JP2016531158A - Hsct関連血栓性微小血管症の治療のための組成物及び方法 - Google Patents
Hsct関連血栓性微小血管症の治療のための組成物及び方法 Download PDFInfo
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Abstract
Description
本出願は、2013年9月16日に出願された米国特許仮出願第61/878,119号に対する優先権を主張し、その出願はその全体が本参照によりあらゆる目的のため組み込まれる。
HSCT−TMAは同種異系HSCT後により一般的であるが、なおも自家移植の著しい合併症でもある。後ろ向き研究において同種異系HSCT後のHSCT−TMAの発症と関連づけられるリスク因子は、移植及び感染性合併症の過程で使用される薬を含む。ブスルファン、フルダラビン、シスプラチン、及び放射線を含む条件調節剤は、より後のHSCT−TMAのリスクを上昇させうる。HSCT−TMAと関連すると一般に報告される他の薬は、カルシニューリン阻害剤タクロリムス及びシクロスポリン、並びにより新しい哺乳類ラパマイシン標的(mTOR)阻害剤を含む。小血管損傷の徴候を示す患者はCMV、アデノウィルス、パルボウィルスB19、HHV−6、及びBKウィルスなどの同時感染もまた有しうるため、ウィルス感染はしばしばHSCT−TMAに対する「引き金」であるとみなされる。
一態様においては、造血幹細胞移植(HSCT)を受けた患者においてHSCT関連血栓性微小血管症(HSCT−TMA)を治療するための使用のために、補体経路を阻害することが可能な薬剤が開示される。
HSCTを受けた患者においてHSCT関連血栓性微小血管症(HSCT−TMA)に対する補体阻害剤を使用する治療の有効性をモニタリングするための方法も、また開示される。その方法は、患者の血清試料中の全補体活性(CH50)を測定するステップを有しうる。一定の態様においては、患者は、患者からの血清中のCH50測定値が、酵素免疫測定法により測定される場合は約0〜3CAE単位となるまで、または患者におけるCH50測定値が、溶血法により測定される場合は15CH50単位より低くなるまで、補体阻害剤を投与されうる。
HSCT関連TMAを有する患者においては、腎細動脈中に補体堆積が見られる
我々の構想であるHSCT後の補体媒介性血管損傷に取り組むため、出願人は、HSCT−TMAになった患者及びならなかったHSCT後の患者からの腎臓組織標本を調べた。出願人は、HSCT−TMAの組織学的証拠を有する患者は、腎細動脈中に古典的補体媒介性血管損傷を意味する顕著なC4d堆積を有すると判断した。
HSCT−TMAにおける終末補体遮断薬エクリズマブの使用の構想を支持するであろう、HSCT−TMAの発病機序における終末補体の関与の可能性に取り組むため、出願人は、HSCT−TMAを有するまたは有さないHSCT患者の血清中のsC5bー9を測定することにより、終末補体活性を調べた。sC5bー9試験は、臨床患者試験に関して認可された方法を使用してCCHMC血液学実験室にて実施された(CLIA認可実験室)。
我々は、補体系活性化に関するHSCT−TMAのリスク特徴を調べるため、小児及び若年成人患者100人に対し前向き研究を実施した。患者39人(39%)が、発表されているHSCT−TMAに対する基準を満たした。HSCT−TMAを有する患者は、HSCT−TMAを有さない患者と比較して、HSCT後1年において、有意により高い非再発死亡率を有した(43.6%対7.8%、p<0.0001)(図1)。高い乳酸脱水素酵素(LDH)、定期的検尿でのタンパク尿症、及び高血圧は、HSCT−TMAの最も早期のマーカーであった(図5)。
補体活性化はHSCT−TMAを有する患者において全身性血管損傷の要因であるという我々の構想に基づき、出願人は予備の患者群をエクリズマブで治療した。
酵素免疫測定法により測定されるCH50レベル0〜3CAE単位は、>99μg/mLのエクリズマブ濃度に対応した(図7)。反対に、≧4CAE単位のCH50カウントを有する全ての試料採取時点において、患者のエクリズマブ濃度は99μg/mL(p=0.0001)より低かった。CH50<3CAE単位は、少なくとも99μg/mLまたはより高い血清エクリズマブと相関した(本方法による正常なCH50レベルは、60〜144CAEである)。
