JP6067575B2 - ヒト抗sod1抗体 - Google Patents
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- JP6067575B2 JP6067575B2 JP2013543832A JP2013543832A JP6067575B2 JP 6067575 B2 JP6067575 B2 JP 6067575B2 JP 2013543832 A JP2013543832 A JP 2013543832A JP 2013543832 A JP2013543832 A JP 2013543832A JP 6067575 B2 JP6067575 B2 JP 6067575B2
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Description
タンパク質蓄積、修飾および凝集は、非常に多くの神経変性病、例えばハンチントン病、アルツハイマー病(AD)およびパーキンソン病(PD)の病的態様である(Taylorら、Science 296(2005)、1991−1995)。タンパク質のミスフォールディング、凝集および沈殿は、これらの疾病では神経毒性に直接関係しているようである。天然ホモ二量体、銅−亜鉛スーパーオキシドジスムターゼ(SOD1)タンパク質(野生型とALS1変異体の両方)は、分子内ジスルフィド結合の不在下または結合した亜鉛イオンの不在下では線維状凝集体を形成する傾向がある。ルー・ゲーリック病またはシャルコー病としても公知の、筋萎縮性側索硬化症(ALS)などの疾患は、ミスフォールド/凝集SOD1に関係づけられる。さらに、前に述べたように、同じくタンパク質のミスフォールディングを誘導し得るSOD1の酸化修飾がADおよびPDにおいて認められており、SOD1の凝集は、AD患者におけるアミロイド班および神経原線維変化と関連づけられ(Choiら、J.Biol.Chem.280(2005)、11648−11655)これは、これらの疾病の病態における可能性のあるSOD1の役割を含意する。
Interactions」In Fundamental Immunology、Paul,W.E.編、Raven Press New York、NY
(1984)、Kuby,Janis Immunology、W.H.Freeman and Company New
York、NY(1992)、および本明細書に記載の方法を参照されたい。抗原に対する抗体の親和性を測定するための一般技術としては、ELISA、RIA、および表面プラズモン共鳴が挙げられる。特定の抗体−抗原相互作用の測定親和性は、異なる条件、例えば塩濃度、pHのもとで測定すると変動し得る。したがって、親和性および他の抗原結合パラメータ、例えば、KD、IC50の測定は、好ましくは、抗体および抗原の標準溶液、ならびに標準緩衝液を用いて行う。
本発明は、実施例において例証する抗体について略述するような免疫学的結合特性および/または生物学的特性を好ましくは明示するヒト抗SOD1抗体およびそれらの抗原結合フラグメントに一般に関する。本発明に従って、SOD1に対して特異的なヒトモノクローナル抗体を健常ヒト被験体のプールからクローニングした。
nMの、最も好ましくは約100pMから10nMのEC50;またはNI−204.11F11、NI−204.67E12、NI−204.12G3およびNI−204.25H3について示すように約100pMから10nMの、最も好ましくは約10
pMから1nMのEC50を有する。
およびK)は、脊髄腹側角におけるこれらの凝集体を染色し、これに対してNI204−10D12、NI204−10A8およびNI204−67E12(図9A、Dおよび
E)は、これらの構造を染色せず、可溶性ミスフォールド形態の突然変異体ヒトSOD1に対して特異的である参照抗体C4F6(図9L)に類似している(Boscoら、2010、Nat Neuroscience 13(11);1396−1403)。加えて、抗体NI204−10D12、NI204−6H1およびNI204−7G5は、脊髄背側角切片における膠様質のびまん性染色を示す。
抗体、またはその抗原結合フラグメント、変異体、もしくは誘導体をコードするポリヌクレオチドは、任意のポリリボヌクレオチドまたはポリデオキシリボヌクレオチドからなり得、それらは、非修飾RNAもしくはDNA、または修飾RNAもしくはDNAであり得る。例えば、抗体、またはその抗原結合フラグメント、変異体、もしくは誘導体をコードするポリヌクレオチドは、一本鎖および二本鎖DNA、一本鎖と二本鎖領域の混合物であるDNA、一本鎖および二本鎖RNA、および一本鎖と二本鎖領域の混合物であるRNA、一本鎖、もしくはさらに典型的には、二本鎖もしくは一本鎖と二本鎖領域の混合物であり得るDNAおよびRNAを含む、ハイブリッド分子からなり得る。加えて、抗体、またはその抗原結合フラグメント、変異体、もしくは誘導体をコードするポリヌクレオチドは、RNAもしくはDNA、またはRNAおよびDNAの双方を含む、三本鎖領域からなり得る。抗体、またはその抗原結合フラグメント、変異体、もしくは誘導体をコードするポリヌクレオチドはまた、安定性もしくは他の理由のために修飾された、1つ以上の修飾塩基、またはDNAもしくはRNA骨格を含み得る。「修飾された」塩基は、例えば、トリチル化塩基およびイノシン等の異常塩基を含む。様々な修飾を、DNAおよびRNAに対して行うことができるので、「ポリヌクレオチド」は、化学的に、酵素的に、または代謝的に修飾された型を包含する。
表II:SOD1特異的抗体のVHおよびVL領域のヌクレオチド配列。
