JP6951479B2 - IL−15及びIL−15Rαスシドメインに基づくモジュロカイン - Google Patents
IL−15及びIL−15Rαスシドメインに基づくモジュロカイン Download PDFInfo
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Description
本発明は、本明細書においてモジュロカイン(modulokine)と呼ばれる新たな「イムノサイトカイン」、及び、腫瘍浸潤性リンパ球(TIL)を活性化することによる特に癌の処置のための医薬品としてのその使用に関する。
脊椎動物免疫系は、腫瘍に対する最適な免疫応答を達成するために複数の分子性及び細胞性相互作用を必要とする。
今回、本発明者らはまた、同じモジュレーターを同じ抗体と融合させた別の組合せを試みて、これにより本発明者らが「モジュロカイン」と呼ぶ新たな種類のイムノサイトカインが得られた。驚くべきことに、以前の組合せと比較して、この組合せは強力なTIL再活性化をもたらし、その再活性化は大半のTIL(すなわち約80%)に観察された。
A)コンジュゲート、及び
B)該コンジュゲートに共有原子価によって直接的に又は間接的に連結された免疫調節抗体又はその断片を含む、イムノサイトカインに関し、
該コンジュゲートは、
(i)インターロイキン15又はその誘導体のアミノ酸配列を含むポリペプチド、及び
(ii)IL−15Rαのスシドメイン又はその誘導体のアミノ酸配列を含むポリペプチド
を含む。
(i)上記のイムノサイトカイン、それをコードする核酸配列、又はこのような核酸配列を含むベクター、及び
(ii)治療剤、好ましくは抗癌剤
を含有する製品に関する。
(i)上記のイムノサイトカイン、それをコードする核酸配列、又はこのような核酸配列を含むベクター、及び
(ii)治療剤、好ましくは抗癌剤
の治療有効量を同時に、別々に、又は順次投与する工程を含む、癌を処置するための方法に関する。
「イムノサイトカイン」という用語は、サイトカイン又はその誘導体に共有原子価によって直接的に又は間接的に連結された抗体又はその断片を含む分子を指す。該抗体と該サイトカインとはリンカーペプチドによって連結されていてもよい。
「インターロイキン15」という用語は当技術分野におけるその一般的な意味を有し、これはIL−2に類似した構造を有するサイトカインを指す(Grabsteinet al., Science, vol.264(5161), p:965-968, 1994)。このサイトカインはまたIL−15、IL15、又はMGC9721としても知られる。このサイトカインとIL−2は多くの生物学的活性を共有し、それらは共通のヘマトポエチン受容体サブユニットに結合することが判明した。したがって、それらは同じ受容体に対して競合し得、互いの活性を負に調節している。IL−15はT細胞及びナチュラル―キラー細胞の活性化及び増殖を調節し、CD8+メモリー細胞の数は、このサイトカインとIL−2との間の平衡によって制御されることが示されることが確立されている。IL−15の活性は、実施例に開示されているように、kit225細胞株に対するその増殖誘導を決定することによって測定され得る(HORI et al., Blood, vol.70(4), p:1069-72, 1987)。
「抗体」という用語は、ジスルフィド結合によって相互接続された、2本の同一な重鎖(H)(完全長の場合には約50〜70kDa)と2本の同一な軽鎖(L)(完全長の場合には約25kDa)という4本のポリペプチド鎖を含む四量体に相当する免疫グロブリン分子を指す。軽鎖は、κ(カッパ)及びλ(ラムダ)として分類される。重鎖は、γ(ガンマ)、μ(ミュー)、α(アルファ)、δ(デルタ)、又はε(イプシロン)として分類され、それぞれIgG、IgM、IgA、IgD及びIgEとして抗体のアイソタイプを規定する。各々の重鎖は、N末端の重鎖可変領域(本明細書においてHCVRと略称される)及び重鎖定常領域から構成される。重鎖定常領域は、IgG、IgD及びIgAについては3つのドメイン(CH1、CH2及びCH3)から構成され;IgM及びIgEについては4つのドメイン(CH1、CH2、CH3及びCH4)から構成される。各々の軽鎖は、N末端の軽鎖可変領域(本明細書においてLCVRと略称される)及び軽鎖定常領域から構成される。軽鎖定常領域は、1つのドメイン、すなわちCLから構成される。HCVR及びLCVR領域はさらに、フレームワーク領域(FR)と呼ばれるより保存された領域の介在する、相補性決定領域(CDR)と呼ばれる超可変性領域にさらに細分され得る。各々のHCVR及びLCVRは、アミノ末端からカルボキシ末端まで以下の順序に並んだ、3つのCDR及び4つのFRから構成される:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。各ドメインへのアミノ酸の割り当ては、周知の慣習による。特定の抗原に対する抗体の機能的結合能力は、軽鎖/重鎖の各対の可変領域に依存し、これは主にCDRによって決定される。
