JP2020529970A - 標的化タンパク質分解 - Google Patents
標的化タンパク質分解 Download PDFInfo
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Abstract
Description
本発明の第1の態様によれば、
ポリペプチド配列のレベルを制御する方法であって、以下:
a) 前記ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とを含む融合タンパク質を投与すること、及び
b) 上記ユビキチン標的化タンパク質とセレブロンとの結合を媒介する化合物を投与することにより上記ポリペプチド配列のレベルを制御すること
を含む、上記方法が提供される。
a) A-B
(式中、
Aはポリペプチド配列であり;
Bは、整列させた場合に表1にリストされるアミノ酸残基のそれぞれの間のバックボーン原子から約6.0Åの二乗平均平方根偏差(rmsd)以内の一連の構造座標を有する構造モチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質であり、ここで上記構造モチーフは、表1のGLY56に対応する位置にグリシン残基を含む)
を含む融合タンパク質を投与すること;及び
b) 上記ポリペプチド配列をユビキチンリガーゼに近づけるような方法でa) ユビキチン標的化タンパク質とb) ユビキチンリガーゼとの結合を媒介する化合物(ここで上記ポリペプチド配列は、上記化合物の存在下でユビキチン化され得る)を投与することによりポリペプチド配列のレベルを制御すること
を含む、上記方法が提供される。
細胞外リガンド結合ドメイン;
膜貫通ドメイン;
細胞内シグナル伝達ドメイン;及び
化合物の存在下でユビキチンリガーゼにより結合され得る、本明細書中に記載されるユビキチン標的化タンパク質
を含むキメラ抗原受容体(CAR)が提供される。
A-B
(式中、
Aはポリペプチド配列であり;
Bは、配列番号6〜14からなる群から選択される配列からなるユビキチン標的化タンパク質である)
を含む融合タンパク質が提供される。
本明細書中には、標的タンパク質の有効なユビキチン化に必要とされる必須の構造モチーフが記載される。特に、標的細胞に投与される異種タンパク質が、いずれかの有害作用のリスクを回避するため厳密に制御されることが必要とされる治療タンパク質である場合、この構造モチーフを用いて、標的細胞に投与された異種タンパク質のレベル及び/又は活性を制御することができる。有効なユビキチン化に必要とされるモチーフのサイズを最小化することは、とりわけ異種タンパク質が、スペースが希少なウイルスベクターを介して導入される場合に有利である。
別段に定義されない限り、本明細書中で使用される全ての技術用語及び科学用語は、当業者(例えば、細胞培養、分子遺伝学、核酸化学、ハイブリダイゼーション技術及び生化学の分野における当業者)に一般的に理解される意味と同じ意味を有する。分子法、遺伝子法及び生化学法のための標準技術(一般的には、Sambrook et al., Molecular Cloning:A Laboratory Manual, 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al., Short Protocols in Molecular Biology (1999) 4th Ed, John Wiley & Sons, Inc.(これらはその全体が参照により本明細書中に組み込まれる)を参照)及び化学法のための標準技術が用いられる。本明細書中で言及される全ての特許及び刊行物は、その全体が参照により組み込まれる。
CK1及びGSTP1について、セレブロン結合部位の構造的保存が観察された。Ikaros1及びIkaros3について、構造的保存は、Eos(Ikaros4、PDB 2MA7)又はPDB iD2I13由来のジンクフィンガータンパク質などの構造的に特徴づけられたタンパク質との相同性により推測された。本発明者らは、前記タンパク質のレベル及び/又は活性を制御する方法を提供するため、この保存された構造モチーフを異種タンパク質に融合することを提案した。当技術分野において用いられる現在のPROTAC法とは対照的に、本方法は、ユビキチン標的化タンパク質(ユビキチン標的化ドメインとも呼ばれ得る)を制御されるべきタンパク質に直接融合することを含み、その結果、ユビキチン化をもたらすユビキチンリガーゼへの結合を誘導するためには外部化合物を添加するだけでよい。
