JP5478254B2 - 抗ノッチ3アゴニスト抗体とノッチ3関連疾患の治療におけるその使用 - Google Patents
抗ノッチ3アゴニスト抗体とノッチ3関連疾患の治療におけるその使用 Download PDFInfo
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- JP5478254B2 JP5478254B2 JP2009533527A JP2009533527A JP5478254B2 JP 5478254 B2 JP5478254 B2 JP 5478254B2 JP 2009533527 A JP2009533527 A JP 2009533527A JP 2009533527 A JP2009533527 A JP 2009533527A JP 5478254 B2 JP5478254 B2 JP 5478254B2
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5152—Tumor cells
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
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- C—CHEMISTRY; METALLURGY
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- C07K2317/75—Agonist effect on antigen
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Description
本出願は、その開示を出典明示によりここに援用する2006年10月19日出願の米国仮出願第60/852861号及び2007年1月6日出願の米国仮出願第60/879218号の優先権を主張する。
この出願を通して使用される用語は、当業者にとって通常の典型的な意味を持つものと解されるものである。しかしながら、本出願人は、次の用語には、以下に記載される特定の定義が与えられることを所望する。
可溶型標的又はその断片は抗体の生産のための免疫原として使用することができる。抗体は対象の標的に対してつくられる。好ましくは、標的は生物学的に重要なポリペプチドであり、疾患又は障害を被っている哺乳類への投与がその哺乳類において治療的効果を生じうる。全細胞を、抗体を作製するための免役原として使用することができる。免役原は組換え的に生産され又は合成法を使用して作製されうる。免役原は天然源から単離することもまたできる。
本発明の抗体は、当該分野で周知のいかなる適切な方法により生産してもよい。本発明の抗体は、ポリクローナル抗体を含みうる。ポリクローナル抗体の調製方法は、当業者に周知である(出典明示によりここに援用するHarlow等, Antibodies: a Laboratory Manual, Cold spring Harbor Laboratory Press, 2nd ed. (1988))。
Suresh等, Meth In Enzym 121:210 (1986)を参照。
本発明は、リガンド結合とは独立してノッチ3媒介性シグナル伝達を活性化するアゴニストモノクローナル抗体を提供する。特に、本発明の抗体はノッチ3に結合し、それを活性化する。本発明の抗体は、256A-13に対する抗体を含む。本発明はまた、256A-13と同じエピトープに結合する抗体を含む。
別の態様において、本発明は、ここに開示の抗体変異体をコードする単離された核酸配列、本発明の抗体をコードするヌクレオチド配列を含むベクターコンストラクト、かかるベクターを含む宿主細胞、及び抗体を生産するための組換え技術を提供する。
