JP2018505139A - 抗cd70キメラ抗原受容体 - Google Patents
抗cd70キメラ抗原受容体 Download PDFInfo
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- JP2018505139A JP2018505139A JP2017530742A JP2017530742A JP2018505139A JP 2018505139 A JP2018505139 A JP 2018505139A JP 2017530742 A JP2017530742 A JP 2017530742A JP 2017530742 A JP2017530742 A JP 2017530742A JP 2018505139 A JP2018505139 A JP 2018505139A
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Abstract
Description
本願は、2014年12月8日に出願した米国仮特許出願第62/088,882号について優先権を主張し、その全体が本明細書に援用される。
本明細書と同時に提出され、コンピューターで読み取り可能な以下のヌクレオチド/アミノ酸配列リストは、その全体が本明細書に援用される:2014年12月3日付けの「719062ST25.TXT」という名前の55,121バイトのASCII(テキスト)ファイル1件
本発明の一実施形態は、CD70に対する抗原特異性を有し、以下:CD27細胞内T細胞シグナル伝達ドメインの全て又は少なくとも配列番号2によって定義される237から260番目のアミノ酸残基からなる一部分を欠くCD27アミノ酸配列を含む抗原結合・細胞膜貫通ドメイン;4−1BB細胞内T細胞シグナル伝達ドメイン;CD3ζ細胞内T細胞シグナル伝達ドメイン;及び任意でCD28細胞内T細胞シグナル伝達ドメインを含む、キメラ抗原受容体(CAR)を提供する。本明細書において以後、「CAR」は別段の定めがない限りCARの機能的部分及び機能的変異体のことも指す。
本実施例は、完全長マウスCD27及びマウスCD3ζ細胞内T細胞シグナル伝達ドメインを含むCAR(mCD27−CD3ζCAR)をコードし、配列番号25のアミノ酸配列を有するレトロウイルスベクターの形質導入効率、及びmCD70を発現している腫瘍細胞に対するインビトロでのmCD27−CD3ζCARの反応性を実証する。
本実施例は、完全長マウスCD27及びマウスCD3ζ細胞内T細胞シグナル伝達ドメインを含むCAR(mCD27−CD3ζCAR)及び配列番号25のアミノ酸配列をコードするヌクレオチド配列で形質導入した脾細胞から作製したマウスT細胞は、腫瘍の負荷を軽減し、CD70を発現している腫瘍マウスの生存率を増加させることを実証する。
本実施例は、腫瘍マウスに対するmCD27−CD3ζCAR形質導入細胞の投与が示した毒性を実証する。本実施例ではマウスが該毒性から回復できることも実証する。
本実施例は、mCD27−CD3ζCARの投与が非腫瘍マウスの長期間における免疫機能に測定可能な影響を及ぼさないことを実証する。
本実施例は、形質導入細胞数を増幅(expansion)後、完全長ヒトCD27及びヒトCD3ζ細胞内T細胞シグナル伝達ドメインを含むCAR(fCD27−CD3ζCAR)をコードするヌクレオチド配列で形質導入したT細胞が、該CARを発現することを実証する。
本実施例は、完全長ヒトCD27及びヒトCD3ζ細胞内T細胞シグナル伝達ドメインを含むCAR(fCD27−CD3ζCAR)をコードするヌクレオチド配列で形質導入したT細胞を、CD70発現細胞との共培養で増殖し(proliferate)、インビトロでCD70発現腫瘍細胞を特異的に認識することを実証する。
本実施例は、ヒト抗CD70CARコンストラクトの形質導入効率を実証する。
本実施例はfCD27−CD3ζ(配列番号7)、ΔCD27−4−1BB−CD3ζ(配列番号9)、ΔCD27−CD28−4−1BB−CD3ζ(配列番号10)、fCD27−4−1BB-CD3ζ(配列番号12)又はfCD27−CD28−4−1BB−CD3ζ(配列番号13)で形質導入したヒトT細胞が、インビトロでCD70発現RCC腫瘍細胞を認識することを実証する。
