JP6656926B2 - pKal関連疾病の評価、アッセイおよび治療 - Google Patents
pKal関連疾病の評価、アッセイおよび治療 Download PDFInfo
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- JP6656926B2 JP6656926B2 JP2015553859A JP2015553859A JP6656926B2 JP 6656926 B2 JP6656926 B2 JP 6656926B2 JP 2015553859 A JP2015553859 A JP 2015553859A JP 2015553859 A JP2015553859 A JP 2015553859A JP 6656926 B2 JP6656926 B2 JP 6656926B2
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Description
本願は、2013年1月20日出願の米国仮出願第61/754,600号の出願日の利益を主張する。同参照出願の全体が参照によりここに組み込まれる。
a)i)活性型第XII因子もしくはそのC1−INH結合断片、
ii)活性型カリクレインもしくはそのC1−INH結合断片、または
iii)i)およびii)の組み合わせ
を含む捕捉試薬と、
b)C1−INHに結合する検出試薬と
任意にc)C1−INHと
を含む。
便宜上、本発明の更なる説明の前に、明細書、実施例、添付の特許請求の範囲で使用される特定の用語を以下に定義する。他の用語は、明細書で用いた際に定義する。
[Bound]=N・[Free]/((1/Ka)+[Free])
のように、ターゲット分子に対する結合部位の数である。
活性カリクレインおよび/または活性FXIIに結合し、阻害するC1−INHの性能に基づき、機能的C1−INHレベルを測定する方法およびキットを本明細書において提供する。当該方法は、本明細書に記載の捕捉試薬と、C1−INHを含有する検体を接触させ、捕捉試薬に結合するものにおけるC1−INHレベルを測定することにより、行ってもよい。一部の実施形態において、総C1−INHレベル(例えば、C1−INHが本明細書に記載の捕捉試薬に結合するかどうかは別として、検体中のC1−INHタンパク質レベル)も測定される。
本明細書に記載のアッセイ方法は、本明細書に記載の捕捉試薬と結合するC1−INHレベルの評価(例えば、測定)を可能にする。捕捉試薬と結合するC1−INHレベル(例えば、量)は、本明細書に記載のアッセイおよび/または当技術分野において既知のアッセイを用いて測定することができる。捕捉試薬と結合するC1−INHレベルを査定するために使用することができるアッセイは、限定するものではないが、ウェスタンブロット、ELISA(酵素結合免疫吸着法、例えば、サンドイッチELISA)、放射免疫測定、電気化学発光に基づく検出アッセイおよびそれらに関連する技術等の免疫測定法を含む。これら例示的なアッセイ法を実施する方法は、当技術分野において既知であり、市販されている(例えば、「Current Protocols in Molecular Biology」(現行版、Wiley Online Library)参照)。
本明細書に記載のアッセイ法で使用される捕捉試薬は、キニン形成カスケードを抑制する機能、例えば、PKal、FXII、またはその両方を抑制する機能のあるC1−INで補体を形成することができる。一部の実施形態において、捕捉試薬は、活性型第XII因子もしくはそのC1−INH結合断片を含む成分、または活性型カリクレインもしくはそのC1−INH結合断片を含む成分のうち一方または両方を含んでもよい。一部の実施形態において、本発明の捕捉試薬は、天然資源から単離および/または精製される。一部の実施形態において、本発明の捕捉試薬は、組み換えまたは合成により生成される。一部の実施形態において、捕捉試薬は、基材、例えば、不溶性基材に配置(例えば、それらと結合)される。捕捉試薬は、共有結合または非共有結合により基材と結合してもよい。捕捉試薬は、基材と直接結合してもよいし、基材と間接的に、例えばリンカーを介して結合してもよい。リンカーの例としては、限定するものではないが、炭素含有鎖、ポリエチレングリコール(PEG)、核酸、単糖単位、ビオチン−アビジンおよびペプチドを含む。一部の実施形態において、基材は、1つ以上のウェルを含む容器、例えばマイクロタイタープレートである。活性型第XII因子またはカリクレインのC1−INH結合断片は、完全長の捕捉試薬の断片を生成し、断片がC1−INHと結合するかどうかと決定することにより作製することができる。
