JP4776228B2 - Tヘルパー(th)細胞の発生および機能を調節するための方法および組成物 - Google Patents
Tヘルパー(th)細胞の発生および機能を調節するための方法および組成物 Download PDFInfo
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Description
本発明は、部分的には、サイトカインインターロイキン−21(IL−21)がTヘルパー(Th)細胞のサブセット(Th2細胞)によって発現され、そして、Th1細胞発生の間に、選択的にインターフェロンγ(IFNγ)レベルを阻害するという発見に、一部基づく。より具体的には、本明細書において、IL−21が、インビトロおよびインビボにおいて生成されたTh2細胞によって優先的に発現されることが、示された。1つの実施形態において、発生中のTh細胞のIL−21への暴露は、発生中のTh1細胞からのIFNγレベルを特異的に減少し、従って、Th2応答を増強する。さらに、発生中のTh細胞のIL−21への暴露は、Stat4シグナル伝達を減少し(例えば、Stat4タンパク質および/またはmRNA発現を減少することによる)、それによって、他のサイトカイン(例えば、IL−12)に対するTh細胞応答を調節する。従って、Th細胞発生および活性を調節する方法および組成物が、開示される。本明細書に記載される方法および組成物(例えば、IL−21のアゴニストまたはアンタゴニスト)は、Th2関連障害のようなTh細胞関連および/またはIFNγ関連障害または状態(例えば、喘息、アレルギー、および抗体成分と関連する障害(例えば、慢性関節リウマチ、多発性硬化症、および狼瘡));およびTh1関連障害(例えば、自己免疫障害(例えば、とりわけ、多発性硬化症、慢性関節リウマチ、I型糖尿病、クローン病、乾癬および重症筋無力症)の、処置(例えば、治癒、寛解、発症の遅延もしくは予防、または、再発予防もしくは置換)、あるいは、予防において有用である。
本発明は、Tヘルパー細胞の分化、発生、および活性を、IL−21とIL−21レセプターとの間の相互作用を調節することによって調節するための方法および、組成物を提供する。細胞集団中のIL−21、またはIL−21レベルもしくはIL−21レセプターレベルを増加する試薬が、Tヘルパーの集団に添加されて、Thp細胞またはTh1細胞の集団におけるIFNγレベルを抑制する。IL−21、またはIL−21レベルを増加する試薬をまた使用して、Th2発生を促進し得るか、またはTh2媒介性免疫応答を増強し得るか、および/もしくはTh1発生を抑制し得る。
(必要に応じて)IFNγ活性レベルの調節(例えば、増加または減少)が所望される細胞(例えば、T細胞)または細胞集団(例えば、T細胞集団)を同定する工程;および
その細胞または細胞集団を、その細胞または細胞集団中のIFNγの活性またはレベルを調節(例えば、増加または減少)するのに十分な量のIL−21モジュレーター(例えば、IL−21アゴニストまたはアンタゴニスト)と接触させる工程、を包含する。
(必要に応じて)、増殖、生存、および/または分化が所望される、細胞(例えば、T細胞(例えば、ThpまたはTh1細胞))または細胞集団を同定する工程;ならびに、
その細胞または細胞集団を、増殖、生存、および/またはTh1細胞への分化(例えば、Thp細胞のTh1細胞への分化を増加する)の1つ以上を増加し、それによってTh1細胞の活性および/または細胞数を増加するのに十分な量のIL−21アンタゴニストと接触させる工程。
(必要に応じて)IL−21の調節が所望される細胞(例えば、T細胞)、細胞集団、または被験体を同定する工程;および
その細胞または細胞集団とIL−21モジュレーターを接触させるか、またはIL−21モジュレーターをその被験体に投与して、その細胞、細胞集団、または被験体におけるIL−21活性またはレベルを調節する工程。
(必要に応じて)Stat活性またはレベルの調節が所望される細胞(例えば、T細胞)細胞集団または被験体を同定する工程、および;
その細胞または細胞集団を、IL−21モジュレーター(例えば、IL−21のアゴニストまたはアンタゴニストを、その細胞、細胞集団、または、被験体において、Stat活性を調節するのに十分な量において)と接触するか、またはその被験体にIL−21モジュレーターを投与する工程。
