JP6126532B2 - 抗il−23抗体 - Google Patents
抗il−23抗体 Download PDFInfo
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- JP6126532B2 JP6126532B2 JP2013537771A JP2013537771A JP6126532B2 JP 6126532 B2 JP6126532 B2 JP 6126532B2 JP 2013537771 A JP2013537771 A JP 2013537771A JP 2013537771 A JP2013537771 A JP 2013537771A JP 6126532 B2 JP6126532 B2 JP 6126532B2
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Description
本発明は、一般的に、診断的及び治療的使用のための抗IL−23p19抗体に関する。より具体的には、ヒト化抗IL−23p19抗体及び種々の疾患又は障害の処置のための使用方法が開示される。そのような化合物を含む医薬的組成物及びキットも開示される。
より高等な真核生物は、自然免疫応答により開始され、適応免疫応答が続く、病原体への複雑な応答を進化させてきた。一緒に、これらの2つの機構は、生物に感染する病原体を根絶するだけでなく、しかし、また、将来の曝露に対する長期免疫学的応答を確立する。これらの応答における欠損は、感染への増加した感受性及び/又は慢性炎症と自己免疫に導く適応免疫応答の変化をもたらしうる。IL−12(p40及びp35タンパク質サブユニットからなるヘテロ二量体サイトカイン)は、適応免疫に対する主要な影響を伴う自然免疫応答の特徴的サイトカインと長く考えられてきた。しかし、このサイトカインの生物学的役割の研究からのデータは、混乱する結果に導いた。例えば、p40欠損マウスはコラーゲン誘導関節炎(CIA)及び実験的自己免疫性脳脊髄炎(EAE)に耐性であり、p35欠損マウスは両方に感受性であり、悪化した疾患さえ呈した。そのような難問は、1990年代後半の、免疫応答において異なる役割を伴うIL−12サイトカインファミリーの新しいメンバー(IL−23)の発見を用いて解決され始めた。
本発明は、上の必要性に対処し、IL−23タンパク質のp19サブユニットに結合する抗体を提供する。一局面において、本発明の抗体は、高い親和性を伴いヒトIL−23に結合する。別の局面において、本発明の抗体は、マウス脾細胞からのIL−17のIL−23刺激産生を阻害する。別の局面において、本発明の抗体は、IL−23に密接に関連するファミリーメンバーであるIL−12に結合も拮抗もしない。
IL−23のp19サブユニット(また、「IL−23p19」及び「P19サブユニット」として本明細書において言及される)は、21aaリーダー配列を含む189アミノ酸ポリペプチドである(Oppmann et al.Immunity 13:715 (2000)、配列番号181)。分子の生物学的活性は、それがIL−12p40サブユニットとパートナーになり、IL−23を形成する場合にのみ検出される。IL−23は、活性化樹状細胞(DC)及び食細胞により主に発現される。IL−23についての受容体は、IL−23Rと呼ばれる固有のサブユニットとパートナーとなる、IL−12受容体のIL−12Rβ1サブユニットから構成されていることが見出された(Parham et al. J. Immunol. 168: 5699 (2002))。受容体の発現は、主に記憶T細胞及びNK細胞上で検出される。このように、このサイトカイン:受容体対の発現は、免疫細胞の特定の集団に制限されるように見える。最初にIL−12及びIL−23が多くの機能を共有しうると考えられたが、データによって画像が異なることが示されている。IL−12がTh1細胞の産生において主な役割を有するのに対し、IL−23が、Th17と名付けられた、最近認識されたTh細胞サブセットの産生及び維持に決定的に含まれることが見出された(Kikly et al. Curr. Opin. Immunol. 18: 670 (2006), Kastelein et al. Ann. Rev. Immunol. 25: 221 (2007))。これらの細胞は、IL−17A、IL−17F、IL−22ならびに他の前炎症性サイトカイン(例えばIL−6及びTNF−αなど)を産生する。下に記載する通り、これらのTh17細胞の役割に関する動物モデル試験は、慢性炎症及び自己免疫における原動力としてのそれらの重要性を示す。