多くのベクターが利用できる。ベクター成分は通常、限定するものではないが、以下のもの:シグナル配列、複製起点、一又は複数のマーカー遺伝子、エンハンサー要素、プロモーター、及び転写終結配列の一又は複数を含む:。本発明の抗体をコードするヌクレオチド配列を含む組換え発現ベクターは、周知の技術を用いて調製できる。発現ベクターは、適切な転写又は翻訳制御ヌクレオチド配列、例えば哺乳類、微生物、ウィルス、又は昆虫遺伝子由来のものに作用可能に連結されたヌクレオチド配列を含む。制御配列の例としては、転写プロモーター、オペレーター、エンハンサー、mRNAリボソーム結合部位、及び/又は転写及び翻訳の開始及び終結を制御する他の適切な配列が挙げられる。ヌクレオチド配列は、制御配列が適切なポリペプチドのヌクレオチド配列と機能的に関連するとき「作用可能に連結」する。このように、プロモーターヌクレオチド配列は、該配列が適切なヌクレオチド配列の転写を制御する場合、例えば抗体重鎖配列と作用可能に連結する。
本発明の抗体は、任意の適切な宿主細胞から発現できる。本発明で有用な宿主細胞の例としては、原核、酵母、又は高等真核細胞が挙げられ、及び、限定するものではないが、抗体コード配列を含む組換えバクテリオファージDNA、プラスミドDNA又はコスミドDNA発現ベクターで形質転換されたバクテリア(例えば大腸菌、枯草菌)といった微生物;抗体コード配列を含む組換え酵母発現ベクターで形質転換された酵母(例えばサッカロミセス、ピチア);抗体コード配列を含む組換えウィルス発現ベクター(例えばバキュロウィルス)で感染させた昆虫細胞系;組換えウィルス発現ベクター(例えばカリフラワーモザイクウィルス,CaMV;タバコモザイクウィルス,TMV)で感染させた、又は抗体コード配列を含む組換えプラスミド発現ベクター(例えばTiプラスミド)で形質転換した植物細胞系;又は哺乳類細胞のゲノム由来のプロモーター(例えばメタロチオネインプロモーター)又は哺乳類ウィルス由来のプロモーター(例えばアデノウィルス遅発性プロモーター;ワクシニアウィルス7.5Kプロモーター)を含む組換え発現コンストラクトを内部に持つ哺乳類細胞系(例えばCOS、CHO、BHK、293、3T3細胞)が含まれる。
本発明は更に、本発明の抗体及びその断片をコードするヌクレオチド配列を含むポリヌクレオチド又は核酸、例えばDNAを提供する。例示的なポリヌクレオチドとしては、ここに記載の一又は複数のアミノ酸配列を含む抗体鎖をコードするものが挙げられる。本発明はまた、本発明の抗体をコードするポリヌクレオチドにストリンジェントな又はより低いストリンジェンシーのハイブリダイズ条件下でハイブリダイズするポリヌクレオチドも包含する。
本発明の抗体は、抗体合成のための当該分野で周知の任意の方法によって、特に化学合成によって、又は好ましくは組換え発現技術によって生産できる。
組換え技術を利用する場合、抗体変異体は、細胞内のペリプラズム空間に生産するか、又は培地に直接分泌することができる。抗体が細胞内で生産される場合、第一工程として、微粒子状破片、宿主細胞か溶解断片のいずれか、が例えば遠心分離又は限外ろ過によって除去されうる。Carter等, Bio/Technology 10:163 (1992)に、大腸菌のペリプラズム空間に分泌される抗体を単離する手順が記載されている。簡潔には、細胞ペーストが酢酸ナトリウム(pH3.5)、EDTA、及びフッ化フェニルメチルスルホニル(PMSF)の存在下で約30分以上溶解される。細胞破片は遠心分離により除去できる。抗体変異体が培地に分泌されると、通常、かかる発現系からの上清が、市販のタンパク質収集フィルター、例えばAmicon又はMillipore Pellicon限外ろ過ユニットを用いてまず収集される。PMSFといったプロテアーゼインヒビターが、タンパク質分解を阻害するために前述の工程のいずれかに含まれてよく、そして抗生物質が、外来性汚染物質の増殖を防止するために含まれてよい。
ポリペプチド又は抗体の治療製剤は、所定の純度を持つポリペプチドを、当該分野で典型的に用いられる任意の「製薬的に許容される」担体、賦形剤又は安定化剤、つまり緩衝剤、安定化剤、保存料、等張化剤、非イオン性洗浄剤、酸化防止剤及び他の添加剤と混合することにより凍結乾燥製剤又は水溶液として調製され保存されうる。Remington's Pharmaceutical Sciences, 16th ed., Osol編, (1980)を参照。このような添加剤は、用いられる用量及び濃度で受容者に非毒性でなければならない。
