JP2010519512A - 甲状腺障害リスクの同定方法 - Google Patents
甲状腺障害リスクの同定方法 Download PDFInfo
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Abstract
Description
本願は、2007年2月16日に出願された米国特許仮出願第60/901,732号の利益を主張する。上記出願の全教示は参照によって本明細書に援用される。
甲状腺の主な機能は、甲状腺ホルモンL-チロキシン(T4)およびL-トリヨードサイロニン(T3)を分泌することである。これらの甲状腺ホルモンは、代謝の重要な局面を調節している。T3およびT4の血中レベルが異常に低い場合に甲状腺機能低下症の状態が存在し、そのレベルが異常に高い場合に甲状腺機能亢進症が存在する。治療されていない重度の甲状腺機能低下症は、体重増加、低エネルギーおよび抑鬱、寒さに耐えられないこと、ならびに皮膚および髪の変化を特徴とする。治療されていない重度の甲状腺機能亢進症は、甲状腺中毒症と呼ばれる状態を示し、体重低下、神経質または感情の不安定、暑さに耐えられないこと、震え、ならびに速い心拍数を特徴とし、心臓心房細動を生じ得る。いくつかの場合に、甲状腺機能低下症または甲状腺機能亢進症は、実験室の試験で甲状腺機能の異常が発見されるにも関わらず、識別可能な症状または徴候がなく生じ得る(例えば、無症状甲状腺障害)。
CAMMS223は、初期、進行性、再発-寛解性MSを有する患者の治療におけるインターフェロンβ-1a(Rebif(登録商標))と比較してアレムツズマブ(alemtuzumab)の2つの用量レベルの安全性および有効性を調査する第2相臨床試験の名称である。CAMMS223への参加に当てはまる患者を、登録前に抗甲状腺刺激ホルモン(TSH)受容体抗体(以下、TSHRA)についてスクリーニングし、陽性の場合は排除した。また、患者を抗甲状腺ペルオキシダーゼ抗体(以下、TPOA)について試験したが、これは、適格性または治療に影響を及ぼさなかった。合計334名の患者をIFN-β-1a (44mcg SC週3回)、またはアレムツズマブ高用量(24mg/日静脈内(IV))もしくは低用量(12mg/日 IV)に無作為化した。アレムツズマブは、1日1回、0ヶ月目に5日間および12ヶ月目に3日間、ならびに一部の患者では24ヶ月目に再度与えた。
TPOタンパク質に特異的な間接的非競合的酵素イムノアッセイを含む定性的方法を、実施例2に記載のTPOA測定に使用した。該方法は、Phadia GmbH(以前のSweden Diagnostics)によって製造され、Somagenカタログ番号12396によって販売されている市販のキット(Varelisa)TPO抗体試験の使用を含んだ。簡単に、提供された希釈剤を用いて患者血清試料を1/100に希釈し、100マイクロリットルの希釈試料を、精製TPOタンパク質で予めコーティングしたプラスチックウェルに入れた。試料を30分間インキュベートし、次いで、300マイクロリットルの提供された洗浄溶液で3〜5回洗浄した。次いで、各ウェルに、抗免疫グロブリンG(IgG)アイソタイプ特異的抗体に共有結合された酵素ホースラディッシュペルオキシダーゼ(HRP)を含む100マイクロリットルの提供された試薬を添加した。さらに30分間のインキュベーション工程後、コンジュゲートを300マイクロリットルの提供された洗浄溶液で3〜5回洗浄した。次いで、各ウェルに、付着したHRPコンジュゲートの量および反応持続時間に比例した可視的比色定量的シグナルを生成し、HRPによって触媒される化学反応に有効な基質である、3,3',5,5'-テトラメチルベンジジンを含有する100マイクロリットルの溶液を添加した。10分間のインキュベーション工程後、50マイクロリットルの硫酸溶液の添加によって比色定量的反応を終了した。分光光度計を用いて比色定量的シグナルを測定し、硫酸溶液の添加10〜30分後、波長450nmでの吸光度を測定した。結果を、陰性(陽性対照の吸光度/試料の吸光度<1)、陽性(陽性対照の吸光度/試料の吸光度>1.4)、または不定(比>1.0<1.4)のいずれかとして定性的に解釈した。