一局面において、本明細書に記載及び開示されるのは抗IL−23抗体、特に、ヒト化抗IL−23抗体であり、及び、1つ又は複数の抗IL−23抗体、特に、本発明の1つ又は複数のヒト化抗IL−23抗体を含む組成物及び製造品である。また、記載するのは、抗IL−23p19抗体、特にヒト化抗IL−23p19抗体の抗原結合フラグメントを含む結合薬剤である。ヒト化抗IL−23抗体及び結合薬剤は、慢性自己免疫疾患及び炎症性疾患に寄与する、Th17に関連するサイトカインの産生を阻害することができる。ヒト化抗IL−23p19抗体及び結合薬剤は、このように、種々の疾患又は障害の処置において使用することができる。ヒト化抗IL−23p19抗体及びIL−23p19結合薬剤は、各々が、IL−23p19エピトープ(即ち、抗原結合フラグメント)を特異的に認識する少なくとも部分を含む。
抗体A:IgK−66を伴う6B8−IgG1KO−2(重鎖可変領域6B8CVH−02及び軽鎖可変領域6B8CVK−66);
抗体B:IgK−66を伴う6B8−IgG1KO−5(重鎖可変領域6B8CVH−05及び軽鎖可変領域6B8CVK−66);
抗体C:IgK−65を伴う6B8−IgG1KO−2(重鎖可変領域6B8CVH−02及び軽鎖可変領域6B8CVK−65);
抗体D:IgK−65を伴う6B8−IgG1KO−5(重鎖可変領域6B8CVH−05及び軽鎖可変領域6B8CVK−65)。
・ インビトロでヒトIL−23R/FcへのIL−23結合を遮断する。
・ ヒトIL−12への結合なし。
・ IC50≦20pMを伴いマウス脾細胞においてヒトIL−23誘導性IL−17産生を阻害する。
・ IC50≦40pMを伴いヒトDB細胞においてヒトIL−23誘導性STAT3リン酸化を阻害する。
・ ADCC/CDCにおける予測される活性なし。
・ カニクイザルIL−23についてKD≦1pM。
・ マウス又はラットIL−23への交差反応性なし。
・ マウス耳においてヒトIL−23誘導性IL−17及びIL−22産生を阻害する(1mg/kgでの両方のサイトカインの≧80%阻害)。
・ 安定性83℃(示差走査熱量測定により決定された融解温度83℃)。
・ 溶解性≧100mg/ml(UV分光法により測定し、濁度によりモニターした)。
・ 3匹のカニクイザルにおける1.0mg/kgの皮下投与は、持続的な≧10nM曝露を約28日間にわたり示し、約70%のバイオアベイラビリティを伴う。
・ インビトロでヒトIL−23R/FcへのIL−23結合を遮断する。
・ ヒトIL−12への結合なし。
・ IC50≦20pMを伴いマウス脾細胞においてヒトIL−23誘導性IL−17産生を阻害する。
・ IC50≦40pMを伴いヒトDB細胞においてヒトIL−23誘導性STAT3リン酸化を阻害する。
・ ADCC/CDCにおける予測される活性なし。
・ カニクイザルIL−23についてKD≦1pM。
・ マウス又はラットIL−23への交差反応性なし。
・ マウス耳においてヒトIL−23誘導性IL−17及びIL−22産生を阻害する(1mg/kgでの両方のサイトカインの≧80%阻害)。
・ 安定性83℃(示差走査熱量測定により決定された融解温度83℃)。
・ 溶解性≧100mg/ml(UV分光法により測定し、濁度によりモニターした)。
・ ヒトIL−12への結合なし。
・ カニクイザルIL−23についてKD≦1pM。
・ マウス又はラットIL−23への交差反応性なし。
・ IC50≦20pMを伴いマウス脾細胞においてヒトIL−23誘導性IL−17産生を阻害する。
・ IC50≦40pMを伴いヒトDB細胞においてヒトIL−23誘導性STAT3リン酸化を阻害する。