a) 前記ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とを含む融合タンパク質を投与すること、及び
b) 上記ユビキチン標的化タンパク質とセレブロンとの結合を媒介する化合物を投与することによりポリペプチド配列のレベルを制御すること
を含む、上記方法が提供される。
a) A-B
(式中、
Aはポリペプチド配列であり;
Bは、整列させた場合に表1にリストされるアミノ酸残基のそれぞれの間のバックボーン原子から約6.0Åの二乗平均平方根偏差(rmsd)以内の一連の構造座標を有する構造モチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質であり、ここで上記構造モチーフは、表1のGLY56に対応する位置にグリシン残基を含む)
を含む融合タンパク質を投与すること;及び
b) 上記ポリペプチド配列をユビキチンリガーゼに近づけるような方法でa) ユビキチン標的化タンパク質とb) ユビキチンリガーゼとの結合を媒介する化合物を投与することによりポリペプチド配列のレベルを制御すること(ここで上記ポリペプチド配列は、上記化合物の存在下でユビキチン化され得る)
を含む、上記方法が提供される。
X1X2X3X4X5GX7X8X9X10
(式中、Xは任意のアミノ酸を表すか又は存在しない)を含む。さらなる実施形態において、配列番号1の構造モチーフは、1、2、3個又はそれ以上のアミノ酸をさらに含む。なおさらなる実施形態において、構造モチーフは、配列番号15のアミノ酸配列:
X1X2X3X4X5GX7X8X9X10X11X12
(式中、Xは任意のアミノ酸を表すか又は存在しない)を含む。
X1は、バリン(V)、イソロイシン(I)を表すか又は存在せず;
X2は、アスパラギン酸(D)、アスパラギン(N)を表すか又は存在せず;
X3は、リシン(K)、イソロイシン(I)を表すか又は存在せず;
X4は、グルタミン(Q)、リシン(K)又はトレオニン(T)を表し;
X5は、システイン(C)、セリン(S)又はアスパラギン(N)を表し;
X7は、アラニン(A)又はグルタミン酸(E)を表し;
X8は、セリン(S)、リシン(K)又はグルタミン酸(E)を表し;
X9は、フェニルアラニン(F)、セリン(S)又はバリン(V)を表し;
X10は、トレオニン(T)、リシン(K)又はアラニン(A)を表し;
X11は、グルタミン(Q)、トレオニン(T)又はバリン(V)を表し;且つ/又は
X12は、リシン(K)又はアルギニン(R)を表す。
一実施形態において、化合物は免疫調節イミド薬(IMiD)である。かかる薬は、イミド基を含む免疫調節薬のクラスである。現在、IMiDの主な用途は、がん及び自己免疫疾患の治療である。
本発明のさらなる態様によれば、以下:
細胞外リガンド結合ドメイン;
膜貫通ドメイン;
細胞内シグナル伝達ドメイン;及び
ある化合物の存在下でユビキチンリガーゼにより結合され得る本明細書中に記載されるユビキチン標的化タンパク質
を含むキメラ抗原受容体(CAR)が提供される。
(a) 免疫調節細胞に、本明細書中に記載されるキメラ抗原受容体をコードするポリヌクレオチドを形質導入又はトランスフェクトすること;
(b) 免疫調節細胞中で前記ポリヌクレオチドを発現させること;
(c) 化合物の添加によりキメラ抗原受容体の活性化を制御すること;
を含み、ここで上記化合物は、キメラ抗原受容体をユビキチンリガーゼに近づけるような方法でa) ユビキチン標的化タンパク質とb) ユビキチンリガーゼとの結合を媒介し、上記キメラ抗原受容体は上記化合物の存在下でユビキチン化され得る、上記方法が提供される。
本明細書中に記載される融合タンパク質の成分は、ある成分が細胞中で発現される場合、その新生タンパク質を小胞体に向け、その後それが発現され得る細胞表面に向けるようにシグナルペプチドを含み得る。
本発明のさらなる態様によれば、本明細書中に記載されるユビキチン標的化タンパク質をコードする単離されたポリヌクレオチドが提供される。本発明のさらなる態様によれば、本明細書中に記載される融合タンパク質をコードするポリヌクレオチドが提供される。本発明のなおさらなる態様によれば、本明細書中に記載されるキメラ抗原受容体をコードするポリヌクレオチドが提供される。
