JP2018522547A - Il−37バリアント - Google Patents
Il−37バリアント Download PDFInfo
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- JP2018522547A JP2018522547A JP2017565833A JP2017565833A JP2018522547A JP 2018522547 A JP2018522547 A JP 2018522547A JP 2017565833 A JP2017565833 A JP 2017565833A JP 2017565833 A JP2017565833 A JP 2017565833A JP 2018522547 A JP2018522547 A JP 2018522547A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Animal Behavior & Ethology (AREA)
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- General Chemical & Material Sciences (AREA)
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- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Epidemiology (AREA)
Abstract
【選択図】なし
Description
本出願は、オーストラリア仮出願第2015902262号及び同第2016900703号に基づく優先権を主張し、参照により両出願の内容全体が本明細書に組み込まれる。
本発明は、インターロイキン-37(IL-37)のバリアントを含むポリペプチド、並びにそれに関連する治療法及び組成物に関する。本発明はまた、炎症性疾患又は状態の治療方法におけるポリペプチド及び組成物の使用に関する。
炎症は、宿主防御及び免疫介在性疾患の進行において基本的な役割を果たす。炎症反応は、組織障害(例えば、外傷、虚血、及び異質粒子など)並びにケミカルメディエーター(例えば、サイトカイン及びプロスタグランジンなど)及び炎症細胞(例えば、白血球など)を含む、事象の複雑なカスケードによる感染、に応答して惹起される。炎症反応は、血流の増加、毛細血管透過性の増大、及び食細胞の流入によって特徴づけられる。これらの事象は、膨張、発赤、温感(ヒートパターンの変化)、及び外傷の部位における化膿をもたらす。
本発明は、IL-37単量体のアミノ酸配列を含む単量体抗炎症性ポリペプチドを提供し、該アミノ酸配列は、抗炎症性ペプチドがホモ二量体を形成することを防止する突然変異又は改変を有する。
配列番号1中の位置71における、又はそれと同等の位置におけるアミノ酸残基がValではなく;
配列番号1中の位置72における、又はそれと同等の位置におけるアミノ酸残基がLeuではなく;
配列番号1中の位置73における、又はそれと同等の位置におけるアミノ酸残基がAspではなく;
配列番号1中の位置74における、又はそれと同等の位置におけるアミノ酸残基がSerではなく;
配列番号1中の位置78における、又はそれと同等の位置におけるアミノ酸残基がIleではなく;
配列番号1中の位置80における、又はそれと同等の位置におけるアミノ酸残基がValではなく;
配列番号1中の位置83における、又はそれと同等の位置におけるアミノ酸残基がLysではなく;
配列番号1中の位置84における、又はそれと同等の位置におけるアミノ酸残基がAsnではなく;
配列番号1中の位置85における、又はそれと同等の位置におけるアミノ酸残基がTyrではなく;
配列番号1中の位置86における、又はそれと同等の位置におけるアミノ酸残基がIleではなく;
配列番号1中の位置87における、又はそれと同等の位置におけるアミノ酸残基がArgではなく;
配列番号1中の位置88における、又はそれと同等の位置におけるアミノ酸残基がProではなく;かつ/又は
配列番号1中の位置184における、又はそれと同等の位置におけるアミノ酸残基がAsnではない。好ましくは、アミノ酸残基は、配列番号1中のその位置に存在するアミノ酸に関して、非保存的置換である。1つの実施態様において、位置85におけるアミノ酸はアラニンであり、位置83におけるアミノ酸はグルタミン酸であり、位置73におけるアミノ酸はアラニンであり、かつ/又は位置73におけるアミノ酸はリジンである。1つの実施態様において、配列番号1中の位置71、72、73、74、78、80、83、84、85、86、87、88及び/又は184におけるアミノ酸残基、又はそれらと同等の位置におけるアミノ酸残基は欠失している。