1)CTL−A4、PD−1、BTLA、LAG3、HAVCR2、ADORA2A又は抑制性KIRなどの免疫抑制受容体又はそのリガンドに結合することによってこの受容体を阻害し、よって、ダウンレギュレーションシグナルを防ぐことによって免疫活性化を促進することによって;又は
2)CD40、CD137、CD134又はTNFRSF18(GITR)などの共刺激受容体を刺激し、よってT細胞及び/又はNK細胞の活性化を促進することによって
のいずれかによって作用する抗体を指す。
第二の態様では、本発明は、上記のイムノサイトカイン、好ましくは融合タンパク質に対応するイムノサイトカインをコードする核酸に関する。
本発明のさらなる目的は、最終的に薬学的に許容される担体を伴う、上記のイムノサイトカイン、それをコードする核酸、又は該核酸を含むベクターを含む、医薬組成物に関する。
さらなる態様では、本発明は、被験者における癌の処置のための前記のような医薬組成物、好ましくは、前記のイムノサイトカインを含む医薬組成物に関する。
(i)上記のイムノサイトカイン、それをコードする核酸配列、又はこのような核酸配列を含むベクター、及び
(ii)治療剤、好ましくは抗癌剤
を含有する製品に関する。
(i)上記のイムノサイトカイン、それをコードする核酸配列、又はこのような核酸配列を含むベクター、及び
(ii)治療剤、好ましくは抗癌剤
の治療有効量を同時に、別々に、又は順次投与する工程を含む、癌を処置するための方法に関する。
1)RLIに基づくモジュロカイン
抗PD−1抗体(hBAT)RLIイムノサイトカインの構築
CT−011(hBAT又はhBAT−1)の1つに対応する抗PD−1抗体軽鎖をコードする発現プラスミド。該抗体のキメラIgG重鎖配列が、22アミノ酸のリンカー(配列番号16)を用いて又は用いずに、3’末端においてIL15(配列番号3、93位のアミノ酸はKである)に融合されるように設計した。これらのヌクレオチド配列を合成し、pcDNA3.1プラスミドにGENEARTによってクローニングした。抗PD−1抗体の軽鎖及び重鎖の完全配列は、国際特許出願の国際公開公報第2009/101611号に開示されている。
40kDaの鎖状PEIをPolyscienceから入手した。PEIを加熱しながら水中に溶解し、NaOHによって中和し、0.22μmのフィルターを通した濾過によって滅菌することによって1mg/mLのストック溶液を調製した。ストック溶液を分注し、−20℃で保存した。
1−懸濁液中での一過性トランスフェクション
慣用的に維持されたCHO−S(Invitrogen)細胞を1×106個の細胞/mLの密度でPowerCHO2培地(Lonza)中に播種し、5%CO2を含む振盪インキュベーター(100rpm)中37℃で一晩培養した。トランスフェクションのために、その後、細胞をCD−CHO培地(Invitrogen)で2×106個の細胞/mLまで希釈した。150mM NaClを使用して培養容量の10%中にトランスフェクション複合体を調製した。発現構築物DNA(2.5mg/Lの培養容量、重鎖をコードするプラスミドと軽鎖をコードするプラスミドを1:2の比で使用して)をNaCl中に希釈されたPEI(10mg/Lの最終培養容量)と混合し、室温で10分間インキュベートし、その後、培養液に加えた。細胞を振盪インキュベーター(130rpm)中37℃で5時間培養し、その後、PowerCHO2培地を用いて培養容量を倍加させた。上清をトランスフェクションから5日後に回収した。