IL−21媒介性Tヘルパー細胞効果を阻害するために、IL−21とIL−21レセプターとの相互作用をブロックするか、そうでなければ阻害する因子を、T細胞またはT細胞(例えば、Tヘルパー細胞)の集団に添加し得る。便利さのために、これらのインヒビターを本明細書において、「IL−21アンタゴニスト」という。IL−21アンタゴニストの例としては、例えば、IL−21またはIL−21レセプターの可溶性フラグメント、これらのフラグメントを含む融合タンパク質、およびこれらのフラグメントに対する抗体が挙げられる。IL−21アンタゴニストは、Th2媒介性疾患(抗体媒介性疾患を含む)におけるIL−21のブロッキングのために有用である。これらの疾患としては、喘息、アレルギー、慢性関節リウマチ、多発性硬化症、および狼瘡が挙げられる。
IL−21またはIL−21レセプター、あるいはこれらタンパク質の活性フラグメントを、本明細書に記載の方法における使用のために、免疫グロブリンのようなキャリア分子を融合し得る。例えば、IL−21レセプターの可溶性形態を、「リンカー」配列を介して免疫グロブリンのFc部分か、または免疫グロブリンのFc部分に対して融合し得る。他の融合タンパク質(例えば、GST(すなわち、グルタチオンS−トランスフェラーゼ)、LexA、またはMBP(すなわち、マルトース結合タンパク質)との融合タンパク質)もまた、使用され得る。
本明細書において使用する場合、用語「抗体」は、免疫グロブリン分子および免疫グロブリン(Ig)分子の免疫学的に活性な部分(すなわち、抗原と特異的に結合する(免疫反応する)抗原結合部位を含む分子)をいう。そのような抗体としては、例えば、ポリクローナル、モノクローナル、キメラ、単鎖、Fab、Fab’、およびF(ab’)2フラグメント、ならびにFab発現ライブラリーが挙げられる。一般に、ヒトから得られた抗体分子は、IgG、IgM、IgA、IgEおよびIgDのいずれかのクラスに関連し、そして、分子に存在する重鎖の性質によって、お互いに異なる。特定のクラスは、サブクラスも有する(例えば、IgG1、IgG2および他のサブクラス)。さらに、ヒトにおいて、軽鎖は、κ鎖またはλ鎖であり得る。本明細書における抗体に対する言及は、ヒト抗体種の全てのクラス、サブクラス、およびタイプへの言及を含む。IL−21またはIL−21レセプターポリペプチドに対する抗体は、IL−21またはIL−21レセプターポリペプチドあるいはIL−21またはIL−21レセプターポリペプチドのフラグメントを含む融合タンパク質に対する抗体をもまた、含む。
ポリクローナル抗体の産生のために、種々の適切な宿主動物(例えば、ウサギ、ヤギ、マウス、または他の哺乳動物)が、ネイティブタンパク質、その合成改変体、またはそれらの誘導体の1回以上の注射により免疫され得る。適切な免疫原性調製物は、例えば、天然に存在する免疫原性タンパク質、免疫原性タンパク質を表す化学合成ポリペプチド、または組み換え発現された免疫原性タンパク質を含み得る。さらに、このタンパク質は、免疫される哺乳動物において免疫原性であることが公知の第2のタンパク質に結合体化され得る。このような免疫原性タンパク質の例としては、キーホールリンペットヘモシアン、血清アルブミン、ウシサイログロブリン、およびダイズトリプシンインヒビターが挙げられるがこれらに限定されない。
本明細書中で使用される場合、用語「モノクローナル抗体」(MAb)または「モノクローナル抗体組成物」は、単一の軽鎖遺伝子産物および単一の重鎖遺伝子産物からなる1分子種のみの抗体を含む抗体分子の集団をいう。特に、モノクローナル抗体の相補性決定部位(CDR)は、この集団の全ての分子において同一である。従って、MAbは、それに対する固有の結合親和性により特徴付けられる抗原の特定のエピトープと免疫反応し得る抗原結合部位を含む。
