JP2008541733A - ヒト化抗cd40抗体およびその使用方法 - Google Patents
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- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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Abstract
Description
「CD40」および「CD40表面抗原」とは、正常および腫瘍性B細胞の表面に発現される50kDの糖タンパク質を意味し、この糖タンパク質は細胞の増殖・分化に関与するシグナルの受容体として作用し、ときにBp50とも称される (Ledbetterら, 1987, J. Imunol. 138:788-785)。CD40をコードするcDNA分子は、バーキットリンパ腫細胞株Rajiから作製されたライブラリーより単離されている (Stamenkovicら. 1989, EMBOJ. 8:1403)。CD40を発現する細胞は、CD40の表面発現によって特徴づけられる細胞であり、かかる細胞には、限定するものではないが、正常および腫瘍性B細胞、指状嵌入細胞(interdigitating cells)、基底上皮細胞、癌腫細胞、マクロファージ、内皮細胞、濾胞樹状細胞、扁桃細胞、および骨髄由来の形質細胞が含まれる。ある実施形態では、CD40分子がヒトCD40分子である。
(a) Lowry法で測定して、抗体の95重量%以上、別の態様では99重量%以上の単離、
(b) スピニングカップ(spinning cup)配列決定装置を用いて、少なくとも15残基のN-末端または内部アミノ酸配列を得るのに十分な程度の単離、または
(c) クーマシーブルー染色、好ましくは銀染色を用いて可視化したとき、還元または非還元条件下でのSDS-PAGEにより均一な単離。
団および関連色素タンパク質エンジイン抗生物質発色団、アクラシノマイシン類(aclacinomysins)、アクチノマイシン、アウスラマイシン、アザセリン、ブレオマイシン類、カクチノマイシン、カラビシン、カルミノマイシン、カルジノフィリン、クロモマイシン類、ダクチノマイシン、ダウノルビシン、デトルビシン、6-ジアゾ-5-オキソ-L-ノルロイシン、ドキソルビシン(アドリアマイシン(商標)) (モルホリノ-ドキソルビシン、シアノモルホリノ-ドキソルビシン、2-ピロリノ-ドキソルビシン、デオキシドキソルビシンを含む)、エピルビシン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシン類(例えば、マイトマイシンC)、ミコフェノール酸、ノガラマイシン、オリボマイシン類、ペプロマイシン、ポトフィロマイシン、ピューロマイシン、クエラマイシン(quelamycin)、ロドルビシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシン;代謝拮抗物質、例えばメトトレキサート、5-フルオロウラシル(5-FU);葉酸アナログ、例えばデノプテリン、メトトレキサート、プテロプテリン、トリメトレキサート;プリンアナログ、例えばフルダラビン、6-メルカプトプリン、チアミプリン、チオグアニン;ピリミジンアナログ、例えばアンシタビン、アザシチジン、6-アザウリジン、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、フロクスウリジン;アンドロゲン類、例えばカルステロン、ドロモスタノロンプロピオネート、エピチオスタノール、メピチオスタン、テストラクトン;抗アドラナール剤(anti-adranals)、例えばアミノグルテチミド、ミトタン、トリロスタン;葉酸補充剤、例えばフロリン酸(frolinic acid);アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;エニルウラシル;アムサクリン;ベストラムブシル;ビスアントレン;エダトラキサート;デフォファミン;デモコルシン;ジアジクオン;エルフォルニチン;酢酸エリプチニウム;エポチロン;エトグルシド;硝酸ガリウム;ヒドロキシウレア;レンチナン;ロニダミン;メイタンシノイド類(maytansinoids)、例えばメイタンシンおよびアンサミトシン類;ミトグアゾン;ミトキサントロン;モピダモール;ニトラクリン;ペントスタチン;フェナメット;ピラルビシン;ロソキサントロン;ポドフィリン酸;2-エチルヒドラジド;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジコン;2,2',2''-トリクロロトリエチルアミン;トリコテセン類(特に、T-2毒素、ベラクリンA、ロリジンAおよびアングイジン);ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミタブロニトール;ミトラクトール;ピポブロマン;ガシトシン;アラビノシド(Ara-C);シクロフォスファミド;チオテパ;タキソイド、例えばパクリタキセル(TAXOL(登録商標)、Bristol-Myers