JP2009518446A - Ctla−4抗体投与量漸増レジメン - Google Patents
Ctla−4抗体投与量漸増レジメン Download PDFInfo
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Abstract
Description
本明細書は、参照により本明細書に組み入れられる2005年12月7日出願の米国特許仮出願第60/748,688号の優先権を明確に主張する。
本発明は、CTLA-4抗体を漸増投与レジメンで最適な投与に達するまで患者に投与することによって、患者における癌または感染症のような疾病を処置する方法に関する。
脊椎動物免疫系は、最適な免疫活性化を達成するために多数のシグナルを要する(たとえば、Janeway, Cold Spring Harbor Symp. Quant. Biol. 1989;54:1-14、Paul William E., ed. Raven Press, N.Y., Fundamental Immunology, 4th edition (1998)、特に12章および13章、411〜478ページを参照)。Tリンパ球(T細胞)と抗原提示細胞(APC)との相互作用が免疫応答に不可欠である。T細胞およびAPCに見られる多くの凝集性分子のレベルが免疫応答中に増大する(Springer et al., A. Rev. Immunol. 1987;5:223-252、Shaw and Shimuzu, Current Opinion in Immunology, 1988 Eds. Kindt and Long, 1:92-97およびHemler, Immunology Today 1988;9:109-113)。これらの分子の増大したレベルは、抗原特異的T細胞増殖を刺激する際に活性化されたAPCが休息中のAPCよりも効果的である理由を説明するのに役立つ(Kaiuchi et al., J. Immunol. 1983;131:109-114、Kreiger et al., J. Immunol. 1985;135:2937-2945; McKenzie, J. Immunol. 1988;141:2907-2911およびHawrylowicz and Unanue, J. Immunol. 1988;141:4083-4088)。
本発明は、漸増投与量のCTLA-4抗体を最適な投与量に達するまで患者に投与することによって、癌または感染症のような疾病または症状を処置するための、CTLA-4抗体を投与量漸増レジメンで患者に投与する方法に関する。
驚くべきことに、本発明の漸増投与レジメンでCTLA-4抗体を投与された患者は最適用量の抗体を耐容できることがわかった。本発明の方法は、以前に報告された最大投与量より約3倍多いCTLA-4抗体投与量を患者が耐容することを可能にする投与量漸増レジメンを含む。たとえば、本発明は、9mg/kg用量のCTLA-4抗体を患者に投与する方法を提供するが、以前の研究では、3mg/kgの最大CTLA-4抗体用量しか報告していない(たとえば、米国特許公開公報第2004/0241169号で開示されている臨床試験を参照すること)。
本発明は、患者に投与されるCTLA-4抗体の投与量を、部分的または完全な応答が患者において顕在化するまで、または所定の最大投与量に達するまで漸増させる方法を含む。
特記する場合を除き、「患者」または「被検体」は互換可能に使用され、ヒト患者および非ヒト霊長類などの哺乳動物、ならびに実験動物、たとえばウサギ、ラットおよびマウスならびに他の動物を指す。動物は、すべての脊椎動物、たとえば哺乳動物および非哺乳動物、たとえばヒツジ、イヌ、ウシ、ニワトリ、両生類および爬虫類を含む。
「細胞毒性Tリンパ球会合抗原4」、「CTLA-4」、「CTLA4」、「CTLA-4抗原」および「CD152」(たとえば、Murata (1999) Am. J. Pathol. 155:453-460を参照)という用語は、互換可能に使用され、ヒトCTLA-4の変異体、イソ型、種相同体およびCTLA-4とで少なくとも一つの共通のエピトープを有する類似体を含む(たとえば、Balzano (1992) Int. J. Cancer Suppl. 7:28-32を参照)。ヒトCTLA-4の完全な配列はGenBankアクセッション番号L15006に記載されている。