本発明のさらなる態様によれば、本明細書中に記載される融合タンパク質を含む細胞が提供される。本発明の別の態様によれば、本明細書中に記載されるポリヌクレオチド又は発現ベクターを含む細胞が提供される。
本明細書中に記載される発明は、安全スイッチの一部としての最小のユビキチン標的化タンパク質の使用を提供する。従って、本発明の一態様によれば、安全スイッチとしての本明細書中に記載されるユビキチン標的化タンパク質の使用が提供される。
本発明のさらなる態様によれば、本明細書中で定義される複数の細胞を含む医薬組成物が提供される。一実施形態において、上記細胞は、ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とをコードするポリヌクレオチド配列を含む。一実施形態において、上記細胞は、ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とをコードする発現ベクターを含む。一実施形態において、ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とをコードするポリヌクレオチド配列又は発現ベクターを含む細胞は、免疫調節細胞である。一実施形態において、ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とをコードするポリヌクレオチド配列又は発現ベクターを含む細胞は、T細胞である。
。
本発明のさらなる態様によれば、本明細書中に記載される融合タンパク質、キメラ抗原受容体、ポリヌクレオチド、発現ベクター、細胞及び/又は医薬組成物を含むキットが提供される。
本発明のさらなる態様によれば、免疫調節細胞(すなわち、本明細書中に記載される融合タンパク質を発現するための免疫調節細胞)を操作する方法であって、
(a) 免疫調節細胞を提供すること;
(b) 本明細書中で定義されるポリヌクレオチド又は発現ベクターを、前記免疫調節細胞に形質導入又はトランスフェクトすること;及び
(c) 前記ポリヌクレオチド又は前記発現ベクターを免疫調節細胞中で発現させること
を含む、上記方法が提供される。
(a) 細胞(1つ又は複数)を提供するステップ;
(b) 本明細書中で定義されるポリヌクレオチド又は発現ベクターを前記細胞(1つ又は複数)に形質導入又はトランスフェクトするステップ;
(c) 前記ポリヌクレオチド又は前記発現ベクターを細胞(1つ又は複数)中で発現させるステップ;及び
(d) 細胞(1つ又は複数)を患者に投与するステップ
を含み得る。
この実施例は、レナリドミドの存在下におけるGFPの選択的分解を示す。GFP構築物は、長さN=1、3、5の(グリシン-セリン) x Nリンカー及びそれに続くヒトIkaros 1由来のデグロン配列とインフレームのGFPコーディング配列で構成される。HeLa細胞にトランスフェクトされた構築物を用いて実験を行い、フローサイトメトリーにより分解を追跡した。
構築物の作製:GFP構築物を、長さN=1、3、5の(グリシン-セリン) x Nリンカー及び残基141〜168(配列番号27)を含むヒトIkaros 1(IKFZ1、Uniprot Q13422)配列に融合したpTT5ベクター(図2)にクローン化した。構築物の全配列の詳細は以下に示される。
構築物1、2及び3中にコードされるGFPのレナリドミド誘導分解を、GFP陽性細胞の中央蛍光強度(MFI)の測定により評価した。レナリドミドがGFPの発現レベルに与える影響は、図3に示される。
構築物の作製:レナリドミドが受容体(CAR)の発現レベルの調節に与える影響を評価するため、2つの構築物を作製した。構築物4は、B細胞成熟抗原(BCMA)(Uniprot Q02223)に結合し、これにより活性化される抗原認識scFvを有する従来のCARである。このscFvの後ろに、ヒトCD8αヒンジ及び膜貫通ドメイン、ヒト4-1BB共刺激ドメイン及びヒトCD3ζ細胞内ドメインが続く(図1)。構築物5は、構築物4と同じエレメントに加えて、ヒトIkaros3タンパク質(Uniprot Q9UKT9)の2つの断片のC末端付加を含む。第1断片は残基131〜175(配列番号27)を含み、その後ろに残基231〜249(配列番号28)を含む断片が続く。構築物の全配列の詳細は以下に示される。
図5は、レナリドミド処理がJurkat細胞の表面上のCAR分子の発現レベルに与える影響を示す。任意のデグロン配列を含まない構築物4は化合物による影響を受けないが、構築物5の発現は、10μMレナリドミドの添加により低下する。
