JP5249282B2 - 新生物を治療するためのErbB3に基づく方法および組成物 - Google Patents
新生物を治療するためのErbB3に基づく方法および組成物 Download PDFInfo
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- JP5249282B2 JP5249282B2 JP2010101148A JP2010101148A JP5249282B2 JP 5249282 B2 JP5249282 B2 JP 5249282B2 JP 2010101148 A JP2010101148 A JP 2010101148A JP 2010101148 A JP2010101148 A JP 2010101148A JP 5249282 B2 JP5249282 B2 JP 5249282B2
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Description
i)二量体形成を増大させて自己リン酸化するように遺伝子操作したいくつかのErbB-2変異体が細胞形質転換に影響を与えないこと、
ii)ErbB-2の細胞外ドメインに結合し、おそらく二量体形成を促進する抗体によりErbB-2発現癌細胞成長が促進されるが、他の抗体は癌細胞成長を阻害すること。
これらのデータは、ErbB-2のホモ二量体形成が細胞成長の促進または細胞の形質転換に不十分であり、おそらく二量体の特異的配向または高次構造を含む他の条件が必要であることを示す。
i)ErbB-2は優先的にErbB-3とヘテロ二量体を形成すること、
ii)NIH3T3細胞のErbB-2およびErbB-3との同時トランスフェクションによりErbB-2のみでのトランスフェクションよりも細胞形質転換レベルがはるかに高くなること、
iii)ErbB-2過剰発現関連乳癌細胞では、ErbB-3もまた高度に発現すること、および
iv)ErbB-3もまたErbB-2トランスジェニックマウス由来のErbB-2過剰発現腫瘍細胞で過剰発現されること。
1つの局面では、哺乳動物の新生物の予防、治療、または遅延の方法であって、このような予防、治療、または遅延が必要または望ましい哺乳動物に有効量の ErbB-3タンパク質もしくはその機能的断片または前記ErbB-3タンパク質をコードする核酸もしくはその機能的断片を投与し、それにより前記新生物に対する免疫応答が得られ、前記新生物が予防、治療、または遅延する工程を含む方法に関する。
a)配列番号:2または配列番号:3に記載のアミノ酸配列を含む前記ErbB-3タンパク質の細胞外ドメインまたはその機能的断片、配列番号:14に記載のアミノ酸配列の少なくともアミノ酸残基24〜81を含むアミノ酸配列、または配列番号:16に記載のアミノ酸配列の少なくともアミノ酸残基2〜139を含むアミノ酸配列を含むタンパク質またはペプチドと、
b)i)結合体の親和性単離または親和性精製、
ii)結合体の表面への付着、または
iii)結合体の検出を促進する、直接またはリンカーを介してErbB-3タンパク質の細胞外ドメインまたはその機能的断片に連結した促進薬と
を含む結合体に関する。
他で定義されない限り、本明細書中で使用される全ての技術用語および科学用語は、本発明の属する技術分野の当業者に一般に理解されている意味を有する。本明細書中で言及されている全ての特許、出願、公開された出願、および他の刊行物は、その全体が参照として組み入れられる。本節に記載の定義が、参照として本明細書に組み入れられる特許、出願、公開された出願、および他の刊行物中に記載の定義と対照的であるか一致しない場合、参照として組み入れられる定義よりも本節に記載の定義を優先する。
1)高ストリンジェンシー:0.1×SSPE、0.1%SDS、65℃;
2)中間のストリンジェンシー:0.2×SSPE、0.1%SDS、50℃(中程度のストリンジェンシーともいう);および
3)低ストリンジェンシー:1.0×SSPE、0.1%SDS、50℃。
