JP5350793B2 - 改変抗il−23抗体 - Google Patents
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- JP5350793B2 JP5350793B2 JP2008529203A JP2008529203A JP5350793B2 JP 5350793 B2 JP5350793 B2 JP 5350793B2 JP 2008529203 A JP2008529203 A JP 2008529203A JP 2008529203 A JP2008529203 A JP 2008529203A JP 5350793 B2 JP5350793 B2 JP 5350793B2
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
本発明は、全般的にインターロイキン−23p19(IL−23p19)特異的な抗体およびその使用に関する。より具体的には、本発明は、ヒトIL−23p19を認識し、特に炎症性、自己免疫性および増殖性障害においてその活性を調節するヒト化抗体に関する。
免疫系は、感染体、例えば細菌、多細胞生物およびウィルス、ならびに癌から個人を防護するように機能する。この系には、単球、マクロファージ、樹状細胞(DC)、好酸球、T細胞、B細胞、好中球などのリンパ球様および骨髄性細胞が幾種も含まれる。こうしたリンパ球様および骨髄性細胞は、サイトカインの名で知られるシグナル伝達タンパク質をしばしば産生する。免疫応答には、炎症、即ち全身または特定の身体部位における免疫細胞の蓄積が含まれる。感染体または異物に応答して、免疫細胞がサイトカインを分泌し、次いでサイトカインが、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、例えば、自己免疫障害の場合のように過剰な炎症を伴うと、病的結末を生じ得る(例えば、非特許文献1;非特許文献2;非特許文献3;非特許文献4を参照されたい)。
Abbasら(編)(2000年)、Cellular and Molecular Immunology、W. B. Saunders Co., Philadelphia, PA Oppenheim and Feldman(編)(2001年)、Cytokine Reference、Academic Press, San Diego, CA von Andrian and Mackay(2000年)、New Engl. J. Med.、343巻、1020〜1034頁 Davidson and Diamond(2001年)、New Engl. J. Med.、345巻、340〜350頁 Cuaら(2003年)、Nature 421巻、744〜748頁 Oppmannら(2000年)、Immunity、13巻、715〜725頁 Wiekowskiら(2001年)、J. Immunol.、166巻、7563〜7570頁 Parhamら(2002年)、J. Immunol.、168巻、5699〜708頁 Frucht(2002年)、Sci STKE、2002、E1〜E3 Elkinsら(2002年)、Infection Immunity、70巻、1936〜1948頁 Liuら(1987年)、Proc. Natl. Acad. Sci. USA、84巻、3439〜43頁 Jonesら(1986年)、Nature、321巻、522頁 Verhoeyen等(1988年)、Science、239巻、1534頁 Kabatら(1991年)、J. Immunol.、147巻、1709頁 Queenら(1989年)、Proc. Natl. Acad. Sci. USA、86巻、10029頁 Gormanら(1991年)、Proc. Natl. Acad. Sci. USA、88巻、4181頁 Hodgsonら(1991年)、Biotechnology(NY)、9巻、421〜5頁
本発明は、IL−23の遮断が、炎症、自己免疫および異常増殖を抑制するという観察に基づいている。
付随する特許請求の範囲を含め、本明細書で使用する場合、「a」、「an」、「the」などの単語の単数形は、文脈上明らかにそうでないことを示していない限り、相当する複数への言及も包含する。下記の表7には、本願で使用される配列識別子の一覧が示されている。本明細書で引用した全ての参考文献は、個々の各刊行物、特許出願または特許が、参照により組み込まれることを明確かつ個別に示した場合と同程度に、参照により組み込まれる。