この実施例は、デグロン配列を含むCARが初代T細胞中で機能的であり、レナリドミドの添加により分解されることを示す。
レンチウイルスベクター産生のため、3.0x107 LentiX 293T(HEK293T)細胞を20mL DMEM (Gibco)中に播種し、5%CO2と共に37℃で一晩インキュベートした。LentiX細胞を、例えば、上記の構築物を含む21μgのトランスファーベクター、3.75μg ViraSafe pRSV-Rev、5.25μg ViraSafe pCMV-VSVG、7.5μg ViraSafe pCgp V-(gag-pol)、75μg jetPRIME(Polyplus)及び1500μg jetPRIMEバッファー(Polyplus)を混合することによりトランスフェクトした。2日後、上清を清澄化してウイルスを濃縮し、50mLオークリッジPPCO超遠心分離管(ThermoFisher)中、Ultrapure sucrose(ThermoFisher)を用いた20%スクロースクッション上の超遠心分離により精製した。上記の方法を用いて、構築物4及び構築物5のレンチウイルスベクターを産生した。
レナリドミド処理が、形質導入された初代T細胞における構築物4及び構築物5の発現レベルに与える影響は、図6に示される。抗原提示後、T細胞上清を、それらのTNFα、IL2及びIFN-γレベルについて分析した。構築物4(デグロンドメインを有さないCAR構築物)に対応する上清は、無レナリドミド処理と比較した場合にサイトカイン濃度のレベルの増加を示し、これは公開データ(Otahal P et al. 2016 Oncoimmunology Vol. 5, No. 4)と一致していた(図7)。この影響は、構築物5(CARにデグロンエレメントを加えたもの)が形質導入された細胞についても観察されたが、対照CAR(構築物4)と比較した場合、程度は低かった(図7)。
Claims (40)
- ポリペプチド配列のレベルを制御する方法であって、以下:
a) 前記ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とを含む融合タンパク質を投与すること、及び
b) ユビキチン標的化タンパク質とセレブロンとの結合を媒介する化合物を投与することによりポリペプチド配列のレベルを制御すること
を含む、前記方法。 - ヘアピンモチーフが、配列番号2〜5、又は各アミノ酸配列中に存在するGLY残基を除いて1又は2個のアミノ酸が置換、付加又は欠失されていてもよいその機能的変異体からなる群から選択される配列を含む、請求項1に記載の方法。
- ヘアピンモチーフが、配列番号2〜5からなる群から選択される配列を含む、請求項1〜2のいずれか1項に記載の方法。
- ユビキチン標的化タンパク質が、100未満のアミノ酸長からなるポリペプチド配列である、請求項1〜3のいずれか1項に記載の方法。
- ユビキチン標的化タンパク質が、ユビキチン化部位として機能するリシン残基を含む、請求項1〜4のいずれか1項に記載の方法。
- ユビキチン標的化タンパク質が、配列番号6〜14及び27からなる群から選択される配列を含む、請求項1〜5のいずれか1項に記載の方法。
- ユビキチン標的化タンパク質とセレブロンとの結合を媒介する化合物を投与することにより制御されるポリペプチド配列が、膜貫通タンパク質である、請求項1〜6のいずれか1項に記載の方法。
- ユビキチン標的化タンパク質とセレブロンとの結合を媒介する化合物を投与することにより制御されるポリペプチド配列が、キメラ抗原受容体(CAR)である、請求項1〜7のいずれか1項に記載の方法。
- 化合物が免疫調節イミド薬(IMiD)である、請求項1〜8のいずれか1項に記載の方法。
- IMiDが、サリドマイド、レナリドミド、ポマリドミド又はその機能的誘導体若しくは類似体から選択される、請求項9に記載の方法。
- キメラ抗原受容体(CAR)であって、以下:
細胞外リガンド結合ドメイン;
膜貫通ドメイン;
細胞内シグナル伝達ドメイン;及び
ある化合物の存在下でユビキチンリガーゼにより結合され得る請求項1〜6のいずれか1項に記載のユビキチン標的化タンパク質
を含む、前記キメラ抗原受容体。 - 細胞外リガンド結合ドメインが、抗B細胞成熟抗原(BCMA)一本鎖Fvアミノ酸配列である、請求項11に記載のCAR。
- 抗BCMA一本鎖Fvアミノ酸配列が配列番号29を含む、請求項12に記載のCAR。
