JP2010518820A - Erbb3に対する抗体およびその使用 - Google Patents
Erbb3に対する抗体およびその使用 Download PDFInfo
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- JP2010518820A JP2010518820A JP2009549644A JP2009549644A JP2010518820A JP 2010518820 A JP2010518820 A JP 2010518820A JP 2009549644 A JP2009549644 A JP 2009549644A JP 2009549644 A JP2009549644 A JP 2009549644A JP 2010518820 A JP2010518820 A JP 2010518820A
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Classifications
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Abstract
Description
さらなる態様では、本発明の特定のモノクローナル抗体およびその抗原結合部分は、配列番号1、配列番号3、配列番号5、配列番号35、または配列番号37に記載される重鎖可変領域アミノ酸配列と少なくとも80%(例えば、85%、90%、95%、96%、97%、98%または99%)同一であるアミノ酸配列を含む重鎖可変領域を含む。本発明の他の特定のモノクローナル抗体およびその抗原結合部分は、配列番号2、配列番号4、配列番号6、配列番号36、または配列番号38に記載される軽鎖可変領域アミノ酸配列と少なくとも80%(例えば、85%、90%、95%、96%、97%、98%または99%)同一であるアミノ酸配列を含む軽鎖可変領域を含む。また、抗体は、前記の重鎖および軽鎖可変領域の両方を含んでもよい。
用語「ErbB3」、「HER3」、「ErbB3受容体」、および「HER3受容体」とは、本明細書中で互換可能に使用されるとき、ヒトErbB3タンパク質を指し、米国特許第5,480,968号、並びにPlowmanら、Proc.Natl.Acad.Sci.USA,87:4905−4909(1990)に記載されている;また、Kaniら、Biochemistry 44:15842−857(2005),ChoおよびLeahy,Science 297:1330−1333(2002))を参照されたい。
(i)モノクローナル抗体
本発明のモノクローナル抗体は、種々の知られている技術、例えば、KohlerおよびMilstein(1975)Nature 256:495に記載される標準的な体細胞のハイブリダイゼーション技術、Bリンパ球のウイルス性または発癌性形質転換またはヒト抗体遺伝子のライブラリーを用いたファージディスプレイ技術を用いて生成することができる。特定の態様では、抗体は、完全なヒトモノクローナル抗体である。
本発明の二重特異性抗体は、ErbB3に対する少なくとも1つの結合特異性、および癌遺伝子の生成物などの別の抗原に対する少なくとも1つの結合特異性を含む。二重特異性抗体は、全長の抗体または抗体断片(例えば、F(ab’)2二重特異性抗体)として調製することができる。
本発明の免疫結合体(immunoconjugate)は、本明細書に記載される抗体またはその抗原結合部分を別の治療薬に結合させることによって形成することができる。適切な薬剤には、例えば、細胞傷害性剤(例えば、化学療法剤)、毒素(例えば、細菌、真菌、植物もしくは動物起源の酵素的に活性な毒素、またはそれらの断片)、および/または放射性同位体(即ち、放射線結合体)が挙げられる。このような免疫結合体の生成に有用な化学療法剤は、上記されている。用いることができる酵素的に活性な毒素およびそれらの断片には、ジフテリアA鎖、ジフテリア毒素の非結合性の活性な断片、外毒素A鎖(Pseudomonas aeruginosa)、リシンA鎖、アブリンA鎖、モデクシンA鎖、アルファ−サルシン、Aleurites fordiiタンパク質、ジアンシンタンパク質、Phytolaca americanaタンパク質(PAPI、PAPII、およびPAP−S)、ニガウリ(momordica charantia)阻害剤、クルシン、クロチン、sapaonaria officinalis阻害剤、ゲロニン、マイトゲリン、レストリクトシン、フェノマイシン、エノマイシンおよびトリコテセン(tricothecene)が含まれる。種々の放射性核種が、放射線結合された抗ErbB3郊外の生成に利用可能である。例としては、212Bi、131I、131In、90Yおよび186Reが挙げられる。