細胞または受容体に適用した場合の「活性化」、「刺激」および「処理」は、文脈上または明確にそうでないと示されない限り、同一の意味、例えば、リガンドによる細胞または受容体の活性化、刺激または処理の意味を有し得る。「リガンド」は、天然および合成のリガンド、例えば、サイトカイン、サイトカインの改変体、類縁体、ムテイン、および抗体由来の結合性組成物を包含する。「リガンド」は、小分子、例えば、サイトカインのペプチド模倣物質、および抗体のペプチド模倣物質も包含する。「活性化」とは、内部機構、ならびに外的因子または環境因子により調節される場合の細胞活性化を指すことができる。例えば細胞、組織、器官または生物の「応答」は、生化学的もしくは生理的挙動、例えば生物学的区画内での濃度、密度、接着性もしくは移動、遺伝子発現の割合、または分化の状態の変化を包含するが、その変化は、活性化、刺激もしくは処理、または遺伝的プログラミングなどの内部機構と相関している。
本発明は、改変抗IL−23抗体、ならびに炎症性、自己免疫性および増殖性傷害を処置するためのその使用を提供する。
モノクローナル抗体を産生する適当な任意の方法が使用できる。例えば、IL−23ヘテロ二量体の連結型もしくは非連結(例えば、天然)型、またはその断片で受容者を免疫してもよい。適当な任意の免疫法が使用できる。このような方法は、アジュバント、他の免疫賦活剤、反復追加免疫、および1つ以上の免疫経路の使用を包含することができる。
IV.IL−23特異抗体のヒト化
超可変領域源として、適当な任意の非ヒト抗体を使用することができる。非ヒト抗体源には、それだけに限らないが、ネズミ類、ウサギ目(ウサギを含む)、ウシおよび霊長類が挙げられる。大抵の場合、ヒト化抗体は、受容抗体の超可変領域残基を、所望の特異性、親和性および能力を有する、マウス、ラット、ウサギ、非ヒト霊長類などの非ヒト種の超可変領域残基(供与抗体)で置換したヒト免疫グロブリン(受容抗体)である。幾つかの例では、ヒト免疫グロブリンのFvフレームワーク領域(FR)残基が、対応する非ヒト残基で置換されている。更に、ヒト化抗体は、受容抗体、供与抗体のいずれにも見出されない残基を含み得る。こうした改変は、所望の生物活性の抗体性能を一層精緻にするためになされる。更なる詳細については、Jonesら(1986年)、Nature、321巻、522〜525頁;Reichmannら(1988年)、Nature、332巻、323〜329頁;およびPresta(1992年)、Curr. Op. Struct. Biol.、2巻、593〜596頁を参照されたい。
ヒト化抗IL−23抗体において望ましいと本明細書で認めた特性を有する抗体を、インビトロでの阻害的生物活性または適当な結合親和性についてスクリーニングすることができる。対象とする抗体が結合するヒトIL−23上のエピトープ(即ちp19サブユニット)に結合する抗体(例えば、このサイトカインのその受容体への結合を遮断する抗体)を求めてスクリーニングするために、「ANTIBODIES, A LABORATORY MANUAL」、Cold Spring Harbor Laboratory, Ed Harlow and David Lane(1988年)に記載のものなどの慣用的な交差遮断(cross−blocking)アッセイを行うことができる。同一のエピトープに結合する抗体同士は、このようなアッセイで交差遮断する可能性が高いが、交差遮断は、近在している、または重複さえしているエピトープに結合した抗体による、抗体結合の立体障害から生じることもあり得るので、交差遮断性抗体が全て、全く同一のエピトープに必ず結合することはない。
IL−23、そのサイトカイン類縁体またはムテインの作動薬または拮抗薬を含む医薬または滅菌組成物を調製するために、それに対する抗体またはその核酸が、医薬として許容可能な担体または賦形剤と混合される。例えば、「Remington’s Pharmaceutical Sciences and U. S. Pharmacopeia: National Formulary」、Mack Publishing Company, Easton, PA(1984年)を参照されたい。
本発明の抗体の組換え産生のために、2本の連鎖をコードする核酸を単離し、1種以上の複製可能なベクター中に挿入して、更にクローニング(そのDNAの増幅)するか、または発現させる。モノクローナル抗体をコードするDNAは、従来の手順を用いて容易に単離され、(例えば、該抗体の重鎖および軽鎖をコードする遺伝子に特異的に結合できるオリゴヌクレオチドプローブの使用によって)配列決定される。多くのベクターが利用できる。ベクターの構成要素には、それだけに限らないが、一般に以下のもの:シグナル配列、複製起点、1種以上のマーカー遺伝子、エンハンサー要素、プロモーターおよび転写終止配列のうち、1種以上が含まれる。一実施形態では、本発明のヒト化抗IL−23p19抗体の軽鎖、重鎖の双方が、同一のベクター、例えばプラスミドまたはアデノウィルスベクターから発現される。
本発明は、例えば、中枢神経系、末梢神経系および消化管の炎症性の障害および状態、ならびに自己免疫性および増殖性の障害の処置および診断のために、改変抗IL−23を使用する方法を提供する。
全般的方法