後に、出願人は、高リスクHSCT−TMAを有する別の患者12人を治療した。これらの患者におけるCH50レベルは、標準ヒツジ赤血球を使用する溶血法を使用して決定された(図8)。図8は、標準ヒツジ赤血球を使用する溶血法を使用することによる、CH50の濃度の、>99μg/mLのエクリズマブ濃度との相関付けを示す(n=12)。CH50レベル0〜15CH50単位は、全治療の間(A)、並びに別々に解析された最初及び2回目の用量の間(B)、>99μg/mLのエクリズマブ濃度に対応した(図8)。(本方法による正常なCH50レベルは、101〜300CH50単位である)。
機能的補体活性の決定のための伝統的な方法は、全溶血(CH50)分析である。本分析法は、試験試料の、抗赤血球抗体で被覆されたヒツジ赤血球の標準懸濁液の50%を溶解する能力を測定する。古典活性化及び終末補体成分の両者が、この反応においては測定される。
CH50補体試験は、感作されたヒツジ赤血球を使用する溶血分析であり、Diamedix Corporationから入手可能である。これらの細胞は、ヒツジ赤血球に対する抗体により感作され、抗原抗体複合体が形成される。ヒト血清中で補体に暴露されると、赤血球の溶解が起こり、遊離ヘモグロビンが放出される。溶解の度合いは、ヒト血清中の全補体の濃度と比例する。生じる溶血は415nmにて読まれ、既知濃度のレファレンス血清と比較される。
24時間以内の試料については、ヒト血清は−20℃にて冷凍保存される。溶血済みの試料は使用されない。試験中は、試料は解凍されて混合され、それから使用までの間2〜8℃にて冷却保存した。
EZ Complement Cells(Diamedix Corporation、カタログ番号789−001)
EZ Complement Reference Serum(EZ Complement Standard、Diamedix Corporation、カタログ番号789−006)
EZ Complement Low Control、及びEZ Complement High Control(Diamedix Corporation、カタログ番号789−008&789−009)
EZ Complement Cellsは、2から8℃にて保存されるべきである。Control及びReference血清は、0℃から−20℃にて保存される。試薬は箱に掲載される有効期限日まで安定である。
ピッペット
チューブラック
ボルテックス
タイマー
遠心分離機
マイクロプレートリーダー(415nm)
Reference Serum、及びQuality Control材料は、凍結乾燥されたヒト血清である。それらは、使用前に冷たい蒸留水300μlを用いて元に戻されて穏やかに混合され、5分間室温にて保持される。バイアル瓶は、使用前さらに10分、氷上で保持された。元にもどったら、8時間以内に試験される。
1. 存在する患者と同じ数のチューブが、またLow及びHigh QC、Blank(自発的溶解)、並びにReference(標準)に対しチューブ1本ずつが、準備される。
Blank(自発的溶解)の吸光度は、0.150より低くなければならない。品質管理値は、期待される範囲内でなければならない。
試験試料中で起こりうる自発的溶解の度合いを補正するため、Blankチューブの吸光度が、試験試料の吸光度から引かれる。
試料の吸光度 X CH50値 = 試料のCH50値
品質管理
2つのレベルの品質管理がキットと共に提供される。
実験各回に対し、品質管理、キットのロット番号、及び有効期限日を記録文書化するために、ワークシートが使用される。各対照の範囲は、ワークシート上で見ることができる。実施された各解析についての品質管理及び患者の結果を報告するには、The Cerner Laboratory Reporting Systemが使用される。
無しまたは低い 0〜100
正常 101〜300
高い >301
報告形式 結果は、CH50単位で報告される。実験はゼロから400CH50単位まで線形である。
線形性試験は、「ゴールドスタンダード」材料と比較された場合、本分析は400CH50単位まで線形であることを示した。