炭素14−標識された1−イソチオシアナトベンジル−3−メチルジエチレン トリアミンペンタ酢酸(MX−DTPA)は、抗体に放射性ヌクレオチドを結合させるための典型的なキレート剤である(例えば、国際公開第94/11026号を参照されたい)。
ErbB3に結合する抗体または抗原結合部分を生成後、このような抗体、またはその部分は、当該技術分野において周知である種々のアッセイを用いて、種々の特性、例えば本明細書に記載される特性についてスクリーニングすることができる。
抗体またはその抗原結合部分が存在しない場合のレベルまたは活性と比較して、1以上のヘレグリン、エピレグリン、エピゲンまたはビレグリン媒介のシグナル伝達を阻害する抗体または抗原結合部分を示す。
別の局面では、本発明は、薬学的に許容される担体とともに調合される、本発明のモノクローナル抗体またはその抗原結合部分(単数または複数)の1つまたは組み合わせを含む組成物、例えば、医薬組成物を提供する。一態様では、組成物は、ErbB3の異なるエピトープに結合する、本発明の複数(例えば、2以上)の単離された抗体の組み合わせを含む。
また、本発明は、様々なエクスビボおよびインビボにおける診断用途および治療用途において、ErbB3に結合する抗体およびその抗原結合部分を用いる方法を提供する。例えば、本発明の抗体は、種々の癌を含む、ErbB3に依存したシグナル伝達と関連した疾患を処置するために用いることができる。
実施例の全体を通して、下記の材料および方法は、特に記述がない限り用いられる。
下記に記載される実験に用いられる全ての細胞系統は、National Cancer Instituteから得られ、または指示されるように研究者によって提供された。
細胞系統:
MCF7−ATCC cat.No.HTB−22
T47D−ATCC cat.No.HTB−133
Colo357−これらの細胞は、アカデミックな研究者から得られ、Kolbら(2006)Int.J.Cancer,120:514−523によって記載されている。
OVCAR8−仮出願に既に記載されている供給源
H1975 ATCC cat.No.CRL−5908
腫瘍細胞の粉砕
腫瘍の粉砕のために凍結粉砕機(cryopulverizer)(Covaris Inc)を用いた。特別のバック(腫瘍を添加する前に予め計量される)に腫瘍を保存し、それらを操作しながら液体窒素に入れた。小さな腫瘍については、200μLのLysisバッファー(Lysis buffer)が、腫瘍を含むバックに初めに添加され、液体窒素中で凍結され、次に、バックからの腫瘍の回収を改善するために粉砕された。粉砕された腫瘍を2mLのエッペンドルフチューブに移し、更なる処理の直前まで液体窒素に置いた
腫瘍細胞の溶解
プロテアーゼおよびホスファターゼで補充されたLysisバッファー中で腫瘍を溶解させた。約62.5mg/mLの最終濃度の腫瘍アリコートにLysisバッファーを添加した。腫瘍試料は、30秒間ボルテックスしてホモジナイズし、氷上で約30分間インキュベートした。溶解物は、試料の更なる均質化のために、Qiagen Qiashredderカラム中で約10分間回転させた。澄明になった溶解物は、さらに処理するために新しいチューブに分注された。
BCAアッセイ(Pierce)は、全ての腫瘍試料について、製造業者のプロトコールに従って行われた。各腫瘍試料の全タンパク質濃度(mg/mLで)は、後に、ELISA結果の標準化において用いられた。
全体およびホスホ−ErbB3 ELISAのための全てのELISA試薬は、DuosetキットとしてR&D Systemsから購入した。96ウェルのNunc Maxisorbプレートは、50μLの抗体を用いて被覆され、室温で一晩インキュベートされた。翌朝、プレートは、PBST(0.05% Tween−20)を用いて、BioTekプレートウォッシャーで1000μl/ウェルを用いて3回洗浄した。その後、PBSに含まれる2%BSAを用いて、約1時間、室温でプレートをブロックした。PBST(0.05% Tween−20)を用いて、BioTekプレートウォッシャーで1000μl/ウェルを用いてプレートを3回洗浄した。50%Lysisバッファーおよび1%BSAで希釈された50μLの細胞溶解物と標準物は、更なる処理のために2点測定に用いられた。プレートシェーカー上で2時間、4℃で試料をインキュベートし、PBST(0.05% Tween−20)を用いて、BioTekプレートウォッシャーで1000μl/ウェルを用いて3回洗浄した。2%BSA、PBSTで希釈された約50μLの検出抗体を添加し、約1時間、室温でインキュベートした。