本発明の抗体、またはその抗原結合フラグメント、変異体、もしくは誘導体を提供するために単離遺伝物質を操作した後、抗体をコードするポリヌクレオチドは、典型的には、所望の量の抗体を産生するために使用され得る宿主細胞に導入するために発現ベクターに挿入される。抗体もしくはそのフラグメント、誘導体、または類似体の組み換え発現、例えば、標的分子に結合する抗体の重鎖または軽鎖を、本明細書に記載した。本発明の抗体分子または抗体の重鎖もしくは軽鎖をコードするポリヌクレオチド、またはその一部(好ましくは、重鎖または軽鎖可変ドメインを含有する)が得られた後、抗体分子の産生のためのベクターは、当技術分野において公知の技法を使用して、組み換えDNA技術により産生され得る。したがって、ヌクレオチド配列をコードする抗体を含有するポリヌクレオチドを発現することによりタンパク質を調製する方法を本明細書に記載する。当業者に公知の方法を使用して、配列、ならびに適切な転写および翻訳制御シグナルをコードする抗体を含有する発現ベクターを構築することができる。これらの方法としては、例えば、体外組み換えDNA技法、合成技法、および生体内遺伝子組み換えが挙げられる。本発明は、したがって、本発明の抗体分子をコードするヌクレオチド配列、またはその重鎖もしくは軽鎖、またはプロモーターに作動可能に連結される、重鎖もしくは軽鎖可変ドメインを含む、複製可能なベクターを提供する。このようなベクターは、抗体分子の定常領域をコードするヌクレオチド配列を含み得(例えば、国際公開第WO86/05807号、国際公開第WO89/01036号、および米国特許第5,122,464号を参照されたい)、抗体の可変ドメインを、重鎖または軽鎖全ての発現に対するこのようなベクターにクローンし得る。
ある実施形態において、抗体ポリペプチドは、アミノ酸配列、または通常、抗体と関連しない1つ以上の部分を含む。例示的な修飾物を、さらに詳細を以下に記載する。例えば、本発明の一本鎖fv抗体フラグメントは、柔軟性リンカー配列を含む、または修飾し、機能部分(例えば、PEG、薬物、毒素、または蛍光、放射性、酵素、核磁気、重金属などの標識)を加えることができる。
本発明は、組成物であって、上述のSOD1結合分子、例えば本発明の抗体もしくはその抗原結合フラグメントまたはそれらの誘導体もしくは変異体、あるいは本発明のポリヌクレオチド、ベクターまたは細胞を含む組成物に関する。本発明の組成物は、医薬的に許容される担体をさらに含むことがある。さらに、本発明の医薬組成物は、該医薬組成物の所期の用途に依存してインターロイキンまたはインターフェロンなどのさらなる薬剤を含むことがある。ミスフォールド/凝集SOD1の出現を示すまたはミスフォールド/凝集SOD1に関連した神経変性病の治療、例えば、筋萎縮性側索硬化症、アルツハイマー病またはパーキンソン病の治療において使用するための追加の薬剤は、有機小分子、抗SOD1抗体、およびそれらの組み合わせから成る群より選択することができる。それ故、特定の好ましい実施形態において、本発明は、神経変性病の予防的および治療的処置用の、被験体における神経変性病の進行もしくは神経変性病処置に対する反応のモニター用の、または被験体の神経変性病発現危険度の判定用の医薬組成物または診断用組成物を調製するための、SOD1結合分子、例えば、本発明の抗体もしくはその抗原結合フラグメント、またはそれらのうちのいずれか1つの結合特異性と実質的に同じ結合特異性を有する結合分子、本発明のポリヌクレオチド、ベクターまたは細胞の使用に関する。
抗体を生細胞に、それらを害することなく、シャトルすることができると言われている技術プラットフォーム、いわゆる「スーパー抗体技術」が記載されている。このような細胞透過抗体は、新たな診断および治療の窓を開く。用語「TransMabs」は、これらの抗体のために作られた。
さらなる態様において、本発明は、本発明の任意の抗体によって特異的に認識されるSOD1のエピトープを有するペプチドに関する。好ましくは、このようなペプチドは、配列番号2、配列番号51、配列番号52、配列番号53、配列番号54、配列番号55、配列番号56、配列番号57、配列番号58もしくは配列番号59で示されるアミノ酸配列、または1つ以上のアミノ酸が置換、欠失および/もしくは付加されているそれらの修飾配列を含み、または該配列から成り、該ペプチドは、本発明の任意の抗体によって、好ましくは抗体NI−204.10D12、NI−204.12G7、NI−204.10A8、NI−204.11F11、NI−204.6H1、NI−204.12G3、NI−204.7G5、NI−204.7B3、NI−204.34A3それぞれによって抗体NI−204.25H3によって、認識される。
12(1994)、352−364に与えられている。
850673 2に提供されているような定義が与えられている。本明細書の本文を通して幾つかの文書が引用されている。完全な文献引用情報は、特許請求の範囲の直ぐ前の本明細書末尾において見つけることができる。全ての引用参考文献(本願中の至る所で引用されている参考文献、発行特許、公開特許出願、ならびに製造業者の仕様書および説明書などを含む)の内容は、参照により本明細書に特に組み込まれているが、引用されているいずれかの文書が実際に本発明についての先行技術であることを認めるものではない。
本明細書において用いるものなどの従来の方法についての詳細な説明は、引用文献の中で見つけることができる;BeersおよびBerkowにより編集された「The Merck Manual of Diagnosis and Therapy」、第17版(Merck&Co.、Inc.2003)も参照されたい。
1984);Culture Of Animal Cells(FreshneyおよびAlan、Liss,Inc.、1987);Gene Transfer Vectors for Mammalian Cells(MillerおよびCalos編);Current Protocols in Molecular Biology and Short Protocols in Molecular Biology、第3版(Ausubelら編);およびRecombinant DNA Methodology(Wu編、Academic Press);Gene Transfer Vectors For Mammalian Cells(MillerおよびCalos編、1987、Cold Spring Harbor Laboratory);Methods In Enzymology、第154および155巻(Wuら編);Immobilized Cells And Enzymes(IRL
