JP2019521981A - セリアック病、非セリアックグルテン過敏症及び難治性セリアック病を治療するための方法及び組成物 - Google Patents
セリアック病、非セリアックグルテン過敏症及び難治性セリアック病を治療するための方法及び組成物 Download PDFInfo
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Abstract
Description
便宜上、この節では、本明細書、実施例及び添付の請求項で用いられている特定の用語がまとめられている。別段の定めのない限り、本明細書で用いられているすべての技術的用語及び科学的用語は、本開示が属する分野の当業者によって一般に理解される意味と同じ意味を有する。
本発明は、一態様では、治療用抗体又はその抗原結合断片(例えば、IL−15と結合するヒトモノクローナル抗体又はその抗原結合断片)を治療有効量有する医薬組成物であって、製薬学的に許容可能な担体とともに調合できる医薬組成物を含む。
セリアック病は、遺伝的感受性の高い個体において、グルテンの消費によって誘発される全身性自己免疫疾患である(Green and Cellier,2007)。現在、米国(US)と欧州連合(EU)の人口の約1%が、セリアック病に罹患しており、それにもかかわらず、診断されているのは、10〜20%のセリアック病患者に過ぎない。セリアック病は、グルテン(非常に多く見られる穀物(例えば、小麦、大麦、ライ麦)のいくつかに存在する主要なタンパク質)という抗原が特定された最初の自己免疫疾患であった。現代の食事においては、グルテンの量が増え続けており、グルテンは、加工食品、化粧品及び経口薬物において添加剤としても使用されている。グルテンは、糖に続いて、2番目に多い食品成分であり、いくつかの国では、最大で食品の80%に存在している。
まれではあるが、セリアック病における、グルテンへの持続的暴露の特有の合併症が、難治性セリアック病(RCD)の発現であり、セリアック病患者のおよそ1%がRCDを罹患している(Lebwohl et al.,2013)。RCDは、グルテンを消費していない状態、かつ小腸異型IELの存在下における重度の腸管粘膜萎縮と消化器症状によって特徴付けられる(Verbeek et al.,2008,vanWanrooij et al.,2014)。
例示的な臨床試験では、AMG714を成人CD患者に投与できる。この試験の第1の目的は、AMG714が、CDの成人において、グルテン暴露の作用を低減する有効性を評価することである。第2の目的は、グルテン感作した成人セリアック病患者に投与したときのAMG714の安全性と忍容性を評価することである。診査目的は、AMG714の薬物動態(PK)、薬力(PD)及びPK/PDの相関関係を評価することである。
(1)12週時点において、グルテン誘導性小腸管粘膜炎症が、ベースラインよりも低減したか(組織切片における上皮内リンパ球(IEL)の計数によって測定)。タイムフレーム:ベースライン及び12週間。小腸生検標本を処理して、ヘマトキシリン−エオシン染色によって染色して、上皮細胞100個当たりのIELを計数できる。
(2)12週時点において、グルテン誘導性血清抗体がベースラインよりも低減したか(抗脱アミド化グリアジンペプチド(DGP))及び自己抗体(抗トランスグルタミナーゼ(ATG))。タイムフレーム:ベースライン及び12週間。DGPとATG抗体は、血清において、ELISA法によって測定できる。
(3)12週時点において、グルテン誘導性臨床症状がベースラインよりも軽減したか(Gastrointestinal Symptom Rating Scale(GSRS)によって測定)。タイムフレーム:ベースライン及び12週間。毎回の診察時に(おおむね月に1回)、GSRSの質問書に記入することができる。
プロトコールは、グルテン感作中の成人セリアック病患者において、グルテン暴露の作用を低減するためのAMG714の有効性と安全性を評価する第2a相無作為化二重盲検プラセボ対照並行群間試験となるように設計する。
・スクリーニングの少なくとも12カ月前に、腸生検によって、セリアック病と診断された
・少なくとも12カ月、グルテンフリー食を摂取している
・セリアック病血清反応が陰性である
・妊娠の回避
・重篤なセリアック病合併症(難治性セリアック病など)
・セリアック病症状
・他の併発自己免疫疾患
・慢性活動性GI疾患
・感染症、併発疾患
・薬物の禁止
例示的な臨床試験では、II型難治性セリアック病の成人患者において、AMG714の有効性と安全性を試験できる。この試験の第1の目的は、AMG714が成人患者のRCD−IIを治療する有効性を評価することとなる。この試験の第2の目的は、RCD−IIの成人患者に投与した場合のAMG714の安全性と忍容性を評価することとなる。この試験の診査目的は、AMG714の薬物動態(PK)、薬力(PD)及びPK/PDの相関関係を評価することとなる。
(1)組織学的応答:小腸形態のベースラインからの改善(腸生検物質における絨毛の高さと陰窩の深さ(VH:CD)の比によって測定)。タイムフレーム:ベースライン及び12週間。
(2)臨床応答:臨床症状のベースラインからの変化(Gastrointestinal Symptom Rating Scale(GSRS)によって測定)。タイムフレーム:ベースライン及び12週間。
プロトコールは、成人RCD−II患者を治療するためのAMG714の有効性と安全性を評価する第2a相無作為化二重盲検プラセボ対照並行群間試験となるように設計する。
・2型難治性セリアック病(RCD−II)の診断が確認された
・異型上皮内リンパ球(IEL)が20%超(フローサイトメトリーによって評価)
・少なくとも6カ月間、グルテンフリー食を摂取している
・妊娠の回避
・腸管症型T細胞リンパ腫(EATL)
・感染症
・免疫抑制
・臨床的に有意な共存症
EFS−Webを介して本明細書とともに提出した「A2082PCT.txt」という名称のASCIIテキストファイル(2016年6月15日に作成、サイズ4,623バイト)は、参照により、その全体が本明細書に援用される。
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Claims (30)