リン(phosphor)−ErbB3について、検出抗体は、西洋ワサビペルオキシダーゼ(HRP)に直接結合させ、2時間、室温でインキュベートした。PBST(0.05% Tween−20)を用いて、BioTekプレートウォッシャーで1000μl/ウェルを用いてプレートを3回洗浄した。約50μlのストレプトアビジン−HRPを添加し、30分間、室温でインキュベートした(pErbB3を除く)。PBST(0.05% Tween−20)を用いて、BioTekプレートウォッシャーで1000μl/ウェルを用いてプレートを3回洗浄した。約50μLのSupersignal Pico ELISA基質を添加し、プレートをFusionプレートリーダーで読んだ。データはEXCELを用いて分析された。2点測定の試料は、平均され、エラーバーは、2つの複製物間での標準偏差を表すために用いられた。
ファージディスプレイを用いた抗体の生成
本明細書においてAb#6、Ab#3、Ab#14、Ab#17、およびAb#19と称されるヒト抗ErbB3抗体を得るために、ヒトドナーから得られた免疫グロブリン配列の独自の組み合わせを含むヒトFab−ファージライブラリー(Hoet et al. 上掲、その全てが本明細書中に参照として援用される)が、ErbB3結合物について最初にスクリーニングされた。
抗ErbB3 Fabの最適化
ErbB3リガンドであるヘレグリンによるErbB3への結合をブロックしたFabの同定に続いて、FabのVHおよびVL配列を下記のようにコドン最適化した。
ErbB3に対する結合親和性
抗ErbB3抗体の解離定数は、2つの独立した技術、即ち、表面プラズモン共鳴アッセイおよびMALME−3M細胞を用いた細胞結合アッセイを用いて測定された。
表面プラズモン共鳴アッセイ(またはFlexchipアッセイとも称される)は、Wassafら(2006)Analytical Biochem.,351:241−253に記載されるように行った。KD値は、式KD=Kd/Kaに基づいて計算された。
Ab#6およびAb#3のKD値を決定するための細胞結合アッセイは、下記のように行った。
ErbB3についての結合特異性/エピトープ結合
ErbB3に対するAb#6のIgG2アイソタイプの結合特異性は、下記のようのELISAを用いてアッセイされた。Ab#6によって結合されたエピトープの同定も分析した。
(実施例5)
腫瘍細胞の全ErbB3のダウンレギュレーション
腫瘍細胞におけるインビトロおよびインビボの両方でのErbB3発現をダウンレギュレートするAb#6の能力を下記のように試験した。
更なる実験では、インビボでのADRr異種移植におけるErbB3をダウンレギュレートするAb#6の能力を調べた。
腫瘍細胞増殖の阻害
ErbB3を発現している細胞(例えば、癌細胞)の細胞増殖を阻害するAb#6の能力は、下記のとおり調べられた。
腫瘍細胞におけるErbB3リン酸化の阻害
インビボにおけるErbB3リン酸化を阻害するAb#6の能力を下記のとおり調べた。
腫瘍細胞におけるヘレグリン媒介のシグナル伝達の阻害
ヘレグリン媒介の腫瘍細胞のシグナル伝達を阻害するAb#6の能力を下記のとおり調べた。
卵巣、前立腺、および膵臓の腫瘍増殖の阻害
インビボでのAb#6の有効性を評価するために、ヒト癌のいくつかの異種移植モデルをヌードマウスで構築し、腫瘍増殖の阻害を複数回投薬で評価した。例えば、T細胞欠損nu/nuマウス(NIH起源の3〜4週齢の雌性マウス;異系交配;アルビノバックグラウンド)は、異種移植研究のために、Charles River Labs(Wilmington,MA)から購入された。移植のためのADRr細胞は、回収前に約85%のコンフルエントに培養(RPMI培地、10%FBS、L−グルタミンおよび抗生物質、37℃、5%CO2)して増殖された。移植するまで細胞を氷上で保持した。マウスは、右脇腹に100μlのADRr細胞を用いて皮下注射を介して移植され、初期の腫瘍増殖についてモニターされながら回復された。
腫瘍細胞のErbB3へのErbB3リガンドの結合の阻害
更なる実験では、EGFRに対するEGF様リガンドではなく、ErbB3に対するErbB3リガンドの結合を阻害する本発明の抗体の特異性を下記のとおり調べた。
腫瘍細胞におけるVEGF分泌の阻害
ErbB3を発現している細胞(例えば、癌細胞)のVEGF分泌を阻害するAb#6の能力は、VEGF分泌アッセイ(VEGF ELISAキット、R&D Systems,Minneapolis,MN,Cat.#DY293Bから利用可能である)を用いて試験された。最初に、未処理、並びにHRG−ベータ1処理されたMCF−7、T47D、およびCOLO−357細胞におけるVEGF分泌を阻害するAb#6の能力を分析した。これらの研究は、COLO−357が培地中に最大量のVEGFを分泌したことを示した。また、これらの細胞は非常に高いHRGレベルを有するので(データ示さず)、培地へのHRGの添加は、VEGF分泌をさらに誘導することができなかった(図24A)。対照的に、HRGは、MCF−7およびT47D細胞におけるVEGF分泌を誘導することができた。