本実施例はΔCD27−4−1BB−CD3ζ(配列番号9)レトロウイルスベクターを産生するパッキングクローンの選択について実証する。
Claims (19)
- CD70に対する抗原特異性を有するキメラ抗原受容体(CAR)であって、以下:
CD27細胞内T細胞シグナル伝達ドメインの全部又は一部分を欠くCD27アミノ酸配列を含む抗原結合・細胞膜貫通ドメインであって、前記一部分が少なくとも配列番号2で定義される237から260番目のアミノ酸残基である、抗原結合・細胞膜貫通ドメイン;
4−1BB細胞内T細胞シグナル伝達ドメイン;
CD3ζ細胞内T細胞シグナル伝達ドメイン;及び
任意によりCD28細胞内T細胞シグナル伝達ドメイン
を含む、前記CAR。 - 4−1BB細胞内T細胞シグナル伝達ドメイン、CD3ζ細胞内T細胞シグナル伝達ドメイン及びCD28細胞内T細胞シグナル伝達ドメインを含む、請求項1に記載のCAR。
- 4−1BB細胞内T細胞シグナル伝達ドメイン及びCD3ζ細胞内T細胞シグナル伝達ドメインを含む、請求項1に記載のCAR。
- 前記CD28細胞内T細胞シグナル伝達ドメインが少なくとも配列番号6と約90%同一であるアミノ酸配列を含む、請求項1又は2に記載のCAR。
- 前記4−1BB細胞内T細胞シグナル伝達ドメインが、配列番号5と少なくとも約90%同一であるアミノ酸配列を含む、請求項1〜4のいずれか1項に記載のCAR。
- 前記CD3ζ細胞内T細胞シグナル伝達ドメインが、配列番号4と少なくとも約90%同一であるアミノ酸配列を含む、請求項1〜5のいずれか1項に記載のCAR。
- 前記抗原結合・細胞膜貫通ドメインが、CD27細胞内T細胞シグナル伝達ドメインの全部を欠くCD27アミノ酸配列を含む、請求項1〜6のいずれか1項に記載のCAR。
- 前記CD27抗原結合・細胞膜貫通ドメインが、配列番号3と少なくとも約90%同一であるアミノ酸配列を含む、請求項1〜7のいずれか1項に記載のCAR。
- 少なくとも配列番号8〜10のいずれか1つと約90%同一であるアミノ酸配列を含む、請求項1〜8のいずれか1項に記載のCAR。
- 少なくとも配列番号11〜13のいずれか1つと約90%同一であるアミノ酸配列を含む、CD70に対する抗原特異性を有するCAR。
- 配列番号8〜13のいずれか1つのアミノ酸配列を含む、請求項9又は10に記載のCAR。
- 請求項1〜11のいずれか1項に記載のCARをコードするヌクレオチド配列を含む、核酸。
- 配列番号16、17、19及び20のいずれか1つのヌクレオチド配列を含む、請求項12に記載の核酸。
- 請求項13に記載の核酸を含む、組換え発現ベクター。
- 請求項14に記載の組換え発現ベクターを含む、単離された宿主細胞。
- 請求項15に記載の宿主細胞を少なくとも1つ含む、細胞集団。
- 請求項1〜11のいずれか1項に記載のCAR、請求項12又は13に記載の核酸、請求項14に記載の組換え発現ベクター、請求項15に記載の宿主細胞、又は請求項16に記載の細胞集団、及び医薬的に許容される担体を含む、医薬組成物。
- 哺乳動物におけるがんの存在を検出する方法であって、以下:
(a)哺乳動物由来の1つ以上の細胞を含む試料と、請求項1〜11のいずれか1項に記載のCAR、請求項12又は13に記載の核酸、請求項14に記載の組換え発現ベクター、請求項15に記載の宿主細胞、請求項16に記載の細胞集団、又は請求項17に記載の医薬組成物とを接触させて複合体を形成させ;及び
(b)前記複合体を検出する、
ことを含み、前記複合体の検出が哺乳動物におけるがんの存在の指標である、方法。 - がんの治療又は予防に使用するための、請求項1〜11のいずれか1項に記載のCAR、請求項12又は13に記載の核酸、請求項14に記載の組換え発現ベクター、請求項15に記載の宿主細胞、請求項16に記載の細胞集団、又は請求項17に記載の医薬組成物。
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