JP2019534037A - dsRNAを標的化するためのキメラタンパク質 - Google Patents
dsRNAを標的化するためのキメラタンパク質 Download PDFInfo
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Abstract
Description
2016年9月4日に出願された米国仮特許出願第62/383,466号に対して利益が主張されており、その全内容が参照により本明細書に組み込まれる。
技術分野
配列番号1は、GFP−SCPタンパク質のアミノ酸配列である。
配列番号2は、GFP−SCPタンパク質をコードする核酸配列である。
配列番号3は、dsRB−SCPタンパク質のアミノ酸配列である。
配列番号4は、dsRB−SCPタンパク質をコードする核酸配列である。
配列番号5は、Arg9リンカーペプチドのアミノ酸配列である。
配列番号6および7は、IFN−β定量化のためのフォワードおよびリバースオリゴヌクレオチドプライマーである。
配列番号8および9は、GAPDH定量化のためのフォワードおよびリバースオリゴヌクレオチドプライマーである。
配列番号10は、SCP−Nプライマーの核酸配列である。
配列番号11は、SCP−Cプライマーの核酸配列である。
配列番号12は、GFP−Nプライマーの核酸配列である。
配列番号13は、GFP−Cプライマーの核酸配列である。
配列番号14は、dsRB−Nプライマーの核酸配列である。
配列番号15は、dsRB−Cプライマーの核酸配列である。
配列番号16は、9ARG1プライマーの核酸配列である。
配列番号17は、9ARG2プライマーの核酸配列である。
配列番号18は、PKR dsRNAのアミノ酸配列である。
配列番号19は、PKR dsRNAの核酸配列である。
配列番号20は、ScFvJ591のアミノ酸配列である。
配列番号21は、ScFvJ591の核酸配列である。
1)アラニン(A)、セリン(S)、トレオニン(T)、
2)アスパラギン酸(D)、グルタミン酸(E)、
3)アスパラギン(N)、グルタミン(Q)、
4)アルギニン(R)、リジン(K)、
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V)、
および
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W)。
II. いくつかの実施形態の概要
III.PSMA発現細胞に対してdsRNAを標的化するためのキメラポリペプチド
IV.PSMA関連疾患の治療方法
実施例
実施例1:方法
GFP−SCPおよびdsRB−SCPのクローニング
GFP−SCPおよびdsRB−SCPの発現
GFP−SCPおよびdsRB−SCPの精製
細胞株
フローサイトメトリー
免疫細胞化学
生細胞の画像化
dsRNA電気泳動移動度シフトアッセイ(EMSA)
dsRB−SCP/ポリIC複合体の調製
生存アッセイ
免疫ブロット
ELISAによる分泌ケモカイン(IP−10およびRANTES)の検出
RNA単離、cDNA合成および定量的リアルタイムPCR
PBMCの走化性
共培養システムにおけるバイスタンダー効果の分析
腫瘍スフェロイドモデル
実施例2:PSMAを標的とするキメラタンパク質の構築およびアッセイ
ScFvJ591は、PSMA過剰発現前立腺癌細胞を選択的に標的とし、そのカーゴを細胞内に効率的に送達する。
PSMA過剰発現前立腺癌細胞にポリICを選択的に運搬して内在化することができるキメラタンパク質の設計、発現および精製
ポリICと複合体を形成したdsRB−SCPは、アポトーシスを誘導することによってPSMA過剰発現細胞を選択的に死滅させる。
dsRB−SCP/ポリIC処理が、サイトカインの分泌および免疫細胞の走化性を誘導する。
dsRB−SCP/ポリICによるバイスタンダー効果
dsRB−SCP/ポリICが、腫瘍スフェロイドを破壊する。
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Claims (18)
- 二本鎖RNA(dsRNA)結合ドメインと、
前立腺表面膜抗原(PSMA)に結合する標的結合部分と、を含む、キメラ組換えタンパク質。 - 前記dsRNA結合ドメインと前記標的結合部分との間にスペーサーペプチドをさらに含む、請求項1に記載のキメラ組換えタンパク質。
- 前記dsRNA結合ドメインが、少なくとも1つの二本鎖RNA結合モチーフ(dsRBM)を含む、請求項1または2に記載のキメラ組換えタンパク質。
- 前記少なくとも1つのdsRBMが、dsRNA依存性プロテインキナーゼ(PKR)、TRBP、PACT、Staufen、NFAR1、NFAR2、SPNR、RHA、およびNREBPのdsRBMから選択される、請求項3に記載のキメラ組換えタンパク質。
- 前記少なくとも1つのdsRBMが、配列番号18として示されるヒトPKRのアミノ酸1〜197と少なくとも70%同一であるポリペプチド配列を含む、請求項3に記載のキメラ組換えタンパク質。
- 前記標的結合部分が、ポリペプチド、抗体、抗体断片、または抗体模倣物である、請求項1〜5のいずれか一項に記載のキメラ組換えタンパク質。
- 前記スペーサーペプチドが、プロテアーゼ認識配列を含むオリゴペプチド、正に荷電したアミノ酸のホモオリゴペプチド、およびこれらの組み合わせからなる群から選択される、請求項2に記載のキメラ組換えタンパク質。
- 前記スペーサーペプチドが、アルギニンのホモオリゴペプチドである、請求項7に記載のキメラ組換えタンパク質。
- 前記二本鎖RNA(dsRNA)結合ドメインが、配列番号18に記載のヒトPKRの少なくとも1つのdsRNA結合ドメインであるか、またはその機能的バリアントであり、
前記スペーサーペプチドが、配列番号5に記載のARG9、またはその機能的バリアントであり、
前記標的結合部分が、配列番号20に記載の単鎖抗PSMA抗体、またはその機能的バリアントである、請求項2〜8のいずれか一項に記載のキメラ組換えタンパク質。 - 配列番号3に記載の配列と少なくとも70%同一であるポリペプチドを含む、請求項9に記載のキメラ組換えタンパク質。
- 請求項1〜10のいずれか一項に記載のキメラ組換えタンパク質と、dsRNAと、を含む複合体。
- 前記dsRNAが、ポリイノシン酸鎖とポリシチジル酸鎖(ポリIC)とを含む、請求項11に記載の複合体。
- 請求項1〜10のいずれか一項に記載の組換えタンパク質をコードする核酸配列を含む核酸。
- 前記核酸配列が、細菌または植物宿主細胞における発現のために最適化されている、請求項13に記載の核酸。
- 前立腺癌の治療または腫瘍血管新生の発現の阻害に使用するための、請求項1〜10のいずれか一項に記載のキメラ組換えタンパク質、または請求項11もしくは12に記載の複合体。
- それを必要とする対象に治療有効量の請求項11または12に記載の複合体を投与し、それによって前記癌を治療するか、または前記腫瘍血管新生の発現を阻害することを含む、前立腺癌の治療または腫瘍血管新生の発現の阻害を行うための方法。
- 前記複合体が全身または局所に投与される、請求項16に記載の方法。
- 前記対象に治療有効量の末梢血単核球(PBMC)を投与することをさらに含む、請求項16または請求項17に記載の方法。
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