分子生物学における標準的方法は、記載されている(Maniatisら(1982年)、「Molecular Cloning, A Laboratory Manual」、Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY;Sambrook and Russell(2001年)、「Molecular Cloning, 3rd ed.」、Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY;Wu(1993年)、「Recombinant DNA, Vol. 217」、Academic Press, San Diego, CA)。標準的方法は、Ausbelら(2001年)、「Current Protocols in Molecular Biology, Vols. 1−4」、John Wiley and Sons, Inc. New York, NYにも掲載され、そこには、細菌細胞での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でのクローニング(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ーマティクス(第4巻)が記載されている。
抗ヒトIL−23p19抗体のヒト化
マウス抗ヒトIL−23p19抗体の6H12および7G10のヒト化は、参照により組み込まれるPCT特許出願公開の国際公開第2005/047324号および国際公開第2005/047326号に記載されるように、本質的にそのように行った。
KinExA技術を用いたヒト化抗ヒトIL−23の平衡解離定数(KD)の決定
抗ヒトIL−23抗体の平衡解離定数(KD)を、KinExA 3000機器(Sapidyne Instruments Inc., www.sapidyne.com)を用いて決定した。KinExAは、抗体、抗原および抗体−抗原複合体の混合物中での非複合化抗体の濃度の測定に基づいた、速度排除アッセイ法の原理を使用する。遊離抗体の濃度は、その混合物を固相固定化抗原に非常に短い時間曝すことにより、測定する。実際には、これは、溶液相抗原−抗体混合物をフローセル中に捕捉された抗原被覆粒子を通過するように流すことにより、実現される。該機器が生成したデータは、特注ソフトウェアを用いて分析する。平衡定数は、以下の仮定に基づく数学理論を用いて計算する。
BIAcore技術を用いたヒト化抗ヒトIL−23p19抗体の平衡解離定数(KD)の決定
全てのリガンド(抗IL−23 mAb)は、アミンカップリング標準手順を用いてBIAcore CM5センサーチップ上に固定化した。全ての実験は、PBS中25℃、10μL/分の流速で行った。全てのIL−23形は、PBS中で希釈して様々な濃度にした。様々な相互作用に対する速度定数は、BIAevaluationソフトウェア3.1を用いて決定した。KDは、解離および会合速度定数の計算値を用いて決定した。各タンパク質は、以下の濃度で使用した:抗IL−23 mAb hu7G10はPBS中0.33mg/mL、抗IL−23 mAb hu6H12はPBS中0.2mg/mL、bac−wtヒトIL−23はPBS中0.30mg/mL、eBioscienceヒトIL−23はPBS中0.10mg/mL、N222QヒトIL−23はPBS中0.33mg/mL。
中和用抗IL−23抗体を評価するための増殖バイオアッセイ
モノクローナル抗体の生物学的IL−23中和能は、組換えIL−23受容体を発現する細胞を用いた短期増殖バイオアッセイの適用により、評価した。トランスフェクタントのBa/F3−2.2lo細胞は、ヒトIL−23に応答して増殖し、その応答は、中和用抗IL−23抗体により抑制することができる。抗体の滴定は、用量・応答曲線の直線領域、平坦域近傍、およびEC50超に選んだIL−23の濃度に対して行う。増殖またはその欠如は、代謝活性の検出に基づく増殖指示色素であるアラマーブルーを用いる比色手段により測定する。抗体のIL−23中和能は、そのIC50値、即ちIL−23増殖の半量抑制を誘発する抗体濃度により評価する。
Ba/F3増殖バイオアッセイは、RPMI−1640培地、10%ウシ胎児血清、50μM 2−メルカプトエタノール、2mM L−グルタミン、および50μg/mL ペニシリン−ストレプトマイシンの中で行った。
アッセイは、96穴平底プレート(Falcon3072または類似品)中で行った。試薬および細胞懸濁液の調製には、全て適当な培地を利用した。アッセイ容量は、150μL/穴であった。抗IL−23抗体の滴定液は、室温で30〜60分間IL−23と予備インキュベートし、その間に細胞を調製した。抗体−サイトカインの予備インキュベーション後、細胞をプレートに添加した。バイオアッセイプレートは、加湿した組織培養チャンバー(37℃、5%CO2)中、40〜48時間インキュベートした。培養期間の終了時に、アラマーブルー(Biosource Cat #DAL1100)を16.5μL/穴で添加し、5〜12時間発色させた。次いで、吸光度を570nmおよび600nmで読み取り(VERSAmax Microplate Reader、Molecular Probes)、OD570〜600を得た。各試料に対して測定を2回行った。
