JP2006520781A - Il−23アゴニストおよびil−23アンタゴニスト;関連試薬の使用 - Google Patents
Il−23アゴニストおよびil−23アンタゴニスト;関連試薬の使用 Download PDFInfo
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Abstract
Description
本発明は、哺乳動物のサイトカイン分子および関連試薬の使用に関する。より詳細には、本発明は、増殖性障害の処置に使用され得る哺乳動物のサイトカイン様タンパク質およびそのインヒビターの同定に関する。
癌および腫瘍は、免疫系によって制御または根絶され得る。この免疫系としては、複数の型のリンパ球ならびに骨髄細胞(例えば、単球、マクロファージ、樹状細胞(DC)、好酸球、T細胞、B細胞、および好中球)が挙げられる。これらのリンパ球ならびに骨髄細胞は、サイトカインとして知られる分泌型シグナル伝達タンパク質を産生する。このサイトカインとしては、例えば、インターロイキン−10(IL−10)、インターフェロン−γ(IFNγ)、IL−12、およびIL−23が挙げられる。免疫応答としては、炎症(すなわち、全身または身体の特定の位置における免疫細胞の蓄積)が挙げられる。感染性因子または外来性の物質に対する応答において、免疫細胞は、サイトカインを分泌し、次にこのサイトカインが、免疫細胞の増殖、発生、分化、または移動を調節する。免疫応答は、病理学的の結果を生じ得る(例えば、自己免疫障害における過剰な炎症に関与する場合、免疫応答の障害は、癌を生じ得る)。免疫系による抗腫瘍応答としては、先天性免疫(例えば、マクロファージ、NK細胞、および好中球によって媒介されるような免疫)ならびに適応性免疫(例えば、抗原提示細胞(APC)、T細胞、およびB細胞によって媒介されるような免疫)が挙げられる(例えば、Abbasら(編)(2000)Cellular and Molecular Immunology W.B.Saunders Co.,Philadelphia,PA;OppenheimおよびFeldmann(編)(2001)Cytokine Reference,Academic Press,San Diego,CA;von AndrianおよびMackay(2000)New Engl.J.Med.343:1020−1034;DavidsonおよびDiamond(2001)New Engl.J.Med.345:340−350を参照のこと)。
本発明は、IL−23のアゴニストまたはアンタゴニストが、腫瘍の増殖を調節し得るという発見に基づく。
添付の特許請求の範囲を含め、本明細書中で使用される場合、単語の単数形(例えば、「ひとつの(aおよびan)」ならびに「その(the)」)は、文脈が別の点を明らかに区別しない限り、それらの対応する複数参照を含む。本明細書中において引用される全ての参考文献は、あたかも、各個別の刊行物、特許出願もしくは特許が、参考として援用されることを詳細かつ個別に示されているかのようであるのと同じ程度に、本明細書において参考として援用される。
細胞またはレセプターに対して適用される場合、「活性化」、「刺激」、および「処理」は、文脈によってかもしくは明示的に別の点を示されない限り、同じ意味(例えば、リガンドによる細胞またはレセプターの活性化、刺激または処理)を有し得る。「リガンド」は、天然および合成のリガンドを包含する(例えば、サイトカイン、サイトカイン改変体、アナログ、ムテイン、および抗体に由来する結合組成物)。「リガンド」はまた、低分子(例えば、サイトカインのペプチド模倣物および抗体のペプチド模倣物)を包含する。「活性化」は、内部機構により調節されるような細胞活性化、および外部因子または環境因子によるような細胞活性化に言及し得る。「応答」(例えば、細胞、組織、器官または生体の応答)は、生化学的挙動または生理学的挙動における変化(例えば、生物学的区画内での濃度、密度、接着もしくは移動、遺伝子発現の速度、または分化の状態)を包含する。ここで、この変化は、活性、刺激、もしくは処理に相関するか、または内部機構(例えば、遺伝的プログラミング)に相関する。
「結合組成物」はまた、標的に結合し得る、分子の複合体(例えば、非共有結合性複合体)、イオン化分子、および共有結合性もしくは非共有結合性に改変された分子(例えば、リン酸化、アシル化、架橋、環化、または限定的切断)に言及し得る。「結合組成物」はまた、安定剤、賦形剤、塩、緩衝剤、溶媒もしくは添加剤と組み合わせた分子に言及し得る。「結合」は、結合組成物と標的との結合として定義され得、ここで、この結合は、結合組成物が溶液中に溶解もしくは懸濁され得る場合、結合組成物の正常なブラウン運動を減少させる。
(2)中性親水性:Cys、Ser、Thr;
(3)酸性:Asp、Glu;
(4)塩基性:Asn、Gln、His、Lys、Arg;
(5)鎖の配向に影響する残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe;
(7)低分子アミノ酸:Gly、Ala、Ser。