炎症性疾患又は状態を有する対象を同定する工程;及び
治療有効量の本発明のポリペプチド又は医薬組成物の投与を、それを必要とする対象にし、
それによって対象における炎症性疾患又は状態を治療する工程。
炎症性疾患又は状態を有する対象を同定する工程;及び
治療有効量の本発明のポリペプチド又は医薬組成物の投与を、それを必要とする対象にし、
それによって対象における炎症性疾患又は状態を治療する工程。
本明細書中に開示され、記載された発明は、本文もしくは図面に記述されるか又は本文もしくは図面から明らかである2つ以上の個々の特徴の全ての代替の組み合わせにまで及ぶことが理解されるだろう。全てのこれらの異なる組み合わせは、本発明の種々の代替の局面を構成する。
1)アラニン(A)、セリン(S)、スレオニン(T);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リジン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);及び
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W)。
・ 虚血/再灌流傷害、心虚血、臓器移植後臓器機能障害(TLR 2);
・ 関節リウマチ(TLR 2);
・ 全身性エリテマトーデス(TLR7、8及び/又は9);
・ 敗血症(他のTLRのうち特にTLR 4);並びに
・ 急性及び慢性炎症(TLR 4)。
‐本発明のポリペプチド、ポリヌクレオチド又は医薬組成物を保持する容器;
‐使用のための指示が掲載された表示又は添付文書、を含む。
クローニング及びタンパク質精製
コドン最適化IL-37(46-218)を、pGEX-4T-1の改変タバコエッチ病ウイルスプロテアーゼ−切断可能バージョン(GE Healthcare)(7)内へとクローニングした。組換えタンパク質を、18℃でのIPTG誘導によって、BL21-CodonPlus(DE3)-RIL細胞(Stratagene)中で発現させた。GST-IL-37バリアントを発現する細胞を、2つの完全なEDTAフリープロテアーゼ阻害剤タブレット(Roche)で、20 mM Tris-HCl(pH 8.0)、500 mM NaCl、3 mM β-メルカプトエタノール中で、高圧キャヴィテーション(10〜15 K psi)によって溶解した。細胞を遠心分離によって浄化し、0.45 μmの膜を通して濾過し、グルタチオンSepharose 4B樹脂(GE Healthcare)に1時間、4℃で結合させた。樹脂を、500 mlの20 mM Tris-HCl(pH 8.0)、200 mM NaCl、及び3 mM β-メルカプトエタノールで洗浄した。タンパク質をHis-TEVプロテアーゼと一晩4℃でインキュベートすることによって、GST-タグから切り離した。タンパク質をさらに、HiLoad Superdex75 16/60 prep-gradeカラム(GE Healthcare)上で、20 mM Hepes(pH 7.2)、100 mM NaCl、2 mM DTT、及び1 mM EDTA中で精製した。
IL-37の結晶を、1:1のドロップ比(drop ratio)での2.1 M 硫酸アンモニウム及び0.1 M 酢酸ナトリウム(pH 4.5)中のハンギングドロップ蒸気拡散法によって、20℃で育成させた。結晶を、20 %(v/v)のグリセロールを含む母液中で、液体窒素中でフラッシュ冷却した。X線データを、Australian SynchrotronのMX2ビームライン(微小焦点)で、1°の振動で、0.9537Åの波長で収集した。データを、XDS及びCCP4スイート内の複数のプログラム(8)を使用して、処理及びスケーリングした。MRage and Phaserを使用して、PHENIXにおけるサーチモデルとしてマウスIL-F5(PDBコード1MD6(9))を使用し、分子置換によって構造を解析した(10, 11)。構造は、自動的にPHENIX AutoBuild内に構築された(11)。Buster (12)を使用して、精密化の反復サイクルを実行し、COOT(13)を用いて部分的に再構築し、18.22 %のR- 因子(21.74 %のRfree)及び優れた幾何学的形状を持つモデルを得た(表3)。構造は、Ramachandran外れ値を有さず、98.64 %の残基が好ましい領域にあり、MolProbityの最終スコアは0.95(100番目の百分位数)であった(14)。