細胞移動の阻害
ErbB3を発現している細胞(例えば、MCF−7細胞)の移動を阻害するAb#6の能力は、トランスウェルアッセイ(Millipore Corp.,Billerica,MA,Cat #ECM552)を用いて試験された。最初に、MCF−7細胞は、一晩、血清を枯渇され、次に、Ab#6(最終濃度8uM)の存在および欠如下、15分間、室温でインキュベートされた。その後、細胞が移動できるI型コラーゲンを被覆したメンブレンによって下段チャンバーと分離されている上段チャンバーに細胞を移した。10%FBSは、Ab#6の存在および欠如下で、化学誘引物質として作用するように下段チャンバーの培地に添加された。チャンバーを37℃で16時間インキュベートし、次に、メンブレンを通過して移動した細胞は、脱着バッファーを用いて取り除かれ、細胞結合蛍光色素とともにインキュベートされた。蛍光プレートリーダーを用いて蛍光を定量した。平均の蛍光±SEM(n=2)を図25に示す。
スフェロイド増殖の阻害
ErbB3を発現している細胞のスフェロイド増殖を阻害するAb#6の能力は、発達している腫瘍増殖の状態を近似するアッセイ(Hermanら(2007)Journal of Biomolecular Screening Electronic publication)を用いて調べた。AdrRおよびDU145スフェロイドは、ハンギングドロップ法(Herrmanら、2008)を用いて、96ウェルプレートのウェルあたり1個のスフェロイドの頻度で開始された。次に、個々のスフェロイドは、指示されるようなAb#6(最終濃度8uM)、ヘレグリン−β1EGFドメイン(R&D Systems,Minneapolis,MN,Cat #396−HB、最終濃度3.4nM)、または両方の組み合わせのいずれかで処理された。スフェロイドの直径は、第1日から第13日で光学顕微鏡(10×対物)を用いて測定された。
シグナル伝達の阻害
異なるリガンドによって誘導されるシグナル伝達を阻害するAb#6の能力を調べた。例えば、ErbB3受容体を発現しているAdrR細胞に対するHRGおよびBTC結合におけるAb#6の効果を試験した。図27AおよびBに示されるように、FACS分析を用いて、Ab#6は、AdrR細胞への結合に対してBTCではなくHRGと競合する。したがって、ErbB3に対するHRG結合のAb#6のブロックは、HRGによって誘導されるシグナル伝達を妨げることになる。
上皮細胞増殖因子受容体(EGFR)における活性化変異を担持する非小細胞肺癌は、METおよびHER3を補充することによって、即ち、PI3K−AKT細胞生存経路を活性化することによってチロシンキナーゼインヒビターに耐性を発現することが知られている(Engelmannら(2007)Science 316:1039−1043;Gou(2007)PNAS:105(2):692−697)。活性化EGFR変異を担持する細胞系統におけるEGFRとc−METとの間の関連性は、同時免疫沈降によって十分に確かめられている(Engelmannら、2007;Gou,2007)。Guoらは、最近、c−METおよびErbB3も、同時免疫沈降を用いて、増幅したc−METに依存することが知られている胃の細胞系統MKN45において複合体で存在することを示した。
リガンド(HRG、BTC、EGF、およびHGF)誘導のErbB3のリン酸化を阻害するAb#6の能力は、下記の方法に基づいて調べられた:
1.10%FBSを含むRPMI培地に30,000細胞/ウェル/100μLの密度で96ウェルプレートにAdrR細胞を播種し、一晩増殖させた;
2.翌日、培地をFBSを含まない培地に変えることによって細胞を血清枯渇にし、一晩増殖させた;
3.異なる濃度のAb#6(0.01nM〜100nM)、またはバッファー(対照)を用いて2時間、細胞を前処理した;
4.次に、細胞を10nM HRGおよびHGFで10分間、または10nM BTCおよびEGFで5分間刺激した;
5.培地を除去することによって反応を停止させ、細胞を氷冷PBSで1回洗浄した;
6.その後、1×プロテアーゼインヒビターおよび1×ホスファターゼインヒビターを含む、25mM Tris、pH+7.5、150mM NaCl、1mM EDTA、1.0% Triton X−100、1.0% CHAPS、10%v/vグリセロールに細胞を溶解させ;そして、
