JP2019508022A - 補体活性化を抑制するポリペプチド - Google Patents
補体活性化を抑制するポリペプチド Download PDFInfo
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Images
Classifications
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Abstract
Description
CPおよびLPが、ある種の認識分子が引き金となって開始されるのに対し、APは常時低レベルで活性である。これは、「チックオーバー」と称されるメカニズムで起こるもので、C3b様分子であるC3(H2O)の内部C3チオエステルが、生体活性形態を形成するよう加水分解されることにより開始される。可溶性のB因子(FB)およびD因子(FD)(これはC3(H2O)結合FBを分解する)が作用して、液相C3転換酵素複合体(C3b(H2O)Bb)が形成され、天然C3分子が切断され、活性化される。活性化されたC3bは、チオエステル含有ドメイン(TEDまたはC3dドメイン)を介して、隣接表面のヒドロキシル基に共有結合する。病原体上で、C3bが、形成された部位のすぐ近くに蓄積し、さらなるC3転換酵素(C3bBb)が形成され、それによって補体活性化が増幅される。C3転換酵素に第2のC3bが結合することにより、C5転換酵素(C3bBbC3b)が形成され、これはC5の、強力な免疫エフェクター分子C5aおよびC5bへの分解を引き起こす。C5bは補体成分C6、C7、C8およびC9を動員してC5b−9終末膜侵襲複合体(MAC)を形成し、その結果、病原体が溶解される(Ricklin et al. 2010, Carroll et al. 2011)。
オプソニン化細胞および病原体の迅速な排除のため、および宿主組織損傷をもたらしうる無制限のAP活性化を最小限にするために、APは精密に制御されなければならない。健康な宿主細胞は通常、カスケードの異なる活性化段階で作用する、補体活性化制御因子(regulator of complement activation)(RCA)ファミリーのいくつもの膜結合または可溶性タンパク質(それらのいくつかは機能が重複しており、いくつかは独特の補体制御特性を有する)によって、補体が仲介する侵襲から保護されている(Zipfel et al. 2009)。
H因子/FHRタンパク質ファミリーは、5つの補体H因子関連タンパク質(FHR)であるFHR1、FHR2、FHR3、FHR4、FHR5、H因子(FH)およびスプライスバリアントであるH因子様タンパク質1(FHL−1)を含む、一群の関連性の高い血漿タンパク質を含む。ファミリーメンバーのそれぞれの単一遺伝子は、RCA遺伝子クラスター内において、ヒト染色体1q32上の個別のセグメント上に位置する(Skerka et al. 2013)。FHは第2経路の主要な制御因子であり、FHRの機能は完全にはわかっていない。FHRタンパク質の相互作用は、細胞表面上での補体制御活性を調節すると考えられている(Jozsi et al. 2015)。さらに、それらのホモおよびヘテロオリゴマー化能により、FHR1、FHR2およびFHR5のリガンドに対する親和性が高められうる。これは、補体活性化の認識および調節におけるファインチューニング様メカニズムとして提唱されている(Jozsi et al. 2015)。しかしながら、FHR1およびFHR2について、FH非依存性のユニークな補体制御特性もいくつか報告されている。FH、FHR1およびFHR2は補体活性化をダウンレギュレートしうるので、病的状態下の補体活性化を調節する手段の有望な候補であると考えられている(Licht et al. 2005, Licht et al. 2006, Skerka et al. 2013, Haffner et al. 2015)。
補体成分およびFHのような制御因子の、突然変異、機能不全多型によって引き起こされるAP制御不全、またはAP活性化を促進する抗体は、非典型溶血性尿毒症症候群(aHUS)(Noris et al. 2009)またはC3腎症(C3G)(Barbour et al. 2013)、加齢黄斑変性症(AMD)(Kawa et al. 2014)または発作性夜間ヘモグロビン尿症(PNH)(Holers 2008)のような疾患との関連性が高い。これら以外にも、IgA腎症(Maillard et al. 2015)、全身性エリテマトーデス(SLE)(Wilson et al. 1976)、虚血−再灌流(IR)傷害または移植片拒絶、関節リウマチ(RA)および他の多くの疾患(Holers 2008)(Ricklin et al. 2013)について、APの病原的役割が示されまたは仮定されている。
