JP2019501973A - スーパー抗原媒介性癌免疫療法の能力を増強するための方法および組成物 - Google Patents
スーパー抗原媒介性癌免疫療法の能力を増強するための方法および組成物 Download PDFInfo
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Abstract
Description
本願は、全内容がその全体において参照により本明細書に援用される2016年1月10日に出願された米国仮特許出願第62/276,955号の利益および優先権を主張する。
本発明は一般的に、スーパー抗原媒介性癌免疫療法の能力を増強するための方法および組成物に関し、より具体的には、癌細胞が被験体の免疫系を逃れることを防ぐ免疫増強物質を用いたスーパー抗原媒介性癌免疫療法に関する。
米国癌学会によると、米国において毎年100万人を超える人々が癌であると診断されている。癌は、いったんは自然の制御機構に供されるが制御されない様式で増殖を続ける癌性細胞に変化した制御されない細胞の増殖により生じる疾患である。近年、被験体の免疫系を利用して、癌細胞を発見および破壊することを試みるいくつかの免疫療法が開発されている。かかる免疫療法としては、例えば、身体により作製される自然の分子を使用して癌と戦うための身体の自然防御を加速するように設計されるもの、あるいは代替的に、免疫系機能を向上、より良好に標的化または修復するように設計された組み換え分子の投与によるものが挙げられる。特定の免疫療法としては、サイトカイン、例えばIL-2およびインターフェロンなどの一般的な免疫系促進因子として知られる化合物の投与が挙げられる。今日までに開発された種々の免疫療法は効力を示しているが、それらは、例えば、標的でない活性、サイトカインストーム(storm)についての能力を含む投与される有効成分に対するアレルギー反応、有効成分に結合し中和する抗体の刺激により引き起こされる能力の消失、血液細胞数の減少、および疲労を含む副作用を伴い得る。
近年、被験体の免疫系を利用して癌細胞を発見および破壊することを試みたいくつかの免疫療法が開発されている。ヒト免疫系は癌細胞を排除するための能力を有するが、特定の癌細胞は、宿主の免疫系を「オフにする」か、「下方制御する」か、またはそうでなければ宿主の免疫系を逃れて、チェックされずに癌細胞を成長および増殖し続ける能力を発現する。
本発明は、被験体において癌を治療するための方法および組成物に関する。特に、本発明は部分的に、スーパー抗原系治療と、(a) T細胞シグナル伝達の活性化の刺激、(b) 癌性細胞とT細胞の間のT細胞抑制性シグナル伝達の抑制、(c) ヒトIgG4免疫グロブリン媒介性経路を介するT細胞の拡大、活性化および/または活性をもたらす抑制性シグナル伝達の抑制、または(d) 前述の2つ以上の組合せをなし得る免疫増強物質を組み合わせることにより、被験体における癌に対する標的化された免疫応答が有意に増強され得るという発見に基づく。腫瘍標的化スーパー抗原(tumor-targeted superantigen)(TTS:免疫療法の形態)を、免疫増強物質(例えば、PD-1阻害剤)と一緒に投与することにより、一緒に組み合わせた(すなわち、薬剤が相乗的に作用する)場合に、単独で投与した場合のそれぞれの薬物の加法的効果よりも高い効果を生じるように、スーパー抗原および免疫増強物質の両方についての増強された抗癌効果が生じ得ることが発見された。
そうではないと定義されない限り、本明細書において使用される科学技術用語は、本発明が属する分野における通常の技術を有する者に一般的に理解されるものと同じ意味を有する。本発明のために、以下に、以下の用語を定義する。
A. スーパー抗原
スーパー抗原は、例えばピコモル濃度でTリンパ球を活性化し得る細菌性タンパク質、ウイルスタンパク質およびヒトの作り変えられたタンパク質である。スーパー抗原はまた、Tリンパ球(T細胞)の大きなサブセットを活性化し得る。スーパー抗原は、加工されることなく主要組織適合性複合体I(MHCI)に結合し得、特に、従来のペプチド結合部位における多形性のほとんどを回避して、MHCクラスII分子上の抗原結合溝の外側の保存された領域に結合し得る。スーパー抗原はまた、T細胞受容体の超可変ループに結合するよりもむしろ、T細胞受容体(TCR)のVβ鎖に結合し得る。細菌性スーパー抗原の例としては、限定されないが、ブドウ球菌エンテロトキシン(SE)、化膿連鎖球菌外毒素(SPE)、黄色ブドウ球菌トキシックショック症候群毒素(TSST-1)、連鎖球菌マイトジェン外毒素(SME)、連鎖球菌スーパー抗原(SSA)、ブドウ球菌エンテロトキシンA(SEA)、ブドウ球菌エンテロトキシンA(SEB)およびブドウ球菌エンテロトキシンE(SEE)が挙げられる。