7.ErbB3リン酸化は、Human Phospho−ErbB3 ELISAキット(R&D Systems,Minneapolis,MN,Cat.DYC1769)を用いて、製造業者の指図書に従って、細胞溶解物において測定された。
AdrR細胞は、バッファー(対照)、または250nM Ab#6とともに60分間、室温でプレインキュベートされ、次に10nM HRGもしくは10nM BTCまたは対照バッファーを用いて10分間処理された。0.2mM PMSF、50mTU/mLアプロチニン、および100uMロイペプチンを含む、25mM Tris、pH+7.5、150mM NaCl、1mM EDTA、1.0% Triton X−100、1.0% CHAPS、10%v/vグリセロールに細胞を溶解し、粗製溶解物を簡単に遠心して、不溶性物質を除去した。上清は、新しいエッペンドルフチューブに移され、そして抗ErbB3抗体(Santa Cruz sc−285)を1:500希釈で添加した。上清は、穏やかに振とうしながら、4Cで一晩インキュベートされた。60ulのImmobilized Protein A/Gアガロースビーズ(Pierce,Rockford,IL,Cat#20421)は、初めに1×PBSで洗浄された。細胞溶解物−抗体混合物をPBS洗浄したビーズに添加し、穏やかに振とうしながら4℃で2時間インキュベートした。次に、免疫沈降物を氷冷した溶解バッファーを用いて3回洗浄し、30ulの2×SDS試料バッファーに再懸濁させ、95℃で7分間熱変性し、4〜12%のBis−Trisゲル上で移動させた。SDS−PAGEを行い、10%MeOHを含むTri−グリシンバッファー中でPVDFメンブレンに電気的に移した。10mlのブロッキングバッファー(Li−Cor Biosciences,Lincoln,NE,Cat#927−40000)中でメンブレンを1時間ブロッキングし、次に、10mlのブロッキングバッファー(Li−Cor Biosciences,Cat#927−40000)に含まれる1:1000での抗ErbB2抗体(Cell Signaling Technology,Danvers,MA,Cat#29D8)とともにインキュベートした。シグナルは、10mlのブロッキングバッファー(Li−Cor Biosciences,Cat#927−40000)に含まれる1:5000(2μl)でのヤギ抗ウサギIRDye800を用いて検出された。
当業者は、ほんの日常的な実験を用いて、本明細書に記載されている本発明の特定の態様の多くの均等物を認識し、または確認することができる。このような均等物は、下記の特許請求の範囲によって包含されることが意図される。従属クレームに開示されている態様のいずれかの組み合わせは、本発明の範囲内にあることが意図される。
本明細書に言及されている全ての刊行物、特許、係属している特許出願は、全体として参照により本明細書に援用される。
Claims (54)
- ErbB3に結合し、EGF様リガンド媒介のErbB3のリン酸化を阻害する、単離されたモノクローナル抗体またはその抗原結合部分。
- ErbB3に結合する単離されたモノクローナル抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分は、下記の特性:
(i)ErbB3を介したヘレグリン、エピレグリン、ベータセルリン、エピゲンもしくはビレグリン(biregulin)媒介のシグナル伝達の阻害;
(ii)ErbB3を発現している細胞の増殖の阻害;
(iii)細胞表面上のErbB3レベルを減少させる能力;
(iv)ErbB3を発現している細胞のVEGF分泌の阻害:
(v)ErbB3を発現している細胞の移動の阻害;
(vi)ErbB3を発現している細胞のスフェロイド増殖の阻害;および/または
(vii)ErbB3のドメインIに位置したエピトープへの結合
の1以上を示す単離されたモノクローナル抗体またはその抗原結合部分。 - 請求項1および請求項2のいずれか1項に記載の抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分がErbB3に結合し、表面プラズモン共鳴アッセイまたは細胞結合アッセイによって測定すると、KDが少なくとも約8nMまたはそれよりも良好である、抗体またはその抗原結合部分。
- 請求項1〜3のいずれか1項に記載の抗体またはその抗原結合部分であって、前記EGF様リガンドが、EGF、TGF−α、ベータセルリン、ヘパリン結合上皮細胞増殖因子、アンフィレグリンおよびビレグリンからなる群から選択される、抗体またはその抗原結合部分。