Squibb Oncology, Princeton, NJ)およびドキセタキセル(TAXOTERE(登録商標)、Rhone-Poulenc Rorer, Antony, France);クロラムブシル;:ゲムシタビン (Gemzar(商標));6-オグアニン;メルカプトプリン;メトトレキサート;白金アナログ、例えばシスプラチン、カルボプラチン;ビンブラスチン;エトポシド(VP-16);イホスファミド;ミトキサントロン;ビンクリスチン;ビノレルビン (Navelbine(商標));ノバントロン;テニポシド;エダトレキセート;ダウノマイシン;アミノプテリン;ゼローダ(xeloda);イバンドロネート;トポイソメラーゼ阻害剤RFS 2000;ジフルオロメチルオルニチン(DMFO);レチノイド類、例えばレチノイン酸;カペシタビン;および上記のいずれかの製薬上許容される塩、酸、または誘導体。さらに、この定義には以下のものも含まれる:腫瘍に対するホルモン作用を調節または阻害するように作用する抗ホルモン剤、例えば抗エストロゲン剤および選択的エストロゲン受容体モジュレーター(SERM)、例えばタモキシフェン(Nolvadex(商標)を含む)、ラロキシフェン、ドロロキシフェン、4-ヒドロキシタモキシフェン、トリオキシフェン、ケオキシフェン、LYl17018、オナプリストン、およびトレミフェン(Fareston(商標));副腎でのエストロゲン産生を調節する酵素アロマターゼを阻害するアロマターゼ阻害剤、例えば4(5)-イミダゾール類、アミノグルテチミド、酢酸メゲストロール(Megace(商標))、エキセメスタン、ホルメスタン、ファドラゾール、ボロゾール(Rivisor(商標))、レトロゾール(Femara(商標))、およびアナストラゾール(Arimidex(商標));ならびに抗アンドロゲン剤、例えばフルタミド、ニルタミド、ビカルタミド、ロイプロリド、ゴセレリン;および上記のいずれかの製薬上許容される塩、酸、または誘導体。
本明細書では、ヒト化抗CD40抗体、ならびにヒト化抗CD40抗体を含む組成物および製品を記載し開示する。また、ヒト化抗CD40抗体の抗原結合フラグメントを含む結合物質を記載する。ヒト化抗CD40抗体および結合物質は、細胞の増殖を停止させ、CD40発現細胞の消去を起こし、あるいはまた、標的細胞に対して細胞毒性作用もしくは細胞増殖抑制作用を引き起こすことができる。ヒト化抗CD40抗体および結合物質は、CD40表面抗原を発現する細胞の増殖を特徴とする、さまざまな疾患または障害の治療に使用することができる。
および
の順である。マウス免疫グロブリンは一般にCDCおよびADCC/ADCPを、それぞれ
および
の順で媒介する。別の例として、マウスIgG2aはADCCを媒介するが、マウスIgG2aとIgMの両方はCDCを媒介する。
ヒト化抗CD40抗体および結合物質は、ヒト化抗CD40抗体またはその抗原結合フラグメントの改変体を含み得る。例えば、癌治療における抗体の有効性を増大させるために、エフェクター機能に関して抗体を改変することが望ましい場合がある。こうした改変の1つはFc領域へのシステイン残基の導入であり、それによってこの領域における鎖間ジスルフィド結合の形成を可能とする。こうして生成するホモダイマー抗体は、内在化能(internalization capability)の改善および/または補体介在型細胞殺傷および/もしくは抗体依存性細胞傷害性(ADCC)の増大を有し得る。例えばCaronら、1992、J. Exp. Med. 176:1191-1195;およびShopes、1992、J. Immunol. 148:2918-2922を参照のこと。抗腫瘍活性の増大したホモダイマー抗体はまた、Wolffら、1993、Cancer Research 53: 2560-2565に記載されたようなヘテロ二官能性架橋剤を使用して調製することもできる。あるいはまた、抗体を2つのFc領域を有するように設計して、抗体の補体溶解能およびADCC能を増大させることもできる。Stevensonら、1989、Anti-Cancer Drug Design 3: 219-230を参照のこと。
以下の実施例1には、抗CD40抗体のヒト化のための方法が記載され、実施例2には変異体について記載されている。特定の実施形態において、特にヒト化抗体の結合親和性もしくは他の生物学的性質を改善する場合に、これらのヒト化抗体のアミノ酸配列変異体を作成することが望ましい。
・(1)疎水性:ノルロイシン、met、ala、val、leu、ile;
・(2)中性・親水性:cys、ser、thr;
・(3)酸性:asp、glu;
・(4)塩基性:asn、gin、his、lys、arg;
・(5)鎖の配向性に影響する残基:gly、pro;および
・(6)芳香族:trp、tyr、phe