血漿カリクレインは、接触系(Sainz I.Mら、Thromb Haemost 98,77−83,2007)のセリンプロテアーゼ成分である。接触系は、外部のもしくは負に荷電した表面に晒され、第XIIa因子により、または内皮細胞表面でプロピルカルボキシペプチダーゼにより、のいずれかで活性化される(Sainz I.M.ら、hromb Haemost 98,77−83,2007)。血漿カリクレインの活性化は、第XII因子のフィードバック活性を介して、内因性凝固を促進し、炎症誘発性ノナペプチドブラジキニンの生成を介した炎症を強める。血液の循環における主要なキニノゲナーゼとして、血漿カリクレインは、血管系におけるブラジキニンの生成に大きく関わっている。
第XII因子は、血液凝固の抑制、線溶、ならびにブラジキニンおよびアンギオテンシンの生成に関係する血清グリコプロテインである。プレカリクレインは、第XII因子により切断され、カリクレインを形成し、その後、第XII因子を活性化し、第XIIa因子および第XII因子断片(第XIIf因子)を形成こととなる(「Histidine−rich glycoprotein binds factor XIIa with high affinity and inhibits contact−initiated coagulation」Macquarrieら、Blood 117:4134−4141 2011)。C1インヒビター(C1−INH)は、第XIIa因子および第XIIf因子の両方の重要な血漿インヒビターであるとして、示されている(「Effect of negatively charged activating compounds on inactivation of factor XIIa by C1 inhibitor」Pixleyら、Arch Biochem Biophys 256(2):490−8 1987)。
本発明の方法は、捕捉試薬、例えば、本明細書に開示される捕捉試薬とC1−INHとの間の複合体形成の検出を可能とする。複合体の検出は、任意の利用可能な方法、例えば、ELISA(酵素結合免疫吸着法)により行うことができる。例えば、一部の実施形態において、C1−INHとの抗体が使用される。一部の実施形態において、二次抗体、例えば抗C1−INH抗体が使用される。1つ以上の抗体は、検出成分と結合してもよい。一部の実施形態において、検出成分は、蛍光体であるか、または蛍光体を含む。本明細書において使用される場合、用語「蛍光体(「蛍光ラベル」または「蛍光色素」とも呼ぶ)は、所定の励起波長において光エネルギーを吸収し、異なる波長の光エネルギーを発散する成分を指す。一部の実施形態において、検出成分は、酵素であるか、または酵素を含む。一部の実施形態において、酵素は、色素のない基質から染色された生成物を生成するもの(例えば、β−ガラクトシダーゼ)である。
抗体は、本発明の方法において使用されてもよい。一部の実施形態において、捕捉薬は、抗体であるか、または抗体を含む。一部の実施形態において、検出薬は、抗体であるか、または抗体を含む。一部の実施形態において、pKal関連疾病Mまたはブラジキニン関連疾病の治療のための治療用組成物は、抗体であるか、または抗体を含む。
本開示は、PKalおよび/またはFXIIを阻害する機能のあるC1−INHを評価するために使用するキットも提供する。そのようなキットは、(a)本明細書に記載の捕捉試薬、および(b)こちらも本明細書に記載の、C1−INHと結合する検出試薬、例えば、抗C1−INH抗体、ならびに、場合によっては(c)C1−INHを含んでよい。一部の実施形態において、捕捉試薬は、(i)活性型第XII因子もしくはそのC1−INH結合断片、(ii)活性型カリクレインもしくはそのC1−INH結合断片、または(iii)(i)および(ii)の組み合わせを含む。一部の実施形態において、捕捉試薬は、マイクロプレート等の基材に固定化される。