本発明の抗体は哺乳類を治療するために用いてもよいと考えられる。一実施態様において、抗体は、例えば、臨床前データを得るためにヒト以外の哺乳類に投与される。治療されるヒト以外の哺乳類の例には、ヒト以外の霊長類、イヌ、ネコ、齧歯動物と他の哺乳類が含まれ、それらについて臨床前研究が実施される。このような哺乳類は、抗体で治療される疾患のために確立された動物モデルであってもよく、または、興味の抗体の毒性を研究するために用いられてもよい。これら実施態様の各々において、用量漸増研究が哺乳動物において実施されうる。
本発明の他の実施態様では、前述した疾患の治療に有用な物質を含有する製造品が提供される。製造品は容器及び説明書を含んでなる。適切な容器には、例えばボトル、バイアル、シリンジ、及び試験管が含まれる。容器はガラス又はプラスチックのような様々な材料で形成することができる。容器は病状の治療に有効な組成物を収容しており、滅菌した出入口を有している(例えば、容器は皮下注射針により貫通可能なストッパーを具備する静脈溶液用のバック又はバイアルであってよい)。容器上の又は容器に付随する説明書には、組成物が、選択された病状の治療に使用されることが示されている。さらに製造品は、製薬的に許容可能なバッファー、例えばリン酸緩衝生理食塩水、リンガル液及びブドウ糖液を収容する第2の容器をさらに具備しうる。さらに、他のバッファー、希釈剤、フィルター、針、シリンジ、及び使用指示書を含む、市販及び使用者の観点から望ましい他の材料をさらに含んでいてもよい。
本発明の別の態様において、抗体またはその機能的な誘導体をコードする配列の核酸は、遺伝子療法として、ノッチ3の異常な発現および/または活性に伴う疾患または障害を治療、抑制または予防するために投与される。遺伝子療法とは発現した又は発現可能な核酸を、患者に投与することによって実施される治療法を意味する。本発明の実施態様において、核酸はそれらがコードする、治療効果をもたらタンパク質を産生する。利用可能な遺伝子療法の任意の方法が、本発明によって使用できる。以下に、典型的な方法について説明する。
ヒトノッチ3のLIN12/二量体化ドメイン(以降「LD」)に特異的に結合する抗ノッチ3モノクローナル抗体を、組換えノッチ3-Fc融合タンパク質を、カルボキシ末端がγ1Fc領域に融合したノッチ3LDを含む免疫原として用いて生産した。特に、免疫原は、ノッチ3LDのアミノ酸残基1378から1640(図1参照)とヒトγ1Fc融合タンパク質とを含んだ。制御抗体を、アミノ酸残基43から1377由来のノッチ3EGF反復領域を免疫原として用いて生成した。
8−12週齢の雄A/Jマウス(Harlan, Houston, TX)に、200μlのPBS中のフロイント完全アジュバント(Difco Laboratories, Detroit, MI)中の25μgのノッチ3−EGF/Fc又はノッチ3−LD/Fcを皮下的に注射した。注射の2週間後で屠殺の3日前に、マウスにまたPBS中の同じ抗原25μgを腹腔内注射した。各融合体について、単一の細胞懸濁液を免疫化細胞の脾臓から調製し、Sp2/0ミエローマ細胞との融合に使用した;5×108のSp2/0及び5×108の脾臓細胞を、50%のポリエチレングリコール(分子量1450) (Kodak, Rochester, NY)及び5%のジメチルスルホキシド(Sigma, St. Louis, MO)を含む培地中で融合させた。ついで、細胞を、10%のウシ胎仔血清、100ユニット/mlのペニシリン、100μg/mlのストレプトマイシン、0.1μMのヒポキサンチン、0.4μMのアミノプテリン、及び16μMのチミジンを補填したIscove培地(Invitrogen, Carlsbad, CA)中において200μlの懸濁液中1.5×105脾臓細胞の濃度まで調整した。200マイクロリットルの細胞懸濁液を約96ウェルプレートの各ウェルに加えた。約10日後、培養上清を、ELISAを使用するその抗原結合活性についてのスクリーニングのために取り出した。