治療用の血漿交換(TPE)は、エクリズマブを開始する前に、それを受けている患者において停止された。TPEは薬を洗い流してしまうため、薬を除去しないように、である。エクリズマブの最初の用量は、非典型溶血性尿毒症症候群(aHUS)を有する子供に対する推奨事項に従い与えられた(表2)。エクリズマブは、中心静脈アクセスを介して30〜60分かけて注入された。免疫が低下したHSCTレシピエントは髄膜炎菌ワクチンに応答しないため、エクリズマブが排除されCH50レベルが正常化するまで、全患者はシプロフロキサシンまたはペニシリンVK予防法を受けたままとした。各用量後には、各用量の前に引き起こされるトラフレベルを含む血清中のエクリズマブレベルが、少なくとも週2回調べられた。エクリズマブ薬剤レベルはCambridge Biomedical, Inc.(マサチューセッツ州ボストン)にて臨床試験として実施され、トラフ濃度>99μg/mLが治療量とみなされた。レベルは4〜10日の応答時間で報告され、しばしば直後には入手可能ではなかったので、投薬調節は以下のように相違した。トラフレベルが次の週毎の用量前に報告されかつ治療量であった場合は、図10中のスケジュールに従って用量が与えられた。患者が次の週毎の用量の期限がきていて、かつエクリズマブトラフ濃度が報告され治療量未満であった場合は、次の用量は300mg/用量上昇させられた。治療量未満の結果が前の用量から4〜5日後に報告された場合、追加の週半ばの用量が与えられた。用量調節のために結果が入手できなかった場合は、同じエクリズマブ導入用量が、トラフエクリズマブ濃度が治療量より高いことが記録されるまで毎週継続された。
患者6人の全員が、当初は顕著なHSCT−TMA関連合併症を報告した。患者5及び6は、エクリズマブの開始前に多臓器不全で重篤であった。
患者1〜4は、治療量のエクリズマブレベルを達成した後、エクリズマブに対する完全な臨床応答を示した。HSCT−TMAを治すには、メジアンで7用量(4〜13用量の範囲)のエクリズマブが必要であった。血液学的応答は、エクリズマブ開始からメジアンで28.5日(15〜45日)後に観察された。全応答者が高血圧の劇的な改善を示し、抗高血圧薬の数が、エクリズマブ療法の開始時の6〜9から、エクリズマブ療法完了時の0〜2剤まで減少した。シスタチンC−eGFRの倍加、及び2mg/mg未満のタンパク尿症の改善を含む、全てのHSCT−TMAパラメーターの完全奏功にかかった時間のメジアンは、エクリズマブ開始後69.5日(29〜141日)後であった。HSCT−TMA後メジアンで38.5週間(29〜63週間の範囲)後の時点において、全ての応答者が現在良好である。患者1及び4は、>100ml/分の正常シスタチンC−eGFR、並びにタンパク尿症及び高血圧がないことから証明されるように、腎機能を完全に回復させた。患者2及び3は、両者ともエクリズマブ療法開始時にHSCT−TMAゆえの重度の遷延性の重度の腎臓損傷を有した。両者は、慢性腎疾患、及びシスタチンC−eGFR<50ml/分を有したままだが、血液透析は受けておらず、かつロサルタン療法を受けた状態で正常血圧を示す。
治療の最初の三週間についてのエクリズマブ投薬及びレベルの代表的な実例が、図9に示される。全体的には、患者6人のうち4人が、最初の用量後には治療量未満のエクリズマブレベルを有した。とりわけ、患者3に対する最初のエクリズマブ用量は、彼の体重9kgに対して推奨される(300mg)より高く(600mg)、最初の用量後に治療量をもたらした。追加の用量数または現在推奨されるより高い用量を使用して、応答者4人全員(患者1から4)において、最終的にはエクリズマブの治療量トラフレベル>99μg/mLが達成された。非応答の2症例(患者5及び6)においては、エクリズマブトラフレベルは治療量未満のままであった。患者5は、治療の第24日から開始した毎週900mg二回への著しい用量上昇にもかかわらず、5週間の治療の間には治療量トラフレベルを達成しなかった。患者6は、治療量エクリズマブレベルを達成することなく死亡する前、彼の体重に対して推奨されるとおり、毎週2回の導入用量900mgが投与された。非応答者両者において、最初の用量から3日後、エクリズマブレベルは治療量未満だったが、血清エクリズム濃度の結果は未決定であったため、投薬は適時には調節され得なかった。エクリズマブの消失速度定数及び全身クリアランスは、患者間で著しい変動性を示した。治療時に最も病状が悪く、かつおそらく応答した患者に比べより高い異化作用を有した患者5及び6において、クリアランスが最も迅速であった(データ表示なし)。
エクリズマブ及びCH50レベルが同時点において測定され、互いに強く相関した(図6〜7)。具体的には、第1週における非常に迅速な消失相の間に得られた患者6からの測定値1つを除き、0〜3CAE単位のCH50カウントが>99μg/mLのエクリズマブ濃度に対応した。反対に、≧4CAE単位のCH50を有した試料採取時点全てにおいて、患者のエクリズマブ濃度は<99μg/mLで治療量未満であった(p=0.0001)。