本発明の範囲内で、スーパー抗原は、スーパー抗原がTリンパ球を刺激する能力を維持または増強し、例えばその血清反応性もしくは免疫原性などのスーパー抗原の他の局面を改変し得る修飾を含む種々の方法で作り変えられ得る。修飾されたスーパー抗原としては、スーパー抗原活性(すなわち、Tリンパ球のサブセットを活性化する能力)を有する合成分子が挙げられる。
天然に存在するスーパー抗原または参照スーパー抗原をコードするポリヌクレオチドの生物学的な機能同等物は、異なる配列を含み、同時に天然に存在するスーパー抗原または参照スーパー抗原をコードする能力を保持するように作り変えられたポリヌクレオチドを含み得る。これは、同じアミノ酸をコードする遺伝子コードの縮重、すなわち複数のコドンの存在のために達成され得る。一例において、ポリヌクレオチドがタンパク質をコードする能力を乱さずに、ポリヌクレオチドに制限酵素認識配列を導入することが可能である。他のポリヌクレオチド配列は、参照スーパー抗原とは異なるが、参照スーパー抗原に対して機能的には少なくとも1つの生物学的特性または活性において実質的に同等である(例えば、少なくとも50%、60%、70%、80%、90%、95%、98%の生物学的特性または活性、例えば限定されずに腫瘍細胞の細胞傷害性を生じるT細胞応答を誘導する能力)スーパー抗原をコードし得る。
特異性を高めるために、スーパー抗原は好ましくは、標的化部分にコンジュゲートされて、癌細胞により優先的に発現される抗原、例えば5T4などの細胞表面抗原に結合する標的化されたスーパー抗原コンジュゲートを生成する。標的化部分は、スーパー抗原を癌性細胞、例えば癌性細胞の表面に結合させるために使用され得るビヒクルである。標的化されたスーパー抗原コンジュゲートは、多くのTリンパ球を活性化する能力を保持するべきである。例えば、標的化されたスーパー抗原コンジュゲートは、多くのT細胞を活性化して、T細胞を、標的化部分に結合した腫瘍関連抗原を含む組織に誘導するべきである。かかる状況において、特異的な標的細胞が優先的に殺傷され、身体の残りは比較的無傷で残される。増殖抑制性化学療法薬などの非特異的な抗癌剤は非特異的であり、治療対象である腫瘍とは関連の無い多くの細胞を殺傷するので、この型の治療は望ましい。例えば、標的化されたスーパー抗原コンジュゲートを用いた試験により、細胞傷害性Tリンパ球(CTL)による腫瘍組織への浸潤を伴う炎症は、標的化されたスーパー抗原の第1の注射に応答して急速に増加することが示されている(Dohlsten et al. (1995) PROC. NATL. ACAD. SCI. USA 92:9791-9795)。CTLの腫瘍への浸潤に伴うこの炎症は、標的化されたスーパー抗原の抗腫瘍療法の主要なエフェクターの1つである。
標的化部分に直接または間接的に連結(例えば、リンカーを含むアミノ酸を介する)されるスーパー抗原をコードする遺伝子が、従来の組み換えDNA技術を使用して生成および発現され得ることが企図される。例えば、修飾されたスーパー抗原のアミノ末端は標的化部分のカルボキシ末端に連結され得るか、またはその逆であり得る。抗体または標的化部分として機能し得る抗体断片について、軽鎖または重鎖のいずれかは、融合タンパク質を生成するために使用され得る。例えば、Fab断片について、修飾されたスーパー抗原のアミノ末端は、抗体重鎖の第1の定常ドメイン(CH1)に連結され得る。いくつかの例において、修飾されたスーパー抗原は、VHおよびVLドメインのスーパー抗原への連結によりFab断片に連結され得る。代替的に、ペプチドリンカーを使用して、スーパー抗原と標的化部分を一緒に連結し得る。リンカーを使用する場合、リンカーは、好ましくはGln、Ser、Gly、Glu、Pro、HisおよびArgなどの親水性アミノ酸残基を含む。好ましいリンカーは、1〜10アミノ酸残基、より具体的には3〜7アミノ酸残基からなるペプチド架橋である。例示的なリンカーは、トリペプチド-GlyGlyPro-である。これらのアプローチは、ANYARA(登録商標)スーパー抗原コンジュゲートの設計および製造において成功裡に使用されている。
スーパー抗原が、化学的連結を介して標的化部分に連結され得ることも企図される。標的化部分へのスーパー抗原の化学的連結は、リンカー、例えばペプチドリンカーを必要とし得る。ペプチドリンカーは、好ましくは親水性であり、アミド、チオエーテル、ジスルフィド等から選択される1つ以上の反応性部分を示す(米国特許5,858,363、6,197,299および6,514,498参照)。化学的連結がホモまたはヘテロ二官能性架橋試薬を使用し得ることも企図される。スーパー抗原の標的化部分への化学的連結は、しばしば化合物中の多くの位置に存在する官能基(例えば、一級アミノ基またはカルボキシ基)を利用する。