SEC-MALS測定を、10 mM HEPES(pH 7.3)、100 mM NaCl、1 mM EDTA及び2 mM DTTで平衡化したSuperdex75 10/300カラム(GE Healthcare)上で実行した。全ての実験を、上記のバッファー中、25 ℃で、0.4 mL/分の流量で行った。各ランについて、110 μLの量のタンパク質を、6 mg/mLで注入した。2 mg/mlのウシ血清アルブミン(Thermo Scientific Pierce)の試験的注入を、較正の目的で使用した。SEC-MALSシステムは、Shimadzu DGU-20A5デガッサー、LC-20AD液体クロマトグラフ、SIL-20AHTオートサンプラー、CBM-20A通信バスモジュール、SPD-20A UV/VIS検出器及びCTO-20ACカラムオーブンから構成され、これはOptilab T-rEX屈折率検出器を備えたDAWN HELEO-II多角度光散乱検出器(Wyatt Technology)に連結されていた。モル質量を、18の異なる散乱角での散乱光の強度を測定することによって算出した。モル質量の算出は、Astra 6.1software(Wyatt Technology)を使用して行った。
PBMC実験は、Monash Healthヒト研究倫理委員会(Human Research Ethics Committee)Bによって承認され、明確な同意書を全てのボランティアから(form)得て実施した。PBMCを、記載されたように、健常なボランティアの末梢静脈血から、密度勾配遠心法によって単離した(15)。PBMCを、1% v/vヒト血清及び1:500 MycoZap PRを含有するRPMI培地に播種し、次にビヒクル又はrec IL-37のいずれかで示されるとおりに30分間、前処理し、次に50 pg/ml LPS、又は本明細書中に記載される濃度のHKLM、イミキモド、CpG-AもしくはssRNA40で、20時間刺激した。次に上清をサイトカイン解析に供した。THP-1細胞は、ATCCから調達された。それらは常に、抗生剤、抗真菌剤、及び抗マイクプラズマ剤を含有するMycoZap Plus-CL(Lonza)の存在下で培養した。
サイトカインを、従来のELISA(BD, elisakit.com)によって測定した。製造者によって推奨されるように、両方のELISA法を実施した。
データセット(生データ)を最初に、SigmaPlot 12.5(Systat Software Inc.)を使用して、正規性及び等分散性について検定した(棄却するためのP値 = 0.05)。その後、対応のない(unpaired)t-検定(両側, α=0.05)、Mann-Whitney順位和検定、一元配置ANOVA、又は順位に基づく一元配置ANOVAを含む適当な統計検定を適用した。
マウスにかかわる全ての手順は、Monash Health 動物倫理委員会(Animal Ethics Committee)によって承認されていた。C57Bl/6野生型マウスに、40 μg/kgの組換えIL-37バリアント又はビヒクルの腹腔内注射を行い、60分後にLPS(10 mg/kg)の腹腔内注射を行った。IL-37bについてトランスジェニックなホモ接合体マウス(1, 5)もまた、直接比較のためにLPS(10 mg/kg)又はビヒクルで処置した。室温及び湿度を継続的にモニターした。(1)に記載のように、体温を測定した。LPS注射の24時間後、マウスに麻酔をかけ、ヘパリン処置したチューブ中への眼窩出血によって血漿を取得した。
ヒトIL-1β(ベータ)ELISA: Cat#, 557953、ヒトIL-6 ELISA, Cat#: 555220、マウスIL-1β(ベータ)ELISA, Cat#: 559603(BD Biosciences, New Jersey, USA)、E.Coli由来のLPS 055:85, #L4005-100mg(Sigma, St Louis MO, USA)、CpG-A ODN 2216 Innaxon #INAX-200-005(Adipogen, Switzerland)、イミキモド VacciGrade #vac-img, HKLM #Tlrl-hklm,(Invivogen, San Diego, CA, USA)。
前駆体IL-37及び成熟IL-37は、溶液中でホモ二量体形成する