本発明のタンパク質抗原に対する抗体はさらに、ヒト化抗体またはヒト抗体を含み得る。これらの抗体は、ヒトへの投与に適しており、投与された免疫グロブリンに対するヒトによる免疫応答を引き起こさない。抗体のヒト化形態は、主に、ヒト免疫グロブリンの配列で構成され、非ヒト免疫グロブリン由来の最小配列を含むキメラ免疫グロブリン、その免疫グロブリン鎖またはフラグメント(例えば、Fv、Fab、Fab’、F(ab’)2、または抗体の他の抗原結合部分配列)である。ヒト化は、Winterら(Jonesら(1986)Nature,321:522−525;Riechmannら(1988)Nature,332:323−327;Verhoeyenら(1988)Science,239:1534−1536)の方法に従い、げっ歯類CDRまたはCDR配列とヒト抗体の対応する配列を置換することにより実施され得る(米国特許第5,225,539号を参照のこと)。いくつかの例において、ヒト免疫グロブリンのFvフレームワーク残基は、対応する非ヒト残基で置換される。ヒト化抗体はまた、レシピエント抗体においても移植したCDRもしくはフレームワーク配列においても見出されない残基を含み得る。一般に、ヒト化抗体は、CDR領域の全てまたは実質的に全てが非ヒト免疫グロブリンのそれらに対応し、フレームワーク領域の全てまたは実質的に全てがヒト免疫グロブリンコンセンサス配列のそれらである少なくとも1つ、および代表的には2つの改変ドメインの実質的に全てを含む。ヒト化抗体はまた、最適には、免疫グロブリン定常領域(Fc)、代表的には、ヒト免疫グロブリンの定常領域の少なくとも一部を含む(Jonesら,1986;Riechmannら,1988;およびPresta(1992)Curr.Op.Struct.Biol.,2:593−596)。
完全ヒト抗体は、軽鎖および重鎖の本質的に全体の配列(CDRを含む)が、ヒト遺伝子から生じた抗体分子に関する。このような抗体は、本明細書中で「ヒト抗体」または「完全ヒト抗体」と呼ばれる。ヒトモノクローナル抗体は、トリオーマ技術;ヒトB細胞ハイブリドーマ技術(Kozborら(1983)Immunol Today 4:72を参照のこと)、およびヒトモノクローナル抗体を作製するためのEBVハイブリドーマ技術(Coleら,1985,MONOCLONAL ANTIBODIES AND CANCER THERAPY,Alan R,Liss,Inc.,pp.77−96を参照のこと)により調製され得る。ヒトモノクローナル抗体は、本発明の実施において使用され得、ヒトハイブリドーマを用いることにより(Coteら(1983)Proc Natl Acad Sci USA 80:2026−2030)またはエプスタイン−バーウイルスでヒトB細胞をインビトロ形質転換することにより(Coteら(1985),MONOCLONAL ANTIBODIES AND CANCER THERAPY,Alan R.Liss,Inc.,pp.77−96)生成され得る。
本発明によれば、本発明の抗原性タンパク質に特異的な単鎖抗体の産生のための技術が適用され得る(例えば、米国特許第4,946,778号を参照のこと)。さらに、Fab発現ライブラリーを構築する方法が適用され得(例えば、Huseら(1989)Science 246:1275−1281を参照のこと)、タンパク質またはその誘導体、フラグメント、アナログ、もしくはホモログに対する所望の特異性を有するモノクローナルFabフラグメントの迅速かつ効率的な同定が可能となる。タンパク質抗原に対するイディオタイプを含む抗体フラグメント((i)抗体分子のペプシン消化により生成されるF(ab’)2フラグメント;(ii)F(ab’)2フラグメントのジスルフィド架橋を還元することにより生成されるFabフラグメント;(iii)パパインおよび還元剤による抗体分子の処理により生成されるFabフラグメント;ならびに(iv)Fvフラグメントが挙げられるがこれらに限定されない)は、当該分野で公知の技術により産生され得る。
二特異的抗体は、少なくとも2つの異なる抗原に対する結合特異性を有するモノクローナル抗体(好ましくは、ヒト抗体またはヒト化抗体)である。本発明においては、結合特異性のうちの1つは、本発明の抗原性タンパク質に対する特異性である。第2の結合標的は、任意の他の抗原であり、細胞表面タンパク質またはレセプターもしくはレセプターサブユニットが有利である。