組み換えDNA技術を使用する場合、スーパー抗原またはスーパー抗原-標的化部分コンジュゲートは、標準的な発現ベクターおよび発現系を使用して発現され得る。スーパー抗原をコードする核酸配列を含むように遺伝的に作り変えられた発現ベクターを宿主細胞に導入して(例えばトランスフェクトして)、スーパー抗原を産生する(例えばDohlsten et al. (1994), Forsberg et al. (1997) J. BIOL. CHEM. 272:12430-12436, Erlandsson et al. (2003) J. MOL. BIOL. 333:893-905およびWO2003002143参照)。
スーパー抗原および/またはスーパー抗原-標的化部分コンジュゲートは、好ましくは使用前に精製されて、種々の精製プロトコルを使用して達成され得る。他のタンパク質からスーパー抗原またはスーパー抗原-標的化部分コンジュゲートが分離されて、部分的または完全な精製(または同質への精製)を達成するためにクロマトグラフィーおよび電気泳動技術を使用して目的のタンパク質はさらに精製され得る。純粋なペプチドの調製に特に適した分析方法は、イオン交換クロマトグラフィー、サイズ排除クロマトグラフィー;アフィニティクロマトグラフィー;ポリアクリルアミドゲル電気泳動;等電点電気泳動である。用語「精製される」は、本明細書で使用される場合、他の構成成分から単離可能な組成物をいうことを意図し、ここで目的のマクロ分子(例えばタンパク質)は、その元の状態と比較して任意の程度にまで精製される。一般的に、用語「精製される」は、種々の他の構成成分を除去するために分画に供されるマクロ分子をいい、該マクロ分子は実質的にその生物学的活性を維持する。用語「実質的に精製される」は、目的のマクロ分子が、組成物の含量の約50%、約60%、約70%、約80%、約90%、約95%以上の含有量からなるなどの、組成物の主要な構成成分を形成する組成物をいう。
免疫増強物質の効力は、免疫増強物質を、スーパー抗原および標的化部分を含むスーパー抗原コンジュゲートと一緒に、治療される被験体に投与することにより増強され得ることが企図される。例示的な免疫増強物質は、例えば、(a) T細胞シグナル伝達の活性化の刺激、(b) 癌性細胞とT細胞の間のT細胞抑制性シグナル伝達の抑制、(c) 非ヒトIgG1媒介性免疫応答経路、例えばヒトIgG4免疫グロブリン媒介性経路を介するT細胞の拡大、活性化および/または活性をもたらす抑制性シグナル伝達の抑制、(d) (a)および(b)の組合せ、(e) (a)および(c)の組合せ、(f) (b)および(c)の組合せ、ならびに(g) (a)、(b)および(c)の組合せをなし得る。
抗PD-1抗体、抗PD-L1抗体および抗PD-L2抗体が挙げられる。したがって、一態様において、スーパー抗原コンジュゲートは、(1) PD-1リガンド(例えばPD-L1またはPD-L2)に結合してPD-1リガンドがT細胞上のその同起源PD-1に結合することを防ぐ分子(例えば抗体または小分子)、および/または(2) T細胞上のPD-1に結合して、目的の癌細胞により発現されるPD-リガンドの結合を防ぐ分子(例えば抗体または小分子)を含み得るPD-1系免疫増強物質と共に投与される。
抗体を産生するための方法は当該技術分野で公知である。例えば、CDRおよび目的の抗体の可変領域の配列、例えば米国特許8,952,136において提供される抗体配列ならびに米国特許9,073,994に記載されるハイブリドーマ寄託を使用して、軽鎖可変領域および重鎖可変領域をコードするDNA分子を化学的に合成し得る。合成DNA分子を、例えば定常領域コード配列および発現制御配列を含む適切なヌクレオチド配列に連結して、所望の抗体をコードする従来の遺伝子発現構築物を作製する。所定の遺伝子構築物の産生は、当業者の通常の業務の範囲内である。代替的に、本明細書において提供される配列は、その配列が本明細書に提供される配列情報またはハイブリドーマ細胞中のマウス抗体の重鎖および軽鎖をコードする遺伝子に関する先行技術の配列情報に基づく合成核酸プローブを使用して、従来のハイブリダイゼーション技術またはポリメラーゼ連鎖反応(PCR)によりハイブリドーマからクローニングされ得る。