Press、1986);Perbal、A Practical Guide To Molecular Cloning(1984);the treatise,Methods In Enzymology(Academic Press,Inc.、N.Y.);Immunochemical Methods In Cell And Molecular Biology(MayerおよびWalker編、Academic Press、London、1987);Handbook Of Experimental Immunology、第I−IV巻(WeirおよびBlackwell編、1986);Protein Methods(Bollagら、John Wiley&Sons 1996);Non−viral Vectors for Gene Therapy(Wagnerら編、Academic Press 1999);Viral Vectors(KaplittおよびLoewy編、Academic Press 1995);Immunology Methods Manual(Lefkovits編、Academic Press 1997);ならびにCell and Tissue Culture:Laboratory Procedures in Biotechnology(DoyleおよびGriffiths、John Wiley&Sons 1998)のような標準的教科書の中で見つけることができる。本開示において言及する遺伝子操作のための試薬、クローニングベクターおよびキットは、供給業者、例えば、BioRad、Stratagene、Invitrogen、Sigma−AldrichおよびClonTechから入手できる。細胞培養および培地回収に関する一般技術は、Large Scale Mammalian Cell Culture(Huら、Curr.Opin.Biotechnol.8(1997)、148);Serum−free Media(Kitano、Biotechnology 17(1991)、73);Large Scale Mammalian Cell Culture(Curr.Opin.Biotechnol.2(1991)、375);およびSuspension Culture of Mammalian Cells(Birchら、Bioprocess Technol.19(1990)、251);Extracting information from cDNA arrays、Herzelら、CHAOS 11(2001)、98−107に概説されている。
特に記載のない限り、SOD1特異的B細胞の同定、および所望の特異性を提示する抗SOD1抗体の分子クローニング、ならびにそれらの組み換え発現および機能の特性付けは、一般に、国際公開第WO2008/081008号として公開された国際出願第PCT/EP2008/000053号の実施例および補足的方法の部に記載されているとおりに行った、または行うことができ、該参考文献の開示内容は、その全体が参照により本明細書に組み込まれている。SOD1特異的B細胞の同定および所望の特異性を提示するSOD1抗体の分子クローニングならびにそれらの組み換え発現および機能の特性付けのための新規方法を本願の中で提供する。上で説明したように、本発明の一実施形態では、単一またはオリゴクローナルB細胞の培養物を培養し、該B細胞によって産生された抗体を含有する該培養物の上清を、その中の新規抗SOD1抗体の存在および親和性についてスクリーニングする。このスクリーニング工程は、国際公開第WO2004/095031号パンフレット(この開示内容はその全体が参照により本明細書に組み込まれている)に記載されているような感受性組織アミロイド班免疫反応性(TAPIR)アッセイ段階;実施例4に記載し、図6に示すような、突然変異ヒトSOD1形態を発現するトランスジェニックマウスの脊髄組織を用いてSOD1の病的凝集体についてスクリーニングする段階;類似に実施例5に記載し、図7に示すような配列番号1によって表されるアミノ酸配列のSOD1に由来するペプチドと抗体NI−204.10D12についてのエピトープ立体構造実験によるペプチドの結合についてスクリーニングする段階;配列番号1によって表される前記アミノ酸配列の完全長SOD1の結合についてスクリーニングし、国際公開第WO2008/081008号パンフレットに記載されているように、ならびに実施例1に記載し、図2、5および7に示すように、結合が検出される抗体または該細胞を産生する細胞を単離する段階を含む。
組み換えヒトSOD1は、Biomol(ドイツ国ハンブルク)から購入した。ヒト赤血球からの野生型SOD1(生理的二量体)および他の全ての試薬は、別途言及しなければSigma−Aldrich(スイス国ブーフス)から購入した。
ELISA:
被覆用緩衝液(15mM Na2CO3、35mM NaHCO3、pH9.42、pH9.6)中3.3μg/mLまたは5μg/mLの濃度に希釈した組み換えヒトSOD1(Biomol、ドイツ国ハンブルク)またはBSA(Sigma−Aldrich、スイス国ブーフス)のいずれかで96ウェルマイクロプレート(Corning)を一晩、4℃で被覆した。あるいは、被覆用緩衝液(15mM Na2CO3、35mM NaHCO3、pH9.42)中34μg/mLの濃度の体外酸化ヒトSOD1で被覆した96ウェルマイクロプレート(Corning)を使用する。プレートをPBS−T pH7.6中で洗浄し、2%BSA(Sigma−Aldrich、スイス国ブーフス)を含有する、PBS/0.1%Tween−20を用いて1時間、室温で非特異的結合部位をブロックした。B細胞調整培地を記憶B細胞培養物プレートからELISAプレートに移し、1時間、室温でインキュベートした。ELISAプレートをPBS−T中で洗浄し、ホースラディッシュペルオキシダーゼ(HRP)接合抗ヒト免疫グロブリンポリクローナル抗体(Jackson ImmunoResearch、英国ニューマーケット)を使用して結合を判定し、その後、標準的な比色アッセイでHRP活性を測定した。培地中に含有された抗体の、BSAへの結合ではなく、組み換えSOD1への結合を示したB細胞培養物のみを、抗体クローニングに付した。
