JP6714751B2 - 単鎖trail受容体アゴニストタンパク質 - Google Patents
単鎖trail受容体アゴニストタンパク質 Download PDFInfo
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- JP6714751B2 JP6714751B2 JP2019082671A JP2019082671A JP6714751B2 JP 6714751 B2 JP6714751 B2 JP 6714751B2 JP 2019082671 A JP2019082671 A JP 2019082671A JP 2019082671 A JP2019082671 A JP 2019082671A JP 6714751 B2 JP6714751 B2 JP 6714751B2
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Description
(a)Arg121−Val122−Ala123、及び
(b)(Gly/Ser)121
から選択される。
1.1 ポリペプチド構造
A)アミノ酸Met1−Gly20
Ig−Kappa−シグナルペプチド、アミノ酸Gly20の後に想定シグナルペプチダーゼ開裂部位。
B)アミノ酸Gln21−Gly182
ヒトTRAILリガンドの第1可溶性サイトカインドメイン(TRAIL,配列番号1のアミノ酸120−281)。
C)アミノ酸Gly183−Ser190
配列番号2の第1ペプチドリンカーエレメント。
D)アミノ酸Arg191−Gly351
ヒトTRAILリガンドの第2可溶性サイトカインドメイン(TRAIL,配列番号1のアミノ酸121−281) 。
E)アミノ酸Gly352−Ser359
配列番号2の第2ペプチドリンカーエレメント。
F)アミノ酸Arg360−Gly520
ヒトTRAILリガンドの第3可溶性サイトカインドメイン(TRAIL,配列番号1のアミノ酸121−281)。
G)アミノ酸Gly521−Cys542
配列番号11のヒンジ−リンカーエレメント。
H)アミノ酸Pro543−Lys760
配列番号10の抗体Fcフラグメントドメイン。
合成遺伝子は適切な宿主細胞、例えば昆虫細胞または哺乳動物細胞中での発現のためのそのコドン使用の点で最適化され得る。好ましい核酸配列を配列番号16に示す。
融合ポリペプチドのクローニング、発現及び精製
上記した融合タンパク質を2つの異なる真核宿主細胞において組換え発現させた。
Jurkat A3永久T細胞株を用いる細胞アッセイを使用して、TRAIL受容体アゴニスト融合タンパク質のアポトーシス誘発活性を調べた。Jurkat細胞をフラスコで10% FBS、100単位/mlのペニシリン及び100μg/mlのストレプトマイシンを補充したRPMI 1640培地+GlutaMAX(GibCo)を用いて増殖させた。アッセイ前に、96ウェルのマイクロタイタープレートに100,000細胞/ウェルを接種した。ウェルに対して異なる濃度の融合ペプチドを添加した後、37℃で3時間インキュベートした。溶解バッファー(250mM HEPES,50mM MgCl2,10mM EGTA,5% Triton−X−100,100mM DTT,10mM AEBSF,pH7.5)を添加することにより細胞を溶解し、プレートを氷上に30分間〜2時間置いた。アポトーシスはカスパーゼ、例えばカスパーゼ3の上昇した活性に対応する。よって、アポトーシスの程度を調べるために特定カスパーゼ基質Ac−DEVD−AFC(Biomol)の開裂を使用した。実際、カスパーゼ活性は、細胞をヨウ化プロピジウム及びHoechst−33342で染色した後形態学的に調べたアポトーシス細胞のパーセンテージに相関している。カスパーゼ活性アッセイのために、20μlの細胞ライゼートを黒色96ウェルのマイクロタイタープレートに移した。80μlの50mM HEPES、1% スクロース、0.1% CHAPS、50μM Ac−DEVD−AFC及び25mM DTTを含有するpH7.5のバッファーを添加した後、プレートをTecan Infinite 500マイクロタイタープレートリーダーに移し、蛍光強度(励起波長400nm、発光波長505nm)の増加をモニターした。
HT1080線維細胞肉腫細胞での細胞死を調べるために、15,000細胞を96ウェルプレートで10% FBS(Biochrom)を補充したRPM1 1640培地+GlutaMAX(GibCo)を用いて一晩平板培養した。細胞を2.5g/mlの最終濃度でシクロヘキシミド(Sigma)と共インキュベートした。バッファーKV(0.5% クリスタルバイオレット,20% メタノール)を用いて染色することにより細胞死を定量した。染色後、ウェルを水で洗浄し、風乾した。染料をメタノールで溶出させ、595nmでの光学密度をELISAリーダーを用いて測定した。
4.1 凝集分析の原則(可溶性タンパク質の定義)
モノマー(TRAIL受容体結合モジュールの定義されているトリマーアセンブリ)及び凝集物の含量を実施例2に記載されている分析用SECにより測定した。この特別の目的のために、分析を生理学的pHの生理学的塩濃度を含有するバッファー(例えば、0.9% NaCl,pH7.4;PBS pH7.4)中で実施する。典型的な凝集分析はSuperdex200カラム(GE Healthcare)を用いて行う。このカラムにより、10〜800kDaの範囲のタンパク質が分離する。
(トリマー含量の%=[トリマーのピーク面積]/[全ピーク面積]×100)