細菌から精製した前駆体IL-37(アイソフォームb、本明細書中ではIL-37という)のサイズ排除クロマトグラフィー(SEC)解析は、タンパク質が溶液中でホモ二量体を形成することを示した(図1A及び1B、左軸)。タンパク質がホモ二量体であることを確認するために、SECと組み合わされた多角度光散乱法(MALS)(図1B、右軸)を実行した。前駆体IL-37(残基1〜218)は、43.9 kDaの測定された分子量を有し、IL-37二量体の理論上の分子量である48 kDaと整合していた。これらのデータは、ヒトPBMCにおける二量体IL-37(〜45 kDa)を検出した以前の研究及び組換えIL-37の超遠心による以前の研究(1, 2)と相関する。図1Bにおいて、IL-37(1-218)は9.8 mlで溶出し、IL-37(21-218)は10 mlで溶出し、IL-37(46-218)は11 mlで溶出し、IL-18(37-193)は12.6 mlで溶出する。
IL-37二量体形成の分子的基盤を解明するために、成熟IL-37(残基46-218)をハンギングドロップ蒸気拡散法によって結晶化した。構造を、分子置換によって解析し、2.3Åの分解能で精密化したところ、それぞれ18.22%及び21.74%のRwork/Rfree及び優れた幾何学的形状となった(表3)。非対称ユニットは、ヘッドトゥヘッド型の対称なホモ二量体を形成するIL-37A及びIL-37Bと名付けられた2コピーのIL-37を含んでいる(図1C)。我々の知る限りでは、IL-37サブユニットの、対称なホモ二量体へのこの配置は、今まで解析されたIL-1ファミリーのサイトカインの構造の中で独特である。2つのサブユニットは、高度な構造相同性を有し、142のCα原子上で0.70Åの二乗平均平方根偏差を示す。IL-37Aが最も完全なサブユニットであり、残基48-207を含み、最終的なマップから残基126のみを欠いている。全体的に見て、IL-37Bは、より高いB-因子を有し、より不完全であり、残基49-206を含み、ループ領域から残基125-128、161、及び194-196を欠いている。βトレフォイルフォールドの二次構造は、Lys58にて開始し、N-末端残基48-57の大部分は構造をとらず、残基46-48は電子密度を欠く。成熟IL-37の2つの可能性のある切断部位は、残基21及び46と同定され、その構造に基づいて、それぞれは、切断後にIL-37のβトレフォイルフォールドを維持することと矛盾しない。
対称なヘッドトゥヘッドIL-37二量体界面は、合計487Å2の表面積を覆い隠し、各サブユニットのβ3-β4ループ及び3ストランドのβシート(β2-β3-β11)によって形成されている(図2A)。二量体界面は高度に組織化されているように見え、多数の鏡像的な相互作用が、各IL-37サブユニットのβ3-β4ループ間の中心に位置するC2対称軸を横断して形成されている。界面のコア内には、2つの主鎖水素結合が、各IL-37単量体からのTyr85とArg87との間で形成される(図2B)。各サブユニットの部分的に疎水性であるTyr85側鎖は、β2-β3-β11 βシートの表面に形成された疎水性ポケットに埋もれている。この界面の疎水性コアは、溶媒に曝されている縁において、Lys83とAsp73との間のイオン性相互作用によって遮蔽されている。水素結合はまた、各分子のIle86の主鎖カルボニル基とArg87の側鎖によっても形成されており、β3-β4ループの界面をさらに強化している(図2C)。
IL-37単量体形成の機能的な関わりを評価するために、2つのアプローチを使用した。最初に、新鮮なヒトPBMCを、非常に低濃度でも自発的に二量体形成する天然タンパク質(野生型)、及びアミノ酸73のDからKへの突然変異によってこの二量体形成が防止されるバリアント、を含む異なる組換え(rec)IL-37バリアントで処置した。これらの両方のバリアントを、アミノ酸21及び46でN末端切断して試験した。
内毒素ショックのIn vivoモデル
これらの知見に、in vivoの観点を追加するために、内毒素ショックのマウスモデルを利用した。C57Bl/6野生型マウスに、組換えIL-37バリアント(40μg/kg)又はビヒクルの腹腔内注射を行い、次いで腹腔内へのLPS注射を行った。直接比較のために、IL-37についてトランスジェニックなマウスもまた、LPS又はビヒクルで処置した。各IL-37バリアントが、内毒素ショックを改善した(低体温及び血漿IL-1βを減少させた、図7及び8)一方で、両方の単量体IL-37タンパク質の抗炎症活性は、それらの二量体natIL-37カウンターパートの抗炎症活性よりも大きかった。注目すべきことに、monoIL-37(46-218)によって提供された保護作用は、IL-37トランスジーンによって付与された保護作用とほぼ等しく強力であった。実際、monoIL-37(46-218)群における体温及び血漿IL-1βと、LPSを与えられなかったマウスにおける体温及び血漿IL-1βとの間の差は、極小であった。
