JP2014510082A - インターロイキン−1受容体のアンタゴニスト - Google Patents
インターロイキン−1受容体のアンタゴニスト Download PDFInfo
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Abstract
Description
本発明は、細胞表面IL−1受容体1に結合して人体全体にわたるIL−1の炎症作用に拮抗することができる、IL−1受容体アンタゴニストタンパク質(IL1RA)に由来する短鎖ペプチドを含む新規化合物に関する。IL−1が重要な役割を果たす病理学的状態、例えば身体および中枢神経系の炎症状態、の処置のための抗炎症剤としての前記ペプチドの使用も開示する。
インターロイキン1(IL−1)は、主要な炎症促進性サイトカインである2つの異なるタンパク質、IL−1アルファおよびIL−1ベータ、の総称である。IL−1は、多数の細胞タイプにおける特異的膜貫通型受容体(IL−1RI)への結合によってその効果を発揮する。IL−1の効果は、天然インヒビター、例えば可溶性IL−1受容体およびIL−1Rアンタゴニストタンパク質(IL1RAまたはIL1Ra)、によって中和される。IL1RAは、細胞表面受容体とのIL−1の相互作用を遮断することによりIL−1の効果を阻害する。
本発明は、完全長IL1RAタンパク質およびアナキンラに勝る向上した特性を有するトランケート型のIL1RAに関する。
配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つのアミノ酸配列;または
配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つの5個以上の連続するアミノ酸からなる断片;または
配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つの変異体であって、配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つと少なくとも50%の同一性を有する5から20個のアミノ酸のアミノ酸配列からなる変異体
からなり、
ここで、該ペプチドは、IL−1受容体タイプ1(IL1RI)に結合することができ、およびIL−1のIL1RIへの結合に干渉することができる。
IL1RAまたはIL1Ra:IL−1受容体アンタゴニストタンパク質、本明細書ではIL−1受容体アンタゴニストと表示することもある。
i)極性側鎖を有するアミノ酸(Asp、Glu、Lys、Arg、His、Asn、Gln、Ser、Thr、TyrおよびCys)
ii)非極性側鎖を有するアミノ酸(Gly、Ala、Val、Leu、Ile、Phe、Trp、ProおよびMet)
iii)脂肪族側鎖を有するアミノ酸(Gly、Ala Val、Leu、Ile)
iv)環状側鎖を有するアミノ酸(Phe、Tyr、Trp、His、Pro)
v)芳香族側鎖を有するアミノ酸(Phe、Tyr、Trp)
vi)酸性側鎖を有するアミノ酸(Asp、Glu)
vii)塩基性側鎖を有するアミノ酸(Lys、Arg、His)
viii)アミド側鎖を有するアミノ酸(Asn、Gln)
ix)ヒドロキシ側鎖を有するアミノ酸(Ser、Thr)
x)硫黄含有側鎖を有するアミノ酸(Cys、Met)
xi)中性、弱疎水性アミノ酸(Pro、Ala、Gly、Ser、Thr)
xii)親水性、酸性アミノ酸(Gln、Asn、Glu、Asp)および
xiii)疎水性アミノ酸(Leu、Ile、Val)。
炎症
炎症(ラテン語inflammare、火を放つこと)は、病原体、損傷細胞または刺激物などの有害刺激物に対する脈管組織の複合的生物学的応答の一部である。炎症は、傷害性刺激物を除去しようとする、および治癒過程を開始させようとする、生物による保護的企図である。炎症は、その炎症が感染に起因する場合でさえ、感染の症状ではない。感染は、微生物によって引き起こされるが、炎症は、病原体に対する生物の応答の1つである。
インターロイキンは、白血球細胞(白血球(leukocyte))によって発現されることが最初に見出された1群のサイトカイン(分泌タンパク質/シグナル伝達分子)である。用語インターロイキンは、「コミュニケーションの伝達手段としての」(インター−)と「これらのタンパク質の多くが、白血球によって産生され、白血球において作用するという事実に由来すること」(−ロイキン)に由来する。その後でインターロイキンは多種多様な細胞から産生されることが判明したのだが、この名は、ちょっとした名残である。