本発明は、一部には、免疫療法に応答する癌または免疫無防備状態である患者で出現する癌である腫瘍、特に免疫学的に感応性の腫瘍の処置に関する。本発明の方法で処置される腫瘍は固形腫瘍であることができる。
本発明の他の方法は、病原体に暴露された患者を処置するために使用される。上記で説明した腫瘍への適用と同様に、本発明の投与量漸増レジメンにしたがって投与されるCTLA-4抗体は、単独で使用することもできるし、感染症を処置するためのワクチンと併せて使用することもできる。CTLA-4遮断は、ブラジル鉤虫(Nippostrongylus brasiliensis) (McCoy, K. et al. (1997) 186(2); 183-187)およびドノヴァン・リーシュマニア(Leishmania donovani) (Murphy, M. et al. (1998) J. Immunol. 161:4153-4160)の感染の急性期に効果的であることが示されている。この治療法が特に有用になりうる病原体の例は、現在のところ効果的なワクチンが存在しない病原体または従来のワクチンが完全に効果的とはいえない病原体を含む。そのような例は、HIV、肝炎(A、BおよびC型)、インフルエンザ、ヘルペス、ジアルジア、マラリア、リーシュマニア、黄色ブドウ球菌および緑膿菌を含むが、これらに限定されない。CTLA-4遮断は、感染の過程で変化した抗原を提示する、HIVのような作用因子によって確立された感染に対する追加免疫に特に有用である。これらの新規なエピトープは、抗ヒトCTLA-4投与の時点で異物として認識され、したがって、CTLA-4を介するマイナスのシグナルによって減衰されない強力なT細胞応答を誘発する。
CTLA-4抗体は、本発明の投与量漸増レジメンにしたがって、自己抗原、たとえばアミロイド蓄積物、サイトカイン、たとえばTNFαおよびIgE(アレルギーおよびぜん息の処置の場合)の不適切な蓄積を有する患者を処置するために投与することができる。たとえば、アルツハイマー病は、脳中のアミロイド蓄積物中にAβペプチドの不適切な蓄積を含む。アミロイドに対する抗体応答は、これらのアミロイド蓄積物を浄化することができる(Schenk et al., Nature 1999; 400:173-177)。
4.7.1. 癌処置のためのCTLA-4抗体およびワクチン
本発明の方法にしたがって、CTLA-4抗体は、単独で、または一つまたは複数の他の治療剤と併せて、または腫瘍用の免疫処置ワクチン、たとえば化学療法、放射線処置、サイトカイン、ケモカインおよび他の生物学的シグナル伝達分子、腫瘍特異性ワクチン、自家および同種異系幹細胞救出(たとえば移植片vs腫瘍効果を増強するため)、他の治療抗体、分子標的治療、抗血管形成治療、治療用途の感染剤(たとえば腫瘍限局性細菌)および遺伝子治療とともに、投与量漸増レジメンで投与することができる。抗体は、単独でまたは前述の治療とともにのいずれかで、アジュバントまたは非アジュバント療法で使用することができる。
本発明の投与量漸増レジメンにおけるCLTA-4投与は、標準的な癌処置と併用することができる。このような場合、投与される化学療法剤の用量を減らすことが可能である(Mokyr et al., Cancer Research, 1998; 58:5301-5304)。CTLA-4遮断と化学療法との併用の背後にある化学的根拠とは、大部分の化学療法用化合物の細胞毒性作用の結果である細胞死が抗原提示経路中の腫瘍抗原のレベル増大をもたらすということである。したがって、CTLA-4は、腫瘍細胞の化学療法放出へと初回刺激を受ける免疫応答を追加免疫することができる。そのうえ、CTLA-4の免疫刺激活性は、化学療法の免疫抑制効果に打ち勝つために有用である。