別の緩衝液、塩類、および温度を使用して等価なストリンジェンシーを達成することができると理解される。
1つの局面では、本発明は、哺乳動物の新生物の予防、治療、または遅延の方法であって、このような予防、治療、または遅延が必要または望ましい哺乳動物に有効量のErbB-3タンパク質もしくはその機能的断片またはErbB-3タンパク質をコードする核酸もしくはその機能的断片を投与し、それにより前記新生物に対する免疫応答が得られ、前記新生物が予防、治療、または遅延する工程を含む方法に関する。
別の局面では、本発明は、配列番号:2または配列番号:3に記載のアミノ酸配列を含むErbB-3タンパク質の細胞外ドメインまたはその機能的断片、配列番号:14に記載のアミノ酸配列の少なくともアミノ酸残基24〜81を含むアミノ酸配列、または配列番号:16に記載のアミノ酸配列の少なくともアミノ酸残基2〜139を含むアミノ酸配列をコードするヌクレオチド配列またはその相補鎖と低、中、または高ストリンジェンシーでハイブリッド形成する単離核酸断片に関する。
a)配列番号:2または配列番号:3に記載のアミノ酸配列を含む前記ErbB-3タンパク質の細胞外ドメインまたはその機能的断片、配列番号:14に記載のアミノ酸配列の少なくともアミノ酸残基24〜81を含むアミノ酸配列、または配列番号:16に記載のアミノ酸配列の少なくともアミノ酸残基2〜139を含むアミノ酸配列を含むタンパク質またはペプチドと、
b)i)結合体の親和性単離または親和性精製、
ii)結合体の表面への付着、または
iii)結合体の検出を促進する、直接またはリンカーを介してErbB-3タンパク質の細胞外ドメインまたはその機能的断片に連結した促進薬と
を含む結合体に関する。結合体が融合タンパク質であり得る。または、ErbB-3タンパク質またはその機能的断片および促進薬を、他の手段によって連結することができる。結合体が融合タンパク質である場合、結合体をコードする核酸も提供する。
以下は、例示のみを目的として提供した態様の例である。
B3、De3-1、rhErbB3-f12、およびrhErbB3-f78の調製
本実験に関与するワクチンは、ErbB3の細胞外膜領域中のタンパク質分子および細胞外膜のタンパク質セグメントの一部(B2およびSD32と命名する)を含んでいた。ErbB3の細胞外膜領域中のタンパク質分子および細胞外膜タンパク質の一部(本明細書中で、B3、De3-1、rhErbB3-f12、およびrhErbB3-f78と命名する)を実験試料として使用し、上記ワクチンは、Zensun(Shanghai) Science and Technology Development Co Ltd.によって製造されている。B3およびDE3-1、rhErbB3-f12、およびrhErbB3-f78の調製を以下に示す。
B3遺伝子は、PCRによって増幅されたErbB3細胞外膜領域タンパク質をコードするcDNA配列であり(図1)、プライマー配列は以下であった。
PCRによる同定および酵素消化後、遺伝子操作細菌を、15%SDS-PAGE電気泳動、薄層スキャニング分析、アフィニティクロマトグラフィ、ウェスタンブロッティング同定、および安定な高発現標的化タンパク質遺伝子操作細菌の反復スクリーニングに供した。図4は、B3タンパク質精製(アフィニティクロマトグラフィ精製)を示した。図5は、アミノ酸配列決定後のB3精製タンパク質の標的化タンパク質およびアミノ酸配列を示した。
図6は、PCR増幅標的化遺伝子のコードされた細胞外膜ErbB3タンパク質セグメントのcDNA 配列を示した。発現プラスミドの構造:標的化遺伝子セグメントを、BamHI/XhoIを用いてpGEX4T-1ベクター(Pharmacia company)からから切断し、pET32aベクター(Novagen company)BabHI/XhoIに連結し、T7プロモーターによってタンパク質を発現させ、N末端をTrxタグ、Hisタグ、およびSタグに融合した。図7は、略図を示す。図8は、プラスミド組成の同定を示す。