本明細書に記載のアッセイ法およびキットは、疾患の評価、例えば、疾患の診断および予後に適用することができる。評価が、本明細書に記載の疾患、例えば、HAE(I型および/またはII型HAE)等のpKal関連疾病のおそれがあるかまたはそれに罹患している対象を判断することを含んでもよい。評価は、疾患の治療を監視すること、例えば、HAE(I型および/またはII型HAE)等のpKal関連疾病の治療の有効性を評価することも、含んでもよい。
一部の実施形態において、アッセイ法およびキットは、候補となる対象(例えば、HAE等のPKal関連疾病に罹患している疑いのあるヒト患者)から収集された生体検体(例えば、血液検体または血漿検体)におけるC1−INHレベルを決定するために行われる。その後、C1−INHレベルは、基準値と比較され、対象が、PKal関連疾病に罹患しているまたはPKal関連疾病の疑いがあるかどうかを決定する。基準値は、本明細書に記載の捕捉試薬(例えば、pKalまたはFXII)と結合可能なC1−INHの対照レベルであってよい。一部の実施形態において、対照レベルは、好ましくは、候補となる対象と同一の種である健康な対象または健康な対象の集団から得られた検体(例えば、血液または血漿検体)等の捕捉試薬と結合可能な対照検体におけるC1−INHレベルである。本明細書において使用される場合、健康な対象は、C1−INHレベルが測定された時点で、明らかに標的疾患(例えば、HAE等のPKal関連疾病)でない、または疾患の病歴がない対象である。
本明細書に記載のアッセイ法は、PKal関連疾病(例えば、HAE)の治療の有効性の評価にも適用することができる。例えば、複数の生体サンプル(例えば、血液または血漿検体)は、治療前および治療後または治療間のいずれかで治療を行う対象から収集することができる。(PKalおよび/またはFXIIを抑制可能な)機能的C1−INHレベルは、本明細書に記載のアッセイ法のうちいずれかにより測定することができる。機能的C1−INHレベルが、治療後または治療期間にわたって増加する(以前に収集したものと比較して、後に収集された検体における機能的C1−INHレベルが同一または増加する)場合、治療が有効であることを示している。一部の例において、治療は、本明細書に記載のカリクレイン結合薬、本明細書に記載のブラジキニンB2受容体拮抗薬、または本明細書に記載のC1−INH置換薬等の治療薬を含む。治療薬の例としては、限定するものではないが、DX−2930またはDX88を含む。
HAE等のPKal関連疾病に罹患しているまたはその疑いがある対象を治療するための方法も、本明細書に記載される。対象は、基準値(例えば、本明細書に記載するもの)と比較して、(PKalまたはFXIIを阻害可能な)機能的C1−INHレベルが低下することがあり、それは本明細書に記載のアッセイ法のいずれかにより決定することができる。
血漿カリクレイン結合薬(例えば結合タンパク質、例えばポリペプチド、例えばインヒビターポリペプチド、例えば抗体、例えばインヒビター抗体、または他の結合薬、例えば小分子)は、様々な疾患および状態、例えば、血漿カリクレイン活性に関する疾患および状態に有用な治療薬である。例えば、一部の実施形態において、血漿カリクレイン活性に関する疾患または状態は、遺伝性血管性浮腫(HAE)である。一部の実施形態において、血漿カリクレイン結合タンパク質またはポリペプチドは、pKal関連疾病またはブラジキニン関連疾病の疑いがあるか、またはそれに苦しむ患者に投与される。
一部の実施形態において、ブラジキニンB2受容体拮抗薬は、対象に投与される。例示的なブラジキニンB2受容体拮抗薬としては、天然ブラジキニンのブラジキニンB2受容体との結合を阻害する、10個のアミノ酸を含有するペプチド模倣薬である、Incatibant(Firazyr(登録商標))を含む。
一部の実施形態において、C1−INH置換薬は、対象に投与される。例示的なC1−INH置換薬は、市販されており、例えば、精製されたヒト低温殺菌ナノ濾過C1−INH濃縮物である、Berinert(登録商標)を含む。
