JP7124040B2 - 抗il-13抗体を使用する、il-13活性が有害である疾患の治療方法 - Google Patents
抗il-13抗体を使用する、il-13活性が有害である疾患の治療方法 Download PDFInfo
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Description
本開示は、抗IL-13抗体又はその抗原結合部分を使用して、喘息及び好酸球性障害、例えば、好酸球性食道炎(EoE又はEE)のような、IL-13活性が有害である疾患を有効に治療する問題に対する解決策を提供する。具体的には、本開示は、改善された治療効力を有する投与レジメンを提供する。例えば、抗IL-13抗体を使用する治療の特許請求する方法は、意外なことに、EoEに罹っている患者の食道生検中の食道好酸球計数を有意に減少させることが示された。
表1は、研究に登録された対象の個体群統計学の要約を与える。
本開示は、意外にも、抗IL-13抗体又はその抗原結合部分を使用して、対象における好酸球性障害、例えば、EoEの少なくとも1つの症状を治療又は改善する方法を提供する。意外にも、数百人の患者によるヒトにおける第2相臨床試験を行った後、本発明は、180mg~360mgの投与量で毎週投与された抗IL-13抗体の皮下用量が、例えば、嚥下障害臨床症状を低下させることによって、EoEを治療するのに有効であることが、意外にも見出されたことを、実証する。本発明の具体的実施形態は、以下の下位セクションでより詳細に記載される。
用語「IL-13」及び「IL-13野性型」(IL-13、IL-13wtと本明細書で略記される)は、本明細書で使用される場合、主としてTヘルパー2細胞により分泌されるサイトカインを含む。用語「IL-13」及び「IL-13野性型」(IL-13、IL-13wtと本明細書で略記される)は、13kDaのポリペプチドの単量体タンパク質を含む。IL-13の構造は、例えば、Moy,Diblasioら、J Mol Biol 310219~30頁(2001年)にさらに記載されている。用語IL-13は、標準組換え発現法により調製され得る組換えヒトIL-13(rhIL-13)を含むことが意図される。さらに、この用語は、他の種、例えば、イヌ、ネコ、ウシ、ウマ、ブタ、ニワトリなどにおけるIL-13のオルソログ/ホモログを含んでもよい。
Ig分子の必須のエピトープ結合特徴を保持する、任意の機能性断片、突然変異体、バリアント若しくはそれらの誘導体を指す。そのような突然変異体、バリアント又は誘導抗体フォーマットは、当技術分野で公知である。これらの非限定的な実施形態は、本明細書で検討される。一実施形態では、本開示の組成物及び方法で使用される抗体は、参照により本明細書に組み込まれる、米国特許第7,915,388号に記載された抗IL-13抗体13C5.5である。別の実施形態では、本開示の組成物及び方法で使用される抗体は、抗体6A1、3G4、トラロキヌマブ、レブリキズマブ、デクトレクマブ(QAX-576)、IMA-638又はIMA-026である。
本開示は、IL-13抗体又はその抗原結合部分を対象に投与するステップを含む方法を含み、ここで、IL-13抗体又はその抗原結合部分が医薬組成物内に含有される。医薬組成物は、適当な担体、賦形剤、及び適当な移行、送達、耐容性などを与える他の薬剤と製剤化されてもよい。多数の適当な製剤が、すべての医薬化学者に公知の処方集:Remington’s Pharmaceutical Sciences、Mack Publishing Company、Easton、Paに見出すことができる。これらの製剤には、例えば、散剤、ペースト剤、軟膏剤、ゼリー剤、ワックス剤、油剤、脂質剤、ベシクルを含有する脂質剤(カチオン性又はアニオン性)(LIPOFECTIN(商標)のような)、DNAコンジュゲート剤、無水吸収ペースト剤、水中油型及び油中水型エマルジョン剤、エマルジョンカーボワックス剤(様々な分子量のポリエチレングリコール)、半固体ゲル剤、及びカーボワックスを含有する半固体混合物が含まれる。Powellら、「Compendium of excipients for parenteral formulations」PDA(1998年)J Pharm Sci Technol 52:238~311頁も参照されたい。