・ マウス耳においてヒトIL−23誘導性IL−17及びIL−22産生を阻害する(1mg/kgでの両方のサイトカインの≧80%阻害)。
・ 安定性83℃(示差走査熱量測定により決定された融解温度83℃)。
・ 溶解性≧100mg/ml(UV分光法により測定し、濁度によりモニターした)。
・ 3匹のカニクイザルにおける1.0mg/kgの皮下投与は、持続的な≧10nM曝露を約28日間にわたり示し、約70%のバイオアベイラビリティを伴う。
・ 安定性83℃(示差走査熱量測定により決定された融解温度83℃)。
・ 溶解性≧100mg/ml(UV分光法により測定し、濁度によりモニターした)。
a)それぞれ配列番号1、2、3、33、34、及び35のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
b)それぞれ配列番号4、5、3、36、34、及び37のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
c)それぞれ配列番号1、2、3、38、39、及び35のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
d)それぞれ配列番号6、2、3、40、41、及び42のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
e)それぞれ配列番号7、2、3、43、41、及び44のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
f)それぞれ配列番号8、9、10、45、46、及び47のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
g)それぞれ配列番号8、9、10、48、49、及び50のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
h)それぞれ配列番号11、12、13、51、52、及び53のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
i)それぞれ配列番号7、2、14、54、55、及び56のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
j)それぞれ配列番号15、16、17、57、58、及び59のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
k)それぞれ配列番号18、16、17、60、61、及び62のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
l)それぞれ配列番号19、20、21、63、66、67又は68、64、及び65のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
m)それぞれ配列番号22、23、24、69、70、及び71のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
n)それぞれ配列番号22、25、26、55、72、及び71のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
o)それぞれ配列番号8、9、10、45、73、及び74のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
p)それぞれ配列番号27、28、29、45、75、及び76のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
q)それぞれ配列番号8、9、10、77、78、及び79のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3配列;又は
r)それぞれ配列番号30、31、32、80、81、及び82のL−CDR1、L−CDR2、L−CDR3、H−CDR1、H−CDR2、及びH−CDR3。