本発明は、IL−23ヘテロ二量体、p19サブユニット、p40サブユニット、IL−23レセプターヘテロ二量体、IL−23RサブユニットまたはIL−l2Rβ1サブユニットのポリペプチド、核酸、改変体、ムテインおよび模倣物を用いる方法を提供する。ハイパーカイン(hyperkine)(すなわち、例えばp40サブユニットに連結したp19サブユニットを含む、融合タンパク質)およびハイパーカインをコードする核酸を用いるための方法もまた提供される(例えば、配列番号10または配列番号11を参照のこと)(Oppmannら,上述;Fischerら(1997)Nature Biotechnol.15:142−145;Rakemannら(1999)J.Biol.Chem.274:1257−1266;およびPetersら(1998)J.Immunol.161:3575−3581)。
本発明は、IL−23のアゴニストおよびアンタゴニストを用いる方法を提供する。IL−23のアゴニストは、例えば、IL−23、IL−23改変体、ムテイン、ハイパーカイン、もしくはペプチド模倣物、IL−23Rに対するアゴニスト抗体、およびそのアゴニストをコードする核酸を包含する。IL−23のアンタゴニストとしては、例えば、IL−23に対する抗体、IL−23Rに対するブロッキング抗体、IL−23Rのサブユニットの細胞外領域に基づく可溶性レセプター、それらのペプチド模倣物、およびそれらのアンタゴニストをコードする核酸が挙げられる。
本発明は、例えば、増殖性状態および増殖性障害(癌、腫瘍、新脈管形成、悪液質、癌悪液質、食欲不振、および前癌性障害(例えば、形成異常)を含む)の処置に用いるためのIL−23および抗IL−23Rを提供する。これらの治療用途のための核酸(例えば、IL−23もしくはIL−23Rをコードする核酸、またはこれらの抗原性フラグメント、これらに対応するアンチセンス核酸、およびこれらのハイブリダイゼーション生成物)もまた、提供される。本発明はまた、siRNA干渉のための組成物(例えば、ArenzおよびSchepers(2003)Naturwissenschaften 90:345−359;SazaniおよびKole(2003)J.Clin.Invest.112:481−486;Pirolloら,(2003)Pharmacol.Therapeutics 99:55−77;Wangら,(2003)Antisense Nucl.Acid Drug Devel.13:169−189を参照のこと)も提供する。
本発明は、診断キットにおけるIL−23タンパク質、これらのフラグメント、核酸およびこれらのフラグメントを提供する。IL−23およびIL−23レセプターの検出のための結合組成物(抗体または抗体フラグメントを含む)、ならびにこれらの代謝産物および分解生成物もまた、提供される。代表的には、このキットは、p19ポリペプチドまたはこれらの抗原性フラグメント、それに対する結合組成物、もしくは核酸(例えば、核酸プローブまたはプライマー)のいずれかを含む画分を有する。この核酸プローブまたはプライマーは、ストリジェントな条件下で、p19またはIL−23Rをコードする核酸に特異的にハイブリダイズする。
本発明は、炎症性障害および炎症性状態(例えば、腫瘍性疾患、癌、腫瘍、新脈管形成、前癌状態(例えば、形成異常、食欲不振、悪液質、および癌悪液質))の、免疫応答を調節することによる処置および診断について、IL−23のアゴニストおよびアンタゴニストを使用するための方法を提供する。
分子生物学における標準的方法は、記載される(Maniatisら,(1982)Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;SambrookおよびRussell(2001)Molecular Cloning,第3版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Wu(1993)Recombinant DNA,第217巻,Academic Press,San Diego,CA)。標準的方法はまた、Ausbelら、(2001)Current Protocols in Molecular Biology、第1巻〜第4巻、John Wiley and Sons,Inc.New York,NYに現れ、これらは、細菌細胞におけるクローニングおよびDNA変異誘発(第1巻)、哺乳動物細胞および酵母におけるクローニング(第2巻)、複合糖質およびタンパク質発現(第3巻)、ならびにバイオインフォマティクス(第4巻)を記載する。
IL−23 p19欠損マウスを、Cuaら、前出に記載されるように作製した。IL−23を特異的に欠くマウス(pl9KOマウス;p19ノックアウトマウス;p19−/−マウス)、p19+/−マウス、およびp19+/+野生型コントロールマウスは、B6/129 F2バックグラウンドを有していた。
多くの癌、腫瘍、および細胞株(例えば、胃腸管、生殖管、皮膚、および乳房の癌)において、IL−23のp19サブユニットおよびIL−23レセプターのIL−23Rサブユニットの発現が上昇した(表1)。