プラスミドをBL21株に導入し、株を5mlのLB+APに一晩かけて接種した。100倍希釈物を予め加温しておいたLB+APに37℃で2.5〜3時間接種した(OD=0.6)。37℃で3時間または30℃で8時間IPTGで誘導した。4℃、6Kで10分間遠心分離し、上清を取り出し、沈殿物を氷上に置いた。冷1/20細菌溶液を使用してPBS懸濁液を作製し、超音波処理で破壊した。4℃、12Kで10分間遠心分離し、大量の34KD標的化遺伝子を採取した(図9)。DE3-1タンパク質を精製した。封入体中にDE3-1が出現し、6M塩酸グアニジンに溶解し、NTA-O緩衝液(Hisタグ精製溶液)で透析し(良好な複製条件)、Hisタグアフィニティクロマトグラフィ(Bo-Cai Companyから購入)で精製し(図10)、アミノ酸配列決定後、精製DE3-1タンパク質は標的化タンパク質配列と一致し、図11はアミノ酸配列を示す。
rhErbB3-f12(配列番号:14)遺伝子は、PCRで増幅したErbB3細胞外膜領域のタンパク質をコードするcDNA配列であり、プライマー配列は以下であった。
<腫瘍発達に対するB3、DE3-1の予防効果>
8〜10週齢のFVB/Nトランスジェニックマウス(Jackson Lab USAから購入)を実験動物として選択し、マウスを40頭ずつ5つの群に分け、これらを対照群、B2群、B3群、およびDE3-1群とした。BSA、 B2、SD32、B3、DE3-1を、フロイントアジュバント(CFA、フロイント完全アジュバント、Sigma companyから購入)と混合し、各群に20日毎に7回腹部に注射した。BSA、B2、SD32、B3、およびDE3-1ワクチンの投薬量は、 10μg/マウス/注射、5μg/マウス/注射、10μg/マウス/注射、1μg/マウス/注射、および10μg/マウス/注射であった。毎週腫瘍成長をモニターした。腫瘍発達を、統計的に評価および分析した。
免疫組織学的スクリーニング試験後の移植腫瘍マウス(腫瘍塊約1000mm3)を、neuタンパク質過剰発現FVB/Nトランスジェニックマウスの自発的腫瘍から切り出した。ナイロンネットを用いて腫瘍塊を1細胞に薄く切り、各FVB/Nトランスジェニックマウスの胸部の下への注射量は、5×106細胞であった。接種から約10〜14日後、対照群で腫瘍が明白であり(5mm超)、動物モデルの確立に成功したことが証明された。
動物および移植動物腫瘍モデルの準備:
(腫瘍に対する免疫療法におけるB3ならびにDE3-1 rhErbB3-f12およびrhErbB3-f78ワクチンの治療効果についての実験)と同じ。対照群には治療を施さず、負の対照群にhisタグタンパク質を注射し、正の対照群にアドリアマイシン(Santou MingZhi Pharmaceuticals)を投与し、DE3-1群に5μg、20μg、および80μgをそれぞれ投与した。
FVBトランスジェニックマウスをB2タンパク質およびB3タンパク質でそれぞれ免疫化し、10日後、採血し、ELISAを用いて抗体力価を試験し、 0.3μg/穴のB2およびB3を包み、各プレート上の1000倍希釈のB2およびB3を標準的な血清を使用してそれぞれ滴定し、37℃で30分間培養し、1%BSAでシールし、二重抗体を添加し、DADで15分間発色させ、Bio-Rad 450nm酵素標識装置を使用して試験した。
表1および図12は、B3およびDE3-1の腫瘍阻害効果の実験結果を示す。
表2および図13〜14は、B3ワクチンの抗腫瘍効果の実験結果を示す。
実験群の免疫化マウスに5μg/動物、20μg/動物、および80μg/動物の投薬量を使用し、表3および図15〜16は実験結果を示した。
B2抗原とB3抗原との間の交差免疫実験の目的は、B2抗原とB3抗原との間で交差免疫が存在するかどうかを調査することである。図17〜18は、B2抗原とB3抗原との間にいかなる交差免疫も存在しないことを証明する実験結果を示した。
本研究では、新規の抗腫瘍標的化ErbB3に基づいてデザインされ、且つ腫瘍発達に対する予防効果および腫瘍に対する免疫治療効果を有するB3および DE3-1の新規の有望なワクチンを発見した。
1)乳癌および卵巣癌などの腫瘍細胞中に存在するErbB2遺伝子の増幅がErbB2の過剰発現の原因であること、