標準96ウェル10−Spot MULTI−SPOTプレート(Meso Scale Discovery、米国)を、PBS中30ug/mLのSOD1(Biomol、ドイツ国ハンブルク)で被覆した。3%BSAを含有するPBS−Tで非特異的結合部位を1時間、室温でブロックし、その後、B細胞調整培地と共に1時間、室温でインキュベートした。プレートをPBS−T中で洗浄し、その後、SULFO−Tag接合抗ヒトポリクローナル抗体(Meso Scale Discovery、米国)と共にインキュベートした。PBS−Tでの洗浄後、SECTOR Imager 6000(Meso Scale Discovery、米国)を使用する電気化学発光測定により、抗体の結合を検出した。
記憶B細胞を含有するサンプルを健常ヒト被験体から得た。選択された記憶B細胞培養物の生B細胞を回収し、mRNAを調製する。その後、ネステッドPCRアプローチを用いて、免疫グロブリン重および軽鎖配列を得る。
マウスモノクローナル抗SOD1抗体72B1(Santa Cruz Biotechnology、米国サンタクルーズ)およびウサギモノクローナル抗SOD1抗体EPR1726(Epitomics、米国バーリンゲーム)を製造業者のプロトコルに従って使用した。組み換えヒトまたはキメラSOD1抗体NI−204.10D12、NI−204.10A8、NI−204.12G7、NI−204.9F6、NI−204.11F11、NI−204.67E12、NI−204.6H1、NI−204.12G3、NI−204.7G5、NI−204.7B3,
NI−204.34A3およびNI−204.25H3は、本発明の抗体である。別の言明がない限り、それらをHEK293またはCHO細胞において発現させ、調整培地から精製し、その後の用途に直接使用した。実施例1から4では、本発明の精製組み換え抗体を使用した。
炭酸塩ELISA被覆用緩衝液(15mM Na2CO3、35mM NaHCO3、pH9.42)中3.3/mLの濃度に希釈した組み換えヒトSOD1タンパク質(Biomol、ドイツ国ハンブルク)で、4℃で一晩、96ウェルマイクロプレート(Costar、Corning、米国)を被覆した。2%BSA(Sigma−Aldrich、スイス国ブーフス)と0.5%Tween20とを含有するPBSを用いて2時間、室温で非特異的結合部位をブロックした。HRPと接合したロバ抗ヒトIgGg抗体(Jackson immunoResearch、英国ニューマーケット)を使用して本発明のヒト抗体(NI−204.10D12、NI−204.9F6、NI−204.12G7およびNI−204.10A8)の結合を判定し、その後、標準的な比色アッセイでHRP活性を測定した。GraphPad Prismソフトウェア(米国サンディエゴ)を使用する非線形回帰により、ED50値を推定した。
B6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスを使用して、本発明のSOD1抗体(およびそれらの結合特異性を有する分子)を検証した。
単離された抗体の認識標的としてのSOD1を検証するために、上で説明したようにダイレクトELISAアッセイを行った。例示的組み換えヒトNI−204.10D12、NI−204.12G7、NI−204.9F6およびNI−204.10A8抗体については、炭酸塩ELISA被覆用緩衝液(15mM Na2CO3、35mM NaHCO3、pH9.42)中3.3μg/mLの濃度に希釈した、組み換えヒトSOD1(Biomol、ドイツ国ハンブルク)でまたはBSA(Sigma−Aldrich、スイス国ブーフス)で96ウェルマイクロプレート(Costar、Corning、米国)を被覆し、該抗体の結合効率を試験した。ELISAにより、例示的NI−204.10D12、NI−204.12G7、NI−204.9F6およびNI−204.10A8抗体は、ヒトSOD1に特異的に結合する。BSAへの結合は観察されなかった;図2参照。
NI−204.10A8およびNI−204.9F6抗体は、家族性ALSのための適したヒト由来候補薬であり、スーパーオキシドジスムターゼ1突然変異体を過発現する確立されたトランスジェニックマウスモデルでそれらを研究することができる。
立体構造エピトープへのNI−204.10D12、NI−204.10A8、NI−204.12G7およびNI−204.9F6の結合能力を判定するために、被覆用緩衝液中、異なる4つの被覆濃度(0.1;1;10または30μg/mL)のヒト組み換えSDO1(Biomol、ドイツ国ハンブルク)を用いてダイレクトELISA実験を行った。一次抗体ヒトNI−204.10D12、ヒトNI−204.10A8、ヒトNI−204.9F6およびマウスモノクローナル抗体SOD−1 72B1(Santa Cruz Biotechnology、米国サンタクルーズ)を、示されている濃度(図4)に希釈し、1時間、室温でインキュベートした。HRPと接合したヤギ抗マウスIgG抗体(Jackson
immunoResearch、英国ニューマーケット)またはロバ抗ヒトIgGg(Jackson immunoResearch、英国ニューマーケット)抗体いずれかを使用して結合を判定し、その後、標準的な比色アッセイでHRP活性を測定した。GraphPad Prism(米国サンディエゴ)ソフトウェアを使用する非線形回帰により、ED50値を推定した。
金属触媒酸化反応を用いて体外スーパーオキシドジスムターゼ1凝集を誘導した(Rakhitら、J.Biol.Chem.279 (2004)、15499−504)。ヒト赤血球からの野生型SOD1(二量体)および多の全ての試薬は、Sigma−Aldrich(Sigma−Aldrich、スイス国ブーフス)から購入した。凝集のために、4mMアスコルビン酸と0.2mM CuCl2とを含有する10mM Tris酢酸緩衝液、pH7.0中で10μMヒトSOD1を48時間37℃でインキュベートした。対照として、10μMヒトSOD1を10mM Tris酢酸緩衝液、pH7.0中で48時間、37℃でインキュベートした。
