別の用語で抗原結合部分とも称される標的特異的結合要素を含む。
膜貫通ドメインに関して、CARは、CARの細胞外ドメインと融合した膜貫通ドメインを含むように設計することができる。一実施形態では、CAR内のドメインの1つに天然に結合する膜貫通ドメインを用いる。場合によっては、膜貫通ドメインを選択、またはアミノ酸置換により修飾することにより、同じまたは異なる表面膜タンパク質の膜貫通ドメインに対するそのようなドメインの結合を回避することで、受容体複合体の他のメンバーとの相互作用を最小限に抑えことができる。
本発明のCARの細胞質ドメイン、または別の用語で細胞内シグナル伝達ドメインは、CARが挿入された免疫細胞の正常なエフェクター機能のうち少なくとも1つの活性化を担う。用語「エフェクター機能」は、細胞の特別な機能を指す。T細胞のエフェクター機能は、例えば、細胞溶解活性、またはサイトカインの分泌を含むヘルパー活性であり得る。したがって、用語「細胞内シグナル伝達ドメイン」は、エフェクター機能シグナルを伝達して、細胞に特別な機能を実行させるタンパク質の部分を指す。通常、細胞内シグナル伝達ドメイン全体を利用できるが、多くの場合、その鎖全体を使用する必要はない。細胞内シグナル伝達ドメインの短縮部分を使用する場合には、そのような短縮部分を、それがエフェクター機能シグナルを伝達する限り、無傷の鎖の代わりに使用してもよい。したがって、細胞内シグナル伝達ドメインという用語は、エフェクター機能シグナルを伝達するのに十分な、細胞内シグナル伝達ドメインの任意の短縮部分を含むものとする。
本発明は、CARをコードする配列を含み、当該配列が細胞内ドメインをコードする核酸配列に機能的に連結された抗原結合部分をコードする核酸配列を含む核酸分子を包含する。例えば、一実施形態では、CARをコードする分子は、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、またはその相同ペプチドのいずれかの1つ以上のTACA結合ドメインを含む抗原結合部分をコードする核酸配列を含む。一実施形態では、CARをコードする核酸分子は、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、またはその相同ペプチドのいずれかをコードするヌクレオチド配列を含む核酸配列を含む。一実施形態では、CARをコードする核酸分子は、TACA結合ドメインに結合するペプチドをコードするヌクレオチド配列を含む。例えば、一実施形態では、CARをコードする核酸分子は、レクチン結合ドメインに結合するヌクレオチド配列を含み、当該レクチン結合ドメインはTACAに結合するレクチンまたはレクチン由来のペプチドに結合する。
ある特定の実施形態では、本発明の組成物は、本発明のペプチドを発現するように改変された細胞を含む。例えば、ある特定の実施形態では、細胞は、TACA結合ドメインを含むペプチドを発現するように改変される。ある特定の実施形態では、細胞は、TACA結合ドメイン及びT細胞結合ドメインを含むペプチドを発現するように改変される。ある特定の実施形態では、細胞は、TACA結合ドメインを含むCARを発現するように改変される。
本発明は、TACA結合ドメインを含むペプチド、TACA結合ドメインを含むペプチドをコードする核酸分子、TACA結合ドメインを含むペプチドを発現するように改変された細胞、またはそれらの組み合わせを含む足場または基材組成物を提供する。例えば、一実施形態では、TACA結合ドメインを含むペプチド、TACA結合ドメインを含むペプチドをコードする核酸分子、TACA結合ドメインを含むペプチドを発現するように改変された細胞、またはそれらの組み合わせが足場内部に存在する。別の実施形態では、TACA結合ドメインを含むペプチド、TACA結合ドメインを含むペプチドをコードする核酸分子、TACA結合ドメインを含むペプチドを発現するように改変された細胞、またはそれらの組み合わせが足場の表面に使用される。本発明の足場は、当技術分野で既知であるいかなる種類のものであってもよい。このような足場の非限定的な例としては、ヒドロゲル、エレクトロスピニング足場、発泡体、メッシュ、シート、パッチ、及びスポンジが挙げられる。
本発明はまた、本明細書に記載される1つ以上の組成物を含む医薬組成物を提供する。製剤を、従来の賦形剤、すなわち、創傷または治療部位への投与に適した薬学的に許容される有機または無機担体物質と混合して用いてもよい。医薬組成物は滅菌されていてもよく、また望ましい場合は、補助剤、例えば滑沢剤、防腐剤、安定剤、湿潤剤、乳化剤、浸透圧に作用する塩、緩衝剤、着色剤、及び/または芳香族物質などと混合されていてもよい。製剤はまた、望ましい場合に他の活性剤、例えば、他の鎮痛剤と組み合わせてもよい。
本発明は、それを必要とする対象での癌の治療または予防方法を提供する。この方法は、血液悪性腫瘍、固形腫瘍、原発腫瘍、または転移腫瘍を含む、いずれの癌の治療に使用してもよい。
細胞の悪性形質転換は、ほぼ例外なく細胞表面でのグリコシル化の異常な変化を伴う(Kim and Varki,1997,Glycoconj J,14:569-576)。実際に、細胞表面グリコシル化の変化が、あらゆる種類の実験的なヒト癌で観察されており(Hakomori,2002,PNAS USA,99:10231-10233)、これらの変化した糖構造は腫瘍関連糖鎖抗原(TACA)と呼ばれている(表1)。この腫瘍特異的な特性により、細胞表面のTACAは、多くの一般的な癌を標的とするモノクローナル抗体を産生するための優れた標的抗原となっている。しかしながら、数十年にわたる取り組みに反して、糖鎖抗原に対する抗体の作製が困難なため、TACAに対する高親和性を有する特異性抗体は未だ提供されていない。
