JP4056543B2 - 非抗原性即素複合体およびインターナライジング受容体システムの融合タンパク - Google Patents
非抗原性即素複合体およびインターナライジング受容体システムの融合タンパク Download PDFInfo
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Description
5種のBリンパ腫細胞系ならびに非B細胞系(IL−2Rβ/γcを発現することが判明しているT細胞系、MLA 144、およびAML由来の細胞系、MB−02)の、IL−15およびIL−2結合を分析した。125I標識したrIL−15を使用した。IL−15Rαの全結合への分布の推定を可能にするために、IL−2とIL−15の両者を用いて寒冷リガンド阻害を実施した。
3種の異なるmAb、すなわち、クラスII非変異鎖LL1、抗CD22抗体LL2、および抗トランスフェリン受容体抗体を、2種のRNaseスーパーファミリー毒素、すなわちオンコナーゼおよびEDNに結合させた。結果として生じる複合体を、3種のBリンパ腫細胞系Daudi、Raji、CA−46、乳癌細胞系MDA−MB−231、およびヒトT細胞系HuT102を含む細胞系団で試験した。結果から、LL2−オンコナーゼは、試験した全ての複合体の中で最低のIC50値を有することがわかった。オンコナーゼを主成分とする免疫毒素の、Bリンパ腫細胞系Daudiに対する毒性は、オンコナーゼとLL2複合体でさらに証明された。LL2はCD22に対する抗体であり、効率よくインターナライズする抗原である。全IgG複合体とFab(複合体の両者を調製し、ナノモル濃度未満の範囲でこの細胞系を阻害することを確認した。過剰の冷抗体で阻害作用がほぼ消失するため、その効果は、複合体のCD22反応性次第であることが証明された。
ハイブリドーマ1F5、IgG2a kは、RockvilleのAmerican Type Culture Collectionから入手できる。このハイブリドーマーを使用し、組織培養および/または腹水でのハイブリドーマの成長、およびその後のプロテインA−アガロースによる精製によってmAbを作る。これを、2mL L−グルタミンおよび各50μg/mlのペニシリンおよびストレプトマイシンおよび10%FCSを加えたRPMI1640中で培養する。
sIL−15Rα−VH−GGGGSQPK(GGGGS)2−VL
形質転換コロニーを採取し、LBブロス中でOD600=約0.5まで発育させる。次いでこれを、0.4mM IPTGを用いて37℃で3〜6時間、発現タンパクに導入する。小規模培養由来の細菌細胞をペレット化させ、SDS−PAGE試料緩衝液で溶解し、遠心分離で崩壊物(debris)を除去し、部分標本を10%SDS−PAGEゲルに負荷する。ゲルの一部を切り取り、クマシーブルー(Coomassie Blue)で染色し、その残りをImmobilon-P膜にトランスブロットする。この膜を、ヘキサヒスチジンタグを認識するニッケル−アルカリホスファターゼ複合体(Qiagen, Chatsworth, CA)か、免疫グロブリンを検出するためのヤギ抗マウスアルカリホスファターゼ(Kirkegaard and Perry, Gaithersburg, MD)のいずれかで染色する。ブロットをECL基質CSPDで展開し、写真フィルムに曝露する。
比放射能が20μCi/μgを超えないように、ヨードジェン法によって融合タンパクを125Iで放射標識することにより、融合タンパクの抗原結合活性を分析する。CD20陽性またはCD20陰性であることが判明しているヒト細胞系の一団を、冷1F5、冷融合タンパクおよび冷IL−15の存在下または非存在下で、標準結合分析法で試験する。結合は、抗CD20部分を介して起こる。氷上で1時間後、80/20のジブチルフタレート/オリーブ油のクッションを介してスピンさせ、チューブの先端を細胞を切り取ってガンマーカウンターでカウントする。
融合タンパクおよび親1F5は、同時に125Iで標識する。CD20+細胞系RLを使用する。結合は、両標識とも等しい細胞部分標本を用いて、5nMで、氷上で実施する。インターナリゼーションに対する影響を評価するために、冷IL−15または冷IL−2を同じ試験管に加える。細胞をペレット化させ、洗浄することによって、未結合標識を除去する。t0値を求め、残りの部分標本を37℃に置き、様々な時間間隔で取り出す。異化され、放出された125Iは、10%TCAで沈澱させることによって、解離した、もとのままのタンパク標識と区別される。冷IL−15を標識融合タンパクに加えてコントロールには加えないときにインターナリゼーションの増強が起これば、in vivo状態に近づけるために、標識IL−15と未標識融合タンパクを使用した逆の実験を実施する。