抗ノッチ3MAbsを特徴付けるために使用する細胞ベース結合アッセイには、ベクター、この場合にはpcDNA3.1/Hygro(Invitrogen, Carlsbad, CA)中へのヒトノッチ3オープンリーディングフレームの完全長のクローニングが必要であった。ノッチ3コーディング領域は、鋳型としてヒト肝臓腫瘍RNA (Ambion, Inc., Austin, TX) を使用してRT−PCRによって合成した。最終のプラスミドコンストラクトノッチ3/Hygroは、図1に示されるように完全長ノッチ3タンパク質を発現した。ノッチ3を発現する安定な細胞株は、実施例1に記載されたものと同じ手順に従ってリポフェクタミン2000キッとを使用して、ノッチ3/Hygroプラスミドコンストラクトを293T細胞(ATCC番号CRL−11268)中に形質移入させることによって生産した。形質移入後、細胞をDMEM増殖培地で一晩培養し、ついで200μg/mlのハイグロマイシンを含む増殖培地に再播種し、12−14日間培養した。良好に単離された単一コロニーを取り上げ、別個のウェルで、十分なコロニー細胞が増幅されるまで増殖させた。ハイグロマイシン選択に耐性があり高レベルのノッチ3タンパク質を発現した安定な293Tクローンを、ウェスタンブロット分析と、ポリクローナル抗ノッチ3抗体を使用する蛍光電子顕微鏡観察(R&D Systems, Minneapolis, MN)によって同定した。
変性条件下でのノッチ3レセプターに対する256A−13の結合活性、並びにヒト細胞株中でのノッチ3及び他のノッチ関連タンパク質の発現レベルを評価するためにウェスタンブロットを実施した。精製したノッチ3−LD/Fc融合タンパク質をタンパク質負荷バッファーと組み合わせた。タンパク質試料をまた実施例1に記載された一過性に又は安定に形質移入された細胞から調製し、これを培養皿から収集し、PBSで一回洗浄し、全細胞性タンパク質抽出物バッファー(Pierce, Rockford, IL)に再懸濁させ、等容量の2×タンパク質試料負荷バッファーの添加後に100℃で加熱した。全試料を4−15%勾配のSDS−PAGEでの電気泳動によって分離した。タンパク質をゲルからPVDF膜に移し、256A−13を一次検出抗体としてウェスタンブロット膜に適用した。HRP結合二次抗体を検出に使用し、上述のように化学発光基質を使用してシグナルを生成した。ヒトFc、V5タグ、ノッチ3及びノッチ1に対して陽性のコントロール抗体は(Invitrogen, R&D Systems, Santa Cruz Biotechnologies, 及びOrbigen)から購入した。
A.プラスミドコンストラクト
上の実施例3に記載された完全長ノッチ3発現コンストラクトを配列決定により確認したところ、図1に示された発表されている配列と一致していた。ノッチ3の発現は実施例4に記載されたように一過性トランスフェクションとウェスタンブロットによって確証した。
5’GCTCGAGCTCGTGGGAAAATACCGTGGGAAAATGAACCGTGGGAAAATCTCGTGG(配列番号12)
5’GCTCGAGATTTTCCCACGAGATTTTCCCACGGTTC(配列番号13)
2つの安定な細胞株を、ヒト胚性腎細胞株 (HEK293)を使用して機能的アッセイのために生産した。一つの細胞株は核ゲノム中に組み込まれたノッチ3発現プラスミド及びCBF1−Lucレポータープラスミドを含んでいた。この細胞株は、製造者のプロトコルに従ってリポフェクタミン2000を使用して293T細胞中にノッチ3/ハイグロマイシン及びCBF1−Lucプラスミドを同時形質移入することによって生産した。 安定な形質移入細胞クローンを、DMEM増殖培地において200μg/mlのハイグロマイシンに対して選択し、ルシフェラーゼレポーターアッセイ及びウェスタンブロットによってスクリーニングした。比較的高いレベルのノッチ3レセプター発現(ウェスタンブロットに基づく)及びルシフェラーゼ活性を有する細胞株を機能アッセイに使用するために選択し、NC85と標示した。
NC85細胞をMAb 256−A13の存在下で24から48時間培養した。ついで培地を吸引によって除去し、細胞を1×Passive溶解バッファー(E1501, Promega, Madison, WI)に溶解させ、TD−20/20ルミノメーター(Turner Designs Instrument, Sunnyvale, CA)において製造者のプロトコルに従ってルシフェラーゼアッセイシステム(E1501, Promega, Madison, WI)を使用してルシフェラーゼ活性をアッセイした。図5に示されるように、MAb 256−A13の存在下で培養されたNC85細胞で、ルシフェラーゼ活性はコントロール抗体G3のものと比較してほぼ4倍に増加した。該ルシフェラーゼレポーターアッセイでは、MAb 256−A13がリガンド結合なしでルシフェラーゼ活性の劇的な増加を誘導する一方、アゴニスト抗ノッチ3抗体MAbs 256A−4及び256A−8は誘導しなかったことが実証された(図5)。