遺伝子配列:1604bp(293及びCHO両方によるコドン最適化)
EcoRI-Kozak配列-リーダー配列-L-PHA-リンカー-抗CD3 scFv-Hisタグ-XbaI
EcoRI及びXbaI配列に下線が引かれている。Kozak配列は太字である。
(配列番号18)
Claims (96)
- レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドを含み、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する、癌を治療するための組成物。
- 前記レクチンが、哺乳動物レクチン、ヒトレクチン、植物レクチン、細菌レクチン、ウイルスレクチン、真菌レクチン、及び原生動物レクチンからなる群から選択される、請求項1に記載の組成物。
- 前記レクチンが、ガレクチン、シグレック、セレクチン;C型レクチン;CD301、L-PHA(Phaseolus vulgarisロイコアグルチニン);E-PHA(Phaseolus vulgarisエリスロアグルチニン);トマトレクチン(Lycopersicon esculentumレクチン;LEA);ピーナッツレクチン(Arachis hypogaeaアグルチニン;PNA);ジャガイモレクチン(Solanum tuberosumレクチン)、ヨウシュヤマゴボウマイトジェン(Phytolacca Americanレクチン)、コムギ胚芽アグルチニン(Triticum Vulgarisレクチン);Artocarpus polyphemusレクチン(Jacalinレクチン);Vicia villosaアグルチニン(VVA);Helix pomatiaアグルチニン(HPA);Wisteria floribundaアグルチニン(WFA);Sambucus nigraアグルチニン(SNA)、BC2LCM(グラム陰性菌Burkholderia cenocepacia由来レクチン)、Maackia amurensisロイコアグルチニン(MAL)、Psathyrella velutina(PVL)、Sclerotium rolfsiiレクチン(SRL)、Eucheuma serraアグルチニン(ESA)、CLEC17A(Prolectin)、Aleuria aurantiaレクチン、Sambucus sieboldianaレクチン(SSA)、Glechoma hederaceaレクチン(Gleheda)、Morus nigraアグルチニン(Morniga G)、Salvia sclareaレクチン、Salvia bogotensisレクチン、Salvia horminumレクチン、Clerodendrum trichotomumレクチン、Moluccella laevisレクチン、Griffonia simplicifolia(GsLA4)、Psophocarpus tetragonolobus(酸性WBAI)、Abrus precatoriusレクチン、Molucella laevisレクチン(MLL)、Amaranthus caudatusレクチン、Amaranthus leucocarpusレクチン、Laelia autumnalisレクチン、Artocarpus integrifoliaレクチン、Maclura pomiferaレクチン、Artocarpus lakoochaレクチン、Dolichos biflorusアグルチニン、Dolichos biflorusレクチン、Glycine maxレクチン、及びAgaricus bisporusレクチンからなる群から選択される、請求項1に記載の組成物。
- 前記ガレクチンが、ガレクチン-1、ガレクチン-2、ガレクチン-3、ガレクチン-4、ガレクチン-5、ガレクチン-6、ガレクチン-7、ガレクチン-8、ガレクチン-9、ガレクチン-10、ガレクチン-11、ガレクチン-12、ガレクチン-13、ガレクチン-14、及びガレクチン-15からなる群から選択される、請求項3に記載の組成物。
- 前記シグレックが、シグレック-1(sialoadhesion)、シグレック-2(CD22)、シグレック-3(CD33)、シグレック-4(ミエリン関連糖タンパク質)、シグレック-5、シグレック-6、シグレック-7、シグレック-8、シグレック-9、シグレック-10、シグレック-11、シグレック-12、シグレック-13、シグレック-14、シグレック-15、シグレック-16、シグレック-17、シグレックE、シグレックF、シグレックG、及びシグレックHからなる群から選択される、請求項3に記載の組成物。
- 前記TACA結合ドメインが、β1,6分岐、T抗原、シアリル-Tエピトープ、Tnエピトープ、シアリル-Tnエピトープ、α2,6シアリル化、シアリル化、シアリル-ルイスx/a、ジシアリル-ルイスx/a、シアリル6-スルホルイスx、Globo H、GD2、GD3、GM3、及びフコシルGM1からなる群から選択されるTACAに結合する、請求項1に記載の組成物。
- 前記TACA結合ドメインが、腫瘍細胞のβ1,6GlcNAc分岐型N-グリカンに結合する、請求項1に記載の組成物。
