JP2014155497A - 天然IgM抗体およびその阻害剤 - Google Patents
天然IgM抗体およびその阻害剤 Download PDFInfo
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Abstract
【解決手段】特定の配列を有するペプチド、前記ペプチドをコードする核酸、前記核酸を含むベクターおよび宿主細胞ならびに前記ペプチドを含む組成物であって、前記ペプチドは、単離されたもしくは修飾されたIgMに対して特異的結合部分を有し、それにより抗原および/または補体活性化への結合をブロックするIgM阻害剤となる。
【選択図】なし
Description
本発明は、National Institutes of Healthからの援助金番号GM52585、GM24891、およびGM07560の下で政府の支援によりなされた。政府は本発明においてある種の権利を有する。
本出願は、2004年7月16日に出願された米国仮出願第60/588,648号、および2004年3月1日に出願された米国仮出願第60/549,123号の恩典を主張し、各仮出願内容は具体的に参照として本明細書に組み入れられる。
有核細胞は低酸素症に対して高度に感受性であって、多細胞生物における虚血の短い期間でさえ細胞形態、遺伝子転写、および酵素プロセスに対して劇的な効果を有し得る。酸素代謝の主な部位としてのミトコンドリアは酸素レベルの変化に対して特に感受性であって、低酸素症の間には、脂質およびタンパク質のような細胞内構成要素を化学的に修飾する反応性酸素種を放出する。臨床的には、これらの効果は患者において炎症応答として発現される。低酸素症に対する細胞の応答の広範な調査にもかかわらず、急性炎症の開始についてはほとんど知られていない。
1つの局面において、本発明は単離された天然免疫グロブリン(IgM)を特徴とする。1つの態様において、該抗体はATCC受託番号PTA-3507によって生産される。もう1つの態様において、該抗体はSEQ ID NO:8として示されるアミノ酸配列を含む軽鎖可変領域を有する。なおもう1つの態様において、該抗体はSEQ ID NO:2として示されるアミノ酸配列を含む重鎖可変領域を有する。
を含む。ある阻害性ペプチドはSEQ ID NO:16、18、20、22、24、26、28、30、32、34、36および38として提供される。阻害性ペプチドは、例えば、インビボ半減期または生物学的利用性を増加させるように修飾することができる。阻害性ペプチドは検出を容易とするように標識することもできる。
6.1 定義
便宜上、明細書、実施例、および添付の請求の範囲で使用されるある種の用語を提供する。特記しない限り、本明細書において用いる全ての技術および科学用語は、本発明が属する当業者によって通常理解されるのと同一の意味を有する。
本発明は、部分的には、天然免疫グロブリン(Ig)、特に天然IgMの同定に基づく。あるIgMは、American Type Culture Collectionに寄託され、受託番号PTA-3507が与えられたハイブリドーマから得ることができる。
6.3.1 天然IgM抗体のペプチド阻害剤
本発明は、さらに、IgM阻害剤を特徴とする。1つの態様において、IgM阻害剤は、天然IgMに特異的に結合し、それにより、抗原に対する結合をブロックするペプチドである。そのようなペプチドは、限定されるものではないが、以下の表1に記載されたアスパラギン-リッチなペプチドを含むことができる。
本発明は、前記したペプチドをコードする核酸も特徴とする。例示的な核酸は表3に提供する。
ペプチド阻害剤は、例えば、化学的に、無細胞系にてリボソームにより、細胞内でリボソームにより合成することができる。本発明のペプチドの化学合成は、段階的固相合成、ペプチド断片の立体配座援助再連結を介する半合成、クローン化されたまたは合成ペプチドセグメントの酵素連結、および化学的連結を含む種々の当技術分野において認められた方法を用いて行われることができる。Merrifield et al.in J.Am.Chem.Soc.,Volume 85,page 2149(1964)、Houghten et al.in Proc.Natl.Acad.Sci.USA,Volume 82,page 5132(1985)、およびStewart and Young in Solid Phase Peptide Synthesis, Pierce Chem.Co,Rockford,III.