本明細書中に記載されるIL−21モジュレーターは、従来法により、薬学的組成物として提供され得る。この組成物は、好ましくは、内部使用に適しており、かつ有効量の薬理学的に活性な本発明の化合物を単独でかまたは1つ以上の薬学的に受容可能なキャリアと組み合わせて含む。この化合物は特に、毒性があるとしても非常に低い点で有用である。
そうでないことが示されない限り、6〜8週齢のC57BL/6マウスを全ての実験に使用した。C57BL/6欠損バックグラウンドのStat6欠損マウスを、Kaplan,M.H.ら,Immunity 4:313−9,1996に記載されるようにして作製した。
リンパ球を、(Kaplan,M.H.ら,Immunity 4:313−9,1996)に記載されるように補充したRPMI1640中で培養した。抗CD4および抗CD26Lを用いたセルソーティングにより、未処理のThp細胞をリンパ節および脾臓から、95〜98%純度まで精製した。
T−bet特異的抗血清を、(Szabo,S.J.ら,Cell 100:655−69,2000)に記載されるようにして調製した。Stat4、Stat1、およびアクチンに特異的な抗体を、Santa Cruz Biotechnology(Santa Cruz,CA)から入手した。リン酸化Stat4に特異的な抗体を、Zymed(South San Francisco,CA)から得た。Th分化培養物において使用した抗CD3、抗CD28、抗IL−4、およびIFNγに対する抗体を、Pharmingenから入手した。組み換えIL−4を、Preprotechから入手した。組み換えIL−2は、Chiron(Emeryville,CA)から提供された。組み換えIL−12は、Hoffman−LaRoche(Nutley,NJ)から提供された。COS上清中において発現したマウスIL−21を調製および濃縮した。1ユニットの活性を、IL−21でトランスフェクトしたBAF3細胞の50%最大増殖を誘導するのに必要とされる上清濃度と定義した。IL−21と平行して調製および濃縮したモックトランスフェクトCOS上清を、コントロールとして使用した。
未処理のT細胞を、抗CD3、抗CD28(1μg/ml)をコーティングしたプレート上に、10ng/ml IL−4、10μg/ml抗IFNγ(Th2条件)、または1ng/ml IL−12、10μg/ml 抗IL−4(Th1条件)の存在下、1〜2×106/mlでプレーティングした。3日後に、細胞をIL−2(100U/ml)中で拡張した。培養1週間後、細胞を、PMA/Ionomycinで刺激し、サイトカイン産生を、(Brid,J.J.ら,Immunity 9:229−37,1998)に記載されるような細胞内サイトカイン染色により決定した。
総RNAを、RNeasy(Qiagen;Valencia,CA)を用いて単離した。ノザン分析のために、このRNAを、1.5%アガロース/6%ホルムアルデヒドゲル上で分離し、GeneScreenメンブレン(New England Nuclear)に移した。このメンブレンを、IL−21、Il−4、IFNγ、γ−アクチンに対する放射標識cDNAプローブとハイブリダイズさせた。リアルタイムPCRのために、1μgのRNAを、オリゴ(dT)でプライムし、Superscript(Invitrogen Life Technologies;Carlsbad,CA)を用いてcDNAに変換した。25ngのcDNAを、SYBR Green 2×またはTaqMan 2× PCRミックス(Applied Biosystems;Foster City,CA)を用いるPCR反応においてテンプレートとして使用し、以下のプライマーを用いてABI Prism 7700 Sequence Detector(Applied Biosystems)により分析した。
細胞を50mM Tris、0.5% NP40、5mM EDTA、50mM NaCl中に溶解し、溶解物を遠心分離により洗浄することによって、全細胞抽出物を調製した。タンパク質抽出物を、8〜10%ポリアクリルアミドゲル上で分離し、Optitranメンブレン(SchleicherおよびSchuell;Keene,NH)に移した。イムノブロットを、室温にて1時間、5%ミルクを含有するTBST(50mM Tris Ph7.5、100mM NaCl、0.03% Tween 20)中でブロックし、そして示される抗体と共に、4℃で一晩インキュベートした。ブロットをTBSTで洗浄し、抗ウサギHRP結合抗体(Zymed)と共に室温にてインキュベートした。ブロットをTBSTで洗浄した後、強化化学発光(Amersham;Piscataway,NJ)を用い、販売元の指示に従って検出を実施した。