- 前記TACA結合ドメインが、配列番号1、配列番号1に対して約90%超の相同性を有するアミノ酸配列、配列番号2、配列番号2に対して約90%超の相同性を有するアミノ酸配列、配列番号3、配列番号3に対して約90%超の相同性を有するアミノ酸配列、配列番号4、配列番号4に対して約90%超の相同性を有するアミノ酸配列、配列番号5、配列番号5に対して約90%超の相同性を有するアミノ酸配列、配列番号6、配列番号6に対して約90%超の相同性を有するアミノ酸配列、配列番号7、及び配列番号7に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項1に記載の組成物。
- 前記ペプチドが、Fcドメインに連結された前記TACA結合ドメインを含むFc融合ペプチドである、請求項1に記載の組成物。
- 前記ペプチドが、免疫エフェクター細胞に特異的に結合するドメインをさらに含む、請求項1に記載の組成物。
- 前記免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT(NKT)細胞、マクロファージ、単球、樹状細胞、及び好中球からなる群から選択される、請求項10に記載の組成物。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、T細胞結合ドメインを含み、前記T細胞結合ドメインはT細胞に特異的に結合する、請求項11に記載の組成物。
- 前記T細胞結合ドメインが、CD3、T細胞受容体、CD2、CD28、及びCD25からなる群のうち少なくとも1つに結合する、請求項12に記載の組成物。
- 前記T細胞結合ドメインが、配列番号9、及び配列番号9に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項12に記載の組成物。
- 前記ペプチドが、配列番号11、配列番号11に対して約90%超の相同性を有するアミノ酸配列、配列番号12、配列番号12に対して約90%超の相同性を有するアミノ酸配列、配列番号13、配列番号13に対して約90%超の相同性を有するアミノ酸配列、配列番号14、配列番号14に対して約90%超の相同性を有するアミノ酸配列、配列番号15、配列番号15に対して約90%超の相同性を有するアミノ酸配列、配列番号16、配列番号16に対して約90%超の相同性を有するアミノ酸配列、配列番号17、及び配列番号17に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項12に記載の組成物。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、NK細胞結合ドメインを含み、前記NK細胞結合ドメインはNK細胞に特異的に結合する、請求項11に記載の組成物。
- 前記NK細胞結合ドメインが、CD16及びNKG2Dからなる群のうち少なくとも1つに結合する、請求項16に記載の組成物。
- 前記ペプチドが、前記TACA結合ドメインを含むキメラ抗原受容体(CAR)を含む、請求項1に記載の組成物。
- レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドをコードする単離された核酸分子を含み、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する、癌を治療するための組成物。
- 前記レクチンが、哺乳動物レクチン、ヒトレクチン、植物レクチン、細菌レクチン、ウイルスレクチン、真菌レクチン、及び原生動物レクチンからなる群から選択される、請求項19に記載の組成物。
- 前記レクチンが、ガレクチン、シグレック、セレクチン;C型レクチン;CD301、L-PHA(Phaseolus vulgarisロイコアグルチニン);E-PHA(Phaseolus vulgarisエリスロアグルチニン);トマトレクチン(Lycopersicon esculentumレクチン;LEA);ピーナッツレクチン(Arachis hypogaeaアグルチニン;PNA);ジャガイモレクチン(Solanum tuberosumレクチン)、ヨウシュヤマゴボウマイトジェン(Phytolacca Americanレクチン)、コムギ胚芽アグルチニン(Triticum Vulgarisレクチン);Artocarpus polyphemusレクチン(Jacalinレクチン);Vicia villosaアグルチニン(VVA);Helix pomatiaアグルチニン(HPA);Wisteria floribundaアグルチニン(WFA);Sambucus nigraアグルチニン(SNA)、BC2LCM(グラム陰性菌Burkholderia cenocepacia由来レクチン)、Maackia amurensisロイコアグルチニン(MAL)、Psathyrella velutina(PVL)、Sclerotium rolfsiiレクチン(SRL)、Eucheuma serraアグルチニン(ESA)、CLEC17A(Prolectin)、Aleuria aurantiaレクチン、Sambucus sieboldianaレクチン(SSA)、Glechoma hederaceaレクチン(Gleheda)、Morus nigraアグルチニン(Morniga G)、Salvia sclareaレクチン、Salvia bogotensisレクチン、Salvia horminumレクチン、Clerodendrum trichotomumレクチン、Moluccella laevisレクチン、Griffonia simplicifolia(GsLA4)、Psophocarpus tetragonolobus(酸性WBAI)、Abrus precatoriusレクチン、Molucella laevisレクチン(MLL)、Amaranthus caudatusレクチン、Amaranthus leucocarpusレクチン、Laelia autumnalisレクチン、Artocarpus integrifoliaレクチン、Maclura pomiferaレクチン、Artocarpus lakoochaレクチン、Dolichos biflorusアグルチニン、Dolichos biflorusレクチン、Glycine maxレクチン、及びAgaricus bisporusレクチンからなる群から選択される、請求項19に記載の組成物。