(1984)。天然の化学的連結は、一過性チオエステル連結中間体を生じさせるために、2つの未保護ペプチドセグメントの化学選択的反応を使用する。次いで、一過的チオエステル連結中間体は自然発生的に再編成を受けて、連結部位において天然ペプチド結合を有する全長連結産物を得る。全長連結産物は無細胞合成によって生じたタンパク質と化学的に同一である。全長連結産物は、許容されれば、再度折り畳まれ、および/または酸化されて、天然ジスルフィド含有タンパク質分子を形成することができる(例えば、米国特許第6,184,344号および第6,174,530号;およびT.W.Muir et al.,Curr.Opin.Biotech.(1993):vol.4,p. 420;M.Miller, et al.,Science (1989):vol.246,p1149;A.Wlodawer,et al.,Science (1989):vol.245,p.616;L.H.Huang,et al.,Biochemistry (1991):vol.30,p. 7402;M.Schnolzer.,et al.,Int.J.Pept.Prot.Res.(1992):vol.40,p. 180-193;K.Rajarathnam, et al.,Science (1994):vol.264,p.90;R.E.Offord,「Chemical Approaches to Protein Engineering」, in Protein Design and the Development of New Therapeutics and Vaccines, J.B.Hook, G.Poste eds.,(Plenum Press, New York, 1990)pp.253-282;C.J.A.Wallace,et al.,J.Biol.Chem.(1992);vol.267,p. 3852;L.Abrahmsen,et al.,Biochemistry(1991):vol.30,p 4151;T.K.Chang,et al.,Proc.Natl.Acad.Sci.USA(1994)91:12544-12548;M.Schnlzer,et al.,Science (1992):vol.,3256,p 221;およびK.Akaji, et al.,Chem.Pharm.Bull.(Tokyo)(1985)33:184参照)。
IgM阻害剤は、抗原に結合する天然IgMと競合する抗体でもあり得る。抗体を生産する方法は当技術分野において周知である。例えば、標的(例えば、細胞上の病原性免疫グロブリンまたは虚血特異性抗原)に対するモノクローナル抗体は、慣用的モノクローナル抗体技術、例えば、Kohler and Milstein,Nature 256:495(1975)の標準的体細胞ハイブリダイゼーション技術を含む種々の技術によって生産することができる。体細胞ハイブリダイゼーション手法は好ましいが、原理的には、モノクローナル抗体を生産するための他の技術、例えば、Bリンパ球のウイルスまたは癌遺伝子形質転換を使用することができる。ハイブリドーマを調製するための好ましい動物系はネズミ系である。マウスにおけるハイブリドーマ生産は非常によく確立された手法である。融合用の免疫化脾臓細胞の単離のための免疫化プロトコルおよび技術は当技術分野において公知である。融合パートナー(例えば、ネズミ骨髄細胞)および融合手法も公知である。
また、本発明は、天然免疫グロブリン、例えば、非野生型活性を有する病原免疫グロブリン、例えば、天然に生じる病原免疫グロブリンのアンタゴニスト、アゴニスト、またはスーパーアゴニストを作成する方法を特徴とする。該方法は、例えば、非保存的領域の一つまたは複数の残基、本明細書において開示されたドメインまたは残基の置換または欠失によって、天然免疫グロブリンの配列を改変し、次いで、所望の活性につき改変されたポリペプチドをテストすることを含む。