aHUSまたはC3Gの治療における確立された治療オプションは限られており、その例には、血漿交換または新鮮凍結血漿(FFP)交換、免疫抑制処置、および腎移植があるが、基礎疾患の再発リスクは高い(Braun et al. 2005, Lu et al. 2012, Cataland et al. 2014, Masani et al. 2014)。補体を標的とする多くの治療法が現在研究段階にあるので、将来、治療オプションに加わるかもしれない(Wagner et al. 2010, Ricklin et al. 2013)。その中で、ヒト化モノクローナル抗C5抗体エクリズマブは、TCC形成を抑制するもので、最近aHUS治療用に承認された(Zimmerhackl et al. 2010)。C3Gに対しては、確立された治療法はまだ無い(Masani et al. 2014)。エクリズマブをC3G患者に適用した場合、部分奏功が一部の患者においてのみ得られている(Bomback et al. 2012)。
(1)抑制性C3転換酵素エフェクタードメインおよび抑制性C5転換酵素(C5結合)エフェクタードメインを含むポリペプチド。
(2)抑制性C3転換酵素エフェクタードメインが、解離促進(decay-accelerating)およびコファクター活性によって、C3転換酵素抑制をもたらす、上記項(1)のポリペプチド。
(3)ポリペプチドが解離促進およびコファクター活性を有する、上記項(1)または(2)のポリペプチド。
(4)抑制性C3転換酵素エフェクタードメインが、H因子(FH)の断片である、上記項(1)〜(3)のいずれかのポリペプチド。
(5)抑制性C3転換酵素エフェクタードメインが、FHのショートコンセンサスリピート(SCR)1−4を含むか、またはFHのSCR1−4からなる、上記項(1)〜(4)のいずれかのポリペプチド。
(6)抑制性C3転換酵素エフェクタードメインが、FHR2のSCR1−4を含むか、またはFHR2のSCR1−4からなる、上記項(1)〜(3)のいずれかのポリペプチド。
(7)抑制性C5転換酵素エフェクタードメインが、H因子関連タンパク質1(FHR1)の断片である、上記項(1)〜(6)のいずれかのポリペプチド。
(8)抑制性C5転換酵素エフェクタードメインが、FHR1のSCR1およびSCR2を含むか、またはFHR1のSCR1およびSCR2からなる、上記項(1)〜(7)のいずれかのポリペプチド。
(9)ポリペプチドのC5への結合により、C5の活性化ならびにC5aおよびC5bへの分解が抑制される、上記項(1)〜(8)のいずれかのポリペプチド。
(10)細胞表面に結合することができるドメインをさらに含む、上記項(1)〜(9)のいずれかのポリペプチド。
(11)細胞表面に結合することができるドメインが、FHのSCR19およびSCR20を含む、上記項(1)〜(10)のいずれかのポリペプチド。
(12)ポリペプチドが多量体である、上記項(1)〜(11)のいずれかのポリペプチド。
(13)FHR1のSCR1由来の少なくとも1つの二量体化モチーフを含む、上記項(12)のポリペプチド。
(14)ポリペプチドがTCC(C5b−9)の形成を抑制することができる、上記項(1)〜(13)のいずれかのポリペプチド。
(15)ポリペプチドのC5b−6への結合によりTCC形成が抑制される、上記項(14)のポリペプチド。
(16)構造:
A−B−C
[ここで、
Aは、上記項(1)〜(15)のいずれかにおいて規定される抑制性C5転換酵素エフェクタードメインであり、
Bは、上記項(1)〜(15)のいずれかにおいて規定される抑制性C3転換酵素エフェクタードメインであり、
Cは、存在しないか、または、上記項(1)〜(15)のいずれかにおいて規定される、細胞表面に結合することができるドメインである]
を有するポリペプチド。
(17)AとBが直接に、またはリンカーを介して結合している、上記項(16)のポリペプチド。
(18)BとCが直接に、またはリンカーを介して結合している、上記項(16)または(17)のポリペプチド。
(19)補体系が関連または関与する障害の治療または予防において使用するための、上記項(1)〜(18)のいずれかのポリペプチド。
(20)補体系が関連または関与する障害が、非典型溶血性尿毒症症候群(aHUS)、血栓性微小血管症(TMA)、C3腎症(C3G)、IgA腎症、全身性エリテマトーデスの腎炎、移植片拒絶、発作性夜間ヘモグロビン尿症(PNH)、加齢黄斑変性症(AMD)、感染性疾患、敗血症、SIRS、外傷性傷害、虚血/再灌流傷害、および心筋梗塞からなる群から選択される、上記項(19)に記載される使用のためのポリペプチド。
(21)上記項(1)〜(18)のいずれかのポリペプチドをコードする核酸。