immunoResearch、英国ニューマーケット)またはロバ抗ヒトIgGg抗体(Jackson immunoResearch、英国ニューマーケット)いずれかを使用して結合を判定し、その後、標準的な比色アッセイでHRP活性を測定した。GraphPad Prismソフトウェア(米国サンディエゴ)を使用する非線形回帰により、ED50値を推定した。
疾病末期のB6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスの脊髄をリン酸緩衝4%パラホルムアルデヒド溶液で固定し、パラフィン包埋し、5μm切片に切断した。ギ酸前処理後、切片を異なる抗スーパーオキシドジスムターゼ1抗体:キメラNI−204.10D12(50nM)、ヒトNI204−10A8(50nM)、ヒトNI−204.12G7(20nM)、ヒトNI−204.9F6(50nM)およびEPR1726抗SOD1(Epitomics、1:10000)と共にインキュベートし、その後、ビオチン化ロバ抗マウスまたはビオチン化ロバ抗ヒトまたはビオチン化ロバ抗ウサギ二次抗体(Jackson ImmunoResearch Europe Ltd;1:250)のいずれかと共にインキュベートした。抗体シグナルをVectastain ABCキット(Vector Laboratories)で増幅し、ジアミノベンジジン(Dako)で検出した。
Neuroscience 13(11);1396−1403)に特異的である参照抗体C4F6(図9L)に類似している。加えて、抗体NI204.10D12、NI204.6H1およびNI204.7G5は、脊髄背側角切片において膠様質のびまん性染色を示す。
(NI−204.10D12(図9A)、NI−204.10A8(図9D)およびNI−204.67E12(図9E))は、脊髄組織の強いびまん性染色によって証明されるように、高感度で生理的SOD1も認識するようである。
これらのデータは、NI−204抗体がB6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスモデルにおいて病的スーパーオキシドジスムターゼ1構造を認識することを立証する。
オーバラップペプチドのスキャンをエピトープマッピングのために用いた。ヒトスーパーオキシドジスムターゼ1の全配列を、個々のペプチド間に11aaオーバーラップがある合計36の直鎖状15量体ペプチドとして合成し(JPT Peptide Technologies、ドイツ国ベルリン)、ニトロセルロース膜にスポットした。その膜を5分間、メタノール中で活性化し、その後、室温でTBS中で10分間洗浄した。非特異的結合部位を2時間、室温で、Roti(登録商標)−Block(Carl Roth Gmbh+Co.KG、ドイツ国カールスルーエ)でブロックした。ヒトNI−204.10D12、NI−204.10A8、NI−204.12G7、NI−204.11F11、NI−204.6H1、NI−204.12G3、NI−204.7G5、NI−204.7B3、NI−204.34A3それぞれNI−204.25H3抗体(1μg/mL)を3時間、室温で、Roti(登録商標)−Block中でインキュベートした。HRP接合ロバ抗ヒトIgG二次抗体を使用して、一次抗体の結合を判定した。ECLおよびImageQuant 350検出(GE Healthcare、スイス国オッテルフィンゲン)を使用してブロットを現像した。
スーパーオキシドジスムターゼ1タンパク質のNI−204/10D12結合エピトープをカバーするビオチン化ペプチド(JPT Peptide Technologies、ドイツ国ベルリン)をPBS中50μg/mLの濃度で用いて4℃で一晩、ストレプトアビジン被覆96ウェルマイクロプレート(Fischer Scientific)を被覆した。2%BSA(Sigma−Aldrich、スイス国ブーフス)を含有する、PBS/0.1%Tween−20を用いて1時間、室温で、非特異的結合をブロックした。一次抗体キメラNI−204.10D12を示されている濃度に希釈し、1時間、室温でインキュベートした。HRPと接合したヤギ抗マウスIgG抗体(Jackson immunoResearch、英国ニューマーケット)を使用して結合を判定し、その後、標準的な比色アッセイでHRP活性を測定した。
上で既に説明したしょうに、抗ヒトSDO1抗体の直接脳室内注入に基づく受動免疫アプローチを用いるトランスジェニックマウス系統での研究により、そのような治療が、SOD1 fALSマウスモデルにおいて寿命を延長することおよび運動ニューロン減少を減弱することにより疾病を軽減し得ることは証明されている(Urushitaniら、Proc.Natl.Acad.Sci.USA.104(2007)、2495−2500;Gros−Louisら、J.Neurochem.(2010)113、1188−1199)。対照的に、能動的ワクチン接種アプローチは、有意な防御を付与することができなかった(Urushitaniら、Proc.Natl.Acad.Sci.USA.104
(2007)、2495−2500)。しかし、能動的ワクチン接種は、老人集団の有意な割合がワクチン接種に対する非応答者であると予想されるので、ヒトでは特に利用できないことがある。さらに、SOD1に対する免疫反応に随伴する潜在的副作用は、制御が難しい場合がある。本発明のSOD1結合分子が、マウス抗体について上で説明したのと同様のSOD1凝集体の脳内レベル低減を果たすことは、病的ミスフォールド/凝集SOD1種に対するそれらの同様の結合特性のため、合理的に予想することができる。
York)。
方法
体外スーパーオキシドジスムターゼ1凝集