CHO−K1細胞(ATCC番号CCL−61)を、1−グルタミン、10%FCS及びペニシリン(100単位/ml)/ストレプトマイシン(100μg/ml)の補充されたDMEM中で増殖させ、製造業者によって推奨されるように、リポフェクタミン2000試薬(Invitrogen)を使用して各ベクターを用いてトランスフェクトした。クローンを、それぞれ抗CD20抗体アセチル化ICK及び抗CD20 ICKについて、ジェネテシンとハイグロマイシン(0.5mg/ml)又はブラストサイジンとハイグロマイシン(5μg/mL及び100μg/mL)を含有する培地を用いた限界希釈によって選択した。各クローンの培養上清を、ELISAによって二官能基タンパク質の産生についてアッセイした。ICKの産生について、選択されたクローンを、25%DMEM培地及び75%AIM培地(Invitrogen)中で増殖させた。その後、細胞を100%のAIM中に維持し、上清を回収し、2日間毎に10日間交換した。
回収した上清を3000rpmで4℃で20分間遠心分離にかけ、NaOHを用いてpH7.8に平衡を保ち、0.22μmのフィルターを通して濾過した。馴化培地を、製造業者の説明書に従ってプロテインAカラム(GE)を使用してアフィニティクロマトグラフィーによって精製した。精製されたタンパク質を50kDaのアミコンユニット(ミリポア)を用いて濃縮した。この工程の最中に、溶出緩衝液をPBSと交換した。精製されたタンパク質を最後にELISA及び280nmでの吸光度測定によってアッセイした。純度は電気泳動によって評価された。
Maxisorp平底マイクロタイタープレート(NUNC)を、PBS中で1.5μg/mLに希釈されたヤギ抗ヒト抗体 100μL(UP892370, Interchim)を用いて4℃でコーティングした。その後、プレートを遮断緩衝液 200μL(PBS中1%BSA+0.1%TWEEN20)を用いて37℃で1時間かけて遮断した。その後、プレートを洗浄緩衝液(PBS中0.1%TWEEN20)を用いて3回洗浄し、遮断緩衝液で希釈された試料を加え、37℃で30分間インキュベートした(100μL)。3回洗浄した後、1:10000に希釈されたペルオキシダーゼにコンジュゲートさせたヤギ抗ヒトIgG1抗体(109-036-003, Jackson)を加え、37℃で30分間インキュベートした。TMB基質(Interchim)を使用してタンパク質レベルを決定し、450nmでプレートを解読した。精製リツキシマブ(ロシュ)を使用してプレート上で標準曲線を作成した。
Maxisorp平底マイクロタイタープレート(NUNC)を、炭酸緩衝液中で2μg/mLに希釈された抗IL15抗体B−E29 100μL(Diaclone)を用いて4℃で16時間かけてコーティングした。その後、プレートを遮断緩衝液 200μL(PBS中1%BSA)を用いて37℃で1時間かけて遮断した。その後、プレートを洗浄緩衝液(PBS中0.05%TWEEN20)を用いて3回洗浄した。TBS+0.05%BSA中で希釈された試料を加え、37℃で1時間30分かけてインキュベートした(100μL)。3回洗浄した後、200ng/mLに希釈されたビオチニル化抗IL15抗体BAM247(R&D system)を加え、37℃で1時間30分インキュベートした。プレートを3回洗浄し、1:1000に希釈されたペルオキシダーゼにコンジュゲートさせたストレプトアビジンを加えた。TMB基質(Interchim)を使用してタンパク質レベルを決定し、450nmでプレートを解読した。IL−15(Peprotech)を使用してプレート上で標準曲線を作成した。
腫瘍浸潤性リンパ球(TIL)が、2人の腎細胞癌患者から得られた生検材料又は腎摘出組織から、DNAアーゼ及びコラゲナーゼによる消化後に得られた。これらのTILは殆ど、腫瘍進行を可能とするアネルギー性であった。
抗PD−1抗体 RLIモジュロカインの特異的結合をフローサイトメトリーによって評価した。モジュロカインがエフェクター細胞上のIL−15受容体に結合する能力を、Kit225で試験した。標的化細胞上にコーティングされたモジュロカインを、PEにコンジュゲートさせたヤギ抗ヒトIgGmAb(PN IM0550, Beckman Coulter)を用いて、又はPE−ストレプトアビジン(Sigma-Aldrich)に結合させたビオチニル化マウス抗IL15抗体(BAM247, R&D system)を用いて顕現させた。標的化細胞(1×105個)を各ICKと共に4℃で1時間インキュベートし、洗浄し、その後、PE−コンジュゲートと共に4℃で1時間インキュベートした。洗浄した細胞を最後にFACScalibur(Becton Dickinson)で分析した。