ヒト化抗IL−23p19抗体及び薬剤は、ヒト化抗IL−23p19抗体又はその抗原結合フラグメントの修飾を含むことができる。例えば、癌の処置における抗体の有効性を増強するように、エフェクター機能に関して抗体を修飾することが望ましいであろう。1つのそのような修飾はFc領域中へのシステイン残基の導入であり、それにより、この領域における鎖間ジスルフィド結合形成を許す。このようにして生成されたホモ二量体抗体は、改善された内在化能力及び/又は増加した補体媒介細胞死滅及び/又は抗体依存性細胞傷害(ADCC)を有しうる。例えば、Caron et al., 1992, J. Exp Med.176: 1191-1195;及びShopes, 1992, J. Immunol.148: 2918-2922.を参照のこと。増強された抗腫瘍活性を有するホモ二量体抗体を、また、Wolff et al., 1993, Cancer Research 53: 2560-2565に記載する通りに、ヘテロ二官能性架橋剤を使用して調製することができる。あるいは、抗体を操作し、二重Fc領域を含むことができ、抗体の補体溶解及びADCC能力を増強する。Stevenson et al., 1989, Anti-Cancer Drug Design 3: 219-230を参照のこと。
抗IL−23p19抗体のアミノ酸配列変異体は、抗IL−23p19抗体DNA中に適切なヌクレオチド変化を導入することにより、又はペプチド合成により調製することができる。そのような変異体は、例えば、本明細書における実施例の抗IL−23p19抗体のアミノ酸配列内の残基からの欠失、及び/又はその中への挿入、及び/又はその置換を含む。欠失、挿入、及び置換の任意の組み合わせを、最終コンストラクトが所望の特徴を有するという条件で、最終構築物に達するまで作られる。アミノ酸変化は、また、ヒト化又は変異体抗IL−23p19抗体の翻訳後プロセスを変化させうる(例えばグリコシル化部位の数又は位置の変化など)。
(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)鎖配向に影響する残基:gly、pro;及び
(6)芳香族:trp、tyr、phe。
他の実施態様は、ヒト化抗IL−23p19抗体をコードする配列を含む単離ポリヌクレオチド、ベクター、及びポリヌクレオチドを含む宿主細胞、ならびにヒト化抗体の産生のための組換え技術を包含する。単離ポリヌクレオチドは、抗IL−23p19抗体の任意の所望の形態(例えば、全長モノクローナル抗体、Fab、Fab’、F(ab’)2、及びFvフラグメント、ダイアボディ、直鎖抗体、一本鎖抗体分子、ならびに抗体フラグメントから形成された多特異的抗体を含む)をコードすることができる。
本明細書に記載する抗体は、アフィニティ精製薬剤として有用である。このプロセスにおいて、抗体を、当技術分野において周知の方法を使用して、固相(例えばプロテインA樹脂など)上に固定化する。固定化抗体を、精製するIL−23p19タンパク質(又はそのフラグメント)を含むサンプルと接触させ、その後、支持体を、IL−23p19タンパク質(固定化抗体に結合されている)を除く、サンプル中の実質的に全ての材料を除去する適した溶媒を用いて洗浄する。最後に、支持体を、IL−23p19タンパク質を抗体から放出する別の適した溶媒を用いて洗浄する。
抗IL−23p19抗体は、診断キット、即ち、所定量の試薬と診断アッセイを実施するための指示とのパッケージ化された組み合わせにおいて使用することができる。抗体が酵素を用いて標識される場合、キットは、酵素により要求される基質及び補因子、例えば、検出可能な発色団又はフルオロフォアを提供する基質前駆体などを含んでもよい。また、他の添加剤を含んでもよい(例えば安定化剤、緩衝剤(例えば、ブロック緩衝剤又は溶解緩衝剤)など)。種々の試薬の相対量を広く変動させ、アッセイの感度を実質的に最適化する試薬の溶液中での濃度を提供しうる。試薬は、乾燥粉末(通常は凍結乾燥されており、溶解時に適切な濃度を有する試薬溶液を提供する賦形剤を含む)として提供してもよい。