ThサブセットにおけるIL−21の発現を決定した。ノザン分析を、1週間かけてTh1またはTh2細胞に分化させ、サイトカイン産生を誘導するため4時間再刺激した未処理のThp(Th前駆細胞)由来のmRNAを用いて実施した。その結果を図1A〜1Dに示す。図1Aに示される結果について、Thp細胞は、6日間、Th1およびTh2をゆがめる条件(Th1 and Th2 skewing conditions)下で培養した。この細胞を、静止させる(−)か、またはPMA/Ionomycin(P+I)と共に4時間再刺激した。RNAを精製し、ノザンブロットによりサイトカイン発現について評価した。示される結果は、3回の独立した実験の代表例である。IL−21をコードするメッセージを、刺激したTh2細胞においてのみ検出した。対照的に、IL−21メッセージは、Th1培養物では検出されなかった。これらの結果は、IL−21がTh2特異的サイトカインであることを示している。
Th2細胞におけるインビボ免疫応答の間のIL−21の発現を、病原性原生生物モデル系において決定した。原生生物Leishmania majorの感染は、Th細胞のインビボ応答を研究するための十分に特徴付けられたモデルを提供する(Reiner,S.L.ら,Annu Rev Immunol 13:151−77,1995)。L.majorを感染させてた、いつくかの同系交配マウス系統(例えば、C57BL/6)は、病原体に対する保護的および効果的Th1応答を惹起する。逆に、他の同系交配マウス系統(例えば、BALBマウス系統)は、主に、Th2応答を生じ、感染を除去できない。
IL−21は、IL−4と、Th細胞における類似の発現プロフィールおよび構造的類似性を共有しているので、IL−4と同様に、Th分化に直接影響を及ぼすIL−21の能力を決定した。
IL−21が、IL−21産生を直接的に抑制するか、または代わりに、IFNγ細胞の分化に影響を与えるかを決定するため、精製した未処理のThp細胞を、Th1をゆがめる条件下で培養した。IL−21またはモック上清を、培養開始時(第0日)または再刺激および分析の24時間前(第5日)に添加した。サイトカイン産生を、細胞内サイトカイン染色により評価した。結果を図3Aに示す。
Th1細胞の分化を阻害するIL−4の能力は、Stat6の発現に依存する(Kaplan,M.H.,ら,Immunity 4:313−9,1996,Takeda,K.ら,Nature 380:627−30 1996,およびShimoda,K.ら,Nature 380:630−3,1996)。
IL−21が、IFNγ産生を阻害するのに加えて、Th1の発達の局面に影響を及ぼすか否かを決定するため、IL−21処理したTh1細胞が、他のTh1関連サイトカインを産生する能力を試験した。
T−betは、分化Th1細胞において特異的に発現され、かつIFNγを強力に誘導することもできる、最近同定された転写因子である。分化Th1細胞のIL−21処理が、Th細胞におけるT−bet発現の誘導に影響を及ぼすか否かを決定するため、Thp細胞を、Th1またはTh2をゆがめる条件下で培養した。タンパク質抽出物を、開始時(未処理)および培養48時間後(Th1およびTh2)に回収した。T−betおよびアクチンの発現を、ウェスタンブロットにより決定した。
IL−12シグナル伝達は、Th1細胞の発達において重要な役割を果たすことが報告されている。IL−12R欠損Th細胞は、IFNγを生成する能力が大きく損なわれている(Wu,C.ら,J Immunol 159:1658−65,1997)。さらに、IL−12Rβ2鎖は、Th2細胞の発達において、IL−4により媒介される効果を特異的に失活させる(Szabo,S.J.ら,J Exp Med 185:817−24,1997)。IL−21が、IL−4と同様に、Th1細胞においてIL−12b2鎖の発現に影響を及ぼすか否かを決定するために、Th1およびTh2をゆがめる条件下、IL−21の存在下および非存在下で培養したナイーブThp細胞由来のRNAを、リアルタイムPCRによって、12Rβ2発現について分析した。Thp細胞を、Th1またはTh2をゆがめる条件下で1週間培養した。IL−21またはモック上清が、示される培養物中に含まれた。RNAを、抗CD3による二次刺激の24時間後に回収し、リアルタイムPCRによりIL−12Rβ2について評価した。
