JP2023537799A - Cd28hドメイン含有キメラ抗原受容体および使用方法 - Google Patents
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Abstract
Description
本明細書または添付の配列表に列挙されている任意の核酸およびアミノ酸配列は、米国特許法施行規則§1.822で定義されているように、ヌクレオチド塩基およびアミノ酸についての標準的な文字略語を使用して示されている。少なくともいくつかの場合、各核酸配列の1つの鎖のみが示されているが、相補鎖は、表示された鎖に対する任意の参照によって含まれると理解される。
I.用語
II.キメラ抗原受容体
表1:例示的な細胞外抗原結合ドメイン標的および悪性腫瘍
表2:例示的なCAR
III.キメラアダプタータンパク質を発現する細胞
IV.免疫療法の方法
実施例1
CD28ホモログは、B7H7+腫瘍細胞の溶解のためのナチュラルキラー細胞の強力な活性化因子である
材料および方法
結果
考察
実施例2
NK細胞における阻害抵抗性キメラ抗原受容体は強力かつ持続的な活性化シグナルをもたらす
材料および方法
結果および考察
実施例3
CAR有効性のインビボ評価
実施例4
CD19-CAR発現NK細胞によるB細胞リンパ腫の処置
本発明は、例えば、以下の項目を提供する。
(項目1)
キメラ抗原受容体であって、
(a)標的結合ドメインと、
(b)膜貫通ドメインと、
(c)CD28ホモログ(CD28H)由来の第1の細胞内シグナル伝達ドメインおよび第2の細胞内シグナル伝達ドメインを含む細胞内ドメインであって、前記第1および第2の細胞内シグナル伝達ドメインがどちらの順序であってもよい、細胞内ドメインと、を含むキメラ抗原受容体。
(項目2)
前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282と少なくとも90%の同一性を有するアミノ酸配列を含む、項目1に記載のキメラ抗原受容体。
(項目3)
前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282のアミノ酸配列を含む、項目2に記載のキメラ抗原受容体。
(項目4)
前記第2の細胞内シグナル伝達ドメインが、2B4、TCRζ、FcεR1γまたはDAP12に由来する、項目1~3のいずれか一項に記載のキメラ抗原受容体。
(項目5)
前記第2の細胞内シグナル伝達ドメインが、TCRζに由来する、項目4に記載のキメラ抗原受容体。
(項目6)
前記TCRζ細胞内シグナル伝達ドメインが、配列番号2のアミノ酸283~395と少なくとも90%の同一性を有するアミノ酸配列を含む、項目5に記載のキメラ抗原受容体。
(項目7)
前記TCRζ細胞内シグナル伝達ドメインが、配列番号2のアミノ酸283~395のアミノ酸配列を含む、項目6に記載のキメラ抗原受容体。
(項目8)
前記第2の細胞内シグナル伝達ドメインが、2B4に由来する、項目4に記載のキメラ抗原受容体。
(項目9)
前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291と少なくとも90%の同一性を有するアミノ酸配列を含む、項目8に記載のキメラ抗原受容体。
(項目10)
前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291のアミノ酸配列を含む、項目9に記載のキメラ抗原受容体。
(項目11)
前記細胞内ドメインが、前記膜貫通ドメインと前記第1の細胞内シグナル伝達ドメインとの間に細胞内領域をさらに含む、項目1~10のいずれか一項に記載のキメラ抗原受容体。
(項目12)
前記膜貫通ドメインおよび細胞内領域が、CD16、NKp46、NKp30、NKp44またはKIR2DS4に由来する、項目11記載のキメラ抗原受容体。
(項目13)
キメラ抗原受容体であって、
(a)標的結合ドメインと、
(b)膜貫通ドメインと、
(c)CD28ホモログ(CD28H)由来の第1の細胞内シグナル伝達ドメインと、2B4由来の第2の細胞内シグナル伝達ドメインと、第3の細胞内シグナル伝達ドメインとを含み、前記第1、第2、および第3の細胞内シグナル伝達ドメインが、任意の順序であり得る、細胞内ドメインと、を含む、キメラ抗原受容体。