天然IgM抗体および抗原または補体経路の補体の間の相互作用の他の阻害剤は、(i)天然IgM抗体および抗原または補体経路の補体の結合が起こるのを可能とする条件下で、天然IgM抗体および抗原または補体経路の補体を含む反応混合物を提供し;(ii)天然IgM抗体および抗原または補体経路の補体を一つまたは複数のテスト化合物(例えば、コンビナトリアルライブラリーのメンバー)と接触させ;次いで、(iii)テスト化合物の非存在下で検出されたのに対する所与のテスト化合物の存在下における天然IgM抗体および抗原または補体経路の補体の結合のいずれかの変化を検出することを含む、一つまたは複数の(例えば、複数の)テスト化合物から同定することができる。テスト化合物の非存在下で検出されたものに対するテスト化合物の存在下における天然IgM抗体および抗原または補体経路の補体の間の結合のレベルの変化(例えば、減少)は、テスト化合物が、天然IgM抗体および抗原または補体経路の補体の間の相互作用の阻害剤であることを示す。
IgM阻害剤を修飾して、例えば、溶解性を増大させ、および/または精製、同定、検出および/または構造的特徴付けを容易とすることができる。例示的な修飾は、例えば、グルタチオンS-トランスフェラーゼ(GST)、プロテインA、プロテインG、カルモジュリン結合ペプチド、チオレドキシン、マルトース結合タンパク質、HA、myc、ポリ-アルギニン、ポリ-His、ポリ-His-AspまたはFLAG融合タンパク質およびタグの付加を含む。種々の態様において、IgM阻害剤は一つまたは複数の異種融合を含むことができる。例えば、ペプチドは同一融合ドメインの複数コピーを含有することができるか、あるいは2以上の異なるドメインに対する融合を含むことができる。該融合はペプチドのN末端において、該ペプチドのC末端において、あるいは該ペプチドのNおよびC末端の双方において起こることができる。また、リンカー配列を本発明のペプチドおよび融合ドメインの間に含めて、融合タンパク質の構築を容易とし、あるいはタンパク質発現、または融合タンパク質の構造的拘束を最適化するのは本発明の範囲内のものである。もう1つの態様において、ペプチドは、融合ペプチドおよび本発明のペプチドの間にプロテアーゼ切断部位を含有して、タンパク質発現の後に、またはその後にタグを除去するように構築することができる。適当なエンドプロテアーゼの例は、例えば、Xa因子およびTEVプロテアーゼを含む。
天然IgM抗体結合ペプチドまたは修飾された天然IgM抗体のようなIgM阻害剤は、天然IgM抗体の結合によってトリガーされる多数の炎症性疾患および疾患を治療するのに用いることができる。例えば、阻害剤を用いて、再灌流障害、虚血障害、発作、自己免疫溶血性貧血、特発性血小板減少症紫斑病、慢性関節リウマチ、腹腔病、過剰-IgM免疫不全症、動脈硬化症、冠動脈病、敗血症、心筋炎、脳炎、移植拒絶、肝炎、甲状腺炎(例えば、橋本甲状腺炎、グラーベ病)、骨粗鬆症、多発性筋炎、皮膚筋炎、I型糖尿病、痛風、皮膚炎、円形脱毛症、全身エリテマトーデス、苔癬硬化症、潰瘍性大腸炎、糖尿病性網膜症、胎盤炎症性疾患、歯周疾患、動脈炎、若年性慢性関節炎(例えば、慢性虹彩毛様体炎)、乾癬、骨粗鬆症、真性糖尿病における腎臓障害、喘息、胎盤炎症性疾患、慢性炎症肝臓病、慢性炎症肺病、肺線維症、肝臓線維症、慢性関節リウマチ、慢性炎症肝臓病、慢性炎症肺病、肺線維症、肝臓線維症、クローン病、潰瘍性大腸炎、火傷障害(または熱障害)、および中枢神経系(CNS;例えば、多発性硬化症)、胃腸系、皮膚および関連構造、免疫系、肝臓-胆嚢系、または病理が炎症成分で起こり得る身体中のいずれかの部位の他の急性および慢性炎症性疾患のような炎症性疾患または障害を治療することができる。
本発明は、さらに、生物学的試料中の天然IgM抗体の存在を検出する方法を提供する。対象、特に哺乳動物、特別にはヒトにおける天然IgM抗体の検出は、対象における炎症性疾患または障害の診断のための診断方法を提供するであろう。一般には、該方法は、生物学的試料を、試料中の本発明の天然IgM抗体または本発明の核酸を検出することができる化合物または剤と接触させることを含む。用語「生物学的試料」は、診断アッセイに言及して用いる場合、対象から単離された組織、細胞および生物学的流体、ならびに対象内に存在する組織、細胞および流体を含めることを意図する。
を含む。
本実施例は、補体系が欠乏したマウスが虚血-再灌流障害に対して耐性であったことを示す。
本実施例は、免疫グロブリンが欠乏したマウスが虚血-再灌流障害に対して耐性であったことを示す。