本開示の方法によって対象に投与される、IL-13抗体又はその抗原結合部分の量は、一般に治療有効量である。本明細書で使用される場合、語句「治療有効量」は、(a)好酸球性食道炎の症状の重症度又は期間の減少;(b)食道における好酸球の数の減少;(c)アレルギー反応の防止又は緩和;及び(d)従来のアレルギー治療のための使用又は必要性の減少(例えば、抗ヒスタミン、充血除去剤、鼻又は吸入ステロイド、抗IgE治療、エピネフリンなどの使用の減少又は排除)の1つ以上をもたらす、IL-13抗体又はその抗原結合部分の量を意味する。
用語「組み合わせ治療」は、本明細書で使用される場合、2種以上の治療物質、例えば、抗IL-13抗体及び別の薬剤の投与を指す。他の薬物が、抗IL-13抗体の投与と同時に、前に、又は続いて投与されてもよい。特に、追加の薬剤は、好酸球性障害の診断及び/又は治療に有用である薬剤である。とりわけ、追加の薬剤は、好酸球性胃腸障害(EGID)の治療/診断に有用である薬剤である。
本明細書で使用される場合、用語「IL-13活性が有害である障害」は、障害を患っている対象におけるIL-13の存在が、障害の病態生理又は障害の悪化に寄与する要因の原因である又は疑われることが示されている疾患及び他の障害を含むことが意図される。一実施形態では、IL-13活性が有害である障害は、喘息、例えば、軽度喘息又は中等度喘息である。別の実施形態において、IL-13活性が有害である障害は、好酸球性食道炎(EoE)である。
一実施形態では、本明細書に開示される抗IL-13抗体及びその抗原結合部分を使用して治療され得る好酸球性障害は、好酸球性胃腸障害(EGID)である。好酸球性胃腸障害は、好酸球増加の公知の原因(例えば、薬物反応、寄生虫感染及び悪性)の非存在下での好酸球に富む炎症によって胃腸管を選択的に冒す障害と定義される。本開示の組成物で治療可能であるEGID(「本開示の障害」と集合的に称される)の例には、限定されないが、好酸球性食道炎(EoE)、好酸球性胃炎(EoG)、好酸球性十二指腸炎(ED)、好酸球性空腸炎(EJ)、好酸球性回腸炎(EI)、及び好酸球性大腸炎(EC)が含まれる。
一実施形態では、本方法は、EoEを有する対象を最初の選択するステップを含む。一実施形態では、本方法は、EoEと診断されている対象を最初に選択するステップを含む。特に、対象は、EGIDに伴う少なくとも1つの症状又は適応を示すヒト対象である。とりわけ、対象は、EoE、EG、ED、EI、EJ及びECからなる群から選択されるEGIDに伴う少なくとも1つの症状又は適応を示すヒト対象である。第2のステップは、IL-13抗体又はその抗原結合部分を含む本開示の組成物を投与するステップを含む。
本開示の他の態様によれば、EoEを治療する方法は、治療の有効性の決定に関係している。この実施形態下では、対象は、治療有効量のIL-13アンタゴニストを含む組成物を投与され、EoE関連マーカーの変化が治療前及び/又は後でモニターされる。治療は、少なくとも1種のEoE関連マーカー(例えば、食道好酸球計数、エオタキシン-3、IgEなど)が、投与前の対象におけるマーカーのレベルと比較して、組成物の投与後の時点で低下している場合、有効であると思われる。この実施形態下では、IL-13抗体又はその抗原結合部分を含有する組成物による治療後のマーカーのレベルでの、組成物による治療(又はプラセボによる治療)前のマーカーのレベルと比較して少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%、少なくとも95%以上の低下は、治療が有効であることを意味する。
喘息は、喘鳴、息切れ、胸苦しさ及び咳を特徴とする気道の慢性炎症障害である。喘息は、米国でおよそ2000万人の人々を冒し、喘息患者の約75%は成人である。成人喘息患者の内で、喘息患者のおよそ60%は、軽度疾患を有し、約20%は、中等度疾患を有し、残りの20%は、重度疾患を有する。
好酸球性食道炎のための、組換え、ヒト化、高親和性、選択的抗インターロイキン-13モノクローナル抗体の効力の試験