- ErbB3に結合する単離されたモノクローナル抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、配列番号1、配列番号3、配列番号5、配列番号35、または配列番号37に記載される重鎖可変領域のアミノ酸配列に少なくとも80%同一であるアミノ酸配列を含む重鎖可変領域を含む、単離されたモノクローナル抗体またはその抗原結合部分。
- ErbB3に結合する単離されたモノクローナル抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、配列番号2、配列番号4、配列番号6、配列番号36、または配列番号38に記載される軽鎖可変領域のアミノ酸配列に少なくとも80%同一であるアミノ酸配列を含む軽鎖可変領域を含む、単離されたモノクローナル抗体またはその抗原結合部分。
- ErbB3に結合する単離されたモノクローナル抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、配列番号1、配列番号3、配列番号5、配列番号35、または配列番号37に記載される重鎖可変領域のアミノ酸配列に少なくとも95%同一であるアミノ酸配列を含む重鎖可変領域を含む、単離されたモノクローナル抗体またはその抗原結合部分。
- ErbB3に結合する単離されたモノクローナル抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、配列番号2、配列番号4、配列番号6、配列番号36、または配列番号38に記載される軽鎖可変領域のアミノ酸配列に少なくとも95%同一であるアミノ酸配列を含む軽鎖可変領域を含む、単離されたモノクローナル抗体またはその抗原結合部分。
- 請求項7に記載の抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、配列番号2、配列番号4、配列番号6、配列番号36、または配列番号38に記載される軽鎖可変領域のアミノ酸配列に少なくとも95%同一であるアミノ酸配列を含む軽鎖可変領域をさらに含む、抗体またはその抗原結合部分。
- 請求項1〜9のいずれか1項に記載の抗体によって結合されるエピトープと同じであるかまたは該エピトープと重複しているエピトープに結合する単離された抗体またはその抗原結合部分。
- ErbB3のアミノ酸配列の残基20−202に結合する、請求項1〜10のいずれかに記載の抗体またはその抗原結合部分。
- ErbB3に結合する単離されたモノクローナル抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、
CDR1、CDR2、およびCDR3配列を含む重鎖可変領域;および
CDR1、CDR2、およびCDR3配列を含む軽鎖可変領域
を含み、ここで、該重鎖可変領域CDR3配列は、配列番号9、15、21、41、47、およびその保存されたアミノ酸置換体からなる群から選択されるアミノ酸配列を含む、単離されたモノクローナル抗体またはその抗原結合部分。 - 前記軽鎖可変領域CDR3配列が、配列番号12、18、24、44、50およびその保存されたされた配列改変体からなる群から選択されるアミノ酸配列を含む、請求項12に記載の抗体またはその抗原結合部分。
- 前記重鎖可変領域CDR2配列が、配列番号8、14、20、40、46およびその保存された配列改変体からなる群から選択されるアミノ酸配列を含む、請求項12または13に記載の抗体またはその抗原結合部分。
- 前記軽鎖可変領域CDR2配列が、配列番号11、17、23、43、49、およびその保存された配列改変体からなる群から選択されるアミノ酸配列を含む、請求項12〜14に記載の抗体またはその抗原結合部分。
- 前記重鎖可変領域CDR1配列が、配列番号7、13、19、39、45、およびその保存された配列改変体からなる群から選択されるアミノ酸配列を含む、請求項12〜15に記載の抗体またはその抗原結合部分。
- 前記軽鎖可変領域CDR1配列が、配列番号10、16、22、42、48、およびその保存された配列改変体からなる群から選択されるアミノ酸配列を含む、請求項12〜16に記載の抗体またはその抗原結合部分。
- ErbB3に結合し、
(a)配列番号7を含む重鎖可変領域CDR1;
配列番号8を含む重鎖可変領域CDR2;
配列番号9を含む重鎖可変領域CDR3;
配列番号10を含む軽鎖可変領域CDR1;
配列番号11を含む軽鎖可変領域CDR2;
配列番号12を含む軽鎖可変領域CDR3;および
それらの組み合わせ;
(b)配列番号13を含む重鎖可変領域CDR1;
配列番号14を含む重鎖可変領域CDR2;
配列番号15を含む重鎖可変領域CDR3;
配列番号16を含む軽鎖可変領域CDR1;
配列番号17を含む軽鎖可変領域CDR2;