インターロイキン1(IL−1)は、主要な炎症促進性サイトカインである2つの異なるタンパク質、IL−1アルファ(IL1A)およびIL−1ベータ(IL1B)、の総称である。それらは、免疫応答、炎症反応、組織傷害および造血の調節に関与する。
インターロイキン−1アルファ(IL−1α)は、ヒトの場合はIL1A遺伝子にコードされているタンパク質である。この遺伝子によってコードされているタンパク質は、インターロイキン−1ファミリーのサイトカインである。インターロイキン−1アルファは、広いスペクトルの代謝活性、生理的活性、造血活性を保有し、免疫応答の調節における中心的役割のうちの1つを果たす。それは、インターロイキン−1受容体に結合する。IL−1αは、その初期合成前駆体の構造がシグナルペプチド断片を含有しない(同じことがIL−1βおよびIL−18について公知である)という点で、サイトカインファミリー内のユニークなメンバーである。特異的プロテアーゼによるN末端アミノ酸の除去によるプロセシング後にその結果として生ずるペプチドを「成熟」形態と呼ぶ。形質膜に会合するカルシウム活性化システインプロテアーゼである、カルパインがIL−1α前駆体の成熟分子への切断に主として関与する。IL−1αからの31kDa前駆体形態とその18kDa成熟形態の両方が生物学的に活性である。
カタボリンとしても公知のインターロイキン−1ベータ(IL−1β)は、ヒトではIL1B遺伝子によってコードされているサイトカインタンパク質である。IL−1β前駆体は、カスパーゼ1(インターロイキン1ベータコンバターゼ)によって切断される。サイトゾルチオールプロテアーゼがその産物を切断して、成熟IL−1βを形成する。
インターロイキン−1受容体アンタゴニストタンパク質(IL1RA)は、ヒトではIL1RN遺伝子によってコードされているタンパク質である。それは、IL1AおよびIL1Bの活性を阻害するならびに様々なIL−1関連の免疫応答および炎症応答を変調する、IL−1サイトカインファミリーのメンバーである。この遺伝子と5つの他の近縁サイトカイン遺伝子が、染色体2上でおおよそ400kbにわたる遺伝子クラスターを形成する。異なるアイソフォームをコードしている4つの選択的スプライシング転写変異体が報告されている。IL1RN遺伝子の変異は、インターロイキン−1−受容体アンタゴニスト欠損症(DIRA)と呼ばれる稀な疾患を生じさせる結果となる。IL1RN遺伝子の変異体はまた統合失調症のリスクと関連づけられている。
IL1は、2つの異なる受容体、IL1RIおよびIL1RII(それぞれ、IL−1受容体タイプIおよびII、または1および2)を有する。IL1RIは、IL1結合のための3個の免疫グロブリン様分子を有する細胞外部分と長い細胞質ドメインとを含み、これに対してIL1RIIは、同じ外部ドメインを含有するが、より短い細胞質ドメインを含有する。
本発明は、完全長IL1RAタンパク質およびアナキンラに勝る向上した特性を有するトランケート型のIL1RAを開示する。本発明の短鎖ペプチドの前記向上した特性は、溶解度増加、安定性増加およびより低い合成コストに関係する。さらに、本発明のペプチドは、本明細書中の他の箇所で取り扱う幾つかの望ましい下流効果に加えて、IL−1R1に結合してIL−1ベータのこの受容体への結合に干渉するその能力を保持する。
ペプチドの合成による生成のための方法は、当該技術分野において周知である。合成ペプチドの生成についての詳細な記載ならびに、実際的助言は、Synthetic Peptides:A User’s Guide(Advances in Molecular Biology)、Grant G.A.編、Oxford University Press、2002において、またはPharmaceutical Formulation:Development of Peptides and Proteins、FrokjaerおよびHovgaard編、Taylor and Francis、1999において見出すことができる。
本発明によるペプチドを含むまたは本発明によるペプチドからなる化合物を提供することが、本発明の1つの態様である。1つの実施形態では前記ペプチドを単量体(すなわち、該ペプチドの1個のコピーを含む)として製剤化するが、別の実施形態では前記ペプチドを多量体として製剤化する。
本発明のペプチド配列を化学結合によりまたはリンカー基によって本発明の別の(同一のまたは同一でない)ペプチド配列に接続することができる。一部の実施形態では、本発明のペプチドを単量体のオリゴマーまたは多量体として製剤化することができ、この場合の各単量体は、本明細書において上で定義したのと同様のペプチド配列である。
