JP6241794B2 - 抗cd20抗体の投与を含むb細胞リンパ腫の併用療法 - Google Patents
抗cd20抗体の投与を含むb細胞リンパ腫の併用療法 Download PDFInfo
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Description
本発明は、B細胞リンパ腫の治療における抗CD20抗体またはその断片の使用、特に併用療法におけるそのような抗体と断片の使用に関する。
B細胞リンパ腫のための診断薬および/または治療薬としてのCD20抗原に対する抗体の使用は、従来から報告されている。CD20は、悪性B細胞(すなわち、活発な増殖がB細胞リンパ腫を引き起こすようなB細胞)の表面で高密度に発現されるため、この抗原は、B細胞リンパ腫の有用なマーカーまたは標的である。
本発明は、B細胞リンパ腫の併用療法を開示し、キメラおよび放射能標識抗CD20抗体を用いて再発性または抵抗性B細胞リンパ腫を治療する利点を報告する。特に抗CD20抗体を用いる治療は、サイトカイン、放射線治療法、骨髄機能廃絶療法、または化学療法と併用する時、有効な相乗作用を提供することがわかっている。驚くべきことに、かつて骨髄移植または幹細胞移植を受けた患者は、かつて治療を受けたことのない患者に比較して、全体の応答速度が予想外に上昇した。
本発明は、B細胞リンパ腫の治療のための併用療法を包含する。一般に、このような方法には、かってリンパ腫の治療を受けた患者が再発し、治療上有効量のキメラ抗CD20抗体を投与される、再発性B細胞リンパ腫の治療法を含む。そのような前に受けた治療には、例えば抗CD20抗体を用いた従来の治療、骨髄移植または幹細胞移植を含む治療、放射線治療法、および化学療法がある。従来の化学療法は、広範囲の化学療法剤や併用療法、例えばCHOP、ICE、ミトザントロン(Mitozantrone)、シタラビン(Cytarabine)、DVP、ATRA、イダルビシン(Idarubicin)、ヘルツァー(hoelzer)化学療法、ララ(LaLa)化学療法、ABVD、CEOP、2−CdA、FLAG&IDA(以後のG−CSF治療有りまたは無し)、VAD、M&P、C−Weekly、ABCM、MOPP、およびDHAPよりなる群から選択される。
ステージII − 横隔膜の同じ側の2つまたはそれ以上のリンパ節領域の関与、または単一の関連したリンパ管外臓器または部位および横隔膜の同じ側に他のリンパ節を持つかまたは持たない局所的リンパ節の局在化関与。
ステージIII − おそらくリンパ管外臓器または部位の局在化関与を伴う、横隔膜の両側のリンパ節領域の関与、脾臓の関与、またはその両方。
ステージIV − 関連リンパ節関与が有るかまたは無い1つまたはそれ以上のリンパ管外部位の散在性(多病巣性)関与、または遠隔(非局所的)節関与を有する、孤立性リンパ管外臓器関与。詳細については、国際非ホジキンリンパ腫予後因子プロジェクト:侵攻性非ホジキンリンパ腫の予測モデル、New England J. Med. 329 (14): 987-994 (1993)を参照されたい。
米国で約25,000人が非ホジキンリンパ腫(NHL)に罹っている。NHL患者の大半は、化学療法、放射線治療法、または自己骨髄(ABMT)や末梢血幹細胞(PBSC)支持による高投与量治療により治療されない。
再発性または抵抗性NHLによる単一薬剤試験
リツクシマブ(登録商標)のFDA認可は、主に低悪性度または濾胞性NHLの患者での単一薬剤試験に基づく。10〜500mg/m2の範囲の単一のリツクシマブ(登録商標)注入の初期の第I相試験は、最大許容用量には達しなかったことを証明したが、最高用量での注入時間の長さは、通院治療法では現実的ではないと考えられた。15人の患者のORRは13%であった(表1)(6)。
ワルデンストレームマクログロブリン血症(WM)は、Bリンパ球が過剰量のIgM抗体を分泌する悪性腫瘍である。WMは通常、60才以上の人に発症するが、30歳代初期の成人でも検出されている。今日WMは、まれな不治の無痛性の悪性腫瘍であり、従来は、血清の粘度を低下させるプラズマフェレシスにより治療されている。しばしば、アルキル化剤のような化学療法薬およびコルチコステロイドが処方される。WMの最も推奨される薬剤は、ロイスタチン(Leustatin)(2CdA)である。
CLLは、小リンパ球性リンパ腫(SLL)の流動性(白血病性)相当物である。SLLの患者は、標準用量のリツクシマブ(登録商標)で治療すると、他の低悪性度NHL亜型を有する患者より、血清レベルと応答率が低い。これはおそらく、CLLの患者では循環腫瘍細胞のレベルが非常に高いため、およびCLLに関与する悪性腫瘍細胞は、細胞表面上のCD20発現のレベルが低下していると考えられるためであろう。