原発性ヒト食道上皮細胞のインターロイキン(IL)-13刺激は、好酸球化学誘引タンパク質であるエオタキシン-3及び細胞外マトリックス接着タンパク質であるペリオスチンの発現を誘導する。これらのIL-13誘導タンパク質は、好酸球性食道炎(EoE)に罹っている患者の食道組織で過剰発現され、アレルギー性炎症を強く促進する。抗IL-13抗体、RPC4046(13C5.5とも称される)は、ヒト型IL-13及びIL-13配列変異体、R110Qに結合する。これらのサイトカインは、ヒトアレルギー性炎症を増強することが示されている。RPC4046は、IL-13に対して高度に選択的であり、他のサイトカインには結合しない。
RPC4046の効力及び安全性は、EoEに罹っている患者における第2相臨床試験で評価した。試験の第1の目的は、症候性好酸球性食道炎(EoE)に罹っている患者からの食道生検試料の好酸球計数に対するRPC4046の効果を特徴付けることであった。試験の第2の目的は、抗RPC4046抗体の開発も含めて、EoEの臨床症状に対するRPC4046の効果を特徴付けし;EoE内視鏡スコアに対するRPC4046の効果を特徴付けし;食道組織学的所見に対するRPC4046の効果を特徴付けし;及びRPC4046の安全性及び耐容性を特徴付けすることであった。
二重盲検プラセボ対照用量所見研究を、北米及びスイス国の40のセンター(canter)で行った。EoEに罹っている患者(n=100、18~65齢)を、1日目静脈内負荷用量で180mg(低用量;LD)又は360mg(高用量;HD)のRPC4046又はPBO(1:1:1)に無作為化し、続いて15週間毎週の皮下用量を与えた。表1は、患者個体群統計学の要約を与える。食道好酸球計数は、16週目及び利用可能であれば、早期終止時に、スクリーニング中の生検から測定した。嚥下障害臨床症状の頻度及び重症度は、好酸球性食道炎活性指数(EEsAI)を使用して評価し、そして、標準質問票への回答を含む毎日症状日誌(DSD)に記録して、そこからスコアをコンピュータ算出した(表2)。安全性は、試験全体を通してモニターした。主要エンドポイントは、平均食道好酸球計数におけるベースラインから16週目への変化であった。試験は、主要エンドポイントに力を入れた。副次的エンドポイントは、嚥下障害臨床症状の頻度及び重症度におけるベースラインから16週目への平均変化を含んでいた。
対象を以下の基準に基づいて選択/除外した:
1.スクリーニング前の高用量PPI治療の少なくとも8週後のEoEの文書化された診断;
2.スクリーニング内視鏡検査での食道の3つ(近位、中位及び/又は遠位)レベルの2つからの、≧15/HPFのピーク好酸球計数を有するEoEの組織学的証拠;
3.対象は、最低4日間の嚥下障害を経験しており、かつスクリーニング期間の任意の連続する2週間及びベースライン訪問(baseline visit)2週前における日の70%以上でDSQを終了していなければならなかった;
4.スクリーニング前4週において平均で1週当たり少なくとも2つの嚥下障害のエピソード(抗炎症治療から離れての固形分の摂取による)及びスクリーニングとベースラインの間の週において平均で1週当たり少なくとも2つの文書化された嚥下障害のエピソードの病歴;嚥下障害は、患者報告による、固形食物を飲み込む又は固形食物をくっつかせる困難と定義される;
5.スクリーニング訪問前に3ヶ月以上の安定規定食を受け続けていて、スクリーニング訪問時に事実上いずれかの食事治療及び/又は医療レジメンを継続していなければならない;
1.RPC4046臨床試験への以前の参加;
2.対象は、対象の安全性を損なうか、又はEoEの徴候若しくは症状の評価に干渉するか若しくはそれを複雑にする、何らかの状態又は異常を有する;
3.対象は、スクリーニング8週以内前に免疫調節治療を使用した;
4.対象は、EGDの評価の4週以内にEoEのための飲み込み局所コルチコステロオイド若しくは何らかの状態のための全身性コルチコステロイドを使用してきている又は治療期間中の使用が予測される;
5.対象は、スクリーニング訪問前に吸入若しくは鼻腔内ステロイドを受けており、3ヶ月を超えて治療が安定しなかった又は試験中の変化が予測される。