神経突起伸長を刺激するおよび/またはニューロンの生存を促進するための方法であって、有効量の、本発明によるペプチド、化合物または組成物を、それを必要とする個体に投与するステップを含む方法を提供することも、本発明の1つの態様である。
本発明のペプチドまたは化合物を未加工の化学物質(またはペプチド)として投与することは可能であるが、ときとして、それらを医薬製剤の形態で提供するほうが好ましい。かかる医薬製剤を薬学的組成物、または薬学的に許容され得るもしくは薬学的に安全な組成物と呼ぶこともある。
投薬要件は、用いる特定の薬物組成、投与経路、および処置する特定の被験体によって変わる。化合物の個々の投薬の最適な量および間隔が、処置する状態の性質および程度、投与の形態、経路および部位、ならびに処置する特定の患者によって決まること、ならびにかかる最適条件を従来の技術によって決定できることも、当業者には認識される。最適な処置コース、すなわち、定義した日数にわたって1日に与える化合物の用量数を、処置決定試験の従来のコースを用いて確かめることができることも、当業者には理解される。
化合物を血流に導入して最終的に所望の作用部位にターゲティングするための主投与経路は、経口および非経口経路である。経口投与は、胃腸管での分解のため、本発明のタンパク質化合物にはあまり好ましくない。非経口投与は、経口/経腸経路ではなく、それにより化合物が肝臓での初回通過分解を免れる、任意の投与経路である。したがって、非経口投与は、任意の注射および注入、例えば、ボーラス注射または持続注入、例えば静脈内投与、筋肉内投与および皮下投与を含む。さらに、非経口投与は、吸入および局所投与を含む。
1つの実施形態において、本発明は、本発明によるペプチド、化合物または組成物と1つ以上の他の生物活性剤との共投与に関する。
本発明は、上記の1つ以上のペプチド、化合物または組成物と少なくとも1つの追加の構成要素とを含むキット・オブ・パーツにも関する。前記追加の構成要素は、炎症状態、糖尿病、神経変性状態などの処置のための薬物であり得る。
炎症に関連した異常は、様々なヒト疾患の根底にある大きな無関係の障害群を構成する。免疫系は、多くの場合、炎症性障害に関与し、これはアレルギー反応においても一部のミオパチーにおいても実証されており、多くの免疫系障害が異常炎症を生じさせる結果となる。炎症過程に病因論的起源がある非免疫疾患は、癌、アテローム性動脈硬化症および虚血性心疾患を含むと考えられる。多種多様なタンパク質が炎症に関与し、それらのうちのいずれか1つは、そのタンパク質の正常な機能および発現を損なわせるまたは別様に脱調節する遺伝子変異を受けやすい。
関節リウマチの処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
痛風および/または足部痛風の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
JIAの処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
糖尿病の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
ベーチェット病の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
神経変性障害の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
アルツハイマー病の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
パーキンソン病の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
ハンチントン病の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
多発性硬化症の処置に使用するための、本発明に従うペプチドを提供することが、本発明の1つの態様である。
インターロイキン−1受容体アンタゴニストタンパク質のアミノ酸配列(完全長;配列番号28)
UniProtアクセッション番号:P18510(IL1RA_HUMAN)
略名:IL−1RN、IL1RN、IL−1ra、IRAP、IL1F3、IL1RA
別名(単数または複数):ICIL−1RA、IL1インヒビター、INN=アナキンラ