出願人は、重度のHSCT−TMAの治療における、終末補体阻害剤エクリズマブの使用を報告する。出願人は、患者の66.7%が、治療量のエクリズマブレベルを達成した後、重度のHSCT−TMAの完全奏功を示したことを観察した。出願人の前向きHSCT−TMA研究において、そのような高リスクHSCT−TMAを有する患者の生存率は、補体遮断療法なしで20%であった。非応答可患者は、用量上昇にもかかわらず、治療量の薬剤レベルまたは補体遮断を達成することなく死亡した。治療量エクリズマブレベルに達しかつそれを維持するためには、HSCT−TMAを有する全患者は、aHUSを有する患者に対して現在推奨されている投薬レジメンと比較して、より高いエクリズマブ投薬、及び/またはより頻繁な投与を要した。より早期の、または適時な用量上昇を用いるより積極的な治療は、非応答患者に対して治療をより有効にすることを可能にしたかもしれない。重要なことに、出願人は、臨床応答及びエクリズマブ薬剤レベルが、補体遮断の容易に測定される薬力学マーカーである全補体活性(CH50)と良く相関することを観察した。エクリズマブ血清濃度の測定は広くは利用可能でなく、結果が戻るのに>1週間かかりうる。従って、CH50検査は、補体遮断、及び治療量エクリズマブレベルとの相関のより迅速な評価を提供し、より適時的な方式で実用的な用量調節を可能にする。
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Claims (33)
- 造血幹細胞移植(HSCT)を受けた患者において、HSCT関連血栓性微小血管症(HSCT−TMA)を治療するために使用する、補体経路を阻害することが可能な薬剤。
- 請求項1記載の使用のための薬剤において、前記薬剤が、前記補体経路を阻害することが可能な抗体である、薬剤。
- 請求項1記載の使用のための薬剤において、前記薬剤が、前記補体経路を阻害することが可能なモノクローナル抗体である、薬剤。
- 請求項1記載の使用のための薬剤において、前記薬剤が、前記補体経路を阻害することが可能なヒト化モノクローナル抗体である、薬剤。
- 請求項1〜4記載の使用のための薬剤において、前記薬剤がエクリズマブである、薬剤。
- 請求項1〜5のいずれか一項記載の使用のための薬剤において、前記使用が毎日、2日毎、または3日毎に繰り返される、薬剤。
- 造血幹細胞移植(HSCT)を受けた患者において、HSCT関連血栓性微小血管症(HSCT−TMA)に対する補体阻害剤を用いる治療の効能をモニタリングする方法であって、前記患者の試料における全補体活性(CH50)を測定する工程を有する、方法。
- 請求項7記載の方法において、酵素免疫測定法によって測定される前記CH50測定値が約0〜3CAE単位となるまで、または溶血法によって測定される前記CH50測定値が15CH50単位より低くなるまで、前記患者が補体阻害剤を投与される、方法。
- 請求項7記載の方法であって、さらに、初期CH50測定値を得るために、補体阻害剤を用いる治療の前に、前記患者の試料における全補体活性(CH50)を測定する工程を有する、方法。
- 請求項1〜6のいずれか一項記載の使用のための薬剤において、前記患者において血液学的応答または完全奏功が達成されるまで、前記使用が実行される、薬剤。
- 請求項1〜6のいずれか一項記載の使用のための薬剤において、約4〜約15週間にわたり、またはそれより長く、前記使用が実行される、薬剤。
- 請求項1〜6または10〜11のいずれか一項記載の使用のための薬剤において、前記患者がエクリズマブを毎週投与される、薬剤。
- 前記補体阻害剤が静脈内及び/または経口的に投与される、請求項1〜6もしくは10〜12のいずれか一項記載の使用のための薬剤、または請求項7〜9のいずれか一項記載の方法。
- 骨髄移植を受けた患者において、HSCT関連血栓性微小血管症(HSCT−TMA)を治療する方法であって、
a)補体を阻害することが可能な薬剤または抗体、好ましくは終末補体を阻害することが可能なモノクローナル抗体を投与する工程
を有する、方法。 - 請求項14記載の方法において、前記抗体が終末補体を阻害することが可能なヒト化モノクローナル抗体である、方法。
- 請求項14記載の方法において、前記抗体がエクリズマブである、方法。
- 請求項14記載の方法において、前記投与する工程が、前記患者において治療量レベルを達成するのに十分であるように実行され、好ましくは、前記治療量レベルが、約99μg/mLより高いまたは少なくとも約99μg/mLの血清レベルを有する、方法。
- 請求項14記載の方法において、前記投与する工程が、前記患者において約99μg/mLより高いまたは少なくとも約99μg/mLの血清レベルが達成されるまで、毎日、または2日毎、または3日毎に繰り返されるものである、方法。