金属触媒酸化反応を用いて体外スーパーオキシドジスムターゼ1凝集(Rakhitら、J.Biol.Chem.279(2004)、15499−15504に従って)を誘導した。ヒト赤血球からの天然SOD1(二量体)および多の全ての試薬は、Sigma−Aldrich(Sigma−Aldrich、スイス国ブーフス)から購入した。凝集のために、4mMアスコルビン酸と0.2mM CuCl2とを含有する10mM Tris酢酸緩衝液、pH7.0中で10μMヒトSOD1を48時間37℃でインキュベートした。対照として、10μMヒトSOD1を10mM Tris酢酸緩衝液、pH7.0中で48時間、37℃でインキュベートした。
Zetterstromら、J Neurochem.117(2011)、91−99に従って、スーパーオキシドジスムターゼ1変性反応を行った。ヒト赤血球からの天然SOD1(二量体)および多の全ての試薬は、Sigma−Aldrich(Sigma−Aldrich、スイス国ブーフス)から購入した。変性のために、23μMヒトSOD1を3.5M塩化グアニジウムおよび25mM EDTA、pH7.0中で4時間、22℃でインキュベートした。その後、5mM EDTA、pH7.0を含有するPBSに対して変性溶液を透析し、20,000gで遠心分離してSOD1凝集体を除去し、変性SOD含有上清を回収した。
天然ヒトSOD1二量体または体外変性/酸化ヒトSOD1または組み換えSOD1(Biomol、ドイツ国)のいずれかを被覆用緩衝液(15mM Na2CO3、35mM NaHCO3、pH9.42)中20μg/mLの濃度で用いて96ウェルマイクロプレート(Corning)を被覆した。2%BSA(Sigma−Aldrich、スイス国ブーフス)を含有する、PBS/0.1%Tween(登録商標)−20を用いて1時間、室温で非特異的結合部位をブロックした。一次抗体を示されている濃度に希釈し、1時間、室温でインキュベートした。HRPと接合したロバ抗ヒトIgG Fcγ特異的抗体、またはHRPと接合したヤギ抗マウスIgG(H+L)特異的抗体のいずれかを使用して結合を判定し、その後、標準的な比色アッセイでHRP活性を測定した。
GraphPad Prismソフトウェア(米国サンディエゴ)を使用する非線形回帰により、ED50値を推定した。
天然ヒトSOD1二量体、変性/酸化ヒトSOD1および組み換えSOD1に対する異なるヒト由来SOD1特異的抗体のEC50を、それらの異なるSOD1種を20μg/mL濃度で被覆してダイレクトELISAにより決定した。前記異なるSOD1種に対する前記ヒト由来SOD1特異的抗体について判定された結合親和性を下の表IIIにまとめる。
NI−204.67E12抗体はピコモルの高い総合結合親和性を有し、ならびに抗体NI−204.10A8およびNI−204.9F6はナノモル範囲の親和性を有する。
金属触媒酸化によって誘導されるスーパーオキシドジスムターゼ1凝集体およびフォールディングされていないSOD1は、ALS関連、体内スーパーオキシドジスムターゼ1凝集体に類似したまたは該凝集体と同一の特性を保有する。幾つかのヒト由来SOD1特異的抗体は、治療上意味のあるミスフォールド形態のヒトスーパーオキシドジスムターゼ1、例えば、フォールディングされていない/酸化されたSOD1への顕著な結合を示す。フォールディングされていない/酸化されたスーパーオキシドジスムターゼ1への結合は、天然二量体より選好されるようである。これらの発見は、病理学的に意味のある立体構造のスーパーオキシドジスムターゼ1タンパク質に対して標的化される本発明のヒト由来SOD−1抗体の治療上魅力的なプロファイルを強調する。
抗ヒトSDO1抗体の直接脳室内注入に基づく受動免疫アプローチを用いるトランスジェニックマウス系統での研究により、そのような治療が、SOD1 fALSマウスモデルにおいて寿命を延長することおよび運動ニューロン減少を減弱することにより疾病を軽減し得ることは証明されている(Urushitaniら、Proc.Natl.Acad.Sci.USA.104(2007)、2495−2500;Gros−Louisら、J.Neurochem.(2010)113、1188−1199)。
脳内注入のためのAlzet(登録商標)浸透圧ミニポンプの外科的埋め込み
60日齢B6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスに深麻酔(フェンタニル/ミダゾラム/メデトミジン)し、小さな正中切開を施して頭骨を露出させ、抗体溶液またはPBSを充填した滅菌Alzet(登録商標)ミニポンプ(ALZET Osmotic Pumps;Cupertino、米国カリフォルニア、モデル1004、長さ1.5cm、直径0.6cmおよび空重量0.4g加重)を挿入することができるようにマウスの背部の肩甲骨中央領域に皮下ポケットを作製した。その後、脳定位固定装置内にマウスの頭部を固定し、骨縫合接合部ブレグマを基準点として使用して頭骨に穴をあけ、Alzet(登録商標)脳内注入キット3カニューレを左側脳室へと低下させた;ブレグマに従って調整する;AP、−0.2mm;ML、0.9mm;およびDV、2.5mm。カニューレの配置後、2本の小さなネジを頭骨内に配置し、歯科用セメントを塗布して頭骨にしっかりと取り付けた。ナロキソン(56952(Swissmedic)、OrPha Swiss GmbH、スイス国キュスナハト)、フルマゼニル(48280(Swissmedic)、Roche Pharma(Schweiz)、スイス国ライナッハ)/アチパメゾール(60562(Swissmedic)、Dr.E.Graub AG、スイス国ベルン)およびメタカム(Boehringer Ingelheim、ドイツ国)を解毒剤および術後鎮痛薬として皮下投与し、さらに飲料水中のメタカムおよびブプレノルフィン(41931、44100(Swissmedic)、Reckitt Benckiser Healthcare、英国)/フェニルブタゾン(42726(Swissmedic)、Streuli Pharma AG、スイス国ウツナッハ)/アミノフェナゾン/ベンジルペニシリン(56271(Swissmedic)、Grunenthal Pharma AG、スイス国グラールス)/ジヒドロストレプトマイシン(42790(Swissmedic)、Streuli Pharma AG、スイス国ウツナッハ)を鎮痛薬/抗生物質として1週間与えた。術後、回復を促進するためおよび脱落を低減するために、マウスを3日間、ヒートパッド上で飼育し、カーゴの床に含水飼料を置いた。