骨髄機能廃絶化学療法は、無痛性リンパ腫において応答を示した。しかし、高用量治療法にもかかわらず残存腫瘍細胞が残り、再注入したPBSCが腫瘍細胞を含有するかも知れない。残存CD20+腫瘍細胞を減らしたり、採取する骨髄または幹細胞の汚染を低減するために、リツクシマブ(登録商標)は、幹細胞動員前および移植後に使用されている。中間結果は、採取された細胞中でCD20+細胞は検出されないことを示した。24人の患者のうち18人は、移植を達成し、治療は充分許容された。残存腫瘍細胞を評価するためのPCR試験が行われている(18)。
リツクシマブ(登録商標)に応答し後に再発した53人の患者の再治療を評価する試験が報告されている(19)。56人の評価可能な患者のうち7人(13%)はCRを達成し、16人はPR(29%)、ORRは42%であった。2回目の応答があった4人の患者に3回目の治療を行った(これらのうち3人は応答した)。
シクロホスファミド、ドコソルビシン、ビンクリスチンおよびプレドニソンによる化学療法(CHOP)は、低悪性度または濾胞性NHLの最初の有効な治療法である。初期応答率は高いが、最終的に再発し、以後の化学療法では、緩解の間隔がより短くなる。低悪性度または濾胞性NHLの作用機序は、交差耐性ではなく、リツクシマブ(登録商標)はいくつかの細胞障害性薬剤(ドコソルビシンを含む)と相乗作用を示す(5)ため、新に診断された再発性低悪性度NHLまたは濾胞性NHLにおけるCHOPとリツクシマブ(登録商標)との併用を評価するために第II相試験を開始した。
リツクシマブ(登録商標)+インターフェロンアルファ
インターフェロンは、免疫系の調節に関与するサイトカインである(23)。インターフェロンが抗体の有効性を上昇させる機序は、抗体発現の強化(24)、腫瘍への抗体のターゲティングの上昇(25、26)、および免疫毒素の細胞障害性の上昇(27)がある。
別の試験で、リツクシマブ(登録商標)とG−CSFを、再発性低悪性度NHLで評価されている。健常志願者でのインビトロならびにインビボの試験で、G−CSFは脊髄性前駆細胞に対するその作用を介して、ADCCでエフェクター細胞として機能することができるFcRI陽性好中球を誘発することが証明されている。このために、併用療法の毒性と有効性を評価するために、第I/II相試験を開始した。
NHLを治療するのに、自己末梢血幹細胞(PBSC)または骨髄(BM)レスキューによる高用量療法が使用されているが、再発のリスクが高い(50〜80%)ため、成功率が限定されている。移植後の持続性のある緩解を改善するために、IL−2による高用量および低用量を含む免疫療法が、多くの治療センターで試験されている。このような試験は、IL−2療法が早期の移植後抗腫瘍活性を示すことを示唆している。
リツクシマブ(登録商標)とGM−CSFによる併用療法の有効性を試験するために、2つの別の第II相試験も開始している。1つの試験は、再発性低悪性度B細胞リンパ腫を有する40人の患者を含み、375mg/m2のリツクシマブ(登録商標)を週1回×4(d.1、8、15、22)およびリツクシマブ(登録商標)の最初の投与の1時間前に開始して、240μgのGM−CSF(ロイキン(Leukine)、イムネックス(Immunex))を皮下に週3回で8週間投与する。この試験は、併用療法の臨床的有効性(全体的応答率(ORR)、全体的完全応答率、悪化までの時間と疾患の無い生存)を評価するために、併用療法の安全性(有害事象の定性、定量、持続と可逆性)を解析するために、そして関係のあるリンパ球亜集団とサイトカインに対する併用療法の作用を測定するために、使用される。第2の試験は、死滅の機序を評価するために免疫学的パラメータを追跡することも計画している(補体C3とC4、CH50、CD3、CD4、CD8、CD16、CD19およびCD56のフローサイトメトリー、およびADCC測定法)。
低悪性度またはより高い悪性度のリンパ腫を有する患者を治療するのに、ガンマインターフェロンもリツクシマブ(登録商標)との併用療法が有用かも知れない。ガンマインターフェロンは、多発性骨髄腫(MM)患者の形質細胞、患者B細胞ならびに正常ドナーB細胞上でのCD20発現をアップレギュレーションすることが最近見いだされた(トレオン(Treon)ら、ルガノ(Lugano)、1999)。実際トレオン(Treon)と共同研究者たちは、ガンマインターフェロンがこれらの細胞のリツクシマブ(登録商標)への結合を増強することを証明した。形質細胞上でのCD20発現の誘導は、用量依存性に起き、1U/mlのインターフェロンガンマという少ない量でアップレギュレーションが見られた。48時間で100U/mlでプラトーになった。すなわちガンマインターフェロンもまた、リツクシマブ(登録商標)と組合せて投与することが有用なようである。