別の実施態様において、本明細書に開示するヒト化抗IL−23p19抗体は、本明細書に記載するIL−23p19の発現に関連する種々の障害の処置において有用である。IL−23関連障害を処置するための方法は、治療的に効果的な量のヒト化抗IL−23p19抗体を、それを必要とする被験者に投与することを含む。
抗IL−23p19抗体又は薬剤は、IL−23p19の異常発現により、例えば、免疫細胞(例、リンパ球又は樹状細胞)の不適切な活性化により特徴付けられる免疫学的障害を処置又は防止するために有用である。IL−23のそのような異常発現は、例えば、増加したIL−23タンパク質レベルに起因しうる。抗IL−23p19抗体又はその抗原結合フラグメントでは、また、呼吸器障害、代謝性障害(例えば糖尿病)、及び特定の癌の処置又は防止における使用が見出される。本明細書に記載する方法に従った、免疫学的障害、呼吸器障害、代謝性障害、又は癌の処置又は防止は、そのような処置又は防止を必要とする被験者に、効果的な量の抗IL−23p19抗体又は薬剤を投与することにより達成され、それにより、抗体は、疾患状態に関連するIL−23の活性を減少させる。
IL−23p19結合薬剤(例、抗IL−23p19抗体)を含む組成物を、免疫学的障害、呼吸器障害、又は癌を有する又は有するリスクのある被験者に投与することができる。本発明は、さらに、癌、呼吸器障害、又は免疫学的障害の防止又は処置のための薬物の製造におけるIL−23p19結合薬剤(例、抗IL−23p19抗体)の使用を提供する。用語「被験体」は、本明細書において使用する通り、IL−23p19結合薬剤を投与することができる任意の哺乳動物患者を意味し、例えば、ヒト及び非ヒト哺乳動物、例えば霊長類、齧歯類、及びイヌなどを含む。本明細書に記載する方法を使用した処置について具体的に意図される被験体は、ヒトを含む。抗体又は薬剤は、、免疫学的障害、呼吸器障害、又は癌の防止又は処置において、単独で、あるいは、他の組成物と組み合わせにおいて投与することができる。抗体又は薬剤との組み合わせにおいて投与することができる、そのような組成物は、メトトレキサート(MTX)及び免疫調節剤(例、抗体又は小分子)を含む。
別の局面において、上に記載する障害の処置のために有用な材料を含む製造品が含まれる。製造品は容器及びラベルを含む。適した容器は、例えば、ボトル、バイアル、シリンジ、及び試験管を含む。容器は、種々の材料(例えばガラス又はプラスチックなど)から形成されうる。容器は、状態を処置するために効果的である組成物を保持し、滅菌アクセスポートを有しうる。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有する静脈内溶液バッグ又はバイアルでありうる。組成物中の活性薬剤はヒト化抗IL−23p19抗体である。容器上の又は容器に関連するラベルは、組成物が、選んだ状態を処置するために使用されることを示す。製造品は、さらに、医薬的に許容可能な緩衝液(例えばリン酸緩衝生理食塩水、リンゲル溶液、及びデキストロース溶液など)を含む第2の容器を含みうる。それは、さらに、商業的及び使用者の見地から望ましい他の材料(他の緩衝剤、希釈剤、フィルター、針、シリンジ、及び使用のための指示を伴う添付文書を含む)を含んでもよい。
実施例1:ヒト化抗IL−23p19抗体の産生
マウスリード抗体6B8を、6B8のマウス可変ドメイン及びヒト定常IgG1KOドメインからなるキメラ抗体に変換した。マウス抗体6B8を、本明細書において上の表1及び2に示す。IgG1KO(ノックアウト)は、エフェクター機能(例えばFcγR及び補体結合など)を低下させることにより、ADCC及びCDC活性を除去する2つの置換変異(Leu234Ala及びLeu235Ala)を有する。マウス抗体及びキメラ抗体の可変ドメインは同一である。キメラ抗体を生成し、抗体の機能を確認し、正しい配列が得られたことを確実にする。抗体の可変領域を、次に、設計及びスクリーニングプロセスを通じてヒト化させる。ライブラリーを作製し、そこでは、ヒト及びマウス残基を変化させ、任意の所与の位置で、ヒト又はマウス残基のいずれかがありうるようにした。そのようなライブラリーを、ヒト生殖系列及びマウス抗体の間で異なっているそれらのアミノ酸について作製した。親マウス抗体の機能を保持するクローンだけを選択した。抗体6B8についての代表的なヒト化可変領域を表5及び6に示す。