28日ごとに浸透圧ミニポンプを交換した。B6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスに吸入麻酔(3.5%Sevofluran(53211(Swissmedic)、Abbott AG、スイス国バール)によって深麻酔し、ポンプの上に小切開を施し、ポンプを脳内注入用カニューレから取り外し、取り出した。新たに充填されたポンプを挿入し、注入用カニューレに接続し、創傷クリップを使用して切開部位を閉じた。
握力測定装置(Ugo Basile、イタリア国コメロ、カタログ番号47106)を使用して、マウスの握力を測定した。このシステムにはセンサーに接続しているグリッドが備えられている。4本の足がグリッドをつかむまでマウスを低下させ、その後、握った足を離すまで穏やかに引き戻した。3回の施行にわたってマウスが達成した最大の力を電子的に記録した。
マウスが横向きに寝てから15秒以内に自らを起こすことができないことにより、重症動作不能運動ニューロン病の臨床エンドポイントを定義した。運動ニューロン病の被定義臨床エンドポイントに、実験時間中の任意の時点で、到達していなかったマウスのカプラン・マイヤー生存分析によって、生存確率を試験した。
疾病末期のB6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスの脊髄をリン酸緩衝4%パラホルムアルデヒド溶液で固定し、パラフィン包埋し、5μm切片に切断した。ニッスル染色(0.5%クレシルバイオレット溶液(Sigma−Aldrich、C5042))については、切片をニッスル溶液で3分間、室温で染色し、その後、3分間、蒸留水で洗浄した。標準プロトコルに従って、切片をさらに処理した。NeuN染色については、ギ酸前処理後、切片をモノクローナルNeuN抗体、1:1000希釈(MAB377;Milipore)と共にインキュベートした。抗体シグナルを標準DAB検出システムで増幅した。NeuN染色は、自動Leica BondMax(商標)染色システム(Leica、ドイツ国ヴェッツラー)で行った。
SOD1を標的にするヒト由来抗体の薬理学的治療効果を評価するために、B6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスに、日齢60日で開始して3ヶ月間、直接脳室内脳内注入によりNI−204.10D12抗体を慢性投与した。慢性204.10D12抗体治療は、SOD1トランスジェニックマウスの寿命を11日まで有意に延長し、平均生存時間は、慢性NI−204.10D12注入を受けたマウスでは164±3日であり、これに対してビヒクル処置群では153±4日であった(p<0.05;図10(A))。さらに、B6.Cg−Tg(SOD1*G93A)1Gur/Jトランスジェニックマウスの慢性NI−204.10D12治療は、PBS治療対照群と比較して、全疾病経過を通して体重減少の有意な遅延をもたらした(図10(B))。SOD1トランスジェニックマウスにおいて疾病進行中に観察された重度進行性運動障害は、ビヒクル対照と比較して抗体治療群での握力動作改善によって明らかであるように、NI−204.10D12治療によって改善された(図11)。腰部脊髄側腹角における運動ニューロンの補足の定量分析は、ビヒクル治療マウスと比較してNI−204.10D12で治療したマウスにおける運動ニューロン減少の有意な減弱を明示した。これは、NI−204.10D12治療が突然変異体SOD−1過発現によって媒介される運動ニューロンの変性から保護できることを示唆している(図12)。これらの発見は、慢性投与により疾病発症を遅延することができ、生存を延長することができ、体重および運動動作を向上させることができ、ならびに神経変性を改善することができる、ヒト由来SOD1特異的抗体の絶大な治療効果を強調する。したがって、ヒト由来SOD1特異的抗体は、ALSの治療のための有望な新規候補薬である。
異なるヒトSOD1特異的抗体の可変領域の配列分析により、NI−204抗体を生殖細胞系IgGファミリーに分類することができる(表V)。
Claims (16)
- 記憶B細胞由来ヒトモノクローナル抗SOD1抗体であって、ミスフォールドまたは凝集SOD1に結合できることを特徴とし、生理的SOD1二量体よりミスフォールドもしくは凝集SOD1を優先的に認識する、または生理的SOD1二量体を認識せず、それ自体又はそのSOD1結合フラグメントが、以下の(a)又は(b)を含む抗体:
(a)(i)VHCDR1:配列番号60の位置31−35,
VHCDR2:配列番号60の位置50−66,
VHCDR3:配列番号60の位置99−115,
VKCDR1:配列番号61の位置24−38,
VKCDR2:配列番号61の位置54−60,
VKCDR3:配列番号61の位置93−101;
(ii)VHCDR1:配列番号62の位置31−35,
VHCDR2:配列番号62の位置50−66,
VHCDR3:配列番号62の位置99−112,
VLCDR1:配列番号63の位置23−33,
VLCDR2:配列番号63の位置49−55,
VLCDR3:配列番号63の位置88−97;
(v)VHCDR1:配列番号68の位置31−35,
VHCDR2:配列番号68の位置50−68,
VHCDR3:配列番号68の位置101−116,
VLCDR1:配列番号69の位置24−34,
VLCDR2:配列番号69の位置50−56,
VLCDR3:配列番号69の位置89−97;
(vi)VHCDR1:配列番号70の位置31−35,
VHCDR2:配列番号70の位置50−66,
VHCDR3:配列番号70の位置99−113,
VLCDR1:配列番号71の位置24−34,