一般に、IL−15とオンコナーゼから成る融合タンパクは、Rybak(1995)に略述されているmAbオンコナーゼ融合タンパクを産生するための手順に従って操作する。簡単に記述すると、成熟IL−15タンパクに相応する、配列が確認されたフラグメントを、5(に存在するIL−15配列でオンコナーゼの配列に結合するが、別の方向を評価することもできる。オンコナーゼ遺伝子を2種以上のカエルからクローン化する。C末端ヘキサヒスチジンタグを使用して、融合配列を表す真正フラグメントをpET21dベクターに再度サブクローニングする。IL−15−オンコナーゼ融合タンパク全部をコード化している全配列を、上述のXL1Blue菌株のpETベクターで確認する。適当なクローンを生育させて、AD494(DE3)E. coli発現菌株のトランスフォーメーション用のプラスミドを作る。
オンコナーゼを主成分とする免疫毒素の細胞活性をBリンパ腫細胞系で評価するために、LL2−オンコナーゼ複合体を調製し、その作用をDaudi、Bリンパ腫細胞系で試験した。全IgG複合体とFab(複合体の両者を調製し、ナノモル濃度未満の範囲でこの細胞系を阻害することを確認した。さらに、過剰の冷抗体によって阻害作用がほぼ消失したことから、この作用は、複合体のCD22反応依存性であることもわかった。
例3および4に従って調製したリン酸緩衝食塩水(PBS)中の123I標識融合タンパク、sIL−15Rα−1F5scFの目標量を含む無菌の無発熱物質溶液を、B−CLL患者に静脈内注入する。融合タンパクが悪性B細胞に結合し、ガンマカメラ画像でモニタリングされるように、患者の循環から実質的に取り除かれた後で、例7に従って調製したIL−15/オンコナーゼ免疫毒素の治療用量を含む無菌の無発熱物質溶液を患者に注入する。その後の標識抗CD20を用いた放射免疫検出から、リンパ腫の著明な減少がわかる。
Claims (23)
- 腫瘍を治療するための医薬を製造するための、(i)非免疫原性毒素または治療用放射性核種とIL−15との複合体と、(ii)悪性細胞に特有の細胞マーカーに対する第1の結合部位とIL−15Rαに対する第2の結合部位とを有する二重特異性抗体、抗体フラグメントまたは融合タンパク質との使用。
- 前記毒素がRNaseであることを特徴とする、請求項1に記載の使用。
- 前記第一の結合部位が、CD15,CD19,CD20,CD21,CD22,CD37,CD38またはHLA−DRに結合する、請求項1に記載の使用。
- 前記毒素がオンコナーゼであることを特徴とする、請求項2に記載の使用。
- 前記複合体または前記抗体フラグメントもしくは融合タンパク質が、診断用放射性核種をさらに含む、請求項1に記載の使用。
- 前記医薬がIL−15Rαをさらに含む、請求項1に記載の使用。
- 前記IL−15複合体が腫瘍を有する患者に投与される前に、前記二重特異性抗体、フラグメントまたは融合タンパク質が当該患者に投与される、請求項1に記載の使用。
- (i)IL−15Rαの領域と、(ii)悪性細胞に特有の細胞マーカーに対する第1特異性とIL−15Rαの領域に対する第2特異性を有する二重特異性抗体を含む融合タンパク、または複合物。
- 前記二重特異性抗体がscFvであることを特徴とする、請求項8に記載の融合タンパク。
- 前記scFvが個々scFv分子2個の融合物であることを特徴とする、請求項9に記載の融合タンパク。
- 前記細胞マーカーがB細胞限定抗原であることを特徴とする、請求項8に記載の融合タンパク。
- 前記細胞マーカーがCD20であることを特徴とする、請求項11に記載の融合タンパク。
- 前記IL−15Rαの領域がIL−15Rα細胞外ドメインであることを特徴とする、請求項8に記載の融合タンパク。
- 請求項8に記載の融合タンパクと医薬的に許容できるキャリヤーを含む組成物。
- オンコナーゼとIL−15の複合体と、悪性細胞に特有の細胞マーカーに対する第1特異性とIL−15αの領域に対する第2特異性を有する二重特異性抗体を含む融合タンパクとを含むキット。
- 前記融合タンパクが悪性腫瘍被験者に最初に投与され、その後前記複合体の治療有効量が前記被験者に投与される、悪性腫瘍を治療するための、請求項15に記載のキット。
- 化学療法および放射線療法の少なくとも1つを、腫瘍細胞がDNA修復機構を活性化するのを防止するのに十分な量で投与する前に、前記複合体が投与される、請求項16に記載のキット。