4つのアイソフォーム(1つの分泌アイソフォーム、3つの細胞質アイソフォーム)
アイソフォーム1(識別子:P18510−1)、177アミノ酸長、を「規範」配列として選択した:
このアイソフォームの配列は、次のとおり規範配列とは異なる:aa1−21:MEICRGLRSHLITLLLFLFHS→MAL
アイソフォーム3(識別子:P18510−3)、180aa長(icIL−1raタイプIIとしても公知)
このアイソフォームの配列は、次のとおり規範配列とは異なる:aa1−21:MEICRGLRSHLITLLLFLFHS→MALADLYEEGGGGGGEGEDNADSK
アイソフォーム4(識別子:P18510−4)、143aa長
このアイソフォームの配列は、次のとおり規範配列とは異なる:aa1−34:欠如(欠失)。
イランタフィン−1:RIWDVNQKT(配列番号29)
イランタフィン−2:AGYLQGPNVN(配列番号30)−水溶性、PBSまたは媒体には不溶性
イランタフィン−3:NQLVAGYLQGPNVN(配列番号31)−水溶性でない
イランタフィン−4:VTKFYFQED(配列番号32)−水溶性でない
イランタフィン−5:EGVMVTKFYFQED(配列番号33)−生成されたとき完全不溶性
イランタフィン−6:NQKTFYLRNNQL(配列番号34)−水溶性、PBSまたは媒体には不溶性
イランタフィン−7:TAMEADQPVS(配列番号35)
イランタフィン−8:イランタフィン、配列番号1である
イランタフィン−9:GPNAKLEEKA(配列番号36)
ヒトIL1RaとヒトIL1RIの複合体の結晶構造(図1)におけるイランタフィン(イランチド)配列モチーフ(配列番号1)の位置。
イランタフィンペプチド(配列番号1)は、IL1βおよびIL1RaのIL1RIへの結合親和性と同じ桁内である親和性でIL1RIの固定化エクトドメインと相互作用する(図2および3)。さらに、このペプチドは、IL1βの結合についてその受容体と競合する(図3)。
イランタフィンペプチド配列番号1(デンドリマー/四量体としておよび単量体形態で作製したもの)は、IL1βでの処理により誘導されるマクロファージの活性化を阻害する(図5、図6および図7)。様々な形態のスクランブル配列のイランタフィン、およびリバース配列を有するイランタフィンは、IL1βによるNF−κBの活性化を阻害しないので、イランタフィンの効果は配列特異的である(図8)。イランタフィンの効果は、該ペプチドがIL6によって誘導されるシグナル伝達を阻害しないので、配列特異的である(図9)。
デンドリマー/四量体または単量体、両方としてのイランタフィンペプチド(配列番号1)は、TNF−α分泌によって表されるように、マクロファージのIL1β誘導活性化を用量依存的様式で阻害する(図10、図11)。IL1RaおよびSIL1RIタンパク質もマクロファージ活性化を阻害する(陽性対照、図12)。
イランタフィンペプチド(配列番号1)、IL1RaおよびSIL1RIタンパク質は、小脳の一次ニューロンにおける神経突起伸長を用量依存的様式で誘導するが、IL1β自体は、神経突起生成に影響を及ぼさない。さらに、IL1βは、イランタフィン誘導神経突起伸長およびIL1Ra誘導神経突起伸長を阻害する。これは、IL1RI活性化の阻害がニューロン分化を促進することを示す(図13および図19(同じデータを再計算した)、図14)。
イランタフィンペプチド(配列番号1)は、塩化カリウム濃度を低下させることによって誘導される神経細胞死(アポトーシス)を低減させる。このペプチドの効果は、ニューロン生存因子IGF−1の効果に匹敵する(図15および図20)。
イランタフィンペプチド(配列番号1)は、ラットにおけるCIAの臨床症状発現の増大を抑止する(図16)。
血漿および脳脊髄液中のイランタフィンペプチド(例えば、配列番号1)の検出。
神経細胞傷害性を逆転させることにおける配列番号1などのイランタフィンの効果を次の方法:「カイニン酸誘導細胞傷害性」によって評価することができる。
発作を減弱させる、死亡率を減少させる、および神経変性を減少させることにおける配列番号1などのイランタフィンの効果を次の方法:「カイニン酸誘導発作」によって評価することができる。
Fmoc−(Calbiochem−Novabiochem)保護アミノ酸を使用するTentaGel樹脂(Rapp Polymere、ドイツ国チュービンゲン)でのFmoc保護戦略を用いてペプチドを合成した。リシン主鎖にカップリングさせた4個の単量体でデンドリマーを構成した。リシン残基にカップリングさせた2個の単量体で二量体を構成した。高速液体クロマトグラフィーおよびマトリックス支援レーザー脱離/イオン化飛行時間型質量分光分析(VG TOF Spec E、Fisons Instruments、マサチューセッツ州ベヴァリー)によって推定して、ペプチドは少なくとも95%の純度であった。