A.ノッチ3単一ドメイン及びFc融合タンパク質コンストラクトを使用するエピトープマッピング方策及び原理
ノッチ3LIN12−二量体化ドメイン(ノッチ3−LD)とも呼ばれるノッチ3LIN12/ヘテロ二量体化ドメインは、3つのLIN12ドメイン、第一LIN12(L1)、第二LIN12(L2)及び第三LIN12(L3)からなる(図10参照)。5つのノッチ3単一ドメイン/Fc融合タンパク質発現コンストラクト(図7)を生産し、ウェスタンブロットを実施して、どのドメインがMAb256A−13結合に十分かを評価した。一過性形質移入後、分泌されたノッチ3単一ドメイン/Fc融合タンパク質を伴う上清をSDS−PAGEによって分析した。その結果は、MAb 256A−13はノッチ3−L1にだけ結合し、他のドメインには結合しないことを示している。ELISA実験はまたMAb256A−13がノッチ3−L1に対して非常に強い結合性を、ノッチ3−L3に対して弱い結合性を有し、他のドメインには結合しないことを示している(表5)。
第一に、アゴニストノッチ3MAbの256A−13はノッチ3LIN12/二量体化ドメイン(LD)に結合するが、相同のヒトノッチ1LIN12/二量体化ドメインには結合しない(表5)。第二に、抗ノッチ3 MAbは実施例4及び8において検討されたようにウェスタンブロットにおいて変性ノッチ3タンパク質に結合し、256A−13が単一エピトープに結合するか又は互いに独立の別々のエピトープに結合することを示している。 第三に、ノッチ3及びノッチ1はLIN12/二量体化ドメインにおいておよそ55%のアミノ酸配列相同性を共有しており、従って、この領域内のノッチ3とノッチ1の間のサブドメインスワップはタンパク質のコンフォメーションを破壊しないであろうと結論された。ノッチ1−LD cDNAを標準的なPCR法を使用してPCR増幅させた。 第一ストランドcDNA鋳型はPA−1細胞全RNA(ATCC番号CRL−1572)から合成した。ヒトIgGカッパ鎖リーダーペプチドコード配列をPCR増幅させ、リーダーペプチドとして使用してノッチ1−LDの5’にPCR−SOEによって結合させ、His−γ1Fc/pSecにサブクローニングした。
上のセクションAに提供したELISA解析に基づいて、第一LIN12ドメインの標的ドメイン又はL1を更に3つのサブドメインに分け、ノッチ1−L1の対応するサブドメインと個々にスワップさせた。サブドメインスワップコンストラクトは、図9及び10に示すように、PCR−SOE(Ho等, Gene 77:51 (1989);Horton等, BioTechniques 8:528 (1990))を使用して作製した。PCR及びPCR−SOE反応は、反応に加えた1Mのベタイン及び5%のDMSOでのPCRを使用して実施した。最終PCR−SOE産物をサブクローニングし、配列決定によって証明した。正確な挿入配列を有するプラスミドクローンをNheI及びXhoIで切断して挿入断片を切断し、これをゲル精製してサブクローニングした。5つのノッチ3/ノッチ1サブドメインスワップコンストラクトを図7に示す。エピトープマッピングを容易にするために、ヒトIgGカッパ鎖シグナル伝達ペプチドをドメインスワップコンストラクト中でリーダーペプチドとして使用した。サブドメインコンストラクトのアミノ酸配列は図10に示す。
ノッチ/ノッチ1−LDドメインスワッププラスミドを、リポフェクタミン2000を使用してCHO細胞中で一過性に形質移入した。CHO細胞を6ウェルプレートで1ウェル当たり0.8〜1×106細胞にて10%のFCSを含むDMEM増殖培地に播種し、形質移入前に一晩CO2インキュベーターに維持した。細胞を約3時間の増殖培地での形質移入後に回収した後、2%FCSを含むDMEMに切り替え、3日間培養した。条件培地を集め、3500rpmで10分間遠心分離した。CHOから分泌されたノッチ3−LDドメインスワップタンパク質を含む上清を集め、ウェスタンブロット及びELISA結合解析のために準備した。ELISAは、全てのドメインスワップ融合タンパク質が発現され、条件培地中に分泌された(表4)ことを示しており、これは、更にウェスタンブロット分析によって確認された(データは示さず)。