この試験の目的は、最初の薬物曝露の2年以内のアレムツズマブ関連自己免疫性甲状腺障害のリスクの予測量としての治療前甲状腺ペルオキシダーゼ抗体(TPOA)を調べることであった。上記のCAMMS223臨床試験と関連して、実施例1に記載の試験プロトコルおよびキットを使用し、すべての患者においてTSH、遊離T3、遊離T4、およびTSHRAを四半期毎、および抗甲状腺ペルオキシダーゼ(TPOA)を年2回試験した。
これらのデータから、ベースラインでのTPOAの存在がアレムツズマブでの治療後に甲状腺障害のリスクの増大をもたらしている可能性があることが明らかである。
実施例2に示したCAMMS223のデータの予備解析を、3年間のメジアン追跡後の同じ治験からのデータの解析によって拡張した。以下の表に示されるように、最初のアレムツズマブ曝露から3年以内に発症する甲状腺AEは、ベースラインでのTPOA試験で陰性であったアレムツズマブ治療患者の35名/182名(19.2%)に対して、試験で最初に陽性であった患者の8名/16名(50%)(RR=2.60、p=0.0087)、およびベースラインでのTPOA試験で陰性であったIFN-β-1a治療患者の2名/93名(2.2%)に対して、試験で最初に陽性であった患者の0名/6名(0%)で報告された。顕著なことに、TSHRAは、ベースラインでのTPOA試験で陰性であったアレムツズマブ治療患者の46名/182名のみ(25.3%)に対して、試験で最初に陽性であった患者の10名/16名(62.5%)(RR=2.47、p<0.0031)、およびベースラインでのTPOA試験で陰性であったIFN-β-1a治療患者の2名/93名(2.2%)に対して、試験で最初に陽性であった患者の0名/3名(0%)において生じた。
これらの長期間データは、引き続き、ベースラインでのTPOAの存在がアレムツズマブでの治療後に甲状腺障害のリスクの増大をもたらしている可能性があるという結論を支持する。
Claims (13)
- 甲状腺ペルオキシダーゼまたは甲状腺ミクロソームに対する抗体が患者に存在するかどうかを判定する工程を含み、該抗体が患者に存在する場合に、患者は治療後に甲状腺障害を発症するリスクがある、リンパ球を枯渇させる計画を用いた治療の後に甲状腺障害を発症するリスクがある患者を同定する方法。
- 患者が多発性硬化症(MS)を有する、請求項1記載の方法。
- リンパ球を枯渇させる計画がCD52陽性細胞を枯渇させる薬剤の投与を含む、請求項1または2記載の方法。
- CD52陽性細胞を枯渇させる薬剤がCD52に特異的に結合する抗体である、請求項3記載の方法。
- 抗体がアレムツズマブである、請求項4記載の方法。
- 抗体がCampath-1HのCDRのアミノ酸配列と同じアミノ酸配列を有する1つ以上のCDRを含む、請求項4記載の方法。
- MSが再発性で寛解性の多発性硬化症である、請求項2記載の方法。
- 甲状腺ペルオキシダーゼまたは甲状腺ミクロソームに対する抗体が個体に存在するかどうかを、リンパ球を枯渇させる計画を用いた治療の前に判定する、請求項1または2記載の方法。
- 甲状腺ペルオキシダーゼまたは甲状腺ミクロソームに対する抗体が個体に存在するかどうかを、リンパ球を枯渇させる計画を用いた少なくとも1つの治療の経過後に判定する、請求項1または2記載の方法。
- 甲状腺障害が、甲状腺機能低下症、甲状腺機能亢進症、グレーブス病、自己免疫性甲状腺炎、およびその組み合わせからなる群より選択される、請求項1または2記載の方法。
- リンパ球を枯渇させる計画が骨髄移植法に関して行われる、請求項1または2記載の方法。
- 甲状腺ペルオキシダーゼまたは甲状腺ミクロソームに対する抗体が、酵素結合免疫吸着アッセイ、ラジオイムノアッセイ(RIA)、血球凝集アッセイ、および抗体を誘引し、かつ抗体に結合することを目的とした標的として甲状腺ペルオキシダーゼタンパク質の形態または断片を使用する他のアッセイからなる群より選択されるアッセイを用いて検出される、請求項1または2記載の方法。
- 患者が、GVHD、リウマチ関節炎、脈管炎、臓器移植拒絶、ブドウ膜炎、硬皮症、自己免疫性血球減少症およびリウマチ関節炎からなる群より選択される免疫媒介疾患を有する、請求項1記載の方法。
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