循環IgMの大部分は天然抗体、すなわち、再編成された生殖系遺伝子の産物を表すと考えられるので、リンパ球のB-1画分の欠乏を担うマウスもまた保護される可能性がある。B-1細胞は、それらが低レベルのIgDおよびCD23を発現し、大部分が細胞表面タンパク質CD5を発現する点でより慣用的なB-2細胞とは区別される表現型を有する(Hardy et al.,(1994) Immunol.Rev.:137,91;Kantor et al.(1993) Annu.Rev.Immunol.11,501-538,1993)。B-1細胞は、マウスにおける低下した循環、末梢リンパ節および脾臓における制限された頻度によってやはり区別され、主として、腹腔内に主として局所化される。病原性IgMの源としてのB-1細胞についての役割を調べるために、抗体欠乏マウス(RAG-2-/-)を5×105腹腔B-1細胞で復元し、処理前ほぼ30日休息させた。循環IgMレベルは養子免疫伝達後1ヶ月以内に正常な範囲近くに到達する。腸虚血モデルにおけるB-1細胞復元マウスの特徴付けにより、B-1細胞は病原性IgMの主な源であったことが確認された(Williams et al.(1999)前記参照)。これは重要な観察であった。なぜならば、B-1細胞天然抗体のレパートリーは、慣用的B-2細胞について予測されるよりもかなり限定されているからである。従って、病原性抗体は生殖系の産物を表す可能性がある。
Cr2-/-ノックアウトマウスの初期特徴付けは、B-1aまたはCD5+B-1細胞の頻度のほぼ50%低下を明らかにした(Ahearn et al.(1996)Immunity 4:251-262)。Cr2-欠乏マウスのもう1つの株の特徴付けは同様な低下を同定しなかったが(Molina et al.(1996) Proc.Natl.Acad.Sci.(USA 93,3357-3361)。CD5+細胞の頻度の差が株のバックグラウンドまたは環境の差の変動によるか否かは公知ではない。Cr2-/-マウスにおけるB-1a細胞の低下した頻度にかかわらず、IgMの循環レベルは正常な範囲内にあった。これらの知見は、IgMのレパートリーがCr2-欠乏動物において異なることを示唆した。この仮説を検定するために、腸I/Rモデルにおけるマウスを特徴付けた。驚くべきことに、Cr2-/-マウスは補体-抗体欠乏マウスとして同等に保護された(図3)。腸モデルにおける処理後5日間の期間にわたる生存の比較は、Cr2-欠乏動物と比較したWTの死亡率の有意な増加を示した。増加した死亡率と合致して、障害の劇的な低下が、処理したWTまたはCr2-/-欠乏マウスから収穫された組織切片で観察された。
この実施例は、正常なB-1細胞からの特異的なハイブリドーマクローンの創製、および病原性IgMを精製する1つのクローンの同定を記載する。病原性IgMは、抗体欠乏マウスに対する障害をインビボで回復することが示された。
2つの異なるモデルがB-1細胞の発生を説明するために提唱されている。系列仮説は、B-1細胞が区別される集団として初期胎児生命で発生することを提唱する(Kantor et al.(1993)前記)。あるいは、B-1細胞は、慣用的B細胞として同一先祖から発生するが、それらの環境、すなわち、抗原との遭遇に応じて、それらはB-1に発生し、またはB-2細胞表現型を保有する(Wortis,H.H.(1992) Int.Rev.Immunol.8,235;Clarke,J.(1998) Exp.Med.187,1325-1334)。それらの起源にかかわらず、B-1細胞はB-2細胞と同一の頻度で成人骨髄から補充されず、およびそれらの表現型は初期胎児肝臓B細胞または新生骨髄(BM)細胞のそれとより同様であることが公知である。初期起源と合致して、それらのレパートリーはより近位のVH遺伝子の発現に偏る傾向があり、N-ヌクレオチドの付加は制限されている(Gu et al.(1990) EMBO J9,2133;Feeney J.(1990) Exp.Med.172,1377)。成人BM幹細胞による低下した補充を仮定すれば、B-1細胞は自己-更新され、抗原刺激はそれらの更新、拡大または初期選択においてさえ重要であろうことは合理的に見える(Hayakawa et al.,(1986) Eur.J.Immunol.16,1313)。事実、慣用的モデルに固有なことには、B-1細胞は抗原選択されなければならない。
ファージディスプレイペプチドライブラリーおよびペプチド合成