ヒト化の別法として、ヒト抗体を作成することができる。例えば、免疫後に、内在性免疫グロブリンの産生なしにヒト抗体の全レパートリーを産生できるトランスジェニック動物(例えばマウス)を利用することができる。例えば、キメラマウスおよび生殖系列変異型マウスにおいて抗体の重鎖接合領域(JH)の遺伝子をホモ接合性欠失させると、内在性抗体の産生が完全に阻害されることが記載されている。このような生殖系列変異型マウスにヒト生殖系列免疫グロブリン遺伝子アレイを導入すると、抗原チャレンジによってヒト抗体が産生されるであろう。例えば、Jakobovitsら、1993、Proc. Natl. Acad. Sci. USA 90:2551;Jakobovitsら、1993、Nature 362:255-258;Bruggermannら、1993、Year in Immuno. 7:33;および米国特許第5,591,669号;第5,589,369号;第5,545,807号;第6,075,181号;第6,150,584号;第6,657,103号;および第6,713,610号を参照のこと。
他の実施形態は、ヒト化抗CD40抗体をコードする配列を含む単離されたポリヌクレオチド、ベクター、および該ポリヌクレオチドを含む宿主細胞、およびヒト化抗体の製造のための組換え技術を包含する。単離されたポリヌクレオチドは、抗CD40抗体の所望のどのような形態をもコードすることができ、かかる形態としては、例えば全長モノクローナル抗体、Fab、Fab'、F(ab')2、およびFvフラグメント、ダイアボディ、線状抗体、一本鎖抗体分子、および抗体フラグメントから形成される多重特異性抗体が含まれる。
本明細書に記載のベクター中のDNAをクローニングまたは発現させるために適切な宿主細胞は、上記の原核生物、酵母、または高等真核生物細胞である。この目的のために適した原核生物には、グラム陰性またはグラム陽性生物などの真正細菌、例えば、エシェリキア(大腸菌等)、エンテロバクター、エルウィニア(Erwinia)、クレブシエラ(Klebsiella)、プロテウス(Proteus)、サルモネラ(サルモネラ・チフィムリウム(typhimurium)等)、セラチア(セラチア・マーセスカンス(marcescans)等)、およびシゲラ、並びにB. スブチリスおよびB. リチェニフォルミス(licheniformis)(例えば1989年4月12日に公開されたDD 266,710号に開示されたB. リチェニフォルミス41 P)等のバシルス、P. アエルギノーザ等のシュードモナス、およびストレプトミセスが挙げられる。大腸菌クローニング宿主の好ましい一例は、大腸菌294(ATCC 31,446)であるが、大腸菌B、大腸菌X1776(ATCC31,537)および大腸菌W3110(ATCC27,325)等の他の株も適切である。これらの例は限定的なものではなく、例示的なものである。
更に包含されるのは、本明細書で定義する低、中、および高ストリンジェンシー条件下で、配列番号17で示されるヌクレオチド配列もしくはその相補配列、または配列番号20で示されるヌクレオチド配列もしくはその相補配列の全てまたは一部(例えば可変領域をコードする部分)とハイブリダイズする核酸である。ハイブリダイズする核酸のハイブリダイズする部分は、典型的には長さが少なくとも15(例えば20、25、30または50)ヌクレオチドである。ハイブリダイズする核酸のハイブリダイズする部分は、抗CD40ポリペプチド(例えば重鎖もしくは軽鎖の可変領域)をコードする核酸もしくはその相補配列の一部または全ての配列に対して少なくとも80%(例えば少なくとも90%、少なくとも95%、または少なくとも98%)同一である。本明細書に記載した型のハイブリダイズする核酸は、例えばクローニングプローブ、プライマー(例えばPCRプライマー)、もしくは診断用プローブとして使用することができる。
本明細書に記載した抗体は、アフィニティー精製試薬として有用である。この方法において、抗体は、当分野で周知の方法を用い、Sephadex樹脂または濾紙等の固相上に固定化される。固定化された抗体は、精製すべきCD40タンパク質(またはその断片)を含有するサンプルと接触させ、その後、CD40タンパク質(固定化抗体に結合している)以外のサンプル中の実質的に全ての物質を除去し得る適切な溶媒で支持体を洗浄する。最後に、抗体からCD40タンパク質を放出させ得る別の適切な溶媒(グリシン緩衝液、pH5.0等)で支持体を洗浄する。
(a)放射性同位体、例えば35S、14C、125I、3H、および131I。例えば「免疫学における最近のプロトコル(Current Protocols in Immunology)」 第1および2巻、1991、Coligenら編、Wiley-Interscience, New York, N.Y., Pubsに記載された技術を用いて抗体を放射性同位体で標識することができる。放射活性は、例えばシンチレーション計数によって測定することができる。
(a) 西洋ワサビペルオキシダーゼ(HRPO)と基質としての過酸化水素、ここで過酸化水素はオルトフェニレンジアミン(OPD)または3,3',5,5'-テトラメチルベンジジン塩酸(TMB)等の色素前駆物質を酸化する;
(b) アルカリ性ホスファターゼ(AP)と発色基質としてのp−ニトロフェニルホスフェート;および
(c) β-D-ガラクトシダーゼ(β-D-Gal)と発色基質p-ニトロフェニル-β-D-ガラクトシドまたは発蛍光性基質4-メチルウンベリフェリル-β-D-ガラクトシド。