- 前記ガレクチンが、ガレクチン-1、ガレクチン-2、ガレクチン-3、ガレクチン-4、ガレクチン-5、ガレクチン-6、ガレクチン-7、ガレクチン-8、ガレクチン-9、ガレクチン-10、ガレクチン-11、ガレクチン-12、ガレクチン-13、ガレクチン-14、及びガレクチン-15からなる群から選択される、請求項21に記載の組成物。
- 前記シグレックが、シグレック-1(sialoadhesion)、シグレック-2(CD22)、シグレック-3(CD33)、シグレック-4(ミエリン関連糖タンパク質)、シグレック-5、シグレック-6、シグレック-7、シグレック-8、シグレック-9、シグレック-10、シグレック-11、シグレック-12、シグレック-13、シグレック-14、シグレック-15、シグレック-16、シグレック-17、シグレックE、シグレックF、シグレックG、及びシグレックHからなる群から選択される、請求項21に記載の組成物。
- 前記TACA結合ドメインが、β1,6分岐、T抗原、シアリル-Tエピトープ、Tnエピトープ、シアリル-Tnエピトープ、α2,6シアリル化、シアリル化、シアリル-ルイスx/a、ジシアリル-ルイスx/a、シアリル6-スルホルイスx、Globo H、GD2、GD3、GM3、及びフコシルGM1からなる群から選択されるTACAに結合する、請求項19に記載の組成物。
- 前記TACA結合ドメインが、腫瘍細胞のβ1,6GlcNAc分岐型N-グリカンに結合する、請求項19に記載の組成物。
- 前記核酸分子が、配列番号1、配列番号1に対して約90%超の相同性を有するアミノ酸配列、配列番号2、配列番号2に対して約90%超の相同性を有するアミノ酸配列、配列番号3、配列番号3に対して約90%超の相同性を有するアミノ酸配列、配列番号4、配列番号4に対して約90%超の相同性を有するアミノ酸配列、配列番号5、配列番号5に対して約90%超の相同性を有するアミノ酸配列、配列番号6、配列番号6に対して約90%超の相同性を有するアミノ酸配列、配列番号7、及び配列番号7に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むTACA結合ドメインをコードするヌクレオチド配列を含む、請求項19に記載の組成物。
- 前記ペプチドが、Fcドメインに連結された前記TACA結合ドメインを含むFc融合ペプチドである、請求項19に記載の組成物。
- 前記ペプチドが、免疫エフェクター細胞に特異的に結合するドメインをさらに含む、請求項19に記載の組成物。
- 前記免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT(NKT)細胞、マクロファージ、単球、樹状細胞、及び好中球からなる群から選択される、請求項28に記載の組成物。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、T細胞結合ドメインを含み、前記T細胞結合ドメインはT細胞に特異的に結合する、請求項29に記載の組成物。
- 前記T細胞結合ドメインが、CD3、T細胞受容体、CD2、CD28、及びCD25からなる群のうち少なくとも1つに結合する、請求項30に記載の組成物。
- 前記核酸分子が、配列番号9、及び配列番号9に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むT細胞結合ドメインをコードするヌクレオチド配列を含む、請求項30に記載の組成物。
- 前記核酸分子が、配列番号11、配列番号11に対して約90%超の相同性を有するアミノ酸配列、配列番号12、配列番号12に対して約90%超の相同性を有するアミノ酸配列、配列番号13、配列番号13に対して約90%超の相同性を有するアミノ酸配列、配列番号14、配列番号14に対して約90%超の相同性を有するアミノ酸配列、配列番号15、配列番号15に対して約90%超の相同性を有するアミノ酸配列、配列番号16、配列番号16に対して約90%超の相同性を有するアミノ酸配列、配列番号17、及び配列番号17に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むペプチドをコードするヌクレオチド配列を含む、請求項30に記載の組成物。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、NK細胞結合ドメインを含み、前記NK細胞結合ドメインはNK細胞に特異的に結合する、請求項28に記載の組成物。
- 前記NK細胞結合ドメインが、CD16及びNKG2Dからなる群のうち少なくとも1つに結合する、請求項34に記載の組成物。
- 前記核酸分子が、抗原認識ドメイン及び細胞内ドメインを含むキメラ抗原受容体(CAR)をコードし、前記抗原認識ドメインはTACA結合ドメインを含む、請求項19に記載の組成物。