ペプチド溶解度。
ペプチド安定性。
コラーゲン誘発関節炎(CIA)のラットモデルにおけるイランタフィン配列番号1(SGRKSSKMQA)の効果。
ラットにおけるコラーゲン誘発関節炎(CIA)。
イランタフィンは、CIAを有する動物の罹患率を低減させる、図17参照。罹患率を臨床指数7に達した動物であって、したがって、その試験日までに屠殺した動物の百分率として表した。イランタフィンは、dpi12まで罹患率を有意に低減させた。*−P<0.05(ウェルチ補正を伴う対応のないt検定)。
Claims (68)
- IL−1受容体アンタゴニストタンパク質(IL1RA)に由来する5から20個の隣接するアミノ酸残基のペプチド配列からなる単離されたペプチドであって、
配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つのアミノ酸配列;または
配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つの5個以上の連続するアミノ酸からなる断片;または
配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つの変異体であって、配列番号1、配列番号29、配列番号35もしくは配列番号36のいずれか1つと少なくとも50%の同一性を有する5から20個のアミノ酸のアミノ酸配列からなる変異体
からなり、
IL−1受容体タイプ1(IL1RI)に結合することができ、かつIL−1のIL1RIへの結合に干渉することができる
ペプチド。 - 5から14個の隣接するアミノ酸残基のペプチド配列からなるペプチドであって、配列番号1のアミノ酸配列;配列番号1の5個以上の連続するアミノ酸からなる断片;または配列番号1と少なくとも50%の相同性を有する5から14個のアミノ酸からなるアミノ酸配列からなる、請求項1に記載のペプチド。
- 配列番号29のアミノ酸配列;配列番号29の5個以上の連続するアミノ酸からなる断片;または配列番号29と少なくとも50%の相同性を有する5から20個のアミノ酸からなるアミノ酸配列からなる、請求項1に記載のペプチド。
- 配列番号35のアミノ酸配列;配列番号35の5個以上の連続するアミノ酸からなる断片;または配列番号35と少なくとも50%の相同性を有する5から20個のアミノ酸からなるアミノ酸配列からなる、請求項1に記載のペプチド。
- 配列番号36のアミノ酸配列;配列番号36の5個以上の連続するアミノ酸からなる断片;または配列番号36と少なくとも50%の相同性を有する5から20個のアミノ酸からなるアミノ酸配列からなる、請求項1に記載のペプチド。
- 神経突起伸長を刺激することができ、かつ/またはニューロンの生存を促進することができる、請求項1から5のいずれかに記載のペプチド。
- IL−1によって誘導される生物学的効果、例えばNF−kB活性化およびTNF−アルファ増大、を阻害することができる、請求項1から5のいずれかに記載のペプチド。
- 前記断片が、配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つの6個以上の連続するアミノ酸からなる、請求項1から5のいずれかに記載のペプチド。
- 前記断片が、配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つの5から9個の連続するアミノ酸からなる、請求項1から5のいずれかに記載のペプチド。
- 前記断片が、配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つの6から9個の連続するアミノ酸からなる、請求項1から5のいずれかに記載のペプチド。
- 前記断片が、配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つの6から8個の連続するアミノ酸からなる、請求項1から5のいずれかに記載のペプチド。
- 配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つの5から15個の隣接するアミノ酸残基のペプチド配列からなる、請求項1から5のいずれかに記載のペプチド。