ヒト化抗CD40抗体は診断キット(すなわち、診断アッセイを実施するための使用説明書を含む、所定量の試薬の組み合わせのパッケージ)において使用することができる。抗体を酵素で標識する場合、キットには、基質類、および検出可能な発色団または蛍光発色団を提供する基質前駆物質等の、酵素が必要とする補因子が含まれ得る。更に、他の添加物質、例えば安定化剤、緩衝剤(例えばブロック緩衝剤または溶解緩衝剤)等が含まれ得る。アッセイ感度を実質的に最適にする試薬の溶液中濃度を提供するために、種々の試薬の相対量は広く変えることができる。試薬は、溶解時に適切な濃度の試薬溶液を提供するような添加剤を含む、通常凍結乾燥された、乾燥粉末として提供され得る。
別の実施形態において、本明細書に開示するヒト化抗CD40抗体は、本明細書に記載するようなCD40の発現に関連する種々の障害の治療に有用である。
抗CD40抗体または薬剤は、CD40を発現する癌またはCD40の発現(例えば免疫細胞(リンパ球もしくは樹状細胞等)の不適切な活性化)を特徴とする免疫障害の治療または予防に有効である。このようなCD40の発現は、例えば細胞表面上のCD40タンパク質レベルの増加、および/または発現するCD40の抗原性の変化のためであり得る。本明細書に記載する方法に従い、免疫障害の治療または予防は、そのような治療または予防が必要な被験者に、有効量の抗CD40抗体または薬剤を投与することによって達成され、ここで抗体は(i)CD40を発現し、疾患状態と関連する活性化免疫細胞に結合し、(ii)活性化免疫細胞に対して細胞毒性効果、細胞増殖抑制効果、または免疫抑制効果を発揮する。
CD40結合物質(例えば抗CD40抗体)を含有する組成物は、免疫障害またはCD40発現癌を有するか、その危険のある被験者に投与することができる。本発明は更に、CD40発現癌または免疫疾患の予防または治療のための医薬の製造における、CD40結合物質(例えば抗CD40抗体)の使用を提供する。本明細書において使用する用語「被験者」とは、CD40結合物質を投与することができる任意の哺乳類の患者を意味し、例えばヒトおよび非ヒト哺乳類(例えば霊長類、げっ歯類、およびイヌ)が挙げられる。本明細書に記載する方法を用いた治療のために特に意図される被験者にはヒトが含まれる。該抗体または結合物質は、免疫障害またはCD40発現癌の予防または治療において単独で、あるいは他の組成物と組み合わせて投与することができる。
別の態様において、上記の障害の治療のために有用な物質を含む製品が含まれる。製品は、容器およびラベルを含む。適切な容器としては、例えばビン、バイアル、シリンジおよび試験管が挙げられる。容器は、ガラスまたはプラスティック等の種々の材料から形成することができる。容器は症状を治療するために有効な組成物を保持し、無菌のアクセスポートを有し得る。例えば、容器は、皮下注射用の針で穿孔し得るストッパーを有する静脈注射用溶液の袋またはバイアルであり得る。組成物中の活性剤はヒト化抗CD40抗体である。容器上の、または容器に添付されたラベルには、組成物が選択された症状を治療するために用いられることが示されている。製品は更に、リン酸緩衝生理食塩水、リンゲル液、およびブドウ糖液等の製薬上許容される緩衝液を含む第二の容器を含んでいても良い。商業上の観点および使用者の観点から望ましい他の物質が更に含まれていても良く、それには他の緩衝剤、希釈剤、フィルター、針、シリンジ、および使用上の説明を記載した添付文書が含まれる。
モノクローナル抗体S2C6のATCCへの寄託は、特許手続上の微生物の寄託の国際的承認に関するブダペスト条約の規定に従い、1999年5月25日になされた。ATCCは10801 University Boulevard, Manassas, Virgina 20110-2209, USAに所在している。このATCC寄託には受託番号PTA-110が付与された。いずれの寄託も当業者の便宜のために提供され、35 U.S.C. Section 112に基づいて寄託が必要であることを認めるものではない。本明細書における記載は、寄託されている抗体によってその範囲を制限されるべきものではない。なぜなら寄託された実施形態は本発明の特定の態様の1つの説明として意図されたものであり、機能的に等価な抗体はいずれも本発明の範囲内にある。本明細書に記載の物質の寄託は、本明細書に含まれる記載が、そのベストモードを含めた本発明の態様の実施を可能とするのに不十分であることを容認するものではなく、また、その寄託物が提示する特定の例示に請求の範囲を限定するものと解釈すべきでもない。事実、前述の記載から、本明細書に示し、かつ記載したものに加え、本発明の種々の改変が当業者には明らかであり、それらは添付した請求の範囲内にあるであろう。
ヒト化抗CD40抗体は、一般的には、マウス抗CD40ドナー抗体のCDRをレシピエントヒト抗体にインポートすることにより構築した。ドナー抗体は米国特許第6,838,261号に記載されるマウスモノクローナル抗体S2C6であり、この抗体はBリンパ球に強い増殖促進シグナルを与えることが実証された。例えば、Paulieら, 2000, J. Immunol 142:590を参照のこと。ヒトレシピエント重鎖および軽鎖ドメインとして使用するために、ヒトサブグループIII重鎖可変ドメイン(配列番号2)およびヒトκサブグループI軽鎖可変ドメイン(配列番号13)のコンセンサス配列を、Carterら, 1992, Proc. Natl. Acad. Sci. USA 89:4285; 米国特許第6,037,454号および同第6,054,297号に概説されるとおりに取得した。