製造業者の推奨に従って、IgMCM-22で被覆したMBL-ビーズでの4ラウンドおよびIgMCM-75での2ラウンドによって、12-量体M-13ファージディスプレイライブラリー(New England Biolab,MA)をスクリーニングした。ファージクローンを豊富化されたプールから選択し、関連ファージ遺伝子のヌクレオチド配列を少なくとも10のクローンにつき決定した。選択されたペプチドはHarvard Proteomic CoreまたはNew England Peptide, Inc.(Gardner,MA)において95%を超える純度で合成した。
ELISAは以前に記載されているように行った(Zhang et al.(2004)PMAS USA 101:3886-91)。簡単に述べれば、96-ウェルプレートを飽和量の抗原でコーティングすることによって、ファージまたはファージ特異的ペプチドへのIgM結合を測定した。ブロッキングに引き続いて、IgMを37℃にて2時間加えた(1または10μg/ml)。プレートを洗浄し、次いで、アルカリ性ホスファターゼ標識ヤギ抗マウスIgM(Sigma,MO)で発色させた。特異的ウサギ抗体(NMHC-II A & B;Covance Research Products;NMHC-II C、Adelstein博士からの贈物、NHLBI、NIH、Bethesda,MD)またはpan-ミオシンHc(Sigma,MO)で予め被覆された96-ウェルプレートを、記載されたように(Zhang et al.(2004) PNAS USA 101:3886-91)虚血に対して偽処置または処置されたIgMCM-22復元RAG-1-/-マウスから調製された腸溶解物と共に培養することによって、IgMのNMHC-IIへの結合を測定した。溶解物は免疫沈澱について記載されたように調製された(後記参照)。次いで、アルカリ性ホスファターゼ標識ヤギ抗マウスIgM(Sigma,MO)を用いて結合したIgMを検出した。
RIについての外科的プロトコルは従前に記載されているように行った(Zhang et al.(2004)PNAS USA 101:3886-91)。簡単に述べれば、側腹切開を行い、ミクロクリップ(125g圧力、Roboz、MD)を、空腸の20cmセグメントを近接挟絹縫合で制限した上腸間動脈および両側循環に適用した。虚血の40分後、ミクロクリップを取り外し、腸間血管系の再灌流を、血管弧への拍動の復帰およびピンク色への変化によって確認した。切開を閉じ、全ての動物を3時間温かく保った。復元されたRAG-1-/-動物は、初期側腹切開30分前に、ペプチドと混合したIgMまたは0.2ml容量中の生理食塩水いずれかを静脈内に受けた。再灌流に5分先立って、WT動物を生理食塩水またはペプチドで静脈内処理した。再灌流の最後に、空腸の虚血セグメントを収穫し、中央の4cmを病理学的分析のために切断した。
腸組織の低温槽セクションをヘマトキシリンおよびエオシン(H&E)によって染色し、粘膜損傷について光学顕微鏡によって観察した。記載された空腸の4cmストレッチにわたって全ての微細絨毛の直接的観察を含んだChiuによる手法(Chiu et al.,Arch Surg 101:484-488,1970;Chiu,et al., Arch Surg 101:478-483,1970)に基づいて、病理学スコアを評価した。Zhang et al.(2004) PNAS USA 101:3886-91。免疫蛍光では、4%(w/v)パラホルムアルデヒドで固定した低温セクションを、ビオチン標識抗マウスIgM(Becton Dickinson,CA)と共に種々の時間インキュベートし、続いて、ストレプトアビジン-Alexa-568(1:500希釈, Molecular Probes,OR)と共に1時間インキュベートした。FITC標識ウサギ抗huC4c(DAKO,CO)、続いて、抗ウサギ-Alexa488(Molecular Probes,OR)で染色することによってC4沈積を検出した。抗C4c染色の特異性は、ビオチン標識抗マウスC4で1時間、続いて、ストレプトアビジン-FITC(Becton Dickinson,CA)で系列的セクションを染色することによって確認した。C3沈積は、FITC標識抗C3(DAKO,CO)で処理することによって検出した。セクションは、DAPI(Molecular Probes,OR)と共にAnti-fade Mounting Mediumに設置した。
記載されたように、33,400応答単位(RU)〜33ng/mm2の密度におけるBiaCore SPR CM5(商標)