- 配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つの最大で14個の隣接するアミノ酸残基のペプチド配列からなる、請求項1から5のいずれかに記載のペプチド。
- 配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つと少なくとも60%の同一性を有する、請求項1から5のいずれかに記載のペプチド。
- 配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つと少なくとも70%の同一性を有する、請求項1から5のいずれかに記載のペプチド。
- 配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つと少なくとも80%の同一性を有する、請求項1から5のいずれかに記載のペプチド。
- 前記アミノ酸配列が、配列番号1からなる、請求項2に記載のペプチド。
- 前記アミノ酸配列が、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号26および配列番号27からなる群より選択されるアミノ酸配列からなる、請求項2に記載のペプチド。
- 配列番号1、配列番号29、配列番号35または配列番号36のいずれか1つと少なくとも50%の同一性を有する5から20個のアミノ酸のアミノ酸配列からなり、該アミノ酸配列が、少なくとも1つのアミノ酸置換を含む、請求項1に記載のペプチド。
- 前記アミノ酸配列が、2つのアミノ酸置換、例えば3つのアミノ酸置換、例えば4つのアミノ酸置換、例えば5つのアミノ酸置換を含む、請求項19に記載のペプチド。
- 前記アミノ酸置換が、保存的アミノ酸置換である、請求項19から20のいずれかに記載のペプチド。
- C末端アミノ酸が、遊離カルボン酸(「−OH」)として存在する、請求項1から21のいずれかに記載のペプチド。
- C末端アミノ酸が、アミド化誘導体(「−NH2」)である、請求項1から21のいずれかに記載のペプチド。
- N末端アミノ酸が、遊離アミノ基(「H−」)を含む、請求項1から21のいずれかに記載のペプチド。
- N末端アミノ酸が、アセチル化誘導体(「−アセチル」または「COCH3」)である、請求項1から21のいずれかに記載のペプチド。
- アミノ酸配列RPSGRKSSKMQAFRI(配列番号37)を含まない、またはアミノ酸配列RPSGRKSSKMQAFRI(配列番号37)からならない、請求項1または2のいずれかに記載のペプチド。
- アミノ酸配列LVAGY(配列番号38)を含まない、またはアミノ酸配列LVAGY(配列番号38)からならない、請求項1または2のいずれかに記載のペプチド。
- 請求項1から21のいずれかに記載の少なくとも1つのペプチドを含む化合物。
- 前記ペプチドが、該ペプチドの単一コピーからなる単量体として製剤化される、請求項28に記載の化合物。
- 請求項1から21のいずれかに記載の2個以上のペプチドを含む多量体化合物。
- 前記2個以上のペプチドが、ペプチド結合またはリンカー基によって連結されている、請求項30に記載の化合物。
- 前記リンカー基が、1個以上のリシン残基を含む、請求項31に記載の化合物。
- 二量体である(すなわち、2個のペプチドを含む)、請求項30に記載の化合物。
- 三量体である(すなわち、3個のペプチドを含む)、請求項30に記載の化合物。
- 四量体である(すなわち、4個のペプチドを含む)、請求項30に記載の化合物。
- デンドリマーであり、4、8、16または32個のペプチドを含む、請求項30に記載の化合物。
- 四量体デンドリマーである、請求項30に記載の化合物。
- 前記2個以上のペプチドが、互いに対して同一である、請求項30から37のいずれかに記載の化合物。
- 前記2個以上のペプチドが、互いに対して同一でない、請求項30から37のいずれかに記載の化合物。
- 前記2個のペプチドが、互いに同一であり、それぞれ配列番号1からなる、請求項33に記載の化合物。
- 前記4個のペプチドが、互いに同一であり、それぞれ配列番号1からなる、請求項37に記載の化合物。
- 配列番号1の前記4個のコピーが、複数のリシン残基を有するコア部分によって互いに連結されている、請求項41に記載の化合物。
- 請求項1から21のいずれかに記載のペプチドまたは請求項28から42のいずれかに記載の化合物を含む組成物。
- 薬学的に許容され得るかつ/または薬学的に安全である、請求項43に記載の組成物。