実施例1に記載したように作製した、テンプレートヒト化抗体sgn-0に対して一連の突然変異を行った。sgn-0の軽鎖および重鎖可変ドメインをコードするDNAに部位特異的変異誘発により特定の変異を導入した。テンプレート分子から作製された変異体の配列を以下の表3および4に示す。
CD40+およびCD138++ヒト多発性骨髄腫細胞株MM.1S(デキサメタゾン感受性)およびMM.1R(デキサメタゾン耐性)、ならびに2人の多発性骨髄腫患者から新たに分離された腫瘍細胞 (CD40+、CD138++)を、次第に増加する濃度(0〜100μg/ml)のヒト化S2C6抗体で48時間処理した。DNA合成を3[H]-チミジンの取込みにより測定した。これらの結果は、ヒト化S2C6抗体がMM.1S、MM.1Rまたは2人の患者から得られた腫瘍細胞の増殖を刺激しないことを示した(p>0.1)。
ヒト化抗CD40抗体の抗腫瘍活性はSCIDマウスリンパ腫異種移植モデルでアッセイした。薬物治療を開始する13日前に500万個のRamos腫瘍細胞をSCIDマウス(1群10匹)に皮下注入した。マウス抗CD40抗体またはヒト化S2C6抗体を腹腔内に週3回(4mg/kg/回)投与し、8または5回投与した。腫瘍の増殖についてマウスを検査し、14日の試験期間中腫瘍の大きさを週1回測定した。図2の結果は、対照マウスでは腫瘍増殖が約9倍上昇するのに対して、同じ期間にわたり、マウス抗CD40抗体またはヒト化S2C6抗体で処置したマウスの腫瘍増殖はごくわずかであったことを示している。これらのデータは、ヒト化抗体がこのBリンパ腫異種移植モデルにおいて腫瘍増殖を抑制するのにマウス抗CD40抗体と同程度に有効であったことを実証している。
腫瘍担持マウスの生存に対するヒト化抗CD40抗体の効力をSCIDマウスリンパ腫異種移植モデルでアッセイした。抗体処置の3日前にSCIDマウス(1群10匹)に100万個のRamos腫瘍細胞を静脈内接種した。マウスをマウス抗CD40抗体もしくはヒト化抗CD40抗体、または対照としてのIgで処置したが、これらの抗体は週2回(4mg/kg/回)腹腔内投与し、全部で5回投与した。マウスのケージを死亡について毎日検査した。図3に示す結果は、対照抗体で処置したマウスのどれも腫瘍接種後34日目を超えて生存したものはいなかったが、マウス抗CD40抗体で処置した10匹のうち8匹のマウスと、ヒト化抗CD40抗体で処置した10匹全部のマウスは、腫瘍移植後90日間も生存し続けたことを示している。これらのデータは、ヒト化抗体がこのBリンパ腫異種移植モデルにおいてSCIDマウスの生存を引き延ばすのにマウス抗CD40抗体と同程度に有効であったことを実証している。
Claims (49)
- ヒトCD40と特異的に結合する単離された抗体または抗原結合フラグメントであって、配列番号2のヒト可変ドメイン重鎖サブグループIIIコンセンサスアミノ酸配列のフレームワーク領域のアミノ酸配列に対して少なくとも90%同一であるアミノ酸配列を有するフレームワーク領域を含み、かつ配列番号3の対応する重鎖CDRに対して少なくとも90%同一であるアミノ酸配列を有する少なくとも1つのCDRを含む、ヒト化重鎖可変ドメインを含んでなる、上記抗体または抗原結合フラグメント。
- ヒトCD40と特異的に結合する単離された抗体または抗原結合フラグメントであって、配列番号13のヒト可変ドメイン軽鎖サブグループκIコンセンサスアミノ酸配列のフレームワーク領域に対して少なくとも90%同一であるアミノ酸配列を有するフレームワーク領域を含み、かつ配列番号14の対応する軽鎖CDRに対して少なくとも90%同一であるアミノ酸配列を有する少なくとも1つのCDRを含む、ヒト化軽鎖可変ドメインを含んでなる、上記抗体または抗原結合フラグメント。
- 配列番号13のヒト可変ドメイン軽鎖サブグループκIコンセンサスアミノ酸配列のフレームワーク領域に対して少なくとも90%同一であるアミノ酸配列を有するフレームワーク領域を含み、かつ配列番号14の対応する軽鎖CDRに対して少なくとも90%同一であるアミノ酸配列を有する少なくとも1つのCDRを含む、ヒト化軽鎖可変ドメインをさらに含んでなる、請求項1に記載の抗体または抗原結合フラグメント。
- それぞれの重鎖CDRが配列番号3の対応する重鎖CDRに対して少なくとも90%同一である、請求項1に記載の抗体または抗原結合フラグメント。
- 重鎖CDRが配列番号3の対応する重鎖CDRのアミノ酸配列を有する、請求項4に記載の抗体または抗原結合フラグメント。
- それぞれの軽鎖CDRが配列番号14の対応する軽鎖CDRに対して少なくとも90%同一である、請求項2または3に記載の抗体または抗原結合フラグメント。
- 軽鎖CDRが配列番号14の軽鎖CDRのアミノ酸配列を有する、請求項6に記載の抗体または抗原結合フラグメント。