細胞は、健常な増殖状態、一般に3〜8×105個/mLの濃度で使用した。細胞を計数し、ペレット化し、バイオアッセイ培地中で2度洗浄し、適当な濃度に懸濁した後、播種した。
IL−23は、使用濃度(3ng/mL)に調製し、第1の穴に75μLを添加した。各穴ともバイオアッセイ培地中で25:50μLで滴定し、50μL/穴を残すことにより、1:3の連続希釈液を作製した。細胞は、100μL/穴で播種するために、適当な濃度に懸濁した。
抗体は、使用濃度(30μg/mL)に調製し、第1の穴に75μLを添加した。各穴ともバイオアッセイ培地中で25:50μLで滴定し、50μL/穴を残すことにより、1:3の連続希釈液を作製した。滴定済み抗体を含有する各穴に、適当な濃度のIL−23を50μL/穴で添加した。細胞は、50μL/穴で播種するために、適当な濃度に懸濁し、抗体−サイトカインの予備インキュベーション後に添加した。
IC50の決定
GraphPad Prism 3.0ソフトウェアを用いて、吸光度をサイトカインまたは抗体の濃度に対してプロットし、S字形曲線の用量−応答に対して非線形回帰(曲線の当てはめ)を用いてIC50値を決定する。
抗IL−23p19抗体7G10に対するエピトープ
抗体7G10がヒトIL−23p19(配列番号29)に結合するためのエピトープをX線結晶解析で決定した。抗体7G10のキメラ型のFab断片と、p19およびp40サブユニットからなる非結合型ヒトIL−23との複合体に対して、座標を決定した。ヒトIL−23p19の配列は配列番号29に見出され、ヒトIL−12/IL−23 p40の成熟型の配列は、GenBank受入番号P29460の残基23〜328に見出される。抗体7G10のキメラ型は、i)ヒト重鎖定常領域(配列番号3の残基135〜464)に融合したマウス7G10 VHドメイン(配列番号6)を含む重鎖、およびii)ヒト軽鎖定常領域(配列番号4の残基130〜233)に融合したマウス7G10 VLドメイン(配列番号18)を含む軽鎖を含んでいる。
Claims (22)
- ヒトIL−23に結合する抗体またはその抗原結合性断片であって、
(i) 配列番号2または4の残基43〜53からなるCDRL1;
配列番号2の残基69〜75からなるCDRL2;
配列番号2または4の残基108〜116からなるCDRL3;
配列番号1の残基45〜54からなるCDRH1;
配列番号1の残基69〜85からなるCDRH2;および
配列番号1の残基118〜123からなるCDRH3
を含むか、あるいは
(ii)配列番号2または4の残基43〜53からなるCDRL1;
配列番号4の残基69〜75からなるCDRL2;
配列番号2または4の残基108〜116からなるCDRL3;
配列番号3の残基45〜54からなるCDRH1;
配列番号3の残基69〜85からなるCDRH2;および
配列番号3の残基118〜123からなるCDRH3
を含む、抗体またはその抗原結合性断片。 - 請求項1に記載の抗体またはその抗原結合性断片であって、
CDRL1は、配列番号4の残基43〜53からなり;
CDRL2は、配列番号4の残基69〜75からなり;
CDRL3は、配列番号4の残基108〜116からなり;
CDRH1は、配列番号3の残基45〜54からなり;
CDRH2は、配列番号3の残基69〜85からなり;
CDRH3は、配列番号3の残基118〜123からなる
抗体またはその抗原結合性断片。 - ヒトIL−23に結合する抗体またはその抗原結合性断片であって、
(i) 配列番号2の残基20〜129を含む軽鎖可変領域と、
配列番号1の残基20〜134を含む重鎖可変領域と
を含むか、または、
(ii)配列番号4の残基20〜129を含む軽鎖可変領域と、
配列番号3の残基20〜134を含む重鎖可変領域と
を含む、抗体またはその抗原結合性断片。 - 配列番号2の成熟型(残基20〜233)を含む軽鎖と、
配列番号1の成熟型(残基20〜464)を含む重鎖と
を含む、請求項3に記載の抗体またはその抗原結合性断片。 - 交差遮断アッセイにおいて、ヒトIL−23への第2抗体の結合を遮断することができるモノクローナル抗体またはその抗原結合性断片であって、該第2抗体は、ヒトIL−23に結合し、そして、
配列番号4の残基43〜53からなるCDRL1;
配列番号4の残基69〜75からなるCDRL2;
配列番号4の残基108〜116からなるCDRL3;
配列番号3の残基45〜54からなるCDRH1;
配列番号3の残基69〜85からなるCDRH2;および