配列番号18を含む軽鎖可変領域CDR3;および
それらの組み合わせ;
(c)配列番号19を含む重鎖可変領域CDR1;
配列番号20を含む重鎖可変領域CDR2;
配列番号21を含む重鎖可変領域CDR3;
配列番号22を含む軽鎖可変領域CDR1;
配列番号23を含む軽鎖可変領域CDR2;
配列番号24を含む軽鎖可変領域CDR3;および
(d)配列番号39を含む重鎖可変領域CDR1;
配列番号40を含む重鎖可変領域CDR2;
配列番号41を含む重鎖可変領域CDR3;
配列番号42を含む軽鎖可変領域CDR1;
配列番号43を含む軽鎖可変領域CDR2;
配列番号44を含む軽鎖可変領域CDR3;および
(e)配列番号45を含む重鎖可変領域CDR1;
配列番号46を含む重鎖可変領域CDR2;
配列番号47を含む重鎖可変領域CDR3;
配列番号48を含む軽鎖可変領域CDR1;
配列番号49を含む軽鎖可変領域CDR2;
配列番号50を含む軽鎖可変領域CDR3;
からなる群から選択される重鎖および軽鎖可変領域CDR1、CDR2およびCDR3を含む、単離されたモノクローナル抗体またはその抗原結合部分。 - ErbB3に結合し、
配列番号7を含む重鎖可変領域CDR1;
配列番号8を含む重鎖可変領域CDR2;
配列番号9を含む重鎖可変領域CDR3;
配列番号10を含む軽鎖可変領域CDR1;
配列番号11を含む軽鎖可変領域CDR2;および
配列番号12を含む軽鎖可変領域CDR3
を含む、単離されたモノクローナル抗体またはその抗原結合部分。 - ErbB3に結合し、
CDR1、CDR2、およびCDR3配列を含む重鎖可変領域;および
CDR1、CDR2、およびCDR3配列を含む軽鎖可変領域
を含み、ここで、該重鎖可変領域CDR3配列は、配列番号9、15および21からなる群から選択されるアミノ酸配列と少なくとも90%同一であるアミノ酸配列を含む、単離されたモノクローナル抗体またはその抗原結合部分。 - 前記軽鎖可変領域CDR3配列が、配列番号12、18および24からなる群から選択されるアミノ酸配列と少なくとも90%同一であるアミノ酸配列を含む、請求項20に記載の抗体。
- 前記重鎖可変領域CDR2配列が、配列番号8、14および20からなる群から選択されるアミノ酸配列と少なくとも90%同一であるアミノ酸配列を含む、請求項20または21に記載の抗体。
- 前記軽鎖可変領域CDR2配列が、配列番号11、17および23からなる群から選択されるアミノ酸配列と少なくとも90%同一であるアミノ酸配列を含む、請求項20〜22に記載の抗体。
- 前記重鎖可変領域CDR1配列が、配列番号7、13および19からなる群から選択されるアミノ酸配列と少なくとも90%同一であるアミノ酸配列を含む、請求項20〜23に記載の抗体。
- 前記軽鎖可変領域CDR1配列が、配列番号10、16および22からなる群から選択されるアミノ酸配列と少なくとも90%同一であるアミノ酸配列を含む、請求項20〜24に記載の抗体。
- ErbB3に結合する単離されたモノクローナル抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、ヒトVH3生殖細胞系列遺伝子由来である重鎖可変領域を含む、単離されたモノクローナル抗体またはその抗原結合部分。
- 請求項26に記載の抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、さらにヒトVL2生殖細胞系列遺伝子から得られる軽鎖可変領域を含む、抗体またはその抗原結合部分。
- 請求項1〜27のいずれか1項に記載の抗体またはその抗原結合部分であって、該抗体が、ヒト抗体、ヒト化抗体、二重特異性抗体およびキメラ抗体からなる群から選択される、抗体またはその抗原結合部分。
- 請求項1〜28のいずれか1項に記載の抗体またはその抗原結合部分であって、該抗体またはその抗原結合部分が、Fab、Fab’2、ScFv、SMIP、アフィボディ(affibody)、アビマー(avimer)、ナノボディ(nanobody)、およびドメイン抗体からなる群から選択される、抗体またはその抗原結合部分。
- 請求項1〜29のいずれか1項に記載の抗体またはその抗原結合部分であって、該抗体のアイソタイプが、IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgAsec、IgD、およびIgE抗体からなる群から選択される、抗体またはその抗原結合部分。
- 薬学的に許容される担体に含まれる、請求項1〜30のいずれか1項に記載の抗体またはその抗原結合部分を含む組成物。
- 請求項1〜31のいずれか1項に記載の2以上の抗体を含む組成物であって、該抗体がErbB3の異なるエピトープに結合する、組成物。