内部産生したIL−21は、インビボでのTh1細胞の機能を制限する上で役割を果たすか否かを決定するため、遅延型過敏応答(DTH)の程度を、IL−21R欠損マウスにおいて試験した。DTHは、古典的なTh1細胞媒介炎症応答である。C57BL/6系に戻し交配したIL−21R欠損マウスを、Kasianら,Immunity 16:559−60,2002に記載されるようにして作製した。100mg TNP−KLH(2,4,6−トリニトロフェニル−キーホールリンペットヘモシアン;Biosearch Techologies,Novato,CA)を乳化させたDFAを用いて、8週齢の雌マウスの尻尾の基部を皮下免疫した。6日後に、マウスの一方の後ろ足のフットパッドに50μgのTNP−KLHを、反対側の後ろ足のフットパッドにPBSをチャレンジした。フットパッドの厚さを、チャレンジの24時間後に測定した。
Claims (9)
- T細胞またはT細胞集団においてインターフェロンγ(IFNγ)レベルを増加するための薬学的組成物であって、以下:
該T細胞またはT細胞集団のIFNγレベルを増加するのに十分な量のIL−21/IL−21Rアンタゴニストを含有し、ここで、該アンタゴニストは、アンタゴニストである抗−IL21R抗体、アンタゴニストである抗−IL21R抗体の抗原結合フラグメント、およびIL−21Rの可溶性フラグメントからなる群から選択される、
薬学的組成物。 - 請求項1に記載の薬学的組成物であって、ここで、前記IL−21Rの可溶性フラグメントが、IL−21レセプターの細胞外領域を含む、薬学的組成物。
- 請求項2に記載の薬学的組成物であって、前記可溶性フラグメントが、配列番号4のアミノ酸20〜235と少なくとも85%同一であるアミノ酸配列を含み、そして、IL−21に結合し得る、薬学的組成物。
- 請求項2に記載の薬学的組成物であって、ここで、前記可溶性フラグメントが、配列番号4のアミノ酸1〜235を含む、薬学的組成物。
- 請求項2に記載の薬学的組成物であって、ここで、前記可溶性フラグメントが、さらにFcフラグメントを含む、薬学的組成物。
- 請求項1に記載の薬学的組成物であって、ここで、前記アンタゴニストが、アンタゴニストである抗−IL21R抗体またはその抗原結合フラグメントである、薬学的組成物。
- 請求項1に記載の薬学的組成物であって、ここで、該薬学的組成物が、エキソビボ、インビトロ、またはインビボでの投与に適している、薬学的組成物。
- 請求項1に記載の薬学的組成物であって、ここで、該薬学的組成物が、哺乳動物被験体への投与に適している、薬学的組成物。
- 請求項8に記載の薬学的組成物であって、ここで、前記哺乳動物被験体がヒトである、薬学的組成物。
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IL165990A0 (en) | 2006-01-15 |
US7731946B2 (en) | 2010-06-08 |
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US7314623B2 (en) | 2008-01-01 |
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WO2004007682A2 (en) | 2004-01-22 |
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AU2003251900A1 (en) | 2004-02-02 |
EA200500206A1 (ru) | 2006-06-30 |
BR0312738A (pt) | 2007-06-26 |
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