- 前記細胞マーカーがB細胞限定抗原であり、前記被験者がB細胞悪性腫瘍を有することを特徴とする、請求項16に記載のキット。
- 前記細胞マーカーがCD20であり、前記被験者がリンパ性白血病、非ホジキン型リンパ種、または毛状細胞性白血病を有することを特徴とする、請求項18に記載のキット。
- IL−15Rαの領域からなるペプチドをさらに含む、請求項16に記載のキット。
- 前記細胞マーカーがCD38であり、前記被験者が急性リンパ性白血病または多発性骨髄腫を患う、請求項16に記載のキット。
- 前記細胞マーカーがCD15であり、前記被験者が急性骨髄性白血病または慢性骨髄性白血病を患う、請求項16に記載のキット。
- (i)オンコナーゼとIL−15の複合体と、(ii)悪性細胞に特有の細胞マーカーに結合するビオチン化抗体と、(iii)アビジンまたはストレプトアビジンと、(iv)ビオチン化IL−15Rαとを含み、前記ビオチン化抗体が投与され、その後アビジンまたはストレプトアビジン、その後ビオチン化IL−15Rα、そのごIL−15の複合体が投与される、キット。
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US2843096P | 1996-10-17 | 1996-10-17 |
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JP51840298A Pending JP2001503253A (ja) | 1996-10-17 | 1997-10-14 | 非抗原性即素複合体およびインターナライジング受容体システムの融合タンパク |
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US (4) | US6083477A (ja) |
EP (1) | EP0932417B1 (ja) |
JP (2) | JP2001503253A (ja) |
AT (1) | ATE233573T1 (ja) |
AU (1) | AU729515B2 (ja) |
CA (1) | CA2269060C (ja) |
DE (1) | DE69719529T2 (ja) |
DK (1) | DK0932417T3 (ja) |
ES (1) | ES2191827T3 (ja) |
PT (1) | PT932417E (ja) |
WO (1) | WO1998016254A1 (ja) |
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- 1997-10-14 JP JP51840298A patent/JP2001503253A/ja active Pending
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US20030031669A1 (en) | 2003-02-13 |
ATE233573T1 (de) | 2003-03-15 |
DE69719529T2 (de) | 2003-12-11 |
US7033572B2 (en) | 2006-04-25 |
US20050175582A1 (en) | 2005-08-11 |
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WO1998016254A1 (en) | 1998-04-23 |
JP2001503253A (ja) | 2001-03-13 |
US6083477A (en) | 2000-07-04 |
PT932417E (pt) | 2003-07-31 |
EP0932417B1 (en) | 2003-03-05 |
ES2191827T3 (es) | 2003-09-16 |
EP0932417A1 (en) | 1999-08-04 |
CA2269060A1 (en) | 1998-04-23 |
CA2269060C (en) | 2009-04-07 |
AU4807997A (en) | 1998-05-11 |
US6399068B1 (en) | 2002-06-04 |
AU729515B2 (en) | 2001-02-01 |
DK0932417T3 (da) | 2003-04-14 |
DE69719529D1 (de) | 2003-04-10 |
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