(項目14)
前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282と少なくとも90%の同一性を有するアミノ酸配列を含む、項目13に記載のキメラ抗原受容体。
(項目15)
前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282のアミノ酸配列を含む、項目14に記載のキメラ抗原受容体。
(項目16)
前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291と少なくとも90%の同一性を有するアミノ酸配列を含む、項目13~15のいずれか一項に記載のキメラ抗原受容体。
(項目17)
前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291のアミノ酸配列を含む、項目16に記載のキメラ抗原受容体。
(項目18)
前記第3の細胞内シグナル伝達ドメインが、TCRζ、FcεR1γまたはDAP12に由来する、項目13~17のいずれか一項に記載のキメラ抗原受容体。
(項目19)
前記第3の細胞内シグナル伝達ドメインが、TCRζに由来する、項目18に記載のキメラ抗原受容体。
(項目20)
前記標的結合ドメインが、CD19 scFvまたはCD28H細胞外ドメインを含む、項目1~19のいずれか一項に記載のキメラ抗原受容体。
(項目21)
前記膜貫通ドメインが、CD28H膜貫通ドメインを含む、項目1~10または13から20のいずれか一項に記載のキメラ抗原受容体。
(項目22)
ヒンジドメインをさらに含み、前記ヒンジドメインが、前記標的結合ドメインに対してC末端であり、前記膜貫通ドメインに対してN末端である、項目1~21のいずれか一項に記載のキメラ抗原受容体。
(項目23)
前記ヒンジ領域が、CD8αヒンジ領域を含む、項目22に記載のキメラ抗原受容体。
(項目24)
アミノ末端シグナル配列をさらに含む、項目1~23のいずれか一項に記載のキメラ抗原受容体。
(項目25)
前記シグナル配列が、CD8αシグナル配列である、項目24記載のキメラ抗原受容体。
(項目26)
前記CD8αシグナル配列が、配列番号16のアミノ酸1~21を含む、項目25に記載のキメラ抗原受容体。
(項目27)
配列番号2、6、12、16および20のうちのいずれか1つのアミノ酸配列と少なくとも90%の配列同一性を有するアミノ酸配列を含む、項目1~26のいずれか一項に記載のキメラ抗原受容体。
(項目28)
配列番号2、6、12、16および20のうちのいずれか1つのアミノ酸配列を含む、項目27に記載のキメラ抗原受容体。
(項目29)
項目1~28のいずれか一項に記載のキメラ抗原受容体をコードする核酸分子。
(項目30)
配列番号1、5、11、15、および19のうちのいずれか1つの核酸配列と少なくとも90%の配列同一性を有する核酸配列を含む、項目29に記載の核酸分子。
(項目31)
配列番号1、5、11、15および19のうちのいずれか1つの核酸配列を含む、項目30に記載の核酸分子。
(項目32)
項目29~31のいずれか一項に記載の核酸分子を含むベクター。
(項目33)
前記ベクターが、ウイルスベクターである、項目32に記載のベクター。
(項目34)
前記ウイルスベクターが、レンチウイルスベクターまたはレトロウイルスベクターである、項目33に記載のベクター。
(項目35)
項目1~28のいずれか一項に記載のキメラ抗原受容体を発現する細胞。
(項目36)
項目29~31のいずれか一項に記載の核酸または項目32~34のいずれか一項に記載のベクターを含む細胞。
(項目37)
前記細胞が、ナチュラルキラー細胞またはT細胞である、項目35または項目36に記載の細胞。
(項目38)
項目29~31のいずれか一項に記載の核酸、項目32~34のいずれか一項に記載のベクター、または項目35~37のいずれか一項に記載の細胞および薬学的に許容され得る担体を含む組成物。
(項目39)
がんを有する対象を処置する方法であって、有効量の項目35~37のいずれか一項に記載の細胞または項目38に記載の医薬組成物を前記対象に投与することを含む、方法。
(項目40)