6.対象は、何らかの状態のためのPPI、H2アンタゴニスト、制酸剤、抗ヒスタミン剤又はロイコトリエン阻害剤の投与レジメンを開始、中断、又は変化させた;
7.対象は、診断用成人上部内視鏡の通過を可能にしない食道狭窄を有するか又はスクリーニング3ヶ月前以内に食道拡張を有していた;
8.スクリーニングの2ヶ月又は5半減期(分かる場合)のいずれか長い方以内の、調査用薬物による治療。
試験の重要な主要エンドポイントは、食道生検からの5つの最も炎症を起こした高倍率視野(HPF)で測定される平均食道好酸球計数におけるベースラインから16週目の変化である。試験の重要な副次的エンドポイントは、2週にわたって終了した毎日症状日誌により評価して嚥下障害臨床症状の頻度及び重症度におけるベースラインから16週目の平均変化である。さらに、様々な安全性及び耐容性エンドポイントも測定可能である。安全性及び耐容性パラメータは、有害事象(AE)の出現率、重症度及び関係、重大なAE(SAE)、臨床実験室異常性、バイタルサインの変化、物理的検査異常並びに抗薬物抗体の存在によって評価される。対象はまた、日誌における様々な症状関連質問への答えを記入するように要請され、日誌は、複合日誌スコア(CDS)のコンピュータ化で使用された(表2)。
一貫性を最大化するために、生検を、スクリーニングにおいて近位及び遠位食道から得た(すなわち、各レベルから4つの生検断片)。中位食道からのさらなる生検を促し、同じレベルからその後の生検を得るように努めた。生検を盲検化し、一人の中心的病理学者が読み取った。試験について適格であるために、対象を、スクリーニング内視鏡において食道の3つ(近位、中位及び/又は遠位)のレベルの2つからの、≧15/HPFのピーク好酸球計数について評価した。
90人の患者が、初期の16週の試験を終了した。個体群統計学/疾患特性は、治療選択肢間で同等であった。ベースラインにおいて、平均食道好酸球計数は、92.4(プラセボ;PBO)、116.6(低用量;LD)、及び122.6(高用量;HD)であった。食道生検から5つの最も炎症を起こした高倍率視野で測定された平均食道好酸球計数は、16週の治療期間にわたるRPC4046の両用量についてベースライン(BL)から有意に減少した(平均変化PBO:-4.4、LD:-94.8;及びHD:-99.9[両方ともプラセボに対してp<0.001])。ベースラインにおいて、平均嚥下障害症状複合日誌スコアは、29.4(PBO)、27.63(LD)及び29.03(HD)であった。嚥下障害臨床症状の低下は、複合日誌スコアに基づいてPBOと比較しRPC4046LD及びHDで治療した患者の間で観察した(PBO:-6.4;LD:-5.3[PBOに対してp=0.9959]及びHD:-13.3[PBOに対してp=0.0733]。16週でのステロイド難治性状態による下位群分析は、DSDにより報告されるとおりに嚥下障害で改善を示した。RPC4046は、好都合な安全性プロファイルで十分に耐容した。DSDaにより測定した場合の16週の治療期間にわたる嚥下障害の正味変化を、表3に示す。
第1の試験において、対象に、プラセボ又は低用量若しくは高用量の治療剤を与えた。平均食道好酸球計数(細胞/hpf)は、ベースライン及び16週目において計算した。低用量(180mg)及び高用量(360mg)RPC4046の両方での治療は、対照と比較して16週目で平均食道好酸球計数の統計的に有意な減少をもたらすことがわかった。結果を図1に提示する。図(2a)は、プラセボ対低用量(180mg)のRPC4046で治療された対象での16週目の平均食道好酸球計数(細胞/hpf)(患者の様々な下位群内でのさらなるハイライト細胞計数)を示す。図2(b)は、プラセボ対高用量(360mg)のRPC4046で治療された対象での16週目の平均食道好酸球計数(細胞/hpf)(患者の様々な下位群内でのさらなるハイライト細胞計数)を示す。