この様式において、抗体A、抗体B、抗体C、及び抗体Dは、マウス抗体6B8(ヒトIgG1KO(KO=ノックアウト)/カッパ骨格中にクローニング)に由来するヒト化抗体であった。抗体A、B、C、及びDを表7に示す。
A)組換えヒトIL−23に結合するマウス抗IL−23p19抗体の動態及び親和性を下に示す(表9)。動態及び結合親和性を、単一カラム精製に続いてハイブリドーマから生成された材料を使用し、Fortebio Octet(Fortebio, Menlo Park, CA)を使用して測定した。Octetは流体ベースの技術ではないため、この方法は、オフ率の正確な決定を提供しない。一部の場合において、親和性の推定値だけを得ることができる。
ヒトIL−23R−Fcをバイオセンサー表面に捕捉し、10nMのヒトIL−23を注射した。センサーグラムは、IL−23とIL−23受容体の間での特異的結合を示す(図2、最上部のトレース)。抗体を、次に、10nMのヒトIL−23と同時注射し、IL−23への抗体結合が、IL−23とIL−23受容体の間での相互作用を阻害することができるか否かを評価した。この実施例において、抗体がヒトIL−23に結合し、相互作用を阻害することができる場合、結合低下又は無結合は観察されない(図2、最下部のトレース)。示した実施例において、等モル濃度の抗体Aを、10nMの組換えヒトIL−23と同時注射した。
抗IL−23p19抗体についての1つの機能的細胞アッセイでは、マウス脾臓から単離された単核球からのIL−23刺激IL−17産生を阻害するそれらの能力を測定する。ヒト組換えIL−23タンパク質は、マウス脾細胞からのIL−17放出を刺激することが可能である。また、活性化ヒト単球性THP−1細胞の上清中で見出されるヒトIL−23の天然供給源を使用し、マウス単核球細胞からのIL−17産生を刺激することができる。
マウスにおけるインビボモデルを使用した。組換えヒトIL−23を、マウス耳の皮膚中に4連続日にわたり注射し、表皮肥厚ならびにIL−17及びIL−22タンパク質の上方調節をもたらす。抗IL−23p19抗体を、このモデルにおいて評価した。1mg/kg又は5mg/kg抗体の単回の腹腔内注射を、皮膚中への初回のIL−23注射の1時間前に投与した。組換えヒトIL−23(リンカーを伴う)を、3追加日にわたり毎日1回注射し、組織をサイトカイン評価のために収集した。サイトカイン産生の阻害を、抗体について実証した。3つの実験の結果を下の表中に示す(実験1:列1〜7、実験2:例8〜10、実験3:列11〜14)。
ヒト化抗IL−23p19抗体を、10分間の静脈内注入により、用量1.0mg/kgで、3匹のカニクイザルに投与した。血清サンプルを6週間の時間経過にわたり収集し、遊離抗体濃度を、特異的ELISAを使用して測定した。抗体についての血清濃度−時間プロファイル及び対応する薬物動態パラメーターを、下の表16中にまとめる。
NS0細胞のトランスフェクション及び安定プールの生成:
NS0細胞を、1%FBSの存在において、トランスフェクション前に成長させた。40×10e6個細胞を収集し、2%FBSを含む0.8ml培地中に、20μgの直線化DNA(重鎖及び軽鎖発現ベクター)と再懸濁し、次に、細胞を、氷上で、約15分間にわたり、750V/25uF(Bio-Rad Gene Pulser Xcell)での細胞のエレクトロポレーション前にインキュベートした。細胞を、2%FBSと、約48時間にわたり、37℃及び5% CO2で回収し、次に、96ウェルプレート中に、G418及びミコフェノール酸を含む2×10e5個細胞/mlで、14〜21日間にわたり、コロニーの形成まで蒔いた。