前記医薬組成物が、ナチュラルキラー細胞またはT細胞を含む、項目39に記載の方法。
(項目41)
前記ナチュラルキラー細胞またはT細胞が、処置されている前記対象にとって自家である、項目40に記載の方法。
(項目42)
前記がんが、血液悪性腫瘍または固形腫瘍である、項目39~41のいずれか一項に記載の方法。
(項目43)
前記血液悪性腫瘍が、急性リンパ芽球性白血病、急性骨髄性白血病、慢性リンパ性白血病、非ホジキンリンパ腫、びまん性大細胞型B細胞リンパ腫、または多発性骨髄腫である、項目42に記載の方法。
(項目44)
前記固形腫瘍が、乳がん、卵巣がん、結腸直腸がん、神経膠芽腫、神経芽細胞腫、膵臓がん、肺がん、肝臓がん、膀胱がん、前立腺がん、または肉腫である、項目42に記載の方法。
(項目45)
手術、化学療法、放射線治療、またはそれらの2もしくはそれより多くの組み合わせで前記対象を処置することをさらに含む、項目39~44のいずれか一項に記載の方法。
Claims (45)
- キメラ抗原受容体であって、
(a)標的結合ドメインと、
(b)膜貫通ドメインと、
(c)CD28ホモログ(CD28H)由来の第1の細胞内シグナル伝達ドメインおよび第2の細胞内シグナル伝達ドメインを含む細胞内ドメインであって、前記第1および第2の細胞内シグナル伝達ドメインがどちらの順序であってもよい、細胞内ドメインと、を含むキメラ抗原受容体。 - 前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項1に記載のキメラ抗原受容体。
- 前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282のアミノ酸配列を含む、請求項2に記載のキメラ抗原受容体。
- 前記第2の細胞内シグナル伝達ドメインが、2B4、TCRζ、FcεR1γまたはDAP12に由来する、請求項1~3のいずれか一項に記載のキメラ抗原受容体。
- 前記第2の細胞内シグナル伝達ドメインが、TCRζに由来する、請求項4に記載のキメラ抗原受容体。
- 前記TCRζ細胞内シグナル伝達ドメインが、配列番号2のアミノ酸283~395と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項5に記載のキメラ抗原受容体。
- 前記TCRζ細胞内シグナル伝達ドメインが、配列番号2のアミノ酸283~395のアミノ酸配列を含む、請求項6に記載のキメラ抗原受容体。
- 前記第2の細胞内シグナル伝達ドメインが、2B4に由来する、請求項4に記載のキメラ抗原受容体。
- 前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項8に記載のキメラ抗原受容体。
- 前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291のアミノ酸配列を含む、請求項9に記載のキメラ抗原受容体。
- 前記細胞内ドメインが、前記膜貫通ドメインと前記第1の細胞内シグナル伝達ドメインとの間に細胞内領域をさらに含む、請求項1~10のいずれか一項に記載のキメラ抗原受容体。
- 前記膜貫通ドメインおよび細胞内領域が、CD16、NKp46、NKp30、NKp44またはKIR2DS4に由来する、請求項11記載のキメラ抗原受容体。
- キメラ抗原受容体であって、
(a)標的結合ドメインと、
(b)膜貫通ドメインと、
(c)CD28ホモログ(CD28H)由来の第1の細胞内シグナル伝達ドメインと、2B4由来の第2の細胞内シグナル伝達ドメインと、第3の細胞内シグナル伝達ドメインとを含み、前記第1、第2、および第3の細胞内シグナル伝達ドメインが、任意の順序であり得る、細胞内ドメインと、を含む、キメラ抗原受容体。 - 前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項13に記載のキメラ抗原受容体。
- 前記CD28H細胞内シグナル伝達ドメインが、配列番号2のアミノ酸172~282のアミノ酸配列を含む、請求項14に記載のキメラ抗原受容体。
- 前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291と少なくとも90%の同一性を有するアミノ酸配列を含む、請求項13~15のいずれか一項に記載のキメラ抗原受容体。