検出抗体として抗ヒトFc抗体を使用したELISAの読み取りは、全てのタンパク質が条件培地中に発現されたことを示している。ヒトでIgG/Fcをコントロールとして使用した。各ウェルにおいてコートされたヒトIgG/Fcの開始点は100ngである。
96ウェル平底Immulon IIマイクロテストプレート(Dynatech, Laboratories, Chantilly, VA)を、1×フェノールレッド及び3−4滴のpHix/リットル(Pierce, Rockford, IL)を含むリン酸緩衝生理食塩水(PBS)中の100μlの抗体(0.1μg/ml)を添加することによって抗ヒトFc抗体(Jackson ImmunoResearch)でコートし、室温で一晩インキュベートした。コーティング溶液を、プレートをはじいて除去した後、0.1%のメルチオレート及びPBST中に2%のBSAを含む200μlのブロッキングバッファーを、非特異的結合をブロックするために各ウェルに1時間加えた。ついで、そのウェルをPBSTで洗浄した。ノッチ3/ノッチ1ドメインスワップコンストラクトの各形質移入体から50マイクロリットルの上の条件培地を集め、50μlのブロッキングバッファーと混合し、マイクロプレートの個々のウェルに添加した。1時間のインキュベーション後、ノッチ3/ノッチ1−LDドメインスワップタンパク質をコートした抗Fc抗体によって捕捉し、ウェルをPBSTで洗浄した。抗ノッチ3MAbs及びアイソタイプ一致コントロールMAbsを上のようにブロッキングバッファーで連続希釈し、50μlの希釈したMAbsを各ウェルに添加して、結合ノッチ3/ノッチ1ドメインスワップタンパク質への結合を評価した。セイヨウワサビペルオキシダーゼ(HRP)結合Fc特異的ヤギ抗マウスIgGを検出に使用した。0.1%の3,3,5,5−テトラメチルベンジジン及び0.0003%の過酸化水素を含むHRP基質溶液を、30分間、発色のためにウェルに添加した。50mlの2MのH2SO4/ウェルを添加して反応を終了させた。450nmでのODをELISAリーダーで読み取った。サブドメインスワップコンストラクト及び変異のクラスターを上のELISA分析によって同様にして検査した。
抗体結合特性は重鎖と軽鎖の双方の可変領域に完全に依存するので、256−A13の可変配列をサブタイプ化し、配列決定した。抗体IgGサブタイプを、Isostripマウスモノクローナル抗体キット(Roche Diagnostics, Indianapolis, IN)を使用して決定した。 その結果は、256A−13がIgG1重鎖とカッパ軽鎖を有していることを示した。
ノッチレセプター活性化は膜近傍部位(S2)でのリガンド誘導メタロプロテアーゼ切断を含み、細胞外サブユニットを生じる。この切断は、活性化されたノッチ細胞内領域を放出するためのS3切断に対する必須の条件である。アゴニスト抗体が、2つのタンパク分解性切断を含むリガンド独立性の逐次ノッチ活性化事象を誘導しうるかどうかを試験するために、組換えノッチ3レセプターを安定に発現する293T細胞(NC85細胞)をG3又は256−A13の何れかで処理した。培養培地においてタンパク分解性切断によって生成された可溶型細胞外サブユニットを、ノッチ3切断産物を認識する固体表面に結合した抗体を使用してELISAアッセイによって検出した。図6に示されるように、ノッチ3アゴニストMAbは条件培地において可溶型ノッチ3細胞外サブユニットの生成を増大させたが、コントロール抗体G3は増大させなかった。
ノッチ3関連疾患を同定するために、患者の試料からノッチ3遺伝子を配列決定することができ、又は患者の組織を使用してノッチ3レセプターの過小発現を調べるために免疫組織化学的検査を実施することができる。また、ノッチ3関連疾患に罹患していることが疑われる患者から細胞を単離し、培養し、ノッチ3シグナル伝達に対する本発明のアゴニスト抗体の影響を研究することができる。