実施例1.血漿における機能的Cl−INHの定量のための活性化第XII因子 および/または血漿カリクレインを用いた複合体ELISA
C1インヒビター、C1−INHの機能異常が、II型遺伝性血管性浮腫(HAE)に存在し、それがインヒビターを無効にすることが実証されている。I型HAEは、総C1−INHタンパク質レベルが低い。III型HAEは、正常なレベルのC1−INHに関連している(「Enzymatic pathways in the pathogenesis of hereditary angioedema:The role of C1 inhibitor therapy.」 Kaplan,A.,The Journal of Allergy and Clinical Immunology 126(5):918−25 2010)。C1−INHは、第XIIa因子、第XII因子断片(XIIf)、カリクレイン、およびプラスミンを抑制する。C1−INHの機能がない場合、重篤な血管性浮腫を引き起こす、ブラジキニン形成カスケードの著しい活性化が起こる。I型HAEは、一般的に、総C1−INHレベルを減少させることを特徴とする。II型HAEは、一般的に、正常なC1−INHレベルを増加させることを特徴とするが、C1−INHレベルの機能は以上である。III型HAEを起こす機構は、十分には分かっていないが、III型HAEは、主に、女性患者について記載されている。
方法
患者および検体収集:HAEの診断は、(市販のアッセイを用いて)C1−INHタンパク質および/または機能的レベルの低さといった臨床症状により確認される。42人のHAE患者および23の健康な対照由来のクエン酸血漿を、新たに収集した血液の、4℃、2000rpmで、10分間の遠心分離により分離した。全てのサンブルをすぐに分取し、−80℃で保存した。検体を全ての参加拠点(オーデンセ、デンマーク、ブダペスト、ハンガリー)で同様に取り扱い、ドライアイス上で一晩輸送した。手順は、倫理委員会(Ethics Committee)およびデータ保護局(Data Protection Agency)によって、両参加拠点において、承認された。
C1s抑制によりHAEの診断:正常対照の23個の検体およびI型またはII型HAEのいずれかに罹患している患者の42個の検体を現在市販されているアッセイ(複合体ELISA)を用いて検査した。アッセイの判断によると、「正常」は、68〜100%C1−INH、一方、「異常」は、67%以下であった。使用説明書は、それらが疑わしいと思われるため、41%と67%との間の検体を繰り返すべきと支持したが、繰り返した値が、それら2つの図内にある場合には、異常であると報告した。標準物質を、一定の割合の正常として供給した、すなわち標準物質は、0%、23%、44%、66%および88%であり、未知のものは、曲線から外れて読み取られた。正常対照検体は、80%〜100%の間を変化する一方、HAE検体は、0〜81%の間を変化した。HAE検体の平均標準偏差は、38±17%であった。本アッセイを使用する2つのHAE患者における診断は、失敗した。
本明細書に開示される特徴は全て、任意に組に組み合わされてもよい。本明細書に開示される特徴は、それぞれ、同一、均等、または同様の目的に供する別の特徴に置換されてもよい。従って、明示的に別段の定めがある場合を除き、開示した特徴は、単に、それぞれ、等価または同様の特徴の総称的な系列のうちの一例である。
Claims (16)
- 血漿プロテアーゼC1インヒビター(C1−INH)を含有する検体を捕捉試薬と接触させることと、
基材に固定化されている前記捕捉試薬に結合する前記検体中のC1−INHのレベルを測定することと、
を含む方法であって、
前記捕捉試薬は、
i)活性型第XII因子もしくはそのC1−INH結合断片、
ii)活性型血漿カリクレインもしくはそのC1−INH結合断片、または
iii)i)およびii)の組み合わせ
を含む、
方法。 - 前記捕捉試薬に結合するC1−INHのレベルが、C1−INHに結合する検出薬を用いて測定される、請求項1に記載の方法。