チップフローセルでのアミンカップリングによって、IgM(IgMCM-22またはIgMCM-31)抗体を固定化した。Vorup-Jensen et al, PNAS USA 100: 1873-1878, 2003。簡単に述べれば、参照フローセルを、エタノールアミン-HClのカップリングによって調製した。PBS泳動緩衝液中に希釈したペプチドを、25℃にて10μl/分の速度で、かつ10Hzのデータ収集速度にて、IgM-カップルド表面および参照上を別々に流動させた。注射相は240秒の持続を有した(注射相の最後は、図9A、BおよびDにおける矢印の頭によってマークする)。結合等温線は、IgM-カップルド表面の応答から参照細胞における応答を差し引くことによって導いた。各泳動に続き、40μlの0.05%(v/v)ポリオキシエチレンソルビタンモノラウレート/PBSを注入することによって、表面を再生した。
洗剤および酵素阻害剤のカクテルを含有する溶解緩衝液中で、凍結した組織をホモゲナイズした。溶解物の試料を全タンパク質含有量(Bio-Radキット)につき分析して、分析用のタンパク質の同様なレベルを確認する。溶解物を、ラット抗マウスIgMでコートしたセファロースビーズと4℃にて1時間混合する。引き続いて、ビーズを温和にペレット化し、溶解緩衝液中で洗浄し、次いで、減圧条件下でSDS-試料緩衝液中で沸騰させて、結合した複合体を溶出させた。試料を6%(w/v)ポリアクリルアミドSDSゲルで分画し、引き続いて、固定し、次いで、クーマシーブルーまたは銀染色にて染色して、タンパク質のバンドを同定した。
個々のクーマシーブルー-染色バンドをSDS-ゲルから切り出し、脱染色し、従前に記載されているように酵素消化に供した。Borodovsky et al.,Chem Biol 9:1149-1159,2002。ナノフロー流体カップルドクロマトグラフィーシステム(Waters Cap LC)を用いてペプチドを分離し、タンデム質量分析計(Q-TOF micro,Waters,MA)によってアミノ酸配列を決定した。MS/MSデータを処理し、Swissprot,TREMBL/NewまたはNCBY非冗長データベースに対するMascot(Matrixscience)を用いるデータベースサーチに供した。
本発明者らは、腸RIモデルにおいて虚血組織に結合する天然IgM抗体(IgMCM-22)のハイブリドーマクローンを従前に同定し、これは、虚血組織が正常な組織に対して変化し、および虚血の間に発現されたneo-エピトープは自己に対する先天性応答についての標的であったという本発明者らの仮説を支持する。病原性IgMCM-22によって結合されたリガンドを特徴付けるために、ランダムな12-量体アミノ酸配列のM-13ファージ-ディスプレイライブラリーを、特異的IgMでコートしたビーズを用いてスクリーニングした。
従前の実験は、RAG-1-/-マウスにおける腸RIはIgM-依存性であり、IgMCM-22単独は障害を回復させるのに十分であったことを示した。予測されるように、再灌流に先立っての生理食塩水ではなくIgMCM-22でのRAG-1-/-マウスの復元の結果、RIがもたらされた(図7A(i)および図7B)。対照的に、虚血マウスにおける注射に先立ってのIgMCM-22とP8との混合は見掛けの障害を有意にブロックした(平均病理学的スコア6±3対31±13;p<0.001)(図7Aiiおよび図7B)。IgMCM-22でのペプチドの以前の力価測定は、10μMのP8の最適濃度が50〜100μgのIgMCM-22をブロックするのに十分であったことを示唆した(0.1〜0.2μM)。
P8のアミノ酸配列を用い、ゲノムデータベースの相同性サーチは正確なマッチを明らかにしなかった。従って、免疫-沈殿アプローチを用いて、IgMCM-22で復元したRAG-1-/-マウスにおける虚血抗原/複数抗原を同定した。
N2の病原性IgMとの機能的結合を検定するために、ほぼ100ナノモルのペプチド(または生理食塩水)を、RAG-1-/-マウスの復元およびRIモデルでの処理に先立ってIgMCM-22と混合した。IgMCM-22-および生理食塩水-処理マウスの再灌流された空腸から調製された組織セクションの組織学の分析は、予測されたように、障害およびIgMおよび補体の沈積を同定した(図5Aiおよび5B)。対照的に、再灌流に先立ってのN2ペプチドとIgMCM-22との混合は障害から保護的であった(平均病理学的スコア13±8対31±10;p<0.049)(図10Aiiおよび10B)。加えて、IgMCM-22をRAG-1-/-マウスでの注射に先立ってN2ペプチドと混合した場合、IgMおよび補体の沈積は再灌流した空腸で観察されなかった(図10Ci-viii)。従って、合成ペプチドP8で観察されたように、自己ペプチドN2はインビボにてIgMCM-22の機能的結合をブロックした。