CTLA-4処置と併せることができる化学療法剤の例は、アルデスロイキン、アルトレタミン、アミホスチン、アスパラギナーゼ、ブレオマイシン、カペシタビン、カルボプラチン、カルムスチン、クラドリビン、シサプリド、シスプラチン、シクロホスファミド、シタラビン、ダカルバジン(DTIC)、ダクチノマイシン、ドセタキセル、ドキソルビシン、ドロナビノール、エポエチンα、エトポシド、フィルグラスチム、フルダラビン、フルオロウラシル、ゲムシタビン、グラニセトロン、ヒドロキシウレア、イダルビシン、イホスファミド、インターフェロンα、イリノテカン、ランソプラゾール、レバミソール、ロイコボリン、メゲストロール、メスナ、メトトレキセート、メトクロプラミド、ミトマイシン、ミトタン、ミトキサントロン、オメプラゾール、オンダンセトロン、パクリタキセル(Taxol(登録商標))、ピロカルピン、プロクロルペラジン(prochloroperazine)、リツキシマブ、タモキシフェン、塩酸トポテカン、トラスツズマブ、ビンブラスチン、ビンクリスチンおよび酒石酸ビノレルビンを含むが、これらに限定されない。前立腺癌処置の場合、CTLA-4と併せることができる好ましい化学療法剤はパクリタキセル(Taxol(登録商標))である。黒色腫処置の場合、CTLA-4を併せることができる好ましい化学療法剤はダカルバジン(DTIC)である。
本発明の投与量漸増レジメンで投与されるCTLA-4抗体はまた、他の形態の免疫療法、たとえばサイトカイン処置(たとえば、インターフェロン、GMCSF、GCSF、IL-2または腫瘍抗原の提示増強を提供する二重特異性抗体治療と併用することもできる(たとえば、Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448、Poljak (1994) Structure 2:1121-1123を参照)。
本発明は、投与量漸増レジメンで使用するための、薬学的に許容されうる担体とともに調合されたCTLA-4ヒトモノクローナル抗体および/またはヒト配列CTLA-4抗体(無傷または結合フラグメント)を含む薬学的組成物を包含する。一部の組成物は、多数の(二つまたはそれ以上の)単離されたヒトCTLA-4抗体および/またはヒト配列抗体もしくはその抗原結合部分の組み合わせを含む。
高用量のCTLA-4抗体が自己免疫の増大およびそれに伴う腫瘍退縮を誘発するかどうかを試験するため、進行中のIV期黒色腫を有するHLA-A2陰性患者46名を、CTLA-4抗体用量漸増レジメンを使用して処置した。患者23名はCTLA-4抗体投与を3mg/kgで開始し、23名は5mg/kgで処置を開始した。各群には3週間ごとに1用量を投与した。患者には、投与量漸増レジメンにしたがって、9mg/kgの所定の最大用量まで、または客観的臨床応答もしくはグレードIII/IV自己免疫毒性が観察されるまで、CTLA-4抗体を投与した。
4.9.1. 患者および処置
CTLA-4抗体(MDX-010、Medarex Inc., Bloomsbury, NJ)による処置に適した患者は、HLA-A*0201-であり、計りうるIV期黒色腫を有し、少なくとも16歳以上であり、6ヶ月の期待寿命を有し、ECOG病期≦2であり、なんらかの全身的癌治療を施してから少なくとも3週間が経過していた。患者が、自己免疫疾患、活動中の感染症を有する、妊娠中または授乳中である、全身的または局所的なステロイドの使用を要する任意の並行的な医学的状態を有する、または以前にCTLA-4抗体で処置されたことがある場合には、その患者は除外した。すべての患者は、治験倫理委員会(Investigational Review Board)認可プロトコルにしたがって、National Cancer Institute, Bethesda, Marylandの外科部(Surgery Branch)で処置した。