- 膜貫通ドメインが、CD4、CD8、CD3又はCD28の膜貫通ドメインから選択される、請求項11〜13のいずれか1項に記載のCAR。
- CD8α膜貫通ドメインが配列番号17を含む、請求項14に記載のCAR。
- 細胞内シグナル伝達ドメインが免疫受容体チロシンベースの活性化モチーフ(ITAM)である、請求項11〜15のいずれか1項に記載のCAR。
- ITAMが、CD3ゼータ、FcRガンマ、FcRベータ、FcRイプシロン、CD3ガンマ、CD3デルタ、CD3イプシロン、CD5、CD22、CD79a、CD79b又はCD66dのITAMから選択される、請求項16に記載のCAR。
- CD3ζシグナル伝達ドメインが配列番号20を含む、請求項17に記載のCAR。
- 共刺激ドメインをさらに含む、請求項11〜18のいずれか1項に記載のCAR。
- 共刺激ドメインが、CD28、CD27、4-1BB(CD137)、OX40(CD134)、ICOS(CD278)、CD30、CD40、PD-1(CD279)、CD2、CD7、NKG2C(CD94)又はB7-H3(CD276)の共刺激ドメインから選択される、請求項19に記載のCAR。
- 共刺激ドメインが配列番号21を含む、請求項19〜20のいずれか1項に記載のCAR。
- ユビキチン標的化タンパク質がCARのC末端上にある、請求項11〜21のいずれか1項に記載のCAR。
- ユビキチン標的化タンパク質が、リンカーにより細胞内シグナル伝達ドメインから分離されている、請求項11〜22のいずれか1項に記載のCAR。
- リンカーが、(GS)n及び/又は(GGGGS)pを含み、ここでn=1〜10且つp=1〜3である、請求項23に記載のCAR。
- リンカーが、配列番号23〜26のいずれか1つを含む、請求項24に記載のCAR。
- 化合物が免疫調節イミド薬(IMiD)である、請求項11〜25のいずれか1項に記載のCAR。
- IMiDが、サリドマイド、レナリドミド、ポマリドミド又はその機能的誘導体若しくは類似体から選択される、請求項26に記載のCAR。
- ポリペプチド配列と、セレブロン結合部位のヘアピンモチーフを含む135未満のアミノ酸長からなるユビキチン標的化タンパク質とを含む融合タンパク質。
- ユビキチン標的化タンパク質が、配列番号6〜14及び27からなる群から選択される配列からなる、請求項28に記載の融合タンパク質。
- 請求項1〜10のいずれか1項に記載のユビキチン標的化タンパク質、請求項11〜27のいずれか1項に記載のCAR、又は請求項28〜29のいずれか1項に記載の融合タンパク質をコードする、単離されたポリヌクレオチド。
- 請求項30に記載のポリヌクレオチドを含む発現ベクター。
- 請求項30に記載のポリヌクレオチド又は請求項31に記載の発現ベクターを含む細胞。
- 免疫調節細胞である、請求項32に記載の細胞。
- T細胞である、請求項33に記載の細胞。
- 治療法において使用するための、請求項32〜34のいずれか1項に記載の細胞。
- 請求項32〜34のいずれか1項に記載の複数の細胞を含む医薬組成物。
- 製薬上許容可能な賦形剤、担体、又は希釈剤をさらに含む、請求項36に記載の医薬組成物。
- 治療法において使用するための、請求項36又は請求項37に記載の医薬組成物。
- 治療法が遺伝子療法の方法である、請求項38に記載の医薬組成物。
- 免疫調節細胞を操作する方法であって、以下:
(a) 免疫調節細胞を提供すること;
(b) 請求項30に記載のポリヌクレオチド又は請求項31に記載の発現ベクターを、前記免疫調節細胞に形質導入又はトランスフェクトすること;及び
(c) 前記ポリヌクレオチド又は前記発現ベクターを、免疫調節細胞中で発現させること
を含む、前記方法。
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CN112980882A (zh) * | 2021-03-15 | 2021-06-18 | 上海科技大学 | Crbn基因在构建GSPT1敏感模型中的用途 |
NL2031325B1 (en) | 2022-03-18 | 2023-09-29 | Stichting Het Nederlands Kanker Inst Antoni Van Leeuwenhoek Ziekenhuis | Novel zinc finger degron sequences |
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