本明細書において言及した全ての刊行物、特許および特許出願は、参照により本明細書に、あたかも各個々の刊行物または特許が参照により具体的かつ個々に一体化されることを示すようにその全体が組み入れられる。コンフリクトする場合、本明細書中のいずれの定義も含む本出願が支配する。
当業者であれば、せいぜいルーチン的実験を用いて、本明細書において記載された発明の特定の態様に対する多くの同等物を認識し、それを確認することができるであろう。そのような同等物は特許請求の範囲に含まれることを意図する。
Claims (47)
- SEQ ID NO:14を含むペプチドをコードする単離された核酸。
- 核酸がSEQ ID NO:13である請求項1記載の単離された核酸。
- SEQ ID NO:16、18、20、22、24、26、28、30、または32を含むペプチドをコードする単離された核酸。
- 核酸がSEQ ID NO:15、17、19、21、23、25、27、29、または31である、請求項3記載の単離された核酸。
- ペプチドがSEQ ID NO:30を含む請求項3記載の単離された核酸。
- 核酸がSEQ ID NO:29である請求項4記載の単離された核酸。
- SEQ ID NO:48、50、52、54、56、58、または60の天然IgM抗体結合部分を含むペプチドをコードする単離された核酸。
- SEQ ID NO:36または38を含むペプチドをコードする単離された核酸。
- ペプチドがSEQ ID NO:38を含む請求項8記載の単離された核酸。
- プロモーターに操作可能に連結された、請求項1、3、7、または8記載の単離された核酸。
- 請求項10記載の核酸を含むベクター。
- 請求項11記載のベクターを含む宿主細胞。
- SEQ ID NO:14のアミノ酸配列を有するペプチドを含む組成物。
- SEQ ID NO:16、18、20、22、24、26、28、30、または32のアミノ酸配列を有するペプチドを含む組成物。
- ペプチドがSEQ ID NO:30を含む請求項14記載の組成物。
- SEQ ID NO:36または38のアミノ酸配列を有するペプチドを含む組成物。
- ペプチドがSEQ ID NO:38を含む請求項16記載の組成物。
- ペプチドがペグ化された請求項13、14、または16記載の組成物。
- ペプチドが検出可能な標識で標識された、請求項13、14、または16記載の組成物。
- 請求項13、14、または16記載の組成物を対象に投与する段階を含む、炎症性疾患または障害を治療する方法。
- 炎症性疾患または障害が再灌流障害である請求項20記載の方法。
- 対象が哺乳動物である請求項20記載の方法。
- 哺乳動物がヒトである請求項20記載の方法。
- a)SEQ ID NO:1、SEQ ID NO:3、またはSEQ ID NO:5のヌクレオチド配列に対して少なくとも96%同一であるヌクレオチド配列を含む核酸分子;
b)SEQ ID NO:1、SEQ ID NO:3、またはSEQ ID NO:5のヌクレオチド配列を含む核酸分子;または
c)ストリンジェントな条件下でSEQ ID NO:1のヌクレオチド配列にハイブリダイズする核酸分子
からなる群より選択される、単離された核酸分子。 - SEQ ID NO:2、SEQ ID NO:4、またはSEQ ID NO:6のアミノ酸配列を含むポリペプチドをコードする単離された核酸分子。
- 請求項24記載の核酸を含むベクター。
- 請求項26記載の核酸を含む細胞。
- a)SEQ ID NO:7、SEQ ID NO:9、またはSEQ ID NO:11のヌクレオチド配列に対して少なくとも96%同一であるヌクレオチド配列を含む核酸分子;
b)SEQ ID NO:7、SEQ ID NO:9、またはSEQ ID NO:11のヌクレオチド配列を含む核酸分子;または
c)ストリンジェントな条件下でSEQ ID NO:7のヌクレオチド配列にハイブリダイズする核酸分子