処置開始から28日以内および2サイクルの処置ごとに、すべての患者に胸部、腹部および骨盤部のコンピュータ体軸断層撮影および脳のMRIを受けさせた。RECIST基準を利用して処置に対するX線撮影応答を決定した(Therasse et al., J Natl Cancer Inst 2000, 92:205-216)。治療の前後での全腫瘍の最大直径の合計を計算した。部分的応答は、病変の成長または新たな病変の出現なしに少なくとも1ヶ月間続く指標病変の最大直径の合計の約30%と等しいかまたはそれ以上(ただし100%ではない)の減少と定義した。完全な応答は、1ヶ月と等しいかまたはそれ以上にわたる間のすべての病変の消失と定義した。部分的または完全な応答のいずれも達成しない患者を不応答者とみなした。
ALN=腋窩リンパ節、C=化学療法、CR=完全な応答、F=女性、H=ホルモン治療、I=免疫療法、LN=リンパ節、M=男性、MLN=縦隔リンパ節、NR=応答なし、PR=部分的応答、R=放射線療法、RP=腹膜後、S=外科手術、SQ=皮下
「+」は応答継続中を示す
*2005年5月18日現在での応答
**重篤な眼毒性を含む
4.10.1. 臨床応答
患者46名中5名(11%)(表1)が9mg/kgでの処置の後客観的臨床応答の基準を満たした(表2)。今日まで、患者5名中4名が、6ヶ月を超えて継続中の応答を示している。
患者18名(39%)が、ステロイド処置を要する21種のグレードIII/IV自己免疫事象すなわち重篤な眼毒性を経験した(表1および2)。これらの事象は、前部ブドウ膜炎(1)、関節炎(1)、大腸炎/下痢(7)、皮膚炎(2)、下垂体炎(8)、肝酵素増加(transaminitis)(1)および尿細管性間質性腎炎(1)からなるものであった(表1および3)。重篤な自己免疫毒性を経験したこれら18名の患者のうち、3名(17%)が客観的な臨床応答者であり、重篤な自己免疫疾患を経験しなかった患者28名のうち、2名(17%)が応答者であった(p=0.37、フィッシャーの正確確率検定)。加えて、患者10名が、円形脱毛症(1)、前部ブドウ膜炎/上強膜炎(1)、関節炎(1)、下痢(3)、皮膚炎(4)および色素脱失(1)を含む11種のグレードI/II自己免疫事象を経験した(表3)。これらの患者のうち5名は並行的なグレードIII/IV自己免疫毒性を有した。したがって、患者23名が何らかの程度の自己免疫疾患を経験した。これらの患者を分析すると、自己免疫疾患を有する患者4/23 (17%)が腫瘍退縮を経験し、自己免疫疾患を有しない患者1/23 (4%)が腫瘍退縮を経験したという結果が出た(p=0.35、フィッシャーの正確確率検定)。
抗体のピークおよびトラフ血漿レベルに対する抗体用量増加の効果を分析するため、抗体投与の直前および輸液の1時間後に、CTLA-4抗体3mg/kgで処置を開始した患者から末梢血試料を採取した。トラフレベルは、CTLA-4抗体の用量および濃度の増大と比例して検出レベル未満から68.9ug/mLまで増大した。同様に、ピークレベルは、抗体の用量および濃度の増大と比例して55.8ug/mLから356.3ug/mLまで増大したが、レベルは、9mg/kgでの繰返し投与とともに安定化するように思われた(表4)。3mg/kgの投与の前後で計測したCTLA-4抗体血漿濃度は、患者が3mg/kgの抗体用量を投与された従来プロトコルで処置された患者のピークおよびトラフ血漿レベルに匹敵しうるほどであった。
フローサイトメトリーを使用して、T細胞活性化マーカの表面発現の変化に関して処置前および後の末梢血試料を分析した(表5)。T細胞の活性化に対する抗体用量増加の効果を分析するため、各コースの直前(直前の処置コースの3週間後)に試料を得た。CD3およびCD4表面発現に関して末梢血試料を染色した。応答者5名のうち3名を含む、処置前試料および少なくとも一つの処置コース後試料が入手可能であった患者を分析に使用した。5mg/kgおよび9mg/kgの後、CD4+細胞上のCD25+表面発現は有意に低下した。HLA-DR発現はCD4+およびCD8+の両細胞上で有意に増大した。CD69発現は、CD4+およびCD8+の両細胞上では低下に向かう傾向を示したが、CD45RO+発現はCD4+およびCD8+の両細胞上で増大した。
Claims (19)