- セリアック病又は非セリアックグルテン過敏症の治療を必要とする対象のセリアック病又は非セリアックグルテン過敏症の治療方法であって、治療有効量の抗IL−15抗体又はその抗原結合断片を、前記対象に投与することを含み、前記治療有効量が、それぞれ約1〜12週間おきに投与する1〜20回分の単位用量を含み、各単位用量が独立して、前記抗IL−15抗体又はその抗原結合断片を約50〜1000mg、好ましくは75〜600mg、より好ましくは約75mg、約150mg、約300mg又は約600mg含む、前記方法。
- 前記抗体が、配列番号5〜7の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項1に記載の方法。
- 前記抗体が、配列番号8〜10の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項1又は2に記載の方法。
- 前記抗体が、配列番号2のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項1又は2に記載の方法。
- 前記抗体が、配列番号4のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項3に記載の方法。
- 前記治療有効量が、約2週間おきに投与する6回分の単位用量を含む、請求項1に記載の方法。
- 前記各単位用量を皮下注射又は静脈内注射によって投与する、請求項1又は6に記載の方法。
- セリアック病又は非セリアックグルテン過敏症の治療用の医薬組成物であって、治療有効量の抗IL−15抗体又はその抗原結合断片を含み、前記治療有効量が、それぞれ約1〜12週間おきに投与する1〜20回分の単位用量を含み、各単位用量が独立して、前記抗IL−15抗体又はその抗原結合断片を約50〜1000mg、好ましくは75〜600mg、より好ましくは約75mg、約150mg、約300mg又は約600mg含む、前記医薬組成物。
- 前記抗体が、配列番号5〜7の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項8に記載の医薬組成物。
- 前記抗体が、配列番号8〜10の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項8又は9に記載の医薬組成物。
- 前記抗体が、配列番号2のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項8又は9に記載の医薬組成物。
- 前記抗体が、配列番号4のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項10に記載の医薬組成物。
- 前記治療有効量が、2週間おきに投与する6回分の単位用量を含む、請求項8に記載の医薬組成物。
- 前記各単位用量を皮下注射又は静脈内注射によって投与する、請求項8又は13に記載の医薬組成物。
- 難治性セリアック病の治療を必要とする対象の難治性セリアック病の治療方法であって、治療有効量の抗IL−15抗体又はその抗原結合断片を、前記対象に投与することを含み、前記治療有効量が、それぞれ約1〜12週間おきに投与する1〜20回分の単位用量を含み、各単位用量が独立して、前記抗IL−15抗体又はその抗原結合断片を約1〜50mg/kg、好ましくは約4〜16mg/kg、より好ましくは約4mg/kg、約8mg/kg、約12mg/kg又は約16mg/kg含む、前記方法。
- 前記抗体が、配列番号5〜7の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項15に記載の方法。
- 前記抗体が、配列番号8〜10の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項15又は16に記載の方法。
- 前記抗体が、配列番号2のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項15又は16に記載の方法。
- 前記抗体が、配列番号4のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項17に記載の方法。
- 前記治療有効量が、2週間おきに投与する6回分の単位用量と、1週目における任意の追加的な負荷用量を含む、請求項15に記載の方法。
- 前記各単位用量を皮下注射又は静脈内注射によって投与する、請求項15又は20に記載の方法。
- 前記難治性セリアック病が、I型又はII型である、請求項15に記載の方法。
- 難治性セリアック病の治療用の医薬組成物であって、治療有効量の抗IL−15抗体又はその抗原結合断片を含み、前記治療有効量が、それぞれ約1〜12週間おきに投与する1〜20回分の単位用量を含み、各単位用量が独立して、前記抗IL−15抗体又はその抗原結合断片を約1〜50mg/kg、好ましくは約4〜16mg/kg、より好ましくは約4mg/kg、約8mg/kg、約12mg/kg又は約16mg/kg含む、前記医薬組成物。
- 前記抗体が、配列番号5〜7の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項23に記載の医薬組成物。
- 前記抗体が、配列番号8〜10の1つ又は複数の相補性決定領域又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項23又は24に記載の医薬組成物。
- 前記抗体が、配列番号2のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む重鎖可変領域を有する、請求項23又は24に記載の医薬組成物。
- 前記抗体が、配列番号4のアミノ酸配列又はその配列に対する配列同一性が少なくとも80%である配列を含む軽鎖可変領域を有する、請求項25に記載の医薬組成物。
- 前記治療有効量が、2週間おきに投与する6回分の単位用量と、1週目に投与する任意の追加的な負荷用量を含む、請求項23に記載の医薬組成物。
- 前記各単位用量を皮下注射又は静脈内注射によって投与する、請求項23又は28に記載の医薬組成物。
- 前記難治性セリアック病が、I型又はII型である、請求項23に記載の方法。
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