単一薬剤試験
ヨーロッパとオーストラリアで行われた試験では、54人の再発性または抵抗性中悪性度または高悪性度NHL患者で、代替投与スケジュールを評価した(34)。リツクシマブ(登録商標)を375mg/m2を週1回で8回、または375mg/m2を1回と次に500mg/m2を週1回で7回注入した。ORRは31%(CR 9%、PR 22%)で、投与法の間に有意な差は観察されなかった。びまん性巨大細胞リンパ腫を有する患者(N=30)は、ORRが37%であり、マントル細胞リンパ腫を有する患者(N=12)はORRが33%であった。
別の試験では、中または高悪性度NHLを有する31人の患者(女性19人、男性12人、平均年齢49才)に、6回の21日サイクルのCHOPの1日目にリツクシマブ(登録商標)を投与した(35)。30人の評価可能な患者のうち、19人はCR(63%)で10人はPR(33%)であり、ORRは96%であった。この治療法は充分許容されると考えられ、リツクシマブ(登録商標)またはCHOP単独より高い応答を示すようである。
自己PBSC支持による高用量治療後の再発性中悪性度NHLの患者で、リツクシマブ(登録商標)は有望な初期結果を示した。応答した7人の患者のうちの6人(CR1人、PR5人)と1人の患者は、安定な疾患を有し、治療は充分許容された(36)。
5つの単一薬剤米国試験の315人の患者の有害事象と臨床実験室データを組合せて、低悪性度または濾胞性NHL患者のリツクシマブ(登録商標)の安全性プロフィールを提供する。大半の有害事象は注入関連であり、最初の注入後には頻度が低下して起きた。最も一般的な注入関連事象は、発熱(49%)、寒気(32%)、吐き気(18%)、疲労(16%)、頭痛(14%)、血管浮腫(13%)、かゆみ(10%)、および時々低血圧(10%)と気管支けいれん(8%)であった。治療期間中(最後の投与後30日まで)、10%の患者はグレード3または4の有害事象を示し、これは主に注入関連または血液学関連であった。血小板減少症(<50,000血小板/mm3)が1.3%の患者に、好中球減少症(<1000/mm3)が1.9%に、そして貧血(<8gm/dl)が1.0%に起きた。リツクシマブ(登録商標)は70%〜80%の患者でB細胞枯渇を誘発したが、異常に低い血清免疫グロブリンが少数の患者で観察され、感染頻度は上昇していないようであった。
評価中のNHLへの別の治療的アプローチは、放射能標識抗CD20抗体(IDEC−Y2B8)のリツクシマブ(登録商標)との併用である。IDEC−Y2B8(90Y−イブリツモマブチウキセタン(90Y-ibritumomab tiuxetan))は、キレート剤MX−DTPA(これは抗体に共有結合している)を介して90Yに結合したマウスIgG1 カッパ抗CD20抗体である。リツクシマブ(登録商標)(250mg/m2)は、末梢Bリンパ球を枯渇させかつ放射能標識抗体の生体分布を改善するためにIDEC−Y2B8の前に投与される。
NHLの治癒治療法が存在しない状況下で、治療の目的は、有意義な期間疾患の抑制を達成し、過度の毒性無しで腫瘍関連症状の緩解を提供することである。リツクシマブ(登録商標)による治療は、ほとんどの患者で有害事象が限定された短期の22日間の通院治療法である。臨床試験では、評価可能な再発または化学療法抵抗性低悪性度または濾胞性NHL患者の50%は、完全応答または部分的応答を達成した。これらの応答は、維持治療法無しで永続性があり、重要な試験で応答者の平均TTPは13.2ヶ月で、平均DRは11.6ヶ月であった。
Claims (3)
- リツキシマブを含み、低グレード/濾胞性非ホジキンリンパ腫(NHL)の治療においてヒト患者において化学療法と組み合わせて使用するための、医薬組成物であって、治療上有効量の前記医薬組成物が、前記患者へ前記化学療法の間に投与され、かつ、前記化学療法が、CVPである、上記医薬組成物。
- リツキシマブ及び前記化学療法での治療が、有効な相乗作用を提供する、請求項1に記載の医薬組成物。
- リツキシマブが、375mg/m2の用量として投与される、請求項1又は2に記載の医薬組成物。
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