- 増加投与量のCTLA-4抗体を最適な投与量に達するまで患者に投与することを含む投与量漸増レジメンにしたがって、CTLA-4抗体を患者に投与する工程を含む、患者における癌を処置する方法。
- 漸増投与レジメンがCTLA-4抗体投与量の線形増加を含む、請求項1記載の方法。
- 漸増投与レジメンがCTLA-4抗体投与量の段階的増加を含む、請求項1記載の方法。
- 最適な投与量が、患者における部分的または完全な応答をもたらす投与量である、請求項1記載の方法。
- 最適な投与量が所定の最大投与量である、請求項1記載の方法。
- CTLA-4抗体投与量を3週間ごとに投与する工程を含む、請求項1記載の方法。
- 漸増投与レジメンが、約3mg/kgの第一のCTLA-4抗体投与量、約5mg/kgの第二のCTLA-4投与量、および約9mg/kgの第三のCTLA-4抗体投与量を投与することを含む、請求項2または6記載の方法。
- 漸増投与レジメンが、約5mg/kgの第一のCTLA-4抗体投与量および約9mg/kgの第二のCTLA-4抗体投与量を投与することを含む、請求項2または6記載の方法。
- 漸増投与レジメンが、CTLA-4増加投与量を6週間ごとに投与することを含む、請求項3記載の方法。
- 漸増投与レジメンが、約3mg/kgの第一のCTLA-4抗体投与量、約3mg/kgの第二のCTLA-4抗体投与量、約5mg/kgの第三のCTLA-4抗体投与量、約5mg/kgの第四のCTLA-4投与量、および約9mg/kgの第五のCTLA-4抗体投与量を投与することを含む、請求項3または9記載の方法。
- 漸増投与レジメンが、約5mg/kgの第一のCTLA-4抗体投与量、および約5mg/kgの第二のCTLA-4抗体投与量、および約9mg/kgの第三のCTLA-4抗体投与量を投与することを含む、請求項3または9記載の方法。
- ワクチンを患者に投与する工程をさらに含む、請求項1記載の方法。
- ワクチンが、gp100、チロシナーゼ、MART-1、またはそれらの組み合わせを含む、請求項12記載の方法。
- 化学療法剤を患者に投与する工程をさらに含む、請求項1記載の方法。
- サイトカインを患者に投与する工程をさらに含む、請求項1記載の方法。
- サイトカインがIL-2である、請求項15記載の方法。
- 増加投与量のCTLA-4抗体を最適な投与量に達するまで患者に投与することを含む投与量漸増レジメンにしたがって、CTLA-4抗体を患者に投与する工程を含む、患者における感染症を処置する方法。
- CTLA-4抗体がヒト配列抗体である、請求項1または17記載の方法。
- CTLA-4抗体がMDX-010である、請求項18記載の方法。
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US20150246972A1 (en) | 2015-09-03 |
US20120100101A1 (en) | 2012-04-26 |
EP1954311A2 (en) | 2008-08-13 |
US9573999B2 (en) | 2017-02-21 |
CA2630157C (en) | 2018-01-09 |
WO2007067959A2 (en) | 2007-06-14 |
EP1954311A4 (en) | 2009-12-23 |
CN101325971A (zh) | 2008-12-17 |
NZ568016A (en) | 2011-12-22 |
AU2006321593A1 (en) | 2007-06-14 |
US8110194B2 (en) | 2012-02-07 |
US20070160619A1 (en) | 2007-07-12 |
WO2007067959A3 (en) | 2007-11-29 |
AU2006321593B2 (en) | 2012-10-04 |
US9062111B2 (en) | 2015-06-23 |
CA2630157A1 (en) | 2007-06-14 |
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