- 請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物と、少なくとも1つの追加の構成要素とを含むキット・オブ・パーツ。
- 医薬品として使用するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物。
- 炎症性障害、例えばIL−1が重要な役割を果たす炎症性障害、の処置において使用するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物。
- 炎症性障害、例えばIL−1が重要な役割を果たす炎症性障害、の処置用の医薬品を製造するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物の使用。
- 炎症性障害、例えばIL−1が重要な役割を果たす炎症性障害、の処置のための方法であって、有効量の請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物を、それを必要とする個体に投与するステップを含む方法。
- 前記炎症性疾患が、尋常性ざ瘡、喘息、アテローム性動脈硬化症、自己免疫疾患、ベーチェット病、慢性炎症、慢性前立腺炎、皮膚炎、痛風、糸球体腎炎(Glumerulonephritis)、過敏症(アレルギー性喘息、アレルギー性結膜炎、アレルギー性鼻炎(枯草熱)、アナフィラキシー、血管浮腫、蕁麻疹(じんま疹)、好酸球増加症、ならびにペニシリンおよびセファロスポリンに対する応答を含む、1型(即時型、またはアトピー性、またはアナフィラキシー性);自己免疫性溶血性貧血、グッドパスチャー症候群、肝炎、IBS(過敏性腸疾患)、若年性特発性関節炎(JIA)、天疱瘡、悪性貧血(自己免疫性の場合)、乾癬、乾癬性関節炎、免疫性血小板減少症、輸血反応、橋本甲状腺炎、間質性膀胱炎、グレーブス病、重症筋無力症(Myastenia gravis)、リウマチ熱、新生児溶血性疾患および急性移植拒絶反応を含む、2型(抗体依存性);関節リウマチ、免疫複合体糸球体腎炎(glumerulonephritis)、血清病、亜急性、細菌性心内膜炎、マラリアの症状、全身性エリテマトーデス(SLE)、アルツス反応、農夫肺および結節性多発性動脈炎を含む、3型(免疫複合体);接触皮膚炎、アトピー性皮膚炎(湿疹)、側頭動脈炎、サルコイドーシス、ハンセン病の症状、結核の症状、全身性硬化症、マントー反応、小児脂肪便症および慢性移植拒絶反応を含む、4型(細胞媒介または遅延型過敏症DTH)を含む)、炎症性腸疾患(クローン病、潰瘍性大腸炎、コラーゲン蓄積大腸炎、リンパ球性大腸炎、虚血性大腸炎、空置大腸炎、ベーチェット症候群、感染性大腸炎および病型不定型大腸炎を含む)、ミオパチー(皮膚筋炎、多発性筋炎および封入体筋炎を含む)、骨盤内炎症性疾患、足部痛風、再灌流傷害、関節リウマチ、移植拒絶反応および脈管炎からなる群より選択される、請求項47および48のいずれかに記載の使用、または請求項49に記載の方法。
- 関節リウマチの処置において使用するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物。
- 関節リウマチの処置用の医薬品を製造するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物の使用。
- 関節リウマチの処置のための方法であって、有効量の請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物を、それを必要とする個体に投与するステップを含む方法。
- I型糖尿病などの糖尿病の処置において使用するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物。
- I型糖尿病などの糖尿病の処置用の医薬品を製造するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物の使用。
- I型糖尿病などの糖尿病の処置のための方法であって、有効量の請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物を、それを必要とする個体に投与するステップを含む方法。
- 神経変性障害の処置において使用するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物。
- 神経変性障害の処置用の医薬品を製造するための、請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物の使用。