Claims (23)
- 配列番号3に示すアミノ酸配列を含む可変軽(VL)鎖領域及び配列番号2に示すアミノ酸配列を含む可変重(VH)鎖領域を含む、ノッチ3レセプターに特異的に結合する抗体。
- 配列番号4に示すCDR-H1配列、配列番号5に示すCDR-H2配列及び配列番号6に示すCDR-H3配列を含むVH鎖領域、及び配列番号7に示すCDR-L1配列、配列番号8に示すCDR-L2配列及び配列番号9に示すCDR-L3配列を含むVL鎖領域を含む、ノッチ3レセプターに特異的に結合する抗体。
- 抗体が抗原結合抗体断片である請求項1又は2に記載の抗体。
- 標識を更に含む請求項1から3の何れか一項に記載の抗体。
- ノッチ3レセプターに特異的に結合する抗体であって、該抗体は配列番号10のうちのアミノ酸残基DREを含むエピトープに特異的に結合し、ノッチ3レセプターに結合するリガンドとは独立して、ノッチ3レセプターを介したノッチ3レセプター媒介性シグナル伝達を活性化する、抗体。
- ノッチ3レセプターに特異的に結合する抗体であって、該抗体は配列番号11のうちのアミノ酸残基DREを含むエピトープに特異的に結合し、ノッチ3レセプターに結合するリガンドとは独立して、ノッチ3レセプターを介したノッチ3レセプター媒介性シグナル伝達を活性化する、抗体。
- 抗体がノッチ3レセプターのアゴニストである、請求項5又は6に記載の抗体。
- 抗体が抗原結合性抗体断片である請求項5から7の何れか一項に記載の抗体。
- 抗体が単鎖Fvである請求項5から8の何れか一項に記載の抗体。
- 抗体が10−8から10−10Mの結合親和性(Kd)を有する請求項1から9の何れか一項に記載の抗体。
- ヒト抗体、ヒト化抗体、又はキメラ抗体である請求項1から10の何れか一項に記載の抗体。
- ノッチ3レセプター関連疾病又は疾患を治療するための医薬であって、請求項1から3、及び5から11の何れか一項に記載の抗体を含有する医薬。
- 疾病が神経変性疾患である請求項12に記載の医薬。
- 疾病がカダシル、家族性片麻痺性片頭痛(FHM)、家族性発作性運動失調、又はアラジール症候群である請求項13に記載の医薬。
- (a)配列番号2に示すアミノ酸配列を含む可変重鎖領域、及び(b)配列番号3に示すアミノ酸配列を含む可変軽鎖領域をコードする核酸。
- 配列番号4に示すCDR-H1配列、配列番号5に示すCDR-H2配列及び配列番号6に示すCDR-H3配列を含むVH鎖領域、及び配列番号7に示すCDR-L1配列、配列番号8に示すCDR-L2配列及び配列番号9に示すCDR-L3配列を含むVL鎖領域を含むノッチ3レセプターに特異的に結合するポリペプチドをコードする核酸。
- 請求項15又は請求項16に記載の核酸を含むベクター。
- 請求項17に記載のベクターを含む細胞。
- 請求項18に記載の細胞を抗体の生産に適した条件下で培養し、生産された抗体を単離することを含む抗体の生産方法。
- 配列番号3に示すアミノ酸配列を含むVL鎖領域及び配列番号2に示すアミノ酸配列を含むVH鎖領域を含むポリペプチド。
- 配列番号4に示すCDR-H1配列、配列番号5に示すCDR-H2配列及び配列番号6に示すCDR-H3配列を含むVH鎖領域、及び配列番号7に示すCDR-L1配列、配列番号8に示すCDR-L2配列及び配列番号9に示すCDR-L3配列を含むVL鎖領域のアミノ酸配列を含む、ノッチ3レセプターに特異的に結合するポリペプチド。
- ノッチ3レセプターに特異的に結合する抗体のアミノ酸配列を含むポリペプチドであって、該抗体は配列番号10のうちのアミノ酸残基DREを含むエピトープに特異的に結合し、ノッチ3レセプターに結合するリガンドとは独立して、ノッチ3レセプターを介したノッチ3レセプター媒介性シグナル伝達を活性化する、ポリペプチド。
- ノッチ3レセプターに特異的に結合する抗体のアミノ酸配列を含むポリペプチドであって、該抗体は配列番号11のうちのアミノ酸残基DREを含むエピトープに特異的に結合し、ノッチ3レセプターに結合するリガンドとは独立して、ノッチ3レセプターを介したノッチ3レセプター媒介性シグナル伝達を活性化する、ポリペプチド。
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