JP2021166554A - 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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Abstract
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。
Dis Today 20巻(7号):38頁)。
一般
定義
。結合性タンパク質は、1つより多いタイプの結合活性を有することができる。例えば、ジンクフィンガータンパク質はDNA結合活性、RNA結合活性およびタンパク質結合活性を有する。
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
置し、12位および13位の超可変二残基(hypervariable diresidues)(RVD)の同一性とTALエフェクターの標的配列の中の近接したヌクレオチドの同一性の間に1対1の対応があるようである(MoscouおよびBogdanove、(2009年)Science 326巻:1501頁およびBochら(2009年)Science 326巻:1509〜1512頁を参照のこと)。実験的に、12位および13位のHD配列がシトシン(C)への結合をもたらし、NGがTに結合し、NIがA、C、GまたはTに、NNがAまたはGに結合し、INGがTに結合するように、これらのTALエフェクターのDNA認識のための天然のコードを決定した。これらのDNA結合リピートは、新しい配列と相互作用して、植物細胞中の非内因性レポーター遺伝子の発現を活性化することができる人工転写因子を作製するために、新しい組合せおよび多数のリピートを有するタンパク質に組み立てられた(Bochら、同上)。TALエフェクタードメインヌクレアーゼ融合物(TALEN)を得るために、工学的に操作されたTALタンパク質をFokI切断半ドメインに連結した。例えば、米国特許第8,586,526号;Christianら(2010年)<Genetics epub 10.1534/genetics.110.120717)を参照のこと。ある特定の実施形態では、TALEドメインは、米国特許第8,586,526号に記載されるようにN−キャップおよび/またはC−キャップを含む。なおさらなる実施形態では、ヌクレアーゼは、コンパクトなTALEN(cTALEN)を含む。これらは、TALE DNA結合ドメインをTevIヌクレアーゼドメインに連結する単鎖融合タンパク質である。TALE DNA結合ドメインがTevIヌクレアーゼドメインに関して位置する場所に依存して、融合タンパク質は、TALE領域によって局在化されたニッカーゼとして作用することができるか、または二本鎖切断を生じることができる(Beurdeleyら(2013年)Nat Comm:1〜8頁、DOI: 10.1038/ncomms2782を参照のこと)。任意のTALENを、さらなるTALEN(例えば、1つまたは複数のメガTALを有する1つまたは複数のTALEN(cTALENまたはFokI−TALEN))と組み合わせて使用することができる。
B.切断ドメイン
年)Nucleic Acids Res.31巻:418〜420頁を参照のこと。
標的部位
ドナー
びCTLA4(Sureshら(2014年)J Hematol Oncol 7巻:58頁)、がん/精巣(CT)抗原(例えば、MAGE−A−A4、MAGE−C1、SSX2、SSX4、NY−ESO−1、SCP1、CT7.NH−SAR−35、OY−TES−1、SLCO6A1、PASD1、CAGE−1、KK−LC−1);サイトカイン(IL−2、IL−8、IL−6R、IL−12、IL−23、IL−17、IL−22、IL−26、RANKL)、Jakキナーゼ阻害剤、TGF−β、α4β7インテグリン、α4β1インテグリン、TNFα、CD52、CD25、CD20、アネキシンA2、C1qを含む古典的補体経路に関与するタンパク質、増殖因子および/または脳および他の組織に見出されるタンパク質、例えばα−シヌクレイン、アミロイドβ(Aβ)、NGF、TrkA、CGRPおよび/もしくはNGF。例えば、Tanidaら(2015年)World J Gastro 21巻(29号):8776〜86頁;Neurath(2014年)Nature 7巻(1号):6頁;Riceら(2015年)J Clin Invest 125巻(7号):2795頁;Palmer(2013年)Br J Clin Pharm 78巻(1号):33〜43頁;Turnerら(2015年)Semin Cell Dev Biol.10月8日、pii: S1084-9521(15)00188-3. doi: 10.1016/j.semcdb.2015.10.003);Liuら(2015年)J Neuroinflam 12巻:153頁);Hiroseら(2015年)、Pain Pract doi:10.1111;Bigalら(2015年)Lancet Neurology 14巻(11号):1091頁、Gowら(2015年)Arthritis Res Ther doi:10.1186);CabelleroおよびChen(2009年)Cancer Sci 100巻(11号):2014〜2021頁を参照のこと。抗体標的は、処置および/または予防すべき状態を有する被験体において異常に発現されてもまたは発現されなくてもく、例えばがん抗原およびα−シヌクレインなどのようなタンパク質が、がんまたはシヌクレイノパチーを有する被験体において異常に発現され得る。
送達
と。
されたい)。
きる。
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。
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- 本願明細書に記載の発明。
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