VLCDR2:配列番号71の位置50−56,
VLCDR3:配列番号71の位置89−97;
(vii)VHCDR1:配列番号72の位置31−35,
VHCDR2:配列番号72の位置50−65,
VHCDR3:配列番号72の位置98−111,
VLCDR1:配列番号73の位置23−33,
VLCDR2:配列番号73の位置49−55,
VLCDR3:配列番号73の位置88−98;
(viii)VHCDR1:配列番号74の位置31−35,
VHCDR2:配列番号74の位置50−66,
VHCDR3:配列番号74の位置99−110,
VLCDR1:配列番号75の位置23−33,
VLCDR2:配列番号75の位置49−55,
VLCDR3:配列番号75の位置88−97;
(ix)VHCDR1:配列番号76の位置31−35,
VHCDR2:配列番号76の位置50−66,
VHCDR3:配列番号76の位置99−119,
VLCDR1:配列番号77の位置23−33,
VLCDR2:配列番号77の位置49−55,
VLCDR3:配列番号77の位置88−98;
(x)VHCDR1:配列番号78の位置31−35,
VHCDR2:配列番号78の位置50−66,
VHCDR3:配列番号78の位置99−103,
VLCDR1:配列番号79の位置23−33,
VLCDR2:配列番号79の位置49−55,
VLCDR3:配列番号79の位置88−97;
(xi)VHCDR1:配列番号80の位置31−35,
VHCDR2:配列番号80の位置50−68,
VHCDR3:配列番号80の位置101−111,
VLCDR1:配列番号81の位置23−33,
VLCDR2:配列番号81の位置49−55,
VLCDR3:配列番号81の位置88−98;及び
(xii)VHCDR1:配列番号82の位置31−35,
VHCDR2:配列番号82の位置50−65,
VHCDR3:配列番号82の位置98−108,
VLCDR1:配列番号83の位置23−35,
VLCDR2:配列番号83の位置51−57,
VLCDR3:配列番号83の位置90−100;
から選択される、VH及びVK/VL領域の相補性決定領域(CDR)(但し、その可変領域内に含まれる)、
(b)(i)配列番号60及び配列番号61,
(ii)配列番号62及び配列番号63,
(v)配列番号68及び配列番号69,
(vi)配列番号70及び配列番号71,
(vii)配列番号72及び配列番号73,
(viii)配列番号74及び配列番号75,
(ix)配列番号76及び配列番号77,
(x)配列番号78及び配列番号79,
(xi)配列番号80及び配列番号81,及び
(xii)配列番号82及び配列番号83;
から選択されるVH及びVK/VLのアミノ酸配列。 - ヒト野生型およびマウスSOD1に結合する、請求項1に記載の抗体。
- 一本鎖Fvフラグメント(scFv)、F(ab’)フラグメント、F(ab)フラグメントおよびF(ab’)2フラグメントから成る群より選択される、請求項1又は2に記載の抗体。
- 請求項1から3のいずれか一項に記載の抗体をコードするポリヌクレオチド。
- 請求項4に記載のポリヌクレオチドを含むベクター。
- 請求項4に記載のポリヌクレオチドまたは請求項5に記載のベクターを含む宿主細胞。
- (i)検出可能に標識されており;ならびに/または
(ii)薬物に付けられている、
請求項1から3のいずれか一項に記載の抗体。 - 検出可能標識が、酵素、放射性同位体、蛍光体および重金属から成る群より選択される、請求項7に記載の抗体。
- 請求項1から3、7もしくは8のいずれか一項に記載の抗体、請求項4に記載のポリヌクレオチド、請求項5に記載のベクターまたは請求項6に記載の細胞を含む組成物であって、
(i)医薬組成物であり、および医薬的に許容される担体をさらに含む、または
(ii)診断用組成物であり、免疫または核酸ベースの診断方法に従来使用されている試薬を含む、
組成物。 - 筋萎縮性側索硬化症の治療に有用な追加の薬剤をさらに含む、請求項9に記載の医薬組成物。
- 被験体における筋萎縮性側索硬化症の予防的もしくは治療的処置に使用するための、または筋萎縮性側索硬化症の進行もしくは筋萎縮性側索硬化症の処置に対する反応のモニタリングに使用するための、請求項1から3、7もしくは8のいずれか一項に記載の抗体、請求項4に記載のポリヌクレオチド、請求項5に記載のベクターあるいは請求項6に記載の細胞。
- 被験体における筋萎縮性側索硬化症の進行をモニターする方法であって、モニターすべき被験体からのサンプル中のミスフォールドまたは凝集SOD1の存在を、請求項1から3、7または8のいずれか一項に記載の少なくとも1つの抗体を用いて判定することを含み、生理的SOD1二量体のレベルと比較してミスフォールドまたは凝集SOD1のレベルの増加が、該被験体における筋萎縮性側索硬化症の進行の指標となる方法。
- ヒトまたは動物体内のSOD1の体内検出もしくは画像診断、または該SOD1への治療薬および/もしくは診断薬の標的化に使用するための、請求項1から3、7または8のいずれか一項に記載の抗体。
- 体内画像診断が、陽電子放射断層撮影(PET)、単一光子放射断層撮影(SPECT)、近赤外(NIR)光イメージングまたは磁気共鳴画像診断(MRI)を含む、請求項13に記載の抗体。
- 筋萎縮性側索硬化症の進行の診断またはモニタリングに有用なキットであって、請求項1から3、7もしくは8のいずれか一項に記載の抗体、請求項4に記載のポリヌクレオチド、請求項5に記載のベクター、あるいは請求項6に記載の細胞、を含むキット。
- 試薬および/または使用説明を含む、請求項15に記載のキット。
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PCT/EP2011/073303 WO2012080518A1 (en) | 2010-12-17 | 2011-12-19 | Human anti-sod1 antibodies |
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