(22)上記項(21)の核酸を含むプラスミドまたはベクター。
(23)上記項(21)の核酸、または上記項(22)のプラスミドもしくはベクターを含む細胞。
(24)上記項(1)〜(18)のいずれかのポリペプチドを製造する方法であって、上記項(23)の細胞を、該ポリペプチドの発現を可能にする条件下に培地中で培養し、該細胞または該培地から該ポリペプチドを回収することを含む方法。
本発明は、抑制性C3転換酵素エフェクタードメイン、抑制性C5転換酵素エフェクタードメイン(C5結合ドメイン)、および場合により抑制性TCC形成ドメインおよび/または二量体化モチーフを含むポリペプチドに関する。
Claims (24)
- 抑制性C3転換酵素エフェクタードメインおよび抑制性C5転換酵素エフェクタードメインを含むポリペプチド。
- 抑制性C3転換酵素エフェクタードメインが、解離促進およびコファクター活性によって、C3転換酵素抑制をもたらす、請求項1に記載のポリペプチド。
- ポリペプチドが解離促進およびコファクター活性を有する、請求項1または2に記載のポリペプチド。
- 抑制性C3転換酵素エフェクタードメインが、H因子(FH)の断片である、請求項1〜3のいずれかに記載のポリペプチド。
- 抑制性C3転換酵素エフェクタードメインが、FHのショートコンセンサスリピート(SCR)1−4を含むか、またはFHのSCR1−4からなる、請求項1〜4のいずれかに記載のポリペプチド。
- 抑制性C3転換酵素エフェクタードメインが、FHR2のSCR1−4を含むか、またはFHR2のSCR1−4からなる、請求項1〜3のいずれかに記載のポリペプチド。
- 抑制性C5転換酵素エフェクタードメインが、H因子関連タンパク質1(FHR1)の断片である、請求項1〜6のいずれかに記載のポリペプチド。
- 抑制性C5転換酵素エフェクタードメインが、FHR1のSCR1およびSCR2を含むか、またはFHR1のSCR1およびSCR2からなる、請求項1〜7のいずれかに記載のポリペプチド。
- ポリペプチドのC5への結合により、C5の活性化ならびにC5aおよびC5bへの分解が抑制される、請求項1〜8のいずれかに記載のポリペプチド。
- 細胞表面に結合することができるドメインをさらに含む、請求項1〜9のいずれかに記載のポリペプチド。
- 細胞表面に結合することができるドメインが、FHのSCR19およびSCR20を含む、請求項1〜10のいずれかに記載のポリペプチド。
- ポリペプチドが多量体である、請求項1〜11のいずれかに記載のポリペプチド。
- FHR1のSCR1由来の少なくとも1つの二量体化モチーフを含む、請求項12に記載のポリペプチド。
- ポリペプチドがTCC(C5b−9)の形成を抑制することができる、請求項1〜13のいずれかに記載のポリペプチド。
- ポリペプチドのC5b−6への結合によりTCC形成が抑制される、請求項14に記載のポリペプチド。
- 構造:
A−B−C
[ここで、
Aは、請求項1〜15のいずれかにおいて規定される抑制性C5転換酵素エフェクタードメインであり、
Bは、請求項1〜15のいずれかにおいて規定される抑制性C3転換酵素エフェクタードメインであり、
Cは、存在しないか、または、請求項1〜15のいずれかにおいて規定される、細胞表面に結合することができるドメインである]
を有するポリペプチド。 - AとBが直接に、またはリンカーを介して結合している、請求項16に記載のポリペプチド。
- BとCが直接に、またはリンカーを介して結合している、請求項16または17に記載のポリペプチド。
- 補体系が関連または関与する障害の治療または予防において使用するための、請求項1〜18のいずれかに記載のポリペプチド。
- 補体系が関連または関与する障害が、非典型溶血性尿毒症症候群(aHUS)、血栓性微小血管症(TMA)、C3腎症(C3G)、IgA腎症、全身性エリテマトーデスの腎炎、移植片拒絶、発作性夜間ヘモグロビン尿症(PNH)、加齢黄斑変性症(AMD)、感染性疾患、敗血症、SIRS、外傷性傷害、虚血/再灌流傷害、および心筋梗塞からなる群から選択される、請求項19に記載の使用のためのポリペプチド。
- 請求項1〜18のいずれかに記載のポリペプチドをコードする核酸。
- 請求項21に記載の核酸を含むプラスミドまたはベクター。
- 請求項21に記載の核酸、または請求項22に記載のプラスミドもしくはベクターを含む細胞。
- 請求項1〜18のいずれかに記載のポリペプチドを製造する方法であって、請求項23に記載の細胞を、該ポリペプチドの発現を可能にする条件下に培地中で培養し、該細胞または該培地から該ポリペプチドを回収することを含む方法。
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