- 前記核酸分子によってコードされる前記CARの前記抗原認識ドメインが、配列番号1、配列番号1に対して約90%超の相同性を有するアミノ酸配列、配列番号2、配列番号2に対して約90%超の相同性を有するアミノ酸配列、配列番号3、配列番号3に対して約90%超の相同性を有するアミノ酸配列、配列番号4、配列番号4に対して約90%超の相同性を有するアミノ酸配列、配列番号5、配列番号5に対して約90%超の相同性を有するアミノ酸配列、配列番号6、配列番号6に対して約90%超の相同性を有するアミノ酸配列、配列番号7、及び配列番号7に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むTACA結合ドメインを含む、請求項36に記載の組成物。
- 前記核酸分子によってコードされる前記CARの前記細胞内ドメインが、CD3ゼータシグナル伝達ドメイン及び共刺激ドメインを含む、請求項36に記載の組成物。
- 前記単離された核酸分子が、発現ベクターを含む、請求項19に記載の組成物。
- 前記単離された核酸分子が、in vitro転写されたRNAを含む、請求項19に記載の組成物。
- レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドと結合する薬剤を含み、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する、癌を治療するための組成物。
- 前記薬剤が、レクチン結合ドメインを含む、請求項41に記載の組成物。
- レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドと結合するペプチドをコードする単離された核酸分子を含み、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する、癌を治療するための組成物。
- 前記核酸分子によってコードされる前記ペプチドが、レクチン結合ドメインを含む、請求項43に記載の組成物。
- 前記単離された核酸分子が、抗原認識ドメイン及び細胞内ドメインを含むCARをコードし、前記抗原認識ドメインは前記レクチン結合ドメインを含む、請求項44に記載の組成物。
- レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドを発現するように改変され、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する細胞。
- 前記細胞が、抗原認識ドメイン及び細胞内ドメインを含むCARを発現するように改変され、前記抗原認識ドメインは前記TACA結合ドメインを含む、請求項46に記載の細胞。
- 前記細胞が、T細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)、及び制御性T細胞からなる群から選択される、請求項47に記載の細胞。
- 治療を必要とする対象における癌の治療方法であって、前記方法は、レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドを含み、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する組成物を対象に投与することを含む、前記方法。
- 前記レクチンが、哺乳動物レクチン、ヒトレクチン、植物レクチン、細菌レクチン、ウイルスレクチン、真菌レクチン、及び原生動物レクチンからなる群から選択される、請求項49に記載の方法。
- 前記レクチンが、ガレクチン、シグレック、セレクチン;C型レクチン;CD301、L-PHA(Phaseolus vulgarisロイコアグルチニン);E-PHA(Phaseolus vulgarisエリスロアグルチニン);トマトレクチン(Lycopersicon esculentumレクチン;LEA);ピーナッツレクチン(Arachis hypogaeaアグルチニン;PNA);ジャガイモレクチン(Solanum tuberosumレクチン)、ヨウシュヤマゴボウマイトジェン(Phytolacca Americanレクチン)、コムギ胚芽アグルチニン(Triticum Vulgarisレクチン);Artocarpus polyphemusレクチン(Jacalinレクチン);Vicia villosaアグルチニン(VVA);Helix pomatiaアグルチニン(HPA);Wisteria floribundaアグルチニン(WFA);Sambucus nigraアグルチニン(SNA)、BC2LCM(グラム陰性菌Burkholderia cenocepacia由来レクチン)、Maackia amurensisロイコアグルチニン(MAL)、Psathyrella velutina(PVL)、Sclerotium rolfsiiレクチン(SRL)、Eucheuma serraアグルチニン(ESA)、CLEC17A(Prolectin)、Aleuria aurantiaレクチン、Sambucus sieboldianaレクチン(SSA)、Glechoma hederaceaレクチン(Gleheda)、Morus nigraアグルチニン(Morniga G)、Salvia sclareaレクチン、Salvia bogotensisレクチン、Salvia horminumレクチン、Clerodendrum trichotomumレクチン、Moluccella laevisレクチン、Griffonia simplicifolia(GsLA4)、Psophocarpus tetragonolobus(酸性WBAI)、Abrus precatoriusレクチン、Molucella laevisレクチン(MLL)、Amaranthus caudatusレクチン、Amaranthus leucocarpusレクチン、Laelia autumnalisレクチン、Artocarpus integrifoliaレクチン、Maclura pomiferaレクチン、Artocarpus lakoochaレクチン、Dolichos biflorusアグルチニン、Dolichos biflorusレクチン、Glycine maxレクチン、及びAgaricus bisporusレクチンからなる群から選択される、請求項49に記載の方法。