- 請求項14記載の方法において、前記投与する工程が、前記患者において治療量エクリズマブレベルを達成するのに十分であるように実施され、好ましくは、前記治療量レベルが、約99μg/mLより高いまたは少なくとも約99μg/mLの血清エクリズマブレベルを有する、方法。
- 請求項14記載の方法であって、さらに、全補体活性(CH50)測定値を得るためにCH50を測定する工程を有し、前記患者が、酵素免疫測定法によって測定される前記患者から得られるCH50測定値が約0〜3CAE単位となるまで前記補体阻害剤を投与され、または標準ヒツジ赤血球を使用する溶血法を使用して測定されるCH50測定値が<15CH50単位である、方法。
- 請求項14記載の方法であって、さらに、
b)初期の全補体活性(CH50)測定値を得るため、補体阻害剤を用いる治療の前に、CH50を測定する工程、
c)前記補体阻害剤を投与する工程、及び
d)治療後のCH50測定値を得るために、前記補体阻害剤の投与後の全CH50活性を測定する工程
を有し、前記補体阻害剤は、酵素免疫測定法によって測定される前記治療後のCH50測定値が約0〜3CAE単位となるまで投与され、または標準ヒツジ赤血球を使用する溶血法を使用して測定されるCH50測定値が<15CH50単位である、方法。 - 請求項14記載の方法において、前記投与する工程が、HSCT−TMAを治すのに十分な期間にわたり実行される、方法。
- 請求項14記載の方法において、前記投与する工程が約4〜約15週間にわたり実行され、前記エクリズマブの投与が、酵素免疫測定法によって測定されるCH50レベルを0〜3CAE単位、好ましくは0単位まで低下させるのに十分な用量におけるものであり、または標準ヒツジ赤血球を使用する溶血法を使用して測定されるCH50測定値が<15CH50単位である、方法。
- 請求項14記載の方法において、前記投与する工程が、好適な血液学的応答を達成するのに十分な期間にわたり実行され、好適な血液学的応答が血液学的TMAマーカーの解消を有する、方法。
- 請求項14記載の方法において、前記投与する工程が、完全奏功を達成するのに十分な期間にわたり実行され、前記完全奏功が前記患者の血液学的パラメーターの正常化を有する、方法。
- 請求項14記載の方法において、前記患者がエクリズマブを毎週投与される、方法。
- 請求項14記載の方法において、前記患者がエクリズマブを毎週投与され、前記用量が治療量でない場合、次の週毎の用量が300mg/用量増加される、方法。
- 請求項14記載の方法において、前記投与する工程が、好適な血液学的応答を達成するのに十分な期間にわたり実行され、好適な血液学的応答が、乳酸脱水素酵素(LDH)の正常化と、赤血球及び血小板輸血の必要性の解消と、分裂赤血球の消滅とのうちの1つまたはそれ以上を有する、方法。
- 請求項14記載の方法において、前記投与する工程が、完全奏功を達成するのに十分な期間にわたり実行され、前記完全奏功が、
前記患者の血液学的パラメーターの正常化、
シスタチンC推定糸球体濾過量(eGFR)の倍加として測定される腎臓応答、及び
2mg/mgより低いランダムスポット尿蛋白対クレアチニン比によって定義されるネフローゼ範囲より低い値への、タンパク尿症の改善
を有する、方法。 - 補体阻害剤を投与された患者において、補体阻害剤の相対レベルを決定する方法であって、前記患者の試料中の全補体活性(CH50)を測定する工程を有する、方法。
- 請求項30記載の方法において、前記補体阻害剤がエクリズマブを有する、方法。
- HSCT後であるか否かによらずTMAの何らかの症状を有する患者において、エクリズマブ投薬スケジュールを最適化する方法であって、
a.導入用量のエクリズマブによって治療される前記患者において、全補体活性(CH50)を決定する工程を有し、
CH50レベルが十分に抑制されない場合は、2回目の導入用量が投与され、
CH50レベルが十分に抑制される場合は、前記患者は毎週の導入用量を投与され、
前記2回目の導入用量の後にCH50レベルが十分に抑制されない場合は、前記導入用量が約100mg〜約400mg、好ましくは約300g増加され、
前記患者は、TMAの血液学的兆候が解消されるまでエクリズマブを投与される、方法。 - 請求項32記載の方法であって、さらに、CH50が十分に抑制されるまで維持用量を提供する工程を有する、方法。
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