水素/重水素交換質量分析(HXMS)を用いて、ヒトIL−23p19への抗体A結合のエピトープをマッピングした。この方法によって、D2Oと交換するためのIL−23p19のアミド骨格水素の感受性を決定した。実験を、IL−23単独及び抗体Aを加えたIL−23を用いて行った。抗体Aの結合に起因する交換からの有意な保護を示すIL−23p19配列の領域を、このように、同定した。方法の分解能は、ペプシン又はプロテアーゼXVIIIでの消化により産生されるペプチドにより決定される。これらのIL−23p19由来ペプチドを、標準的で正確な質量及びHPLC MS/MS技術を用いて、非交換サンプルを用いた追加のコントロール実験により同定した。
移動相A=99/1/0.1(水/アセトニトリル/ギ酸)
移動相B=95/5/0.1(アセトニトリル/水/ギ酸)
流速=100ul/分
カラム=Phenomenex Jupiter C5、5u、50x1.0mm
移動相ライン、カラム、インジェクターループは氷浴中である。
勾配=時間0(3%B)、時間2.2(3%B)、時間10.1(90%B)、時間12.0(90%B)、時間12.1(3%B)
質量分析=Thermo Orbitrap Velos(0900865)
方法:
A.断片か(IDペプチドへの):12分間の取得時間(3分間の開始遅延)、30,000分解能でのフルスキャンFTMS、7イオントラップデータ依存的スキャン(CID)。
B.MS実行:12分間の取得時間(3分間の開始遅延)、60,000分解能でのフルスキャンFTMS。
Claims (24)
- 抗体又はその抗原結合フラグメントが、配列番号160のアミノ酸配列を含む軽鎖可変領域及び配列番号166のアミノ酸配列を含む重鎖可変領域か、配列番号160のアミノ酸配列を含む軽鎖可変領域及び配列番号168のアミノ酸配列を含む重鎖可変領域か、配列番号158のアミノ酸配列を含む軽鎖可変領域及び配列番号166のアミノ酸配列を含む重鎖可変領域かを含む、ヒト化抗IL−23p19抗体又はその抗原結合フラグメント。
- 抗体又はその抗原結合フラグメントが、配列番号160のアミノ酸配列を含む軽鎖可変領域及び配列番号166のアミノ酸配列を含む重鎖可変領域を含む、請求項1記載のヒト化抗IL−23p19抗体又はその抗原結合フラグメント。
- 抗体又はその抗原結合フラグメントが、配列番号160のアミノ酸配列を含む軽鎖可変領域及び配列番号168のアミノ酸配列を含む重鎖可変領域を含む、請求項1記載のヒト化抗IL−23p19抗体又はその抗原結合フラグメント。
- 抗体又はその抗原結合フラグメントが、配列番号158のアミノ酸配列を含む軽鎖可変領域及び配列番号166のアミノ酸配列を含む重鎖可変領域を含む、請求項1記載のヒト化抗IL−23p19抗体又はその抗原結合フラグメント。
- 抗体又はその抗原結合フラグメントが、ヒトIgG1重鎖定常領域に連結された配列番号166又は168のアミノ酸配列;及びヒトカッパ軽鎖定常領域に連結された配列番号158又は160のアミノ酸配列を含む、請求項1記載のヒト化抗IL−23p19抗体又はその抗原結合フラグメント。
- 抗体がモノクローナル抗体である、請求項1〜5のいずれか一項記載の抗IL−23p19抗体。
- 抗体が、配列番号174のアミノ酸配列を含む軽鎖及び配列番号176のアミノ酸配列を含む重鎖を含む、請求項1記載のヒト化モノクローナル抗IL−23p19抗体。
- 抗体が、配列番号174のアミノ酸配列を含む軽鎖及び配列番号178のアミノ酸配列を含む重鎖を含む、請求項1記載のヒト化モノクローナル抗IL−23p19抗体。
- 抗体が、配列番号180のアミノ酸配列を含む軽鎖及び配列番号176のアミノ酸配列を含む重鎖を含む、請求項1記載のヒト化モノクローナル抗IL−23p19抗体。
- 医薬における使用のための請求項1〜9のいずれか一項記載の抗体又はその抗原結合フラグメントを含む医薬的組成物。
- 使用が、炎症性疾患の、自己免疫疾患の、呼吸器疾患の、代謝性障害の、又は癌の処置である、請求項10記載の抗体又は抗原結合フラグメントを含む医薬的組成物。
- 使用が、乾癬、炎症性腸疾患、乾癬性関節炎、多発性硬化症、関節リウマチ、クローン病、潰瘍性大腸炎又は強直性脊椎炎の処置のためである、請求項10記載の抗体又は抗原結合フラグメントを含む医薬的組成物。
- 使用が、喘息又はCOPD(慢性閉塞性肺疾患)の処置のためである、請求項10記載の抗体又は抗原結合フラグメントを含む医薬的組成物。