- 前記ガレクチンが、ガレクチン-1、ガレクチン-2、ガレクチン-3、ガレクチン-4、ガレクチン-5、ガレクチン-6、ガレクチン-7、ガレクチン-8、ガレクチン-9、ガレクチン-10、ガレクチン-11、ガレクチン-12、ガレクチン-13、ガレクチン-14、及びガレクチン-15からなる群から選択される、請求項50に記載の方法。
- 前記シグレックが、シグレック-1(sialoadhesion)、シグレック-2(CD22)、シグレック-3(CD33)、シグレック-4(ミエリン関連糖タンパク質)、シグレック-5、シグレック-6、シグレック-7、シグレック-8、シグレック-9、シグレック-10、シグレック-11、シグレック-12、シグレック-13、シグレック-14、シグレック-15、シグレック-16、シグレック-17、シグレックE、シグレックF、シグレックG、及びシグレックHからなる群から選択される、請求項50に記載の方法。
- 前記TACA結合ドメインが、β1,6分岐、T抗原、シアリル-Tエピトープ、Tnエピトープ、シアリル-Tnエピトープ、α2,6シアリル化、シアリル化、シアリル-ルイスx/a、ジシアリル-ルイスx/a、シアリル6-スルホルイスx、Globo H、GD2、GD3、GM3、及びフコシルGM1からなる群から選択されるTACAに結合する、請求項49に記載の方法。
- 前記TACA結合ドメインが、腫瘍細胞のβ1,6GlcNAc分岐型N-グリカンに結合する、請求項49に記載の方法。
- 前記TACA結合ドメインが、配列番号1、配列番号1に対して約90%超の相同性を有するアミノ酸配列、配列番号2、配列番号2に対して約90%超の相同性を有するアミノ酸配列、配列番号3、配列番号3に対して約90%超の相同性を有するアミノ酸配列、配列番号4、配列番号4に対して約90%超の相同性を有するアミノ酸配列、配列番号5、配列番号5に対して約90%超の相同性を有するアミノ酸配列、配列番号6、配列番号6に対して約90%超の相同性を有するアミノ酸配列、配列番号7、及び配列番号7に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項49に記載の方法。
- 前記ペプチドが、Fcドメインに連結された前記TACA結合ドメインを含むFc融合ペプチドである、請求項49に記載の方法。
- 前記ペプチドが、免疫エフェクター細胞に特異的に結合するドメインをさらに含む、請求項49に記載の方法。
- 前記免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT(NKT)細胞、マクロファージ、単球、樹状細胞、及び好中球からなる群から選択される、請求項49に記載の方法。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、T細胞結合ドメインを含み、前記T細胞結合ドメインはT細胞に特異的に結合する、請求項59に記載の方法。
- 前記T細胞結合ドメインが、CD3、T細胞受容体、CD2、CD28、及びCD25からなる群のうち少なくとも1つに結合する、請求項60に記載の方法。
- 前記T細胞結合ドメインが、配列番号9、及び配列番号9に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項60に記載の方法。
- 前記ペプチドが、配列番号11、配列番号11に対して約90%超の相同性を有するアミノ酸配列、配列番号12、配列番号12に対して約90%超の相同性を有するアミノ酸配列、配列番号13、配列番号13に対して約90%超の相同性を有するアミノ酸配列、配列番号14、配列番号14に対して約90%超の相同性を有するアミノ酸配列、配列番号15、配列番号15に対して約90%超の相同性を有するアミノ酸配列、配列番号16、配列番号16に対して約90%超の相同性を有するアミノ酸配列、配列番号17、及び配列番号17に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項60に記載の方法。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、NK細胞結合ドメインを含み、前記NK細胞結合ドメインはNK細胞に特異的に結合する、請求項59に記載の方法。
- 前記NK細胞結合ドメインが、CD16及びNKG2Dからなる群のうち少なくとも1つに結合する、請求項64に記載の方法。
- 前記対象が、TACAを発現する固形腫瘍を有している、請求項49に記載の方法。
- 治療を必要とする対象における癌の治療方法であって、レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドをコードする単離された核酸分子を含み、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する組成物を対象に投与することを含む、前記方法。