位置85におけるチロシンからアラニンへの突然変異は、IL-37二量体界面を破壊するための(D73K突然変異に加えて)別のアプローチである。各サブユニットの位置85における部分的に疎水性のチロシン残基は、二量体界面によって形成される疎水性ポケット中に埋もれている。この残基をアラニンへと変異させることは、これらの相互作用を有意に減少させ、二量体界面を破壊する。したがって、recIL-37 Y85Aは、ホモ二量体を形成することができない。単量体IL-37が、二量体IL-37bよりも大きな生物学的活性を保有するという概念と一致して、recIL-37 Y85Aの抗炎症効果は、recIL-37 D73Kと比較して増加しており、特に、in vitroではTLR2アゴニストである加熱処理リステリア菌(heat-killed listeria monocytogenes)で刺激されたPBMCにおいて(HKLM、図9)、またin vivoではTLR4アゴニストであるLPSを注射されたマウスにおいて(図7)、天然recIL-37bと比較して、増加していた。しかしながら、TLR7及びTLR9のリガンドであるイミキモド及びCpG-Aでそれぞれ刺激されたPBMCにおいて、recIL-37 D73KとY85Aとの生物学的活性の間には小さな差しかなかった。
LPS以外のTLRアゴニストによって誘導される炎症に対するrecIL-37及び単量体バリアントの影響
IL-37は、広範囲の炎症性攻撃によって起こる炎症の強力な緩衝材として作用する。In vitroでは、発明者らは、LPSに加えて、そのような攻撃には、TLR1アゴニストPam3CSK4(Nold et al, Nat Immunol 2010中の図1)、IL-1β(Nold et al, Nat Immunol 2010中の図3及び4)、LPS+IL-12、TNF及びIL-12+IL-18(Nold et al, Nat Immunol 2010中の図7及びNold-Petry et al, Nat Immunol 2015中の図4)が含まれることを示してきた。そのうえ、IL-37は、多数の疾患の動物モデルにおいて防御効果を発揮する;内毒素ショックのモデルに加えて、これらにはDSS大腸炎、道化師様魚鱗癬、接触過敏症等が含まれる。
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Claims (35)
- IL-37ポリペプチドのアミノ酸配列を含む抗炎症性ポリペプチドであって、該アミノ酸配列が、抗炎症性ポリペプチドの二量体形成能を低下させる突然変異又は改変を有する、ポリペプチド。
- 前記突然変異が、IL-37単量体の二量体形成を可能とする二量体形成面をペプチドが形成することを防止する、請求項1に記載のポリペプチド。
- 前記突然変異が、IL-37単量体の二量体形成面を形成するアミノ酸配列と同一のアミノ酸配列を有するペプチドの領域中に位置する、請求項2に記載のポリペプチド。
- 前記突然変異が、IL-37単量体の二量体形成面を形成するβ3ループ又はβ4ループ中に位置する、請求項3に記載のポリペプチド。
- 前記アミノ酸配列が、配列番号1と少なくとも50%の同一性を有し、かつ前記突然変異又は改変が、配列番号1中の残基71〜74、78、80、83〜91及び184の任意の1以上におけるか、又はそれらと同等の残基におけるものである、請求項1〜4のいずれか1項に記載のポリペプチド。
- 前記突然変異又は改変が、配列番号1中の残基83〜91の領域内、又はそれらと同等の領域内に位置する、請求項5に記載のポリペプチド。
- 前記突然変異又は改変が、配列番号1中の位置D73、K83、N84、Y85、I86、R87又はP88における残基、又はそれらと同等の位置における残基において起こる、請求項5又は6に記載のポリペプチド。
- 配列番号1中の位置71における、もしくはそれと同等の位置におけるアミノ酸残基がValではなく;
配列番号1中の位置72における、もしくはそれと同等の位置におけるアミノ酸残基がLeuではなく;
配列番号1中の位置73における、もしくはそれと同等の位置におけるアミノ酸残基がAspではなく;
配列番号1中の位置74における、もしくはそれと同等の位置におけるアミノ酸残基がSerではなく;
配列番号1中の位置78における、もしくはそれと同等の位置におけるアミノ酸残基がIleではなく;
配列番号1中の位置80における、もしくはそれと同等の位置におけるアミノ酸残基がValではなく;
配列番号1中の位置83における、もしくはそれと同等の位置におけるアミノ酸残基がLysではなく;
配列番号1中の位置84における、もしくはそれと同等の位置におけるアミノ酸残基がAsnではなく;
配列番号1中の位置85における、もしくはそれと同等の位置におけるアミノ酸残基がTyrではなく;
配列番号1中の位置86における、もしくはそれと同等の位置におけるアミノ酸残基がIleではなく;