RPC4046による治療は、平均食道好酸球計数を減少させ、これは、両方の活性治療選択肢においてプラセボを上回って統計的に有意であった。嚥下障害スコアにおける改善の重要な副次的エンドポイントに関して、正の数値の傾向が、より高い用量(360mg)のRPC4046でプラセボを上回って観察された(統計的有意性に近い)。患者の様々な下位群に対するRPC4046の効果に関して、非ステロイド難治性下位群と比較してステロイド難治性下位群でより大きい治療効果が観察された。投与に関して、数値的により大きい改善が、RPC360mg用量で観察された(DSD及びEEsAIにより測定して)。疾患重症度の全体的評価(対象のと臨床医のとの両方)に関して、RPC4046による治療は、プラセボを上回る統計的に有意な改善をもたらした。全体としてRPC4046は、一般に安全で対象により十分耐容性であるように思われた。最も頻繁に報告された有害事象は、頭痛、URI、関節痛、鼻咽頭炎、副鼻腔炎、腹部痛及び口腔咽頭炎であった。治療群内で静注過敏症の事象の報告事例はまったくなかった。
当業者は、本明細書に記載された具体的実施形態及び方法に対する多くの均等物を認識し又は単なる日常実験を使用して確認することができる。そのような均等物は、以下の特許請求の範囲の範囲により包含されることが意図される。
Claims (14)
- 抗IL-13抗体又はその抗原結合断片を含む、好酸球性食道炎(EoE)の治療のための医薬組成物であって、前記抗IL-13抗体又はその抗原結合部分は、2つの可変ドメインを含み、
一方の可変ドメインは、下記の重鎖CDR:
配列番号2の残基31~37であるCDR1-H1、
配列番号2の残基52~67であるCDR-H2、及び
配列番号2の残基100~112であるCDR-H3
を含み、
他方の可変ドメインは、下記の軽鎖CDR:
配列番号3の残基24~34であるCDR-L1、
配列番号3の残基50~56であるCDR-L2、及び
配列番号3の残基89~97であるCDR-L3
を含む、医薬組成物。 - 抗IL-13抗体又はその抗原結合断片が、IL-13に結合し、IL-13とIL-13受容体の間の相互作用を防止する、請求項1に記載の医薬組成物。
- 抗IL-13抗体又はその抗原結合断片が、約180mg~360mgの用量で対象に皮下投与される、請求項1又は2に記載の医薬組成物。
- 抗IL-13抗体又はその抗原結合断片が、約180mgの用量で対象に毎週皮下投与される、請求項1~3のいずれか一項に記載の医薬組成物。
- 抗IL-13抗体又はその抗原結合断片が、約360mgの用量で、対象に毎週皮下投与される、請求項1~3のいずれか一項に記載の医薬組成物。
- 対象が、ステロイド治療を以前に受けていないステロイド未経験対象である、請求項3~5のいずれか一項に記載の医薬組成物。
- 対象が、ステロイド治療を以前に受けている、請求項3~5のいずれか一項に記載の医薬組成物。
- 対象が、非ステロイド難治性である、請求項7に記載の医薬組成物。
- 対象が、ステロイド難治性である、請求項7に記載の医薬組成物。
- 抗IL-13抗体又はその抗原結合部分が、対象に少なくとも約16週間投与される、請求項1~9のいずれか一項に記載の医薬組成物。
- 抗IL-13抗体又はその抗原結合部分が、対象にEoE疾患の期間投与される、請求項1~9のいずれか一項に記載の医薬組成物。
- 追加の薬剤をさらに含む、請求項1~11のいずれか一項に記載の医薬組成物。
- 追加の薬剤が、ステロイドであり、好ましくは、ステロイドはブデソニドである、請求項12に記載の医薬組成物。
- 追加の薬剤が、治療剤、画像化剤、細胞毒性剤、血管新生阻害剤、キナーゼ阻害剤、共刺激分子遮断剤、接着分子遮断剤、抗サイトカイン抗体又はその機能性断片、メトトレキサート、シクロスポリン、ラパマイシン、FK506、検出可能標識又はレポータ、TNFアンタゴニスト、抗リウマチ剤、筋肉弛緩剤、麻薬、非ステロイド抗炎症薬(NASAID)、鎮痛剤、麻酔剤、鎮静剤、局所麻酔剤、神経筋遮断剤、抗微生物剤、抗乾癬剤、コルチコステロイド、タンパク質同化性ステロイド、エリトロポエチン、免疫付与剤、免疫グロブリン、免疫抑制剤、成長ホルモン、ホルモン補充薬、放射性医薬、抗鬱剤、抗精神病剤、刺激剤、喘息の医薬品、ベータアゴニスト、吸入ステロイド、経口ステロイド、エピネフリン又はアナログ、サイトカイン及びサイトカインアンタゴニストからなる群から選択される、請求項12に記載の医薬組成物。
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