得られたモジュロカインのインターロイキン−15媒介性の増殖活性を試験し、RLIと比較した。ICKに対するKit225細胞及び32Dβ細胞の増殖応答を、[3H]チミジンの取り込みによって測定した。細胞を培養培地中に3日間維持し、2回洗浄し、それぞれKit225及び32Dβについてサイトカインを含まない培地中で24時間又は4時間かけて枯渇させた。その後、それらをマルチウェルプレートに104個の細胞/ウェルで100μl中に播種し、漸増濃度の試料の補充された培地中で48時間培養した。ヒトrIL−15及びRLIを検量用試料として使用した。細胞に0.5μCi/ウェルの[3H]チミジンを16時間かけてパルス投与し、ガラス繊維フィルター上に収集し、細胞に関連した放射能を測定した。結果は、モジュロカインの増殖活性がRLIの増殖活性と同等であったことを確認した。
腫瘍浸潤性リンパ球(TIL)は、25人の腎細胞癌患者から得られた生検材料又は腎摘出組織から、DNAアーゼ及びコラゲナーゼによる消化後に得られた。これらのTILは殆ど、腫瘍進行を可能とするアネルギー性であった。
CT26は、n−ニトロソ―n−メチルウレタン−(nnmu)により誘発されたマウス未分化大腸癌細胞株である。
腫瘍細胞株TC−1を、C57Bl/6マウスの原発性肺上皮細胞から得た。細胞を両種指向性レトロウイルスベクターlxsn16e6e7を用いて不死化させ、続いて、活性化ヒトc−ha−ras発癌遺伝子を発現しているpvejbプラスミドを用いて形質転換した。細胞はHPV−16E7の発現について陽性である。
3×104個のB16F10細胞をC57BL/6マウスの腹側部に0日目に皮内注射することによってB16F10腫瘍を移植する。腫瘍細胞を生着させた後、4日目に療法を開始する。抗PD−L1抗体−RLIモジュロカインを16又は32μg/マウスで腹腔内注射し、等モル濃度の抗PD−L1抗体のみ(クローン10 F.9G2、Bio-XCell)、RLIのみ(1004−14p)、抗PD−LI抗体(クローン10 F.9G2、Bio-XCell)とRLIの組合せ、又は対照群のPBSと比較する。
MB49腫瘍細胞株は、C57BL/6雄マウスの膀胱上皮を起源とする発癌物質により誘発された腫瘍から派生する。106個のMB49膀胱癌細胞を、C57BL/6マウスの背中の真皮上層に皮下注射した。腫瘍が約15mm2のサイズで明瞭に見えるようになりかつ触診可能となる時に相当する腫瘍接種後の6日目に処置を開始する。抗PD−1抗体−RLI及び抗PD−L1抗体モジュロカインを16又は32μg/マウスで腹腔内注射し、等モル濃度の抗PD1抗体のみ、抗PD−L1抗体のみ(クローン10 F.9G2、Bio-XCell)、RLIのみ(1004−14p)、抗PDI抗体又は抗PD−L1抗体(クローン10 F.9G2、Bio-XCell)とRLIの組合せ、又は対照群のPBSと比較する。
BALB/cマウスの乳腺に、0日目に5×104個の4T1乳癌細胞を接種した。腫瘍が約15mm〜20mm2のサイズで明瞭に見えるようになりかつ触診可能となる時に相当する腫瘍接種後の10日目に処置を開始する。抗PD−1抗体−RLI及び抗PD−L1抗体モジュロカインを16又は32μg/マウスで腹腔内注射し、等モル濃度の抗PD1抗体のみ、抗PD−L1抗体のみ(クローン10 F.9G2、Bio-XCell)、RLIのみ(1004−14p)、抗PDI抗体又は抗PD−L1抗体(クローン10 F.9G2、Bio-XCell)とRLIの組合せ、又は対照群のPBSと比較する。
ID8−VEGF卵巣癌細胞株を、マウス卵巣上皮乳頭状漿液性腺癌細胞株から事前に発達させた。C57BL/6マウスの右腹側部に、5×106個のID8腫瘍細胞を皮下移植した。腫瘍が約15〜20mm2のサイズで明瞭に見えるようになりかつ触診可能となる時に相当する腫瘍接種後の10日目に処置を開始する。抗PD−1抗体−RLI及び抗PD−L1抗体モジュロカインを16又は32μg/マウスで腹腔内注射し、等モル濃度の抗PD1抗体のみ、抗PD−L1抗体のみ(クローン10 F.9G2、Bio-XCell)、RLIのみ(1004−14p)、抗PDI抗体又は抗PD−L1抗体(クローン10 F.9G2、Bio-XCell)とRLIの組合せ、又は対照群のPBSと比較する。
C57BL/6雌マウスに、2×105個のRM−1マウス前立腺癌細胞を皮下接種した。腫瘍が約15〜20mm2のサイズで明瞭に見えるようになりかつ触診可能となる時に相当する腫瘍接種後の3日目に処置を開始する。抗PD−1抗体−RLI及び抗PD−L1抗体モジュロカインを16又は32μg/マウスで腹腔内注射し、等モル濃度の抗PD1抗体のみ、抗PD−L1抗体のみ(クローン10 F.9G2、Bio-XCell)、RLIのみ(1004−14p)、抗PDI抗体又は抗PD−L1抗体(クローン10 F.9G2、Bio-XCell)とRLIの組合せ、又は対照群のPBSと比較する。
