JP2021532176A - ブラジクマブによる潰瘍性大腸炎の処置 - Google Patents
ブラジクマブによる潰瘍性大腸炎の処置 Download PDFInfo
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Abstract
Description
本出願は、2018年7月13日に提出された米国仮特許出願第62/697,939号明細書に対する優先権を主張し、その内容全体を参照により本明細書に組み込むものとする。
本願は、開示の個別部分として、コンピュータで読み取り可能な形態の配列表(ファイル名:53230A_Seqlisting.txt;Size:4,764バイト;作成:2019年7月11日)を含み、その内容全体を参照により本明細書に組み込むものとする。
アッセイ
表2に記載するアッセイは、当技術分野で公知の手順に従って実施され、これらは、本明細書に開示される実験の結果に寄与する。
血清ブラジクマブ濃度測定のために静脈血サンプルを採取した。母集団薬物動態(PK)手法を用いて、血清濃度データを分析し、また、このデータを使用して、母集団PKモデルを用いるブラジクマブの曝露−応答関係を特性決定した。当技術分野で公知の従来の技術を用いて、薬物動態パラメータを決定する。血清採取のために、適切なSSTバキュテイナ(Vacutainer)(PKには5mLサイズ、ADAには15mLサイズ、IL−22には5mL、他の検査バイオマーカには10mL)及びクライオバイアルをコード化ラベルで標識する。血液を採取した後、チューブを穏やかに約5回反転させて、血液をチューブの内容物と混合させる。室温で30分間かけて血液を凝固させる。30分後、且つその時点から45分以内に血液を取り出し、1100〜1300gで15分間遠心分離させる。採取した血清を直ちに(又は血液収集から2時間以内に)、各々PK、ADA、IL−22及び血清検査バイオマーカ用の少なくとも2個、しかし最大7個の、予冷した標識クライオバイアルに移す。各バイアルは、少なくとも1mLの血清を含有するべきである。血清チューブを約−70℃の冷凍庫内又はそれより低温の条件に配置し、直立位置で保存する。
ブラジクマブ毒性学評価
中度から重度の活動性潰瘍性大腸炎患者に対するIL−23特異的抗体の効果を調べるために、ランダム化、二重盲検、ダブルダミー、実薬及びプラセボ対照、並行群試験を設計した。偏りを最小限にするために、二重盲検及びダブルダミー技術並びに参加者の無作為割当てを含む複数の設計特徴を試験に取り込むが、これらは、既知及び未知両方のリスク因子が介入群の間に均等に分布されることを確実にする上で役立つ。実薬−対照群並びにプラセボ−対照群を組み込むことによって、プラセボからの試験介入を識別することができない場合に、それが試験介入の無効性を意味するのか、又は単に実薬を同定する能力が欠如した試験の結果であるかが容易に明らかにされる。プラセボと標準治療薬の比較によって、分析感度の内部エビデンスが提供される。
潰瘍性大腸炎のブラジクマブ処理
本試験の参加者は、年齢18〜80歳(両端の値を含む)で、従来の療法に失敗したか、又は不耐容性であった中度から重度の活動性潰瘍性大腸炎を有する。これは、生物剤を受けたことがない(生物剤ナイーブ)参加者、又はUCの処置のために承認された用量で生物剤(例えば、抗TNFα)を受けたことがあり、早期に応答しなかった(すなわち、一次不応答)、若しくは早期に応答したが、継続療法で応答を喪失した(すなわち、二次不応答)か、若しくは薬剤に対して不耐容性であった参加者を含む。これはまた、後の処置失敗なしに好適な応答で、生物剤(ベドリズマブを含む)を以前受けたことがある患者も含む。しかし、ベドリズマブは実薬対照として使用されることから、ベドリズマブによる処置に失敗した(処置に対する一次若しくは二次不応答についての基準を満たした)か、又はそれに対して不耐容性の参加者は除外される。
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Claims (21)
- 被験者の潰瘍性大腸炎を処置する方法であって、潰瘍性大腸炎を有する被験者に、IL−12を阻害しない抗IL−23抗体を治療有効量で投与することを含む方法。
- 前記被験者が、大腸内視鏡検査により決定される通り、中度から重度の活動性潰瘍性大腸炎を有する、請求項1に記載の方法。
- 前記抗IL−23抗体が、静脈内注入により投与される、請求項1に記載の方法。
- 少なくとも700mg、少なくとも1400mg、少なくとも2100mg、又は少なくとも4200mgの総用量の抗IL−23抗体が投与される、請求項3に記載の方法。
- 前記静脈内注入が、少なくとも30分の期間にわたって送達される約100mlの容積中、少なくとも70mgの抗IL−23抗体を含む、請求項3に記載の方法。
- 複数回の静脈内注入が投与される、請求項1に記載の方法。
- 前記複数回の静脈内注入が、各々、同じ量の抗IL−23抗体を含む、請求項6に記載の方法。
- 前記抗IL−23抗体が皮下投与される、請求項1に記載の方法。
- 前記抗IL−23抗体が、複数回用量で投与される、請求項8に記載の方法。
- 少なくとも105mg又は少なくとも210mgの総用量の抗IL−23抗体が投与される、請求項9に記載の方法。
- 各用量が、約70mgの抗IL−23抗体を含む、請求項9に記載の方法。
- 前記方法が複数回用量の抗IL−23抗体をさらに含み、2回目の用量が、最初の用量から約2週間後に投与され、3回目以降の用量が、前回用量の約4週間後に投与される、請求項1に記載の方法。
- 前記複数回用量が、約10用量である、請求項12に記載の方法。
- 1回目及び2回目用量が静脈内注入により投与され、それに続く用量は全て、皮下投与される、請求項12に記載の方法。
- 各用量が、少なくとも70mgの抗IL−23抗体を含む、請求項13に記載の方法。
- 潰瘍性大腸炎の修正Mayoスコア/疾患活動性インデックスを用いて、治療法の効果を測定することをさらに含む、請求項1に記載の方法。
- 前記治療法が、潰瘍性大腸炎の修正Mayoスコア/疾患活動性インデックスの少なくとも2つの構成要素のスコアを低下させ、ここで、前記構成要素は、排便回数、直腸出血、内視鏡所見及び医師の包括的評価からなる群から選択される、請求項16に記載の方法。
- 前記抗IL−23抗体が、配列番号3のCDRH1、配列番号4のCDRH2、配列番号5のCDRH3、配列番号6のCDRL1、配列番号7のCDRL2及び配列番号8のCDRL3を含む、請求項1に記載の方法。
- 前記抗IL−23抗体が、配列番号1の可変領域配列を含む、請求項1に記載の方法。
- 前記抗IL−23抗体が、配列番号2の軽鎖可変領域配列を含む、請求項1に記載の方法。
- 前記抗IL−23抗体が、配列番号1の重鎖可変領域配列、及び配列番号2の軽鎖可変領域配列を含む、請求項1に記載の方法。
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