- 配列番号25の重鎖可変領域、配列番号26の軽鎖可変領域、配列番号27の重鎖可変領域、配列番号28の軽鎖可変領域、配列番号29の重鎖可変領域、配列番号30の軽鎖可変領域、またはそれらの組み合わせと少なくとも90%同一である配列を含む、ErbB3に結合するヒト抗体の可変領域をコードする単離された核酸。
- 高ストリンジェントな条件下で、配列番号25の重鎖可変領域、配列番号26の軽鎖可変領域、配列番号27の重鎖可変領域、配列番号28の軽鎖可変領域、配列番号29の重鎖可変領域、または配列番号30の軽鎖可変領域のヌクレオチド配列とハイブリダイズする配列を含む、ErbB3に結合するヒト抗体の可変領域をコードする単離された核酸。
- 請求項33または34に記載の核酸を含む発現ベクター。
- 請求項35に記載の核酸を含む宿主細胞。
- 請求項1〜36のいずれか1項に記載の抗体または抗原結合部分と同じエピトープに結合するモノクローナル抗体またはその抗原結合部分を発現するトランスジェニック非ヒト哺乳動物。
- 請求項1〜37のいずれか1項に記載の抗体または抗原結合部分と同じエピトープに結合するモノクローナル抗体またはその抗原結合部分を発現するトランスジェニック植物。
- 請求項1〜38のいずれか1項に記載の抗体またはその抗原結合部分を産生するハイブリドーマ。
- ErbB3に結合するヒト抗体を産生するハイブリドーマであって、該抗体が、
(a)配列番号25に記載の重鎖可変領域ヌクレオチド配列と配列番号26に記載の軽鎖可変領域ヌクレオチド配列、およびそれらの保存された配列改変体;
(b)配列番号27に記載の重鎖可変領域ヌクレオチド配列と配列番号28に記載の軽鎖可変領域ヌクレオチド配列、およびそれらの保存された配列改変体;または
(c)配列番号29に記載の重鎖可変領域ヌクレオチド配列と配列番号30に記載の軽鎖可変領域ヌクレオチド配列、およびそれらの保存された配列改変体
によってコードされる、ハイブリドーマ。 - 請求項1〜40のいずれか1項に記載の1以上の単離されたモノクローナル抗体またはその抗原結合部分を含み、場合により、ErbB3依存性シグナル伝達と関連した疾患の処置または診断における使用のための指図書を含むキット。
- 前記疾患が癌である、請求項41に記載のキット。
- 被験体においてEGF様リガンドが媒介するErbB3のリン酸化を阻害する方法であって、EGF様が媒介するErbB3のリン酸化を阻害するのに十分な量で、請求項1〜42のいずれか1項に記載の単離されたモノクローナル抗体またはその抗原結合部分を被験体に投与する工程を含む、方法。
- 請求項1〜43のいずれか1項に記載の単離されたモノクローナル抗体またはその抗原結合部分を治療的に有効な量で前記被験体に投与することを含む、該被験体における癌を処置する方法。
- 前記癌が、メラノーマ、乳癌、卵巣癌、腎臓癌腫、胃腸/結腸癌、肺癌、明細胞肉腫、および前立腺癌からなる群から選択される、請求項44に記載の方法。
- 前記被験体がヒトである、請求項43〜45のいずれか1項に記載の方法。
- 前記抗体またはその抗原結合部分が、前記被験体に静脈内、筋肉内、または皮下に投与される、請求項43〜45のいずれか1項に記載の方法。
- 前記抗体またはその抗原結合部分が第2の治療用薬物と併用して投与される、請求項44〜47のいずれか1項に記載の方法。
- 前記第2の薬物が第2の抗体またはその抗原結合部分である、請求項48に記載の方法。
- 前記第2の薬物が抗癌剤である、請求項48に記載の方法。
- 前記抗癌剤が、抗体、小分子、代謝拮抗物質、アルキル化剤、トポイソメラーゼ阻害剤、微小管標的化剤、キナーゼ阻害剤、タンパク質合成阻害剤、免疫治療剤、ホルモンまたはその類似体、ソマトスタチン類似体、グルココルチコイド(glucocortocoid)、アロマトース(aromatose)阻害剤、およびmTOR阻害剤からなる群から選択される、請求項50に記載の方法。
- 前記抗体が、抗IGF1R抗体、抗EGFR抗体、または抗cmet抗体である、請求項51に記載の方法。
- 前記小分子が、IGF1R、EGFR、またはcmetに結合する、請求項51に記載の方法。
- (a)前記被験体から得られるエクスビボまたはインビボの細胞と、請求項1〜30のいずれかに記載の単離されたモノクローナル抗体またはその抗原結合部分とを接触させる工程と、(b)該細胞上のErbB3への結合レベルを測定する工程とを含み、ここで、異常に高いレベルのErbB3への結合は、該被験体がErbB3と関連した癌を有することを示す、該被験体におけるErbB3と関連した癌を診断する方法。
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