- 配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、または配列番号11の重鎖可変ドメインのアミノ酸配列を有する、請求項1に記載の抗体または抗原結合フラグメント。
- 配列番号14、配列番号15、または配列番号16の軽鎖可変ドメインのアミノ酸配列を有する、請求項2に記載の抗体または抗原結合フラグメント。
- 配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、または配列番号11の重鎖可変ドメインのアミノ酸配列、および配列番号14、配列番号15、または配列番号16の軽鎖可変ドメインのアミノ酸配列を有する、請求項3に記載の抗体または抗原結合フラグメント。
- ヒトIgG定常領域をさらに含む、請求項1または3に記載の抗体または抗原結合フラグメント。
- IgG定常領域のアイソタイプがIgGl、IgG2、IgG3、またはIgG4である、請求項11に記載の抗体または抗原結合フラグメント。
- IgG定常領域のアイソタイプがIgGlである、請求項12に記載の抗体または抗原結合フラグメント。
- 軽鎖定常ドメインをさらに含む、請求項2または3に記載の抗体または抗原結合フラグメント。
- 軽鎖定常ドメインがκ定常ドメインである、請求項14に記載の抗体または抗原結合フラグメント。
- 重鎖可変ドメインと軽鎖可変ドメインが、それぞれ配列番号3および配列番号14;それぞれ配列番号4および配列番号14;それぞれ配列番号5および配列番号14;それぞれ配列番号6および配列番号14;それぞれ配列番号7および配列番号14;それぞれ配列番号8および配列番号14;それぞれ配列番号9および配列番号14;それぞれ配列番号6および配列番号15;それぞれ配列番号6および配列番号16;それぞれ配列番号7および配列番号16;それぞれ配列番号10および配列番号14;それぞれ配列番号11および配列番号14;それぞれ配列番号10および配列番号16;またはそれぞれ配列番号11および配列番号16のアミノ酸配列を有する、請求項10に記載の抗体または抗原結合フラグメント。
- 重鎖可変ドメインと軽鎖可変ドメインが、それぞれ配列番号7および配列番号14;それぞれ配列番号6および配列番号16;それぞれ配列番号7および配列番号16;それぞれ配列番号10および配列番号14;それぞれ配列番号11および配列番号14;それぞれ配列番号10および配列番号16;またはそれぞれ配列番号11および配列番号16のアミノ酸配列を有する、請求項10に記載の抗体または抗原結合フラグメント。
- 重鎖可変ドメインと軽鎖可変ドメインが、それぞれ配列番号7および配列番号14;それぞれ配列番号6および配列番号16;それぞれ配列番号10および配列番号16;またはそれぞれ配列番号11および配列番号16のアミノ酸配列を有する、請求項10に記載の抗体または抗原結合フラグメント。
- 重鎖可変ドメインと軽鎖可変ドメインが、それぞれ配列番号3および配列番号14のアミノ酸配列を有する、請求項10に記載の抗体または抗原結合フラグメント。
- 重鎖可変ドメインと軽鎖可変ドメインが、それぞれ配列番号10および配列番号16のアミノ酸配列を有する、請求項10に記載の抗体または抗原結合フラグメント。
- 前記抗体がヒト免疫グロブリンの定常領域をさらに含む、請求項16〜20のいずれか1項に記載の抗体。
- 配列番号19および配列番号22に示す、それぞれ重鎖および軽鎖のアミノ酸配列を含む、請求項21に記載の抗体。
- hu sgn-0、hu sgn-1、hu sgn-2、hu sgn-4、hu sgn-14、hu sgn-15、hu sgn-16、hu sgn-17、hu sgn-18、hu sgn-19、hu sgn-22、hu sgn-23、hu sgn-26またはhu sgn-27である、請求項21に記載の抗体。
- 抗原結合性の抗体フラグメントである、請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメント。
- 抗体フラグメントがFab、Fab'、F(ab')2、Fvフラグメント、ダイアボディ、一本鎖抗体、scFvフラグメント、またはscFv-Fcである、請求項24に記載の抗原結合フラグメント。
- 検出可能な標識をさらに含む、請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメント。
- 前記抗体が化学療法剤に結合されている、請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメント。
- 化学療法剤がアウリスタチン(auristatin)である、請求項27に記載の抗体または抗原結合フラグメント。
- アウリスタチンがMMAEまたはMMAFである、請求項28に記載の抗体または抗原結合フラグメント。
- 容器内に、請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメント、および場合により、該抗体を用いて生物学的サンプル中のCD40タンパク質を検出することについての使用説明書、を含んでなるキット。