- 前記捕捉試薬に結合するC1−INHのレベルが、酵素結合免疫吸着法(ELISA)により測定される、請求項1または2に記載の方法。
- 前記C1−INHを含有する検体は対象から得られたものであり、
前記対象はpKal関連疾病の症状を有するか、あるいは前記対象は、前記検体を採取した際にはpKal関連疾病の症状を有さないか、pKal関連疾病の症状の病歴を有さないか、またはpKal関連疾病の病歴を有さない、
請求項1〜3のいずれか1項に記載の方法。 - 前記検体中の前記捕捉試薬に結合するC1−INHのレベルが基準値と比較して減少していることは、前記対象にpKal関連疾病のおそれがあるかまたは前記対象がpKal関連疾病に罹患していることを示す、請求項4に記載の方法であって、
前記pKal関連疾病は、非ヒスタミン依存性突発血管性浮腫、関節リウマチ、クローン病、狼瘡、アルツハイマー病、敗血症性ショック、熱傷、脳虚血/再灌流傷害、脳浮腫、糖尿病網膜症、糖尿病腎症、黄斑浮腫、血管炎、動脈または静脈の血栓症、補助人工心臓またはステントに関連する血栓症;血栓症、血栓塞栓症、および、不安定狭心症を伴う冠動脈疾患、を伴うヘパリン起因性血小板減少症;浮腫、眼疾患、痛風、炎症性腸疾患、口腔粘膜炎、神経因性疼痛、炎症性疼痛、脊柱管狭窄症変性脊椎疾患、術後腸閉塞、大動脈瘤、変形性関節症、遺伝性血管性浮腫(HAE)、静脈血栓症、脳卒中、頭部外傷または腫瘍周辺脳浮腫、敗血症、急性中大脳動脈(MCA)虚血(脳卒中)、再狭窄、全身性エリテマトーデス腎炎、自己免疫疾患、炎症性疾患、心血管疾患、神経疾患、タンパク質のミスフォールディングに関連する疾患、血管新生に関連する疾患、高血圧性腎症および糖尿病腎症、アレルギー性呼吸器疾患、ならびに組織損傷からなる群から選択される、
方法。 - 前記対象は、抗ヒスタミン療法、コルチコステロイド療法、またはその両方に耐性を有する、請求項5に記載の方法。
- 捕捉試薬に結合可能な血漿プロテアーゼC1インヒビター(C1−INH)を検出するためのキットであって、
a)基材に固定化されている捕捉試薬であって、
i)活性型第XII因子もしくはそのC1−INH結合断片、
ii)活性型カリクレインもしくはそのC1−INH結合断片、または
iii)i)およびii)の組み合わせ
を含む捕捉試薬と、
b)C1−INHに結合する検出試薬と、
を含むキット。 - 前記検出試薬は抗C1−INH抗体である、請求項7に記載のキット。
- 対象の遺伝性血管性浮腫(HAE)の治療を評価するための方法であって、
前記治療の前後または前記治療中に前記対象から収集された検体中の、血漿カリクレイン、第XII因子またはその両方を抑制可能な血漿プロテアーゼC1インヒビター(C1−INH)の内在レベルを測定することと、
内在性C1−INHのレベルに基づき、前記治療の有効性を評価することと、
を含み、
前記治療後の、または治療期間にわたる、内在性C1−INHレベルの増加は、前記対象において前記治療が有効であることを示し、
検体中の血漿カリクレイン、第XII因子またはその両方を抑制可能な内在性C1−INHのレベルは、請求項1〜3のいずれか1項に記載の方法によって測定される、方法。 - 前記治療は、カリクレイン結合薬、ブラジキニンB2受容体拮抗薬、またはC1−INH置換薬を含む、請求項9に記載の方法。
- 前記C1−INHに結合する検出薬は、C1−INHに結合する抗体、活性型第XII因子、または活性型血漿カリクレインである、請求項2に記載の方法。
- 前記検体は、前記対象から得られた血液検体または血漿検体である、請求項9に記載の方法。
- 前記症状は、浮腫;腫脹の再発発作;全てまたは大部分が末梢にある腫脹;蕁麻疹;感染症の確証がない発赤、痛みおよび腫脹;および非ヒスタミン関連浮腫からなる群より選択される、請求項4に記載の方法。
- 前記治療は、DX−88、DX−2930、またはEPIKAL−2を含む、請求項10に記載の方法。
- C1−INHをさらに含む、請求項7に記載のキット。
- 前記検体は、血液検体または血漿検体である、請求項1に記載の方法。
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