2) ErbB2の過剰発現によりその細胞機能領域がリン酸化し、細胞内シグナル分子であるShcとErbB2との間の相互作用に影響を与えること、
3)線維芽細胞への野生型ErbB2のトランスフェクションにより細胞を形質転換することができること、
4) ErbB2同種二量体由来のErbB2変異型形成の増強によりその細胞形質転換活性も増強することができること。
Claims (15)
- ErbB−3の細胞外ドメインの断片に特異的に結合する抗体であって、ErbB−3の細胞外ドメインの断片は、
a)配列番号3記載のアミノ酸配列、
b)配列番号14記載のアミノ酸配列のアミノ酸残基24〜81、および
c)配列番号16記載のアミノ酸配列のアミノ酸残基2〜139
からなる群から選択される、抗体。 - ポリクローナル抗体である、請求項1記載の抗体。
- モノクローナル抗体である、請求項1記載の抗体。
- ヒト抗体またはヒト化抗体である、請求項1記載の抗体。
- 請求項1記載の抗体と、薬学的に許容される担体または賦形剤とを含む、哺乳動物の新生物の予防、治療、または遅延のための医薬組成物。
- 免疫応答増強薬をさらに含む、請求項5記載の医薬組成物。
- 抗新生物薬とともに投与される、請求項5記載の医薬組成物。
- 抗新生物薬が、抗血管新生剤、アルキル化剤、代謝拮抗薬、天然産物、白金配位複合体、アントラセンジオン、置換尿素、メチルヒドラジン誘導体、副腎皮質抑制薬、ホルモン、アンタゴニスト、癌遺伝子インヒビター、腫瘍抑制遺伝子またはタンパク質、抗癌遺伝子抗体、および抗癌遺伝子アンチセンスオリゴヌクレオチドからなる群より選択される、請求項7記載の医薬組成物。
- 治療すべき新生物が、副腎、肛門、聴覚神経、胆管、膀胱、骨、脳、乳房、口内、中枢神経系、頸部、結腸、耳、子宮内膜、食道、眼、眼陰部、卵管、胃腸管、頭頸部、心臓、腎臓、咽頭、肝臓、肺、下顎、下顎関節頭、上顎、口、鼻咽頭、鼻、口腔、卵巣、膵臓、耳下腺、陰茎、耳介、下垂体、前立腺、直腸、網膜、唾液腺、皮膚、小腸、脊髄、胃、精巣、甲状腺、扁桃腺、尿道、子宮、膣、内耳神経、および外陰の新生物からなる群より選択される、請求項7記載の医薬組成物。
- 治療すべき新生物が、乳癌、卵巣癌、胃癌、前立腺癌、結腸癌および肺癌からなる群より選択される、請求項7記載の医薬組成物。
- 治療すべき新生物が乳癌である、請求項7記載の医薬組成物。
- 医薬組成物が、静脈内注射、皮下注射、筋肉内注射、皮内注射、経口投与または局所投与により投与される、請求項5〜7のいずれか1項に記載の医薬組成物。
- 医薬組成物が、皮下注射される、請求項5〜7のいずれか1項に記載の医薬組成物。
- 医薬組成物が、インサイチューで新生物に投与される、請求項5〜7のいずれか1項に記載の医薬組成物。
- 請求項1記載の抗体を調製する方法であって、
a)配列番号3に記載されるアミノ酸配列、配列番号14に記載のアミノ酸配列のアミノ酸残基24〜81、または配列番号16に記載されたアミノ酸配列のアミノ酸残基2〜139を含む抗原を提供するステップと、
b)抗体レパートリー又は潜在的抗体レパートリーを上記アミノ酸配列のうちの一つに曝すステップと、
c)上記アミノ酸配列のうちの一つに特異的に結合する抗体を前記レパートリーから選択するステップと
を含む方法。
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CN100424175C (zh) | 2008-10-08 |
US7919098B2 (en) | 2011-04-05 |
AU2003218600A1 (en) | 2003-10-08 |
WO2003080835A1 (en) | 2003-10-02 |
EP1495123A1 (en) | 2005-01-12 |
EP2400021A2 (en) | 2011-12-28 |
JP4660094B2 (ja) | 2011-03-30 |
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