Claims (20)
- a)コンジュゲート、及び
b)免疫調節抗体又はその抗体対応物と同じ抗原と反応することのできるその断片であって、該コンジュゲートに共有原子価によって直接的に又は間接的に連結されている、免疫調節抗体又はその断片
を含むイムノサイトカインであって、
該コンジュゲートが、
(i)インターロイキン15(IL−15)又はその誘導体のアミノ酸配列を含むポリペプチドであって、該誘導体が、配列番号3のアミノ酸配列に対して少なくとも92.5%の同一率を有するアミノ酸配列を有する、ポリペプチド、及び
(ii)インターロイキン15受容体α(IL−15Rα)のスシドメイン又はその誘導体のアミノ酸配列を含むポリペプチドであって、該誘導体が、配列番号8及び配列番号9からなる群より選択されるアミノ酸配列に対して少なくとも92%の同一率を有するアミノ酸配列を有する、ポリペプチド
を含み、
該免疫調節抗体がPD1アンタゴニストから選択される、イムノサイトカイン。 - (i)前記IL−15誘導体が、配列番号3のアミノ酸配列に対して少なくとも96%の同一率を有するアミノ酸配列を有し;及び/又は
(ii)前記IL−15Rαのスシドメインの誘導体が、配列番号8及び配列番号9からなる群より選択されるアミノ酸配列に対して少なくとも96%の同一率を有するアミノ酸配列を有する、
請求項1記載のイムノサイトカイン。 - (i)前記IL−15誘導体が、配列番号3のアミノ酸配列に対して少なくとも99%の同一率を有するアミノ酸配列を有し;及び/又は
(ii)前記IL−15Rαのスシドメインの誘導体が、配列番号8及び配列番号9からなる群より選択されるアミノ酸配列に対して少なくとも98%の同一率を有するアミノ酸配列を有する、
請求項1又は2記載のイムノサイトカイン。 - 前記PD−1アンタゴニストが抗PD−1抗体又は抗PD−L1抗体である、請求項1〜3のいずれか一項記載のイムノサイトカイン。
- 前記PD−1抗体が、ニボルマブ、Merck3745、又はCT−01 1(hBATとしても知られる)である、請求項4記載のイムノサイトカイン。
- a)前記コンジュゲートの前記ポリペプチド(i)と(ii)が融合タンパク質において共有結合されており;及び
b)該コンジュゲートと前記抗体又はその断片が、融合タンパク質において共有結合されている、
請求項1〜5のいずれか一項記載のイムノサイトカイン。 - 前記IL−15が、配列番号3のアミノ酸配列を有し;及び/又は
前記IL−15Rαの前記スシドメインが、配列番号9のアミノ酸配列を有する、
請求項1〜6のいずれか一項記載のイムノサイトカイン。 - 前記IL−15Rαのスシドメイン又はその誘導体のアミノ酸配列を含む前記ポリペプチド(ii)が配列番号12のアミノ酸配列を有する、請求項1〜7のいずれか一項記載のイムノサイトカイン。
- 前記コンジュゲートが、前記IL−15Rαのスシドメイン又はその誘導体のアミノ酸配列に対してC末端位に前記IL−15又はその誘導体のアミノ酸配列を含み、該コンジュゲートのアミノ酸配列が前記抗体又はその断片のアミノ酸配列に対してC末端位にある、請求項8記載のイムノサイトカイン。
- 請求項1〜9のいずれか一項に定義されたイムノサイトカインをコードする、核酸。
- 請求項10に定義された核酸を含む、ベクター。
- 請求項10記載の核酸又は請求項11記載のベクターを用いて遺伝子操作された宿主細胞。
- 前記宿主細胞が、CHO細胞である、請求項12記載の宿主細胞。
- 請求項1〜9のいずれか一項記載のイムノサイトカイン、請求項10記載の核酸、又は請求項11記載のベクターを含む、医薬組成物。
- がんの処置に使用するためのものである、請求項14記載の医薬組成物。
- 前記がんが、癌腫又は肺がんである、請求項15記載の医薬組成物。
- 前記がんが、進行がんである、請求項15記載の医薬組成物。
- 前記進行がんが、腎細胞がん(RCC)である、請求項17記載の医薬組成物。
- がんの処置に同時に、別々に、又は逐次的に使用するための治療剤と組み合わせて使用するためのものである、請求項14記載の医薬組成物。
- 前記治療剤が、抗がん剤である、請求項19記載の医薬組成物。
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