JP6976249B2 - 免疫を工学操作するための方法および組成物 - Google Patents
免疫を工学操作するための方法および組成物 Download PDFInfo
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Description
本出願は、2015年11月23日に出願された米国仮出願第62/258,864号および2016年10月7日に出願されたた米国仮出願第62/405,521号の利益を主張し、これらの開示は、その全体が本明細書において参考として援用される。
したがって、所望の抗体導入遺伝子を発現させるために使用することができるさらなる方法および組成物の必要性が依然としてある。
一般
定義
別のスイッチ系は、そのリガンドに結合したときに立体配座を変更する小分子結合アプタマーを利用し、tet−OFF系と一緒に働く。細胞内で作用するようにデザインされるアプタマーはイントラマーとも呼ばれ、一部の実施形態では、イントラマー系の使用はin vivoで導入遺伝子を調節することができる。イントラマーは、そのリガンド(例えばテオフィリン)の存在下で、tTAおよびTREの相互作用を破壊し、したがって導入遺伝子の発現を阻害する核酸配列である(Auslanderら(2011年)NAR 39巻(22号):e155頁)。
ヌクレアーゼ
A.DNA結合ドメイン
B.切断ドメイン
標的部位
ドナー
送達
適用
アルブミン遺伝子を標的にした工学的に操作されたヌクレアーゼのデザイン、構築および特徴付け
ジンクフィンガータンパク質は、マウスアルブミン遺伝子のイントロン1内の切断部位を標的にするようにデザインされた(米国特許出願公開第20130177983号および第20160060656号を参照のこと、下の表1にも示す)。基本的にUrnovら(2005年)Nature 435巻(7042号):646〜651頁、Perezら(2008年)Nature Biotechnology 26巻(7号):808〜816頁に記載の通りに、および米国特許第6,534,261号に記載の通りに、対応する発現構築物を組み立てて、プラスミド、AAVまたはアデノウイルスベクターに組み入れた。表1は、例示的なマウスアルブミン特異的ZFPのDNA結合ドメイン内の認識ヘリックスを示し、表2はこれらのZFPのための標的部位を示す。ZFP認識ヘリックスに接触する標的部位のヌクレオチドは、大文字で示され、接触しないヌクレオチドは小文字で示される。
アルブミン特異的ヌクレアーゼの活性
5’TCATCTGTCATTGATGCACTGCAGTACAAATTAGAGGGCACCACAAGATTGACAAGAAAAAGGGGATTGAAGTTAGCCACAGCTCTGTCTCTGAGCAACAAATTTGTGGAGGGTAGT(配列番号25)
N’SSVIDALQYKLEGTTRLTRKRGLKLATALSLSNKFVEGS(配列番号26)。
(実施例4)
in vivo研究
A.方法
本発明の実施形態の例として、以下の項目が挙げられる。
(項目1)
がん抗原、細胞受容体、サイトカイン、増殖因子、増殖因子受容体、キナーゼ阻害剤、インテグリン、α−シヌクレイン、アミロイドタンパク質および補体タンパク質の群から選択されるタンパク質に結合する抗体を細胞内で発現させる方法であって、
該細胞が該抗体を生成するように、該抗体をコードする導入遺伝子を該細胞のセーフハーバー遺伝子座に組み込むこと
を含む、方法。
(項目2)
前記セーフハーバー遺伝子座がアルブミン遺伝子である、項目1に記載の方法。
(項目3)
前記導入遺伝子の発現が内因性のプロモーターによって駆動される、項目1に記載の方法。
(項目4)
前記導入遺伝子が、該導入遺伝子によってコードされるアミノ酸、および該導入遺伝子が組み込まれた内因性の前記セーフハーバー遺伝子座によってコードされるアミノ酸を含む融合タンパク質である、項目1に記載の方法。
(項目5)
前記細胞が、肝臓細胞、筋肉細胞および幹細胞からなる群から選択される、項目1に記載の方法。
(項目6)
前記幹細胞が造血幹細胞または人工多能性幹細胞である、項目5に記載の方法。
(項目7)
前記抗体が単鎖可変断片(ScFv)、イントラボディまたはダイアボディを含む、項目1に記載の方法。
(項目8)
前記抗体が被験体の細胞において発現され、さらに該抗体が、がん、自己免疫疾患、神経障害、疼痛および/または骨関節炎を処置および/または予防する、項目1に記載の方法。
(項目9)
前記抗体が前記被験体の肝臓、血清および/または脳において発現される、項目8に記載の方法。
(項目10)
前記導入遺伝子がウイルスベクターを使用して前記細胞に送達される、項目1に記載の方法。
(項目11)
前記ウイルスベクターがAAVベクターである、項目11に記載の方法。
(項目12)
項目1の方法によって産生される、遺伝子改変細胞。
(項目13)
前記導入遺伝子が生きている被験体の細胞に組み込まれる、項目1に記載の方法。