配列番号1中の位置87における、もしくはそれと同等の位置におけるアミノ酸残基がArgではなく;
配列番号1中の位置88における、もしくはそれと同等の位置におけるアミノ酸残基がProではなく;かつ/又は
配列番号1中の位置184における、もしくはそれと同等の位置におけるアミノ酸残基がAsnではない:
請求項5〜7のいずれか1項に記載のポリペプチド。 - 前記突然変異が、非保存的アミノ酸との置換である、請求項5〜8のいずれか1項に記載のポリペプチド。
- 前記突然変異が、アラニン又は反対電荷を持つアミノ酸との置換である、請求項5〜9のいずれか1項に記載のポリペプチド。
- 前記ポリペプチドが、配列番号1と少なくとも60%、70%、75%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%又は99%の配列同一性を有するアミノ酸配列を有する、請求項5〜10のいずれか1項に記載のポリペプチド。
- 前記突然変異が、D73A、D73K、K83E及びY85Aのうちの任意の1つ以上である、請求項5〜11のいずれか1項に記載のポリペプチド。
- 前記突然変異が、D73Aである、請求項5〜2のいずれか1項に記載のポリペプチド。
- 前記突然変異が、D73Kである、請求項5〜12のいずれか1項に記載のポリペプチド。
- 前記突然変異が、K83Eである、請求項5〜12のいずれか1項に記載のポリペプチド。
- 前記突然変異が、Y85Aである、請求項5〜12のいずれか1項に記載のポリペプチド。
- 配列番号1の残基83〜91の位置、又はそれらと同等の位置における1つ以上の残基が欠失している、請求項1〜8のいずれか1項に記載のポリペプチド。
- 前記ペプチドが、N末端トランケーションを有する、上記請求項のいずれか1項に記載のポリペプチド。
- 前記N末端トランケーションが、残基1〜25又は残基1〜45のものであるか、又はそれらと同等のものである、請求項18に記載のポリペプチド。
- 前記ポリペプチドが、炎症性サイトカインの産生又は機能を阻害する、上記請求項のいずれか1項に記載のポリペプチド。
- 前記ペプチドが、IL-1産生を減少させる、請求項20に記載のポリペプチド。
- 請求項1〜21のいずれか1項に記載のポリペプチドと、医薬上許容される希釈剤、賦形剤又は担体とを含む、炎症性疾患又は状態を治療又は予防するための医薬組成物。
- 炎症の抑制を、それを必要とする対象においてする方法であって、該方法が、対象に治療有効量の請求項1〜21のいずれか1項に記載のポリペプチド、又は請求項22に記載の医薬組成物を投与して、それによって炎症を抑制することを含む、方法。
- 炎症性疾患又は状態の治療又は予防を、それを必要とする対象においてする方法であって、該方法が、対象に治療有効量の請求項1〜21のいずれか1項に記載のポリペプチド、又は請求項22に記載の医薬組成物を投与して、それによって対象において炎症性疾患又は状態を治療又は予防することを含む、方法。
- 炎症性疾患又は状態の症状の緩和又は改善を、それを必要とする対象においてする方法であって、該方法が、治療有効量の請求項1〜21のいずれか1項に記載のポリペプチド、又は請求項22に記載の医薬組成物の投与を、それを必要とする対象にし、それによって該対象において炎症性疾患又は状態の症状を緩和又は改善することを含む、方法。
- 炎症性疾患又は状態の治療又は予防を、それを必要とする対象においてするための医薬の製造における、治療有効量の請求項1〜21のいずれか1項に記載のポリペプチドの使用。
- 前記炎症性疾患が、TLR2又はTLR4の活性化によって主に媒介される、請求項23〜25のいずれか1項に記載の方法、又は請求項26に記載の使用。
- 前記炎症性疾患が、TLR7、8又は9の活性化によって主に媒介される、請求項23〜25のいずれか1項に記載の方法又は請求項26に記載の使用。
- 前記炎症性疾患が、自己免疫疾患である、請求項23〜25のいずれか1項に記載の方法又は請求項26に記載の使用。
- 前記炎症性疾患が、内毒素ショックである、請求項23〜25のいずれか1項に記載の方法又は請求項26に記載の使用。
- 前記内毒素ショックが、細菌に起因する、請求項30に記載の方法又は使用。
- 請求項1〜21のいずれか1項に記載のポリペプチドをコードする、核酸分子。
- 請求項32に記載の核酸分子を含む、ベクター。
- 請求項33に記載のベクター又は請求項32に記載の核酸分子を含む、細胞。
- 請求項34に記載の細胞を含む、動物又はその動物由来の組織。
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