IL−23に対するアンタゴニストで処置したマウスにおいて、腫瘍細胞の注射によってか、または化学的発癌によって誘導した腫瘍を、例えば、抗p19抗体での処置によるか、もしくはp19サブユニット(p19KO)の遺伝的切断によって、根絶するか、または減少させた。p19はIL−23のみのサブユニットである一方、p40はIL−23およびIL−12の両方のサブユニットである。対照的に、IL−12での処置は、幾つかの条件下で腫瘍を悪化させた。すなわち、コントロールマウスと比較して、腫瘍体積の増加をもたらした。
配列番号1は、ヒトIL−23 p19の核酸配列である。
Claims (18)
- 腫瘍の増殖を調節する方法であって、該方法は、腫瘍細胞を有効量のIL−23のアゴニストまたはIL−23のアンタゴニストと接触させる工程を包含する、方法。
- 前記IL−23のアンタゴニストが、腫瘍の増殖を阻害または防止する、請求項1に記載の方法。
- 前記腫瘍細胞が、IL−23を発現する、請求項1に記載の方法。
- 請求項1に記載の方法であって、前記IL−23のアゴニストあるいは前記IL−23のアンタゴニストが、以下:
a)p19(配列番号1、配列番号2、配列番号3、もしくは配列番号4);または
b)IL−23R(配列番号5、もしくは配列番号6)
のポリペプチドあるいは核酸と特異的に結合する結合組成物を含む、方法。 - 請求項4に記載の方法であって、前記結合組成物が、以下:
a)抗体の抗原結合部位;
b)IL−23R(配列番号5、もしくは配列番号6)の細胞外領域;
c)低分子;
d)アンチセンス核酸もしくは短い干渉RNA(siRNA);または
e)検出可能な標識
を含む、方法。 - 請求項4に記載の方法であって、前記結合組成物が、以下:
a)ポリクローナル抗体;
b)モノクローナル抗体;
c)ヒト化抗体、もしくはそのフラグメント;
d)Fabフラグメント、Fvフラグメント、もしくはF(ab’)2フラグメント;または
e)抗体のペプチド模倣物
を含む、方法。 - 請求項1に記載の方法であって、前記腫瘍細胞が、以下:
a)結腸癌細胞;
b)卵巣癌細胞;
c)乳癌細胞;または
d)黒色腫細胞
である、方法。 - 癌または腫瘍に罹患する被験体を処置する方法であって、該方法は、有効量のIL−23のアゴニストまたはIL−23のアンタゴニストを、該被験体に投与する工程を包含する、方法。
- 請求項8に記載の方法であって、前記IL−23のアンタゴニストが、以下:
a)癌または腫瘍の増殖;
b)悪液質;
c)食欲不振;または
d)新脈管形成
を阻害する、方法。 - 請求項8に記載の方法であって、前記IL−23のアンタゴニストが、以下:
a)p19(配列番号1、配列番号2、配列番号3、もしくは配列番号4);または
b)IL−23R(配列番号5、もしくは配列番号6)
のポリペプチドあるいは核酸と特異的に結合する結合組成物を含む、方法。 - 請求項10に記載の方法であって、前記結合組成物が、以下:
a)抗体の抗原結合部位;
b)IL−23R(配列番号5、もしくは配列番号6)の細胞外領域;
c)アンチセンス核酸もしくは短い干渉RNA(siRNA);
d)低分子;または
e)検出可能な標識
を含む、方法。 - 請求項10に記載の方法であって、前記結合組成物が、以下:
a)ポリクローナル抗体;
b)モノクローナル抗体;
c)ヒト化抗体、もしくはそのフラグメント;
d)Fabフラグメント、Fvフラグメント、もしくはF(ab’)2フラグメント;または
e)抗体のペプチド模倣物
を含む、方法。 - 請求項8に記載の方法であって、前記癌または腫瘍が、以下:
a)胃腸管;
b)気道;
c)生殖系;または
d)内分泌系
の癌または腫瘍である、方法。 - 請求項8に記載の方法であって、前記癌または腫瘍が、以下:
a)結腸癌;
b)卵巣癌;
c)黒色腫;または
d)乳癌
である、方法。 - 癌または腫瘍を診断する方法であって、該方法は、被験体に由来するサンプルを請求項10に記載の方法の結合組成物と接触させる工程を包含する、方法。
- 請求項15に記載の方法であって、前記結合組成物が、配列番号1、配列番号2もしくは配列番号5のポリヌクレオチドに特異的に結合またはハイブリダイズする核酸プローブまたは核酸プライマーを含む、方法。
- 癌または腫瘍の診断のためのキットであって、該キットは、請求項10に記載の方法の結合組成物、および以下:
a)区画;または
b)使用または廃棄のための指示書
を包含する、方法。 - 請求項17に記載のキットであって、前記結合組成物が、以下:
a)p19(配列番号1、配列番号2、配列番号3、もしくは配列番号4);または
b)IL−23R(配列番号5、もしくは配列番号6)
に特異的に結合する抗体を含む、キット。
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JP2007197453A (ja) * | 2003-03-10 | 2007-08-09 | Schering Plough Corp | Il−23アゴニストおよびil−23アンタゴニスト;関連試薬の使用 |
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