- 前記2B4細胞内シグナル伝達ドメインが、配列番号10のアミノ酸172~291のアミノ酸配列を含む、請求項16に記載のキメラ抗原受容体。
- 前記第3の細胞内シグナル伝達ドメインが、TCRζ、FcεR1γまたはDAP12に由来する、請求項13~17のいずれか一項に記載のキメラ抗原受容体。
- 前記第3の細胞内シグナル伝達ドメインが、TCRζに由来する、請求項18に記載のキメラ抗原受容体。
- 前記標的結合ドメインが、CD19 scFvまたはCD28H細胞外ドメインを含む、請求項1~19のいずれか一項に記載のキメラ抗原受容体。
- 前記膜貫通ドメインが、CD28H膜貫通ドメインを含む、請求項1~10または13から20のいずれか一項に記載のキメラ抗原受容体。
- ヒンジドメインをさらに含み、前記ヒンジドメインが、前記標的結合ドメインに対してC末端であり、前記膜貫通ドメインに対してN末端である、請求項1~21のいずれか一項に記載のキメラ抗原受容体。
- 前記ヒンジ領域が、CD8αヒンジ領域を含む、請求項22に記載のキメラ抗原受容体。
- アミノ末端シグナル配列をさらに含む、請求項1~23のいずれか一項に記載のキメラ抗原受容体。
- 前記シグナル配列が、CD8αシグナル配列である、請求項24記載のキメラ抗原受容体。
- 前記CD8αシグナル配列が、配列番号16のアミノ酸1~21を含む、請求項25に記載のキメラ抗原受容体。
- 配列番号2、6、12、16および20のうちのいずれか1つのアミノ酸配列と少なくとも90%の配列同一性を有するアミノ酸配列を含む、請求項1~26のいずれか一項に記載のキメラ抗原受容体。
- 配列番号2、6、12、16および20のうちのいずれか1つのアミノ酸配列を含む、請求項27に記載のキメラ抗原受容体。
- 請求項1~28のいずれか一項に記載のキメラ抗原受容体をコードする核酸分子。
- 配列番号1、5、11、15、および19のうちのいずれか1つの核酸配列と少なくとも90%の配列同一性を有する核酸配列を含む、請求項29に記載の核酸分子。
- 配列番号1、5、11、15および19のうちのいずれか1つの核酸配列を含む、請求項30に記載の核酸分子。
- 請求項29~31のいずれか一項に記載の核酸分子を含むベクター。
- 前記ベクターが、ウイルスベクターである、請求項32に記載のベクター。
- 前記ウイルスベクターが、レンチウイルスベクターまたはレトロウイルスベクターである、請求項33に記載のベクター。
- 請求項1~28のいずれか一項に記載のキメラ抗原受容体を発現する細胞。
- 請求項29~31のいずれか一項に記載の核酸または請求項32~34のいずれか一項に記載のベクターを含む細胞。
- 前記細胞が、ナチュラルキラー細胞またはT細胞である、請求項35または請求項36に記載の細胞。
- 請求項29~31のいずれか一項に記載の核酸、請求項32~34のいずれか一項に記載のベクター、または請求項35~37のいずれか一項に記載の細胞および薬学的に許容され得る担体を含む組成物。
- がんを有する対象を処置する方法であって、有効量の請求項35~37のいずれか一項に記載の細胞または請求項38に記載の医薬組成物を前記対象に投与することを含む、方法。
- 前記医薬組成物が、ナチュラルキラー細胞またはT細胞を含む、請求項39に記載の方法。
- 前記ナチュラルキラー細胞またはT細胞が、処置されている前記対象にとって自家である、請求項40に記載の方法。
- 前記がんが、血液悪性腫瘍または固形腫瘍である、請求項39~41のいずれか一項に記載の方法。
- 前記血液悪性腫瘍が、急性リンパ芽球性白血病、急性骨髄性白血病、慢性リンパ性白血病、非ホジキンリンパ腫、びまん性大細胞型B細胞リンパ腫、または多発性骨髄腫である、請求項42に記載の方法。
- 前記固形腫瘍が、乳がん、卵巣がん、結腸直腸がん、神経膠芽腫、神経芽細胞腫、膵臓がん、肺がん、肝臓がん、膀胱がん、前立腺がん、または肉腫である、請求項42に記載の方法。
- 手術、化学療法、放射線治療、またはそれらの2もしくはそれより多くの組み合わせで前記対象を処置することをさらに含む、請求項39~44のいずれか一項に記載の方法。
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