- 請求項1〜13のいずれか一項記載の抗体又は抗原結合フラグメント及び医薬的に許容可能な担体を含む、医薬的組成物。
- 炎症性疾患、自己免疫疾患、呼吸器疾患、代謝性障害、又は癌を処置するための医薬的組成物であって、請求項1〜13のいずれか一項記載の抗体又は抗原結合フラグメント、あるいは請求項14記載の医薬的組成物を含み、該抗体又は抗原結合フラグメント、あるいは医薬的組成物の効果的な量がそれを必要とする被験者に投与される、医薬的組成物。
- 疾患が乾癬、炎症性腸疾患、乾癬性関節炎、多発性硬化症、関節リウマチ、クローン病、潰瘍性大腸炎又は強直性脊椎炎である、請求項15記載の医薬的組成物。
- 疾患が喘息又はCOPD(慢性閉塞性肺疾患)である、請求項15記載の医薬的組成物。
- 配列番号160のアミノ酸配列を有する抗体又は抗体フラグメントの軽鎖可変領域をコードする、及び、配列番号166のアミノ酸配列を有する抗体又は抗体フラグメントの重鎖可変領域をコードする配列か、配列番号160のアミノ酸配列を有する抗体又は抗体フラグメントの軽鎖可変領域をコードする、及び、配列番号168のアミノ酸配列を有する抗体又は抗体フラグメントの重鎖可変領域をコードする配列か、配列番号158のアミノ酸配列を有する抗体又は抗体フラグメントの軽鎖可変領域をコードする、及び、配列番号166のアミノ酸配列を有する抗体又は抗体フラグメントの重鎖可変領域をコードする配列かを含む単離ポリヌクレオチド。
- ポリヌクレオチドが、配列番号174のアミノ酸配列を有する抗体の軽鎖をコードする、及び、配列番号176のアミノ酸配列を有する抗体の重鎖をコードする配列か、配列番号174のアミノ酸配列を有する抗体の軽鎖をコードする、及び、配列番号178のアミノ酸配列を有する抗体の重鎖をコードする配列か、配列番号180のアミノ酸配列を有する抗体の軽鎖をコードする、及び、配列番号176のアミノ酸配列を有する抗体の重鎖をコードする配列かを含む、請求項18記載の単離ポリヌクレオチド。
- 請求項18又は19記載のポリヌクレオチドを含む、発現ベクター。
- a)配列番号160のアミノ酸配列を有する抗体又は抗体フラグメントの軽鎖可変領域をコードする配列を含む単離ポリヌクレオチド、及び、
b)配列番号166のアミノ酸配列を有する抗体又は抗体フラグメントの重鎖可変領域をコードする配列を含む単離ポリヌクレオチドか、
c)配列番号160のアミノ酸配列を有する抗体又は抗体フラグメントの軽鎖可変領域をコードする配列を含む単離ポリヌクレオチド、及び、
d)配列番号168のアミノ酸配列を有する抗体又は抗体フラグメントの重鎖可変領域をコードする配列を含む単離ポリヌクレオチドか、
e)配列番号158のアミノ酸配列を有する抗体又は抗体フラグメントの軽鎖可変領域をコードする配列を含む単離ポリヌクレオチド、及び、
f)配列番号166のアミノ酸配列を有する抗体又は抗体フラグメントの重鎖可変領域をコードする配列を含む単離ポリヌクレオチドかを含む、宿主細胞。 - a)配列番号174のアミノ酸配列を有する抗体の軽鎖をコードする配列を含む単離ポリヌクレオチド、及び、
b)配列番号176のアミノ酸配列を有する抗体の重鎖をコードする配列を含む単離ポリヌクレオチドか、
c)配列番号174のアミノ酸配列を有する抗体の軽鎖をコードする配列を含む単離ポリヌクレオチド、及び、
d)配列番号178のアミノ酸配列を有する抗体の重鎖をコードする配列を含む単離ポリヌクレオチドか、
e)配列番号180のアミノ酸配列を有する抗体の軽鎖をコードする配列を含む単離ポリヌクレオチド、及び、
f)配列番号176のアミノ酸配列を有する抗体の重鎖をコードする配列を含む単離ポリヌクレオチドかを含む、宿主細胞。 - a)請求項21又は22記載の宿主細胞を得ること、及び
b)前記宿主細胞を培養すること
を含む、抗体又は抗原結合フラグメントを産生する方法。 - さらに、前記抗体又は抗原結合フラグメントを回収及び精製することを含む、請求項23記載の方法。
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