からなる群より選択される、単離された核酸分子。 - SEQ ID NO:8、SEQ ID NO:10、またはSEQ ID NO:12のアミノ酸配列を含むポリペプチドをコードする単離された核酸分子。
- 請求項28記載の核酸を含むベクター。
- 請求項30記載の核酸を含む細胞。
- SEQ ID NO:2、SEQ ID NO:4、またはSEQ ID NO:6のアミノ酸配列を含む単離されたポリペプチド。
- SEQ ID NO:8、SEQ ID NO:10、またはSEQ ID NO:12のアミノ酸配列を含む単離されたポリペプチド。
- 以下の特性:
(i)虚血特異性抗原と相互作用できる;
(ii)補体を固定することができる;または、
(iii)B細胞の亜集団によって生産される
の一つもしくは複数を有する単離された天然免疫グロブリンまたはその抗原結合部分。 - IgMである請求項34記載の単離された天然免疫グロブリン。
- 免疫グロブリンがB-1細胞によって生産される、請求項34記載の単離された天然免疫グロブリン。
- ATCC寄託番号PTA-3507を有する細胞によって生産される請求項34記載の単離された天然免疫グロブリン。
- 免疫グロブリンが組換え抗体である請求項34記載の単離された天然免疫グロブリン。
- 虚血特異性抗原に結合する、請求項24記載の核酸配列を含む抗体。
- 虚血特異性抗原に結合する、請求項28記載の核酸配列を含む抗体。
- さらに、請求項28記載の核酸配列を含む請求項39記載の抗体。
- SEQ ID NO:2のポリペプチドをコードする核酸配列およびSEQ ID NO:8のポリペプチドをコードする核酸配列を含む、請求項41記載の抗体。
- 補体の結合または活性を改変する突然変異を有する修飾された天然免疫グロブリン。
- 虚血特異性抗原と相互作用できる請求項43記載の修飾された天然免疫グロブリン。
- IgMである請求項43記載の修飾された天然免疫グロブリン。
- IgGである請求項43記載の修飾された天然免疫グロブリン。
- 治療上有効量の請求項43記載の抗体および薬学的に許容される担体を含む組成物。
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JP5557982B2 (ja) | 2014-07-23 |
WO2005085288A3 (en) | 2006-08-03 |
DE602005026260D1 (de) | 2011-03-24 |
EP2290077A2 (en) | 2011-03-02 |
AU2005219839A1 (en) | 2005-09-15 |
IL177825A (en) | 2013-02-28 |
US9657060B2 (en) | 2017-05-23 |
US7442783B2 (en) | 2008-10-28 |
EP2290077A3 (en) | 2011-05-18 |
IL177825A0 (en) | 2006-12-31 |
US20090176966A1 (en) | 2009-07-09 |
JP2011139704A (ja) | 2011-07-21 |
US20050276811A1 (en) | 2005-12-15 |
AU2005219839B2 (en) | 2011-11-24 |
ATE498010T1 (de) | 2011-02-15 |
US20170342109A1 (en) | 2017-11-30 |
JP5618852B2 (ja) | 2014-11-05 |
EP1725659B1 (en) | 2011-02-09 |
WO2005085288A2 (en) | 2005-09-15 |
AU2005219839B9 (en) | 2011-12-22 |
US20160280740A1 (en) | 2016-09-29 |
JP2008504807A (ja) | 2008-02-21 |
HK1154904A1 (zh) | 2012-05-04 |
EP1725659A2 (en) | 2006-11-29 |
US9914751B2 (en) | 2018-03-13 |
US20140127214A1 (en) | 2014-05-08 |
EP2290077B1 (en) | 2016-01-27 |
CA2560066A1 (en) | 2005-09-15 |
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