- 前記レクチンが、哺乳動物レクチン、ヒトレクチン、植物レクチン、細菌レクチン、ウイルスレクチン、真菌レクチン、及び原生動物レクチンからなる群から選択される、請求項67に記載の方法。
- 前記レクチンが、ガレクチン、シグレック、セレクチン;C型レクチン;CD301、L-PHA(Phaseolus vulgarisロイコアグルチニン);E-PHA(Phaseolus vulgarisエリスロアグルチニン);トマトレクチン(Lycopersicon esculentumレクチン;LEA);ピーナッツレクチン(Arachis hypogaeaアグルチニン;PNA);ジャガイモレクチン(Solanum tuberosumレクチン)、ヨウシュヤマゴボウマイトジェン(Phytolacca Americanレクチン)、コムギ胚芽アグルチニン(Triticum Vulgarisレクチン);Artocarpus polyphemusレクチン(Jacalinレクチン);Vicia villosaアグルチニン(VVA);Helix pomatiaアグルチニン(HPA);Wisteria floribundaアグルチニン(WFA);Sambucus nigraアグルチニン(SNA)、BC2LCM(グラム陰性菌Burkholderia cenocepacia由来レクチン)、Maackia amurensisロイコアグルチニン(MAL)、Psathyrella velutina(PVL)、Sclerotium rolfsiiレクチン(SRL)、Eucheuma serraアグルチニン(ESA)、CLEC17A(Prolectin)、Aleuria aurantiaレクチン、Sambucus sieboldianaレクチン(SSA)、Glechoma hederaceaレクチン(Gleheda)、Morus nigraアグルチニン(Morniga G)、Salvia sclareaレクチン、Salvia bogotensisレクチン、Salvia horminumレクチン、Clerodendrum trichotomumレクチン、Moluccella laevisレクチン、Griffonia simplicifolia(GsLA4)、Psophocarpus tetragonolobus(酸性WBAI)、Abrus precatoriusレクチン、Molucella laevisレクチン(MLL)、Amaranthus caudatusレクチン、Amaranthus leucocarpusレクチン、Laelia autumnalisレクチン、Artocarpus integrifoliaレクチン、Maclura pomiferaレクチン、Artocarpus lakoochaレクチン、Dolichos biflorusアグルチニン、Dolichos biflorusレクチン、Glycine maxレクチン、及びAgaricus bisporusレクチンからなる群から選択される、請求項67に記載の方法。
- 前記ガレクチンが、ガレクチン-1、ガレクチン-2、ガレクチン-3、ガレクチン-4、ガレクチン-5、ガレクチン-6、ガレクチン-7、ガレクチン-8、ガレクチン-9、ガレクチン-10、ガレクチン-11、ガレクチン-12、ガレクチン-13、ガレクチン-14、及びガレクチン-15からなる群から選択される、請求項68に記載の方法。
- 前記シグレックが、シグレック-1(sialoadhesion)、シグレック-2(CD22)、シグレック-3(CD33)、シグレック-4(ミエリン関連糖タンパク質)、シグレック-5、シグレック-6、シグレック-7、シグレック-8、シグレック-9、シグレック-10、シグレック-11、シグレック-12、シグレック-13、シグレック-14、シグレック-15、シグレック-16、シグレック-17、シグレックE、シグレックF、シグレックG、及びシグレックHからなる群から選択される、請求項68に記載の方法。
- 前記TACA結合ドメインが、β1,6分岐、T抗原、シアリル-Tエピトープ、Tnエピトープ、シアリル-Tnエピトープ、α2,6シアリル化、シアリル化、シアリル-ルイスx/a、ジシアリル-ルイスx/a、シアリル6-スルホルイスx、Globo H、GD2、GD3、GM3、及びフコシルGM1からなる群から選択されるTACAに結合する、請求項67に記載の方法。
- 前記TACA結合ドメインが、腫瘍細胞のβ1,6GlcNAc分岐型N-グリカンに結合する、請求項67に記載の方法。
- 前記核酸分子が、配列番号1、配列番号1に対して約90%超の相同性を有するアミノ酸配列、配列番号2、配列番号2に対して約90%超の相同性を有するアミノ酸配列、配列番号3、配列番号3に対して約90%超の相同性を有するアミノ酸配列、配列番号4、配列番号4に対して約90%超の相同性を有するアミノ酸配列、配列番号5、配列番号5に対して約90%超の相同性を有するアミノ酸配列、配列番号6、配列番号6に対して約90%超の相同性を有するアミノ酸配列、配列番号7、及び配列番号7に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むTACA結合ドメインをコードするヌクレオチド配列を含む、請求項67に記載の方法。
- 前記ペプチドが、Fcドメインに連結されたTACA結合ドメインを含むFc融合ペプチドである、請求項67に記載の方法。