- ヒトCD40抗原を発現している細胞の増殖を阻害するための方法であって、該細胞に、ヒト細胞表面CD40抗原と特異的に結合する請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメントを投与することを含んでなり、その際、該抗体または抗原結合フラグメントのCD40抗原への結合により、該細胞の増殖または分化が阻害される、上記方法。
- CD40関連障害を有する被験者を治療するための方法であって、該被験者に、ヒトCD40と特異的に結合する請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメントを投与することを含んでなり、その際、該抗体または抗原結合フラグメントのCD40への結合により、CD40関連障害の細胞の増殖または分化が阻害される、上記方法。
- CD40関連障害の細胞がBリンパ芽球様細胞、膵細胞、肺細胞、乳房細胞、卵巣細胞、大腸細胞、前立腺細胞、皮膚細胞、頭頸部細胞、膀胱細胞、骨細胞、または腎細胞である、請求項32に記載の方法。
- CD40関連障害が慢性リンパ性白血病、バーキットリンパ腫、多発性骨髄腫、T細胞リンパ腫、非ホジキンリンパ腫、ホジキン病、ヴァルデンストレームマクログロブリン血症、またはカポジ肉腫である、請求項32に記載の方法。
- 末梢B細胞の枯渇を誘導するための方法であって、該細胞に、ヒト細胞表面CD40抗原と特異的に結合する請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメントを投与することを含んでなり、その際、該抗体または抗原結合フラグメントのCD40抗原への結合により、該細胞の枯渇が誘導される、上記方法。
- 前記抗体または抗原結合フラグメントが免疫障害を有する被験者に投与される、請求項35に記載の方法。
- 免疫障害が慢性関節リウマチまたは全身性エリテマトーデスである、請求項37に記載の方法。
- 前記抗体または抗原結合フラグメントが、ATCC寄託番号PTA-110を有するハイブリドーマにより分泌されるモノクローナル抗体S2C6と結合について競合する、請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメント。
- (i) 請求項1〜3のいずれか1項に記載の抗体または抗原結合フラグメント、および
(ii) 製薬上許容される添加剤、
を含有すね医薬組成物。 - 請求項1に記載の抗体または抗原結合フラグメントのヒト化重鎖可変領域をコードする単離されたポリヌクレオチド。
- 請求項2に記載の抗体または抗原結合フラグメントのヒト化軽鎖可変領域をコードする単離されたポリヌクレオチド。
- 配列番号13のヒト可変領域軽鎖サブグループκIコンセンサスアミノ酸配列のフレームワーク領域に対して少なくとも90%同一であるアミノ酸配列を有するフレームワーク領域を含み、かつ配列番号3の対応する重鎖CDRに対して少なくとも90%同一であるアミノ酸配列を有する少なくとも1つのCDRを含む、ヒト化軽鎖可変領域をさらにコードする、請求項40に記載の単離されたポリヌクレオチド。
- 前記ポリヌクレオチドが配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、または配列番号11の重鎖可変ドメインのアミノ酸配列をコードする、請求項40または42に記載の単離されたポリヌクレオチド。
- 前記ポリヌクレオチドが配列番号14、配列番号15、または配列番号16の軽鎖可変ドメインのアミノ酸配列をコードする、請求項41または42に記載の単離されたポリヌクレオチド。
- 前記ポリヌクレオチドが、それぞれ配列番号3および配列番号14;それぞれ配列番号4および配列番号14;それぞれ配列番号5および配列番号14;それぞれ配列番号6および配列番号14;それぞれ配列番号7および配列番号14;それぞれ配列番号8および配列番号14;それぞれ配列番号9および配列番号14;それぞれ配列番号6および配列番号15;それぞれ配列番号6および配列番号16;それぞれ配列番号7および配列番号16;それぞれ配列番号10および配列番号14;それぞれ配列番号11および配列番号14;それぞれ配列番号10および配列番号16;またはそれぞれ配列番号11および配列番号16の重鎖可変ドメインのアミノ酸配列と軽鎖可変ドメインのアミノ酸配列をコードする、請求項43に記載の単離されたポリヌクレオチド。
- 前記ポリヌクレオチドが、それぞれ配列番号7および配列番号14;それぞれ配列番号6および配列番号16;それぞれ配列番号7および配列番号16;それぞれ配列番号10および配列番号14;それぞれ配列番号11および配列番号14;それぞれ配列番号10および配列番号16;またはそれぞれ配列番号11および配列番号16の重鎖可変ドメインのアミノ酸配列と軽鎖可変ドメインのアミノ酸配列をコードする、請求項43に記載の単離されたポリヌクレオチド。
- 前記ポリヌクレオチドが、それぞれ配列番号7および配列番号14;それぞれ配列番号6および配列番号16;それぞれ配列番号10および配列番号16;またはそれぞれ配列番号11および配列番号16の重鎖可変ドメインのアミノ酸配列と軽鎖可変ドメインのアミノ酸配列をコードする、請求項43に記載の単離されたポリヌクレオチド。