(項目14)
前記導入遺伝子が単離細胞に組み込まれ、生きている被験体に該単離細胞を投与するステップをさらに含む、項目1に記載の方法。
(項目15)
前記抗体が、前記被験体において、がん、自己免疫疾患、神経障害、疼痛および/または骨関節炎を処置および/または予防する、項目13または項目14に記載の方法。
(項目16)
がん、自己免疫疾患、神経障害、疼痛および/または骨関節炎を処置する方法で使用するための1つまたは複数のヌクレアーゼおよび1つまたは複数の抗体コード導入遺伝子であって、該方法は、それを必要とする被験体に該1つまたは複数のヌクレアーゼおよび該1つまたは複数の導入遺伝子を投与して該抗体を生成する細胞を生成することを含み、ここで、該抗体は、該がん、自己免疫疾患、神経障害、疼痛および/または骨関節炎に関与するタンパク質に結合し、該導入遺伝子は天然に存在しないヌクレアーゼを使用して該細胞の内因性アルブミン遺伝子座に組み込まれ、該細胞は該抗体を産生する、1つまたは複数のヌクレアーゼおよび1つまたは複数の抗体コード導入遺伝子。
Claims (12)
- 被験体において、精神障害を処置および/または予防する方法において使用するための、抗体およびグルコセレブロシダーゼ(GBA)の融合タンパク質をコードするポリヌクレオチドを含む組成物であって、該方法が、
細胞が該融合タンパク質を生成および分泌するように、該ポリヌクレオチドを該被験体中の該細胞のセーフハーバー遺伝子座に組み込むことを含み、
ここで、該抗体は、該被験体の脳で発現されたタンパク質に結合し、
該タンパク質は、α−シヌクレインである、組成物。 - 前記セーフハーバー遺伝子座がアルブミン遺伝子である、請求項1に記載の組成物。
- 前記ポリヌクレオチドの発現が内因性のプロモーターによって駆動される、請求項1または2に記載の組成物。
- アミノ酸を含む融合タンパク質が、該ポリヌクレオチド、および該ポリヌクレオチドが組み込まれた内因性の前記セーフハーバー遺伝子座によってコードされる、請求項1〜3のいずれか一項に記載の組成物。
- 前記細胞が、肝臓細胞、筋肉細胞および幹細胞からなる群から選択される、請求項1〜4のいずれか一項に記載の組成物。
- 前記幹細胞が造血幹細胞または人工多能性幹細胞である、請求項5に記載の組成物。
- 前記抗体が単鎖可変断片(ScFv)、イントラボディまたはダイアボディを含む、請求項1〜6のいずれか一項に記載の組成物。
- 前記組成物がウイルスベクターを使用して前記細胞に送達されることを特徴とする、請求項1〜7のいずれか一項に記載の組成物。
- 前記ウイルスベクターがAAVベクターである、請求項8に記載の組成物。
- 神経障害を処置するための、1つまたは複数のヌクレアーゼおよび1つまたは複数の抗体コードポリヌクレオチドを含む組み合わせ物であって、該ポリヌクレオチドは、抗体およびグルコセレブロシダーゼ(GBA)の融合タンパク質をコードし、該組み合わせ物は、それを必要とする被験体に投与されて該融合タンパク質を生成および分泌する細胞を生成することを特徴とし、ここで、該抗体は、該被験体の脳で発現されたタンパク質と結合し、該タンパク質は、神経障害に関与し、該タンパク質は、α−シヌクレインであり、該ポリヌクレオチドは天然に存在しないヌクレアーゼを使用して該細胞の内因性アルブミン遺伝子座に組み込まれ、該細胞は該抗体を産生することを特徴とする、組み合わせ物。
- 神経障害を処置するための、1つまたは複数のヌクレアーゼを含む組成物であって、該組成物は、抗体およびグルコセレブロシダーゼ(GBA)の融合タンパク質をコードする、1つまたは複数の抗体コードポリヌクレオチドと組み合わせてそれを必要とする被験体に投与されて該融合タンパク質を生成および分泌する細胞を生成することを特徴とし、ここで、該抗体は、該被験体の脳で発現されたタンパク質と結合し、該タンパク質は、神経障害に関与し、該タンパク質は、α−シヌクレインであり、該ポリヌクレオチドは天然に存在しないヌクレアーゼを使用して該細胞の内因性アルブミン遺伝子座に組み込まれ、該細胞は該抗体を産生することを特徴とする、組成物。
- 神経障害を処置するための、1つまたは複数の抗体コードポリヌクレオチドを含む組成物であって、該ポリヌクレオチドは、抗体およびグルコセレブロシダーゼ(GBA)の融合タンパク質をコードし、該組成物は、1つまたは複数のヌクレアーゼと組み合わせてそれを必要とする被験体に投与されて該融合タンパク質を生成および分泌する細胞を生成することを特徴とし、ここで、該抗体は、該被験体の脳で発現されたタンパク質と結合し、該タンパク質は、神経障害に関与し、該タンパク質は、α−シヌクレインであり、該ポリヌクレオチドは天然に存在しないヌクレアーゼを使用して該細胞の内因性アルブミン遺伝子座に組み込まれ、該細胞は該抗体を産生することを特徴とする、組成物。
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