本明細書で使用されている可溶性タンパク質についての定義は、0.2〜10.0mg/mlの典型的なタンパク質濃度範囲内で>90%の規定可溶性タンパク質(TRAILドメインのトリマーアセンブリ)含量を含有している生理学的pHで生理学的塩濃度のバッファー中の精製TRAILタンパク質のタンパク質標本を指す。
分子A〜Dの各々は鎖間ジスルフィド結合により共有結合している2つのポリペプチドからなる。これらの特性に影響を及ぼす効果がこれらの化合物の半減期に対して有しているかを調べるために、グリコサイト及び(タンパク質間に鎖間ジスルフィド結合を生じさせる)ヒンジシステインの数を調べた。
6.1 配列番号19のTRAIL受容体アゴニストタンパク質はインビトロでヒト血液系及び固形腫瘍細胞の生存を抑制する
腫瘍細胞を96ウェルプレートで10% FBSを含有している推奨培地中に10,000細胞/ウェルで接種し、配列番号19に示すアミノ酸配列を有する2つのポリペプチドからなるTRAIL受容体アゴニストタンパク質を用いて湿気のある5% CO2雰囲気中37℃で24時間処理した。その後、細胞生存性をCellTiter−Glo(R)試薬を製造業者の説明書(Promega;ウィスコンシン州マディソン)に記載されているように用いて評価した。IC50値は非処理対照細胞に対して正規化した濃度応答データの非線形回帰分析により調べた。配列番号19に示すアミノ酸配列を有する2つのポリペプチドからなるTRAIL受容体アゴニストタンパク質治療に応答して細胞生存性が低下することを示す得られたColo205、Jurkat及びSKM−1細胞についての濃度応答曲線の例を図19に示す。表8は、配列番号19に示すアミノ酸配列を有する2つのポリペプチドからなるTRAIL受容体アゴニストタンパク質で24時間処理した血液系(A;(n=40;非ホジキンリンパ腫,NHL;急性骨髄性リンパ腫,AML;急性リンパ芽球性白血病,ALL)及び固形腫瘍(B;(n=44;非小細胞肺癌,NSCLC;膵臓;結腸直腸癌,CRC;乳癌,BrCa;卵巣;線維肉腫;頭頸部,H&N;小細胞肺癌,SCLC)細胞株のCellTiter−Glo(R)により評価した生存性の結果を示す。配列番号19に示すアミノ酸配列を有する2つのポリペプチドからなるRAIL受容体アゴニストタンパク質媒介の腫瘍細胞生存性に対するIC50の結果を示す。
腫瘍細胞を96ウエルプレートで10% FBSを含有している推奨培地中に10,000細胞/ウェルで接種し、配列番号19に示すアミノ酸配列を有する2つのポリペプチドからなるTRAIL受容体アゴニストタンパク質をベネトクラックス(ABT−199)、ナビトクラックス(ABT−263)またはドセタキセル(DTX)と一緒に用いて湿気のある5% CO2雰囲気中37℃で24時間処理した。その後、細胞生存性をCellTiter−Glo(R)試薬を製造業者の説明書に記載されているように用いて評価した。Bliss独立性モデル(Wongら,2012;Mol.Cancer Ther.,11:1026−1035;Bernebaum,1981,Adv.Cancer Res.,35:269−335;Borisyら,2003,Proc.Natl.Acad.Sci.USA,100:7977−7982)を用いて併用活性を評価し、負の整数は拮抗作用を示し、0の値は相加活性を示し、正の整数は相乗効果を示す。Blissスコアを各配合剤についての用量マトリックスで計算し、総計して、「Bliss合計」を得る。ヒト腫瘍細胞を配列番号19に示すアミノ酸配列を有する2つのポリペプチドからなるTRAIL受容体アゴニストタンパク質とベネトクラックス、ナビトクラックスまたはDTXと一緒に用いて処理することにより誘発される相乗的腫瘍細胞死の例を関連するBliss合計と共に図20(A〜C)に示す。多数の腫瘍細胞株においてこれらの配合剤について調べたBliss合計を表9に示す。
配列番号19に示すアミノ酸配列を有する2つのポリペプチドからなるTRAIL受容体アゴニストタンパク質の腫瘍増殖に対する効果をSCID雌マイス(Charles Rivers Laboratories;マサチューセッツ州ウィルミントン)に皮下移植したColo205(結腸直腸癌)、SKM−1(急性骨髄性白血病)及びH460LM(非小細胞肺癌)異種移植片腫瘍で評価した。簡単に説明すると、研究0日目にヒト癌細胞を雌SCIDマウスの右後方脇腹に皮下接種した。サイズマッチ時に、配列番号19のTRAIL受容体アゴニストタンパク質(指示されているように、0.3、1または3mkd用量でIV,QD×5、またはIP,Q2D×5)の投与を開始した。各群の平均腫瘍容積がColo205及びSKM−1の場合>2000mm3、またはH460LMの場合>2500mm3のエンドポイントに達するまで実験期間中腫瘍容積を測定した。結果を図21〜23に示す。配列番号19に示されているアミノ酸配列を有する2つのポリペプチドからなるTRAIL受容体アゴニストタンパク質を投与すると、Colo205、SKM−1及びH460LM異種移植片腫瘍モデルにおいて著しい腫瘍増殖抑制が誘発された。
Claims (7)
- 配列番号16を含む核酸分子。
- 配列番号16のヌクレオチド79〜2298を含む核酸分子。
- 請求項2に記載の核酸分子を含む発現ベクター。
- 請求項3に記載の発現ベクターを含む単離された細胞。
- 真核細胞である、請求項4に記載の細胞。
- 哺乳動物細胞である、請求項5に記載の細胞。
- チャイニーズハムスター卵巣(CHO)細胞である、請求項5に記載の細胞。
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