配列番号3の残基118〜123からなるCDRH3
を含み、該抗体が、IL−23中和活性を有する、モノクローナル抗体またはその抗原結合性断片。 - IL−23媒介活性を遮断する、請求項2に記載の抗体またはその抗原結合性断片。
- 請求項3に記載の抗体またはその抗原結合性断片の軽鎖可変領域または重鎖可変領域の少なくとも一方をコードする、単離された核酸。
- 宿主細胞にトランスフェクトした際に、該宿主細胞により認識される制御配列に作動可能に連結された請求項7に記載の核酸を含む、発現ベクター。
- 請求項8に記載の発現ベクターを含む宿主細胞。
- 前記核酸配列を発現する条件下で、請求項9に記載の宿主細胞を培地中で培養し、それにより、軽鎖または重鎖可変領域を含むポリペプチドを作製するステップ、および
該宿主細胞または培地から該ポリペプチドを回収するステップ
を含む、ポリペプチドを作製する方法。 - γ1ヒト重鎖定常領域を含む、請求項3に記載の抗体またはその抗原結合性断片。
- γ4ヒト重鎖定常領域を含む、請求項3に記載の抗体またはその抗原結合性断片。
- Fab、Fab’、Fab’−SH、Fv、scFv、F(ab’)2およびダイアボディからなる群から選択される抗体断片を含む、請求項1に記載の抗体またはその抗原結合性断片。
- 請求項1に記載の抗体またはその抗原結合性断片を含む、ヒト被験体における免疫応答を抑制するための組成物。
- 前記免疫応答が炎症性応答である、請求項14に記載の組成物。
- 前記被験体が、関節炎、乾癬および炎症性腸疾患からなる群から選択される障害を有する、請求項15に記載の組成物。
- 前記免疫応答が自己免疫性応答である、請求項14に記載の組成物。
- 前記被験体が、多発性硬化症、全身性エリテマトーデスおよび糖尿病からなる群から選択される障害を有する、請求項17に記載の組成物。
- 前記被験体が癌を有する、請求項14に記載の組成物。
- 請求項3に記載の抗体またはその抗原結合性断片を含む、薬学的組成物。
- 医薬として許容可能な担体または希釈剤と組み合わせて、請求項3に記載の抗体またはその抗原結合性断片を含む薬学的組成物。
- 免疫抑制剤または抗炎症剤を更に含む、請求項21に記載の薬学的組成物。
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JP2008529203A Expired - Fee Related JP5350793B2 (ja) | 2005-08-31 | 2006-08-29 | 改変抗il−23抗体 |
JP2011066727A Pending JP2011130771A (ja) | 2005-08-31 | 2011-03-24 | 改変抗il−23抗体 |
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EP (3) | EP2354160A1 (ja) |
JP (2) | JP5350793B2 (ja) |
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CA (1) | CA2620802A1 (ja) |
CY (2) | CY1118760T1 (ja) |
DK (1) | DK1931710T3 (ja) |
ES (1) | ES2619845T3 (ja) |
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PT (1) | PT1931710T (ja) |
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PL1931710T3 (pl) | 2017-06-30 |
CA2620802A1 (en) | 2007-03-08 |
CY2019041I1 (el) | 2020-05-29 |
US7807160B2 (en) | 2010-10-05 |
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JP2009505677A (ja) | 2009-02-12 |
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EP1931710A2 (en) | 2008-06-18 |
HUE032131T2 (en) | 2017-09-28 |
US20090156788A1 (en) | 2009-06-18 |
SG165322A1 (en) | 2010-10-28 |
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EP3190125A1 (en) | 2017-07-12 |
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