- 神経変性障害の処置のための方法であって、有効量の請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物を、それを必要とする個体に投与するステップを含む方法。
- 前記神経変性障害が、神経炎症性構成要素を有する、請求項57から58のいずれかに記載の使用、または請求項59に記載の方法。
- 前記神経変性障害が、IL−1シグナル伝達に関連している、請求項57から58のいずれかに記載の使用、または請求項59に記載の方法。
- 前記神経変性障害が、アルツハイマー病、パーキンソン病、ハンチントン病および多発性硬化症からなる群より選択される、請求項57から58のいずれかに記載の使用、または請求項59に記載の方法。
- 前記神経変性障害が、アルツハイマー病である、請求項57から58のいずれかに記載の使用、または請求項59に記載の方法。
- 神経突起伸長を刺激するかつ/またはニューロンの生存を促進するための方法であって、有効量の請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物を、それを必要とする個体に投与するステップを含む方法。
- IL1RIのIL−1への結合に干渉するための方法であって、有効量の請求項1から21のいずれかに記載のペプチド、請求項28から42のいずれかに記載の化合物、または請求項43および44のいずれかに記載の組成物を、それを必要とする個体に投与するステップを含む方法。
- 前記個体が、人間である、請求項49、53、56、59、64および65のいずれかに記載の方法。
- 前記個体が、神経変性状態を有する、請求項64および65のいずれかに記載の方法。
- 前記処置が、予防的、軽減的または治癒的である、前記請求項のいずれかに記載の処置。
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- 2012-03-14 AU AU2012228769A patent/AU2012228769B2/en not_active Ceased
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- 2012-03-14 EP EP12710122.8A patent/EP2686431B1/en active Active
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JP2021534187A (ja) * | 2019-01-07 | 2021-12-09 | アストロゲン カンパニー,リミティド | 中枢神経系疾患の予防または治療用のセリン誘導体化合物 |
JP7185813B2 (ja) | 2019-01-07 | 2022-12-08 | アストロゲン カンパニー,リミティド | 中枢神経系疾患の予防または治療用のセリン誘導体化合物 |
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ES2600616T3 (es) | 2017-02-10 |
MX2013010171A (es) | 2013-11-20 |
JP6120782B2 (ja) | 2017-04-26 |
NZ615710A (en) | 2015-10-30 |
CN103476933A (zh) | 2013-12-25 |
EP2686431B1 (en) | 2016-08-03 |
AU2012228769A1 (en) | 2013-10-10 |
ZA201306744B (en) | 2014-11-26 |
RU2013145283A (ru) | 2015-04-20 |
US9359405B2 (en) | 2016-06-07 |
KR20140012127A (ko) | 2014-01-29 |
AU2012228769B2 (en) | 2016-09-08 |
BR112013023309A2 (pt) | 2017-09-19 |
WO2012122985A1 (en) | 2012-09-20 |
CA2828504A1 (en) | 2012-09-20 |
CN103476933B (zh) | 2016-04-13 |
US20140073556A1 (en) | 2014-03-13 |
EP2686431A1 (en) | 2014-01-22 |
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