- 前記ペプチドが、免疫エフェクター細胞に特異的に結合するドメインをさらに含む、請求項67に記載の方法。
- 前記免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT(NKT)細胞、マクロファージ、単球、樹状細胞、及び好中球からなる群から選択される、請求項76に記載の方法。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、T細胞結合ドメインを含み、前記T細胞結合ドメインはT細胞に特異的に結合する、請求項77に記載の方法。
- 前記T細胞結合ドメインが、CD3、T細胞受容体、CD2、CD28、及びCD25からなる群のうち少なくとも1つに結合する、請求項78に記載の方法。
- 前記核酸分子が、配列番号9、及び配列番号9に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むT細胞結合ドメインをコードするヌクレオチド配列を含む、請求項79に記載の方法。
- 前記核酸分子が、配列番号11、配列番号11に対して約90%超の相同性を有するアミノ酸配列、配列番号12、配列番号12に対して約90%超の相同性を有するアミノ酸配列、配列番号13、配列番号13に対して約90%超の相同性を有するアミノ酸配列、配列番号14、配列番号14に対して約90%超の相同性を有するアミノ酸配列、配列番号15、配列番号15に対して約90%超の相同性を有するアミノ酸配列、配列番号16、配列番号16に対して約90%超の相同性を有するアミノ酸配列、配列番号17、及び配列番号17に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むペプチドをコードするヌクレオチド配列を含む、請求項78に記載の方法。
- 免疫エフェクター細胞に特異的に結合する前記ドメインが、NK細胞結合ドメインを含み、前記NK細胞結合ドメインはNK細胞に特異的に結合する、請求項76に記載の方法。
- 前記NK細胞結合ドメインが、CD16及びNKG2Dからなる群のうち少なくとも1つに結合する、請求項82に記載の方法。
- 前記核酸分子が、抗原認識ドメイン及び細胞内ドメインを含むキメラ抗原受容体(CAR)をコードし、前記抗原認識ドメインは前記TACA結合ドメインを含む、請求項67に記載の方法。
- 前記核酸分子によってコードされる前記CARの前記抗原認識ドメインが、配列番号1、配列番号1に対して約90%超の相同性を有するアミノ酸配列、配列番号2、配列番号2に対して約90%超の相同性を有するアミノ酸配列、配列番号3、配列番号3に対して約90%超の相同性を有するアミノ酸配列、配列番号4、配列番号4に対して約90%超の相同性を有するアミノ酸配列、配列番号5、配列番号5に対して約90%超の相同性を有するアミノ酸配列、配列番号6、配列番号6に対して約90%超の相同性を有するアミノ酸配列、配列番号7、及び配列番号7に対して約90%超の相同性を有するアミノ酸配列からなる群から選択されるアミノ酸配列を含むTACA結合ドメインを含む、請求項84に記載の方法。
- 前記核酸分子によってコードされる前記CARの前記細胞内ドメインが、CD3ゼータシグナル伝達ドメイン及び共刺激ドメインを含む、請求項84に記載の方法。
- 前記単離された核酸分子が、発現ベクターを含む、請求項67に記載の方法。
- 前記単離された核酸分子が、in vitro転写されたRNAを含む、請求項67に記載の方法。
- 前記対象が、TACAを発現する固形腫瘍を有している、請求項67に記載の方法。
- 治療を必要とする対象における癌の治療方法であって、レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドを発現するように改変され、前記TACA結合ドメインが腫瘍細胞のTACAに特異的に結合する細胞を対象に投与することを含む、前記方法。
- 前記細胞が、抗原認識ドメイン及び細胞内ドメインを含むCARを発現するように改変され、前記抗原認識ドメインは前記TACA結合ドメインを含む、請求項90に記載の方法。
- 前記細胞が、T細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)、及び制御性T細胞からなる群から選択される、請求項90に記載の方法。
- 前記細胞が、自己由来である、請求項90に記載の方法。
- 治療を必要とする対象での癌の治療方法であって、
a)レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドと結合する薬剤を含む第1の組成物を対象に投与することと、
b)前記TACA結合ドメインを含む前記ペプチドを含む第2の組成物を前記対象に投与することと、を含む、前記方法。 - 治療を必要とする対象での癌の治療方法であって、
a)レクチンに由来する腫瘍関連糖鎖抗原(TACA)結合ドメインを含むペプチドと結合する抗原結合ドメインを含むCARを発現するように改変された細胞を対象に投与することと、
b)前記TACA結合ドメインを含む前記ペプチドを含む組成物を前記対象に投与することと、を含む、前記方法。 - 前記CARの前記抗原結合ドメインが、レクチン結合ドメインを含み、前記レクチン結合ドメインが前記TACA結合ドメインを含む前記ペプチドと結合する、請求項95に記載の方法。
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