- 前記ポリヌクレオチドが、それぞれ配列番号3および配列番号14の重鎖可変ドメインのアミノ酸配列と軽鎖可変ドメインのアミノ酸配列をコードする、請求項43に記載の単離されたポリヌクレオチド。
- 前記ポリヌクレオチドが、それぞれ配列番号10および配列番号16の重鎖可変ドメインのアミノ酸配列と軽鎖可変ドメインのアミノ酸配列をコードする、請求項43に記載の単離されたポリヌクレオチド。
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JP2012519478A (ja) * | 2009-03-06 | 2012-08-30 | エルエフベ−バイオテクノロジース | 抗−rh式血液型dモノクローナル抗体 |
JP2012523838A (ja) * | 2009-04-18 | 2012-10-11 | ジェネンテック, インコーポレイテッド | 抗cd40抗体を用いる治療に対するb細胞性リンパ腫の応答性を評価するための方法 |
JP2020050677A (ja) * | 2014-10-29 | 2020-04-02 | シアトル ジェネティックス, インコーポレイテッド | 非フコシル化抗cd40抗体の投与量および投与 |
JP2020515276A (ja) * | 2017-04-04 | 2020-05-28 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Cd40およびfapに特異的に結合することができる新規な二重特異性抗原結合分子 |
JP6997209B2 (ja) | 2017-04-04 | 2022-02-04 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Cd40およびfapに特異的に結合することができる新規な二重特異性抗原結合分子 |
JP2022511396A (ja) * | 2018-10-01 | 2022-01-31 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Cd40への三価結合を伴う二重特異性抗原結合分子 |
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Publication number | Publication date |
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NO341793B1 (no) | 2018-01-22 |
AU2006249305B2 (en) | 2012-10-18 |
MA29595B1 (fr) | 2008-07-01 |
US20090181015A1 (en) | 2009-07-16 |
US20130023047A1 (en) | 2013-01-24 |
CA2609269C (en) | 2014-08-05 |
RU2007148932A (ru) | 2009-07-10 |
WO2006128103A2 (en) | 2006-11-30 |
RU2407544C2 (ru) | 2010-12-27 |
JP5027804B2 (ja) | 2012-09-19 |
NO20076404L (no) | 2008-02-13 |
KR100991010B1 (ko) | 2010-10-29 |
US8492531B2 (en) | 2013-07-23 |
CA2609269A1 (en) | 2006-11-30 |
EP1885399A4 (en) | 2009-04-22 |
DE602006017690D1 (de) | 2010-12-02 |
EP1885399A2 (en) | 2008-02-13 |
US20140193405A1 (en) | 2014-07-10 |
ECSP078026A (es) | 2008-03-26 |
EP1885399B1 (en) | 2010-10-20 |
ATE485057T1 (de) | 2010-11-15 |
CR9562A (es) | 2008-03-06 |
CN101237882A (zh) | 2008-08-06 |
BRPI0610470A2 (pt) | 2010-06-22 |
KR20080030958A (ko) | 2008-04-07 |
PL1885399T3 (pl) | 2011-04-29 |
AU2006249305A1 (en) | 2006-11-30 |
IL187594A0 (en) | 2008-03-20 |
US8303955B2 (en) | 2012-11-06 |
WO2006128103A3 (en) | 2007-01-18 |
ES2354865T3 (es) | 2011-03-18 |
US20130315900A1 (en) | 2013-11-28 |
CN101237882B (zh) | 2012-08-15 |
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