抗体および抗体断片の抗原性を低減または排除するための方法は当該技術分野で公知である。抗体をヒトに投与する場合、抗体は、ヒトにおける抗原性を低減または排除するために、好ましくは「ヒト化」される。好ましくは、ヒト化抗体は、抗原に対して、それが由来する非ヒト化マウス抗体と同じまたは実質的に同じ親和性を有する。
スーパー抗原コンジュゲートおよび免疫増強物質は、癌を治療するように、例えば癌細胞の成長速度を遅延する、転移の発生率もしくは数を低減する、腫瘍サイズを低減する、腫瘍成長を抑制する、腫瘍もしくは癌細胞への血液供給を低減する、癌細胞または腫瘍に対する免疫応答を促進する、癌の伝播を例えば少なくとも40%、50%、60%、70%、80%、90%、95%、98%、99%または100%予防するまたは抑制するように、被験体に、一緒に、連続的にまたは断続的に投与され得る。代替的に、スーパー抗原コンジュゲートおよび免疫増強物質は、癌を治療するように、例えば、癌を有する被験体の寿命を例えば3ヶ月、6ヶ月、9ヶ月、12ヶ月、1年、5年または10年増加させるように、一緒に、連続的にまたは断続的に被験体に投与され得る。
治療養生法は、同様に、しばしば腫瘍の種類、腫瘍の位置、疾患の進行ならびに患者の健康および年齢に応じる。特定の種類の腫瘍は、より積極的な治療を必要とし得るが、同時に患者はより積極的な治療養生法を許容できないことがある。臨床医はしばしば、当業者の技術ならびに治療製剤の公知の効力および毒性(もしあれば)に基づいて、かかる決定を最も適合するものにし得る。
また、本発明は、例えばスーパー抗原コンジュゲートを含む第1の容器および抗PD-1抗体などの免疫増強物質を含む第2の容器を含むキットを提供する。かかるキットはまた、例えばコルチコステロイドまたは別の脂質調節因子などのさらなる薬剤を含み得る。該容器はそれ自体が、シリンジ、ピペットおよび/または他のそのような装置を意味し、そこから身体の特異的な領域に製剤が適用され得、動物に注射され得、および/または適用され得および/またはキットの他の構成成分と混合され得る。
実施例1:NSCLC腫瘍細胞株に対するANYARA(登録商標)および抗PD-1阻害剤の併用療法
本実施例には、HCC827非小細胞肺(NSCLC)腫瘍細胞株に対する腫瘍標的化スーパー抗原、ANYARA(登録商標)および抗PD-1抗体、KEYTRUDA(登録商標)の組合せの抗癌効果を試験するインビトロ試験が記載される。
この実施例には、インビボにおけるマウスB16-EpCAM黒色腫モデルに対する腫瘍標的化スーパー抗原、C215Fab-SEAおよびマウス抗PD-1抗体の効果を試験する試験が記載される。腫瘍標的化スーパー抗原と抗PD-1の併用療法を、C215抗体により認識されるヒト結腸癌抗原EpCAMによりトランスフェクトされた低免疫原性B16黒色腫を使用した同形腫瘍モデルにおいて試験した。腫瘍標的化スーパー抗原C215Fab-SEAは、腫瘍反応性mAb (C215Fab)および細菌性スーパー抗原ブドウ球菌エンテロトキシンA (SEA)を含む融合タンパク質である。インビボでのマウス実験を容易にするためにANYARA(登録商標)の代わりにC215Fab-SEAを使用した。
本明細書に参照される特許および科学文献のそれぞれの全開示は、全ての目的のために参照により援用される。
本発明は、その精神または本質的な特徴から逸脱することなく、他の具体的な形態において実現され得る。そのため、前述の態様は、全ての観点において、本明細書に記載される発明の限定ではなく例示としてみなされるものである。したがって、本発明の範囲は、前述の記載ではなく添付の特許請求の範囲により示され、特許請求の範囲の均等物の意味および範囲においてなされる全ての変更が、本発明に包含されることを意図する。
Claims (28)
- 癌の治療を必要とする被験体において癌を治療する方法であって、該方法が、
該被験体に、(i) 被検体において癌性細胞により発現される第1の抗原に結合する標的化部分に共有結合するスーパー抗原を含むスーパー抗原コンジュゲートの有効量、ならびに(ii) 以下の活性(a) T細胞シグナル伝達の活性化の刺激、(b) 癌性細胞とT細胞の間のT細胞抑制性シグナル伝達の抑制、および/または(c) ヒトIgG4免疫グロブリン媒介性経路を介するT細胞の拡大、活性化および/または活性をもたらす抑制性シグナル伝達の抑制の1つ以上をなし得る免疫増強物質の有効量を投与し、それにより癌性細胞に対する被験体における免疫応答を強化して、癌を治療する工程
を含む、方法。 - スーパー抗原が、免疫増強物質の前、同時または後に被験体に投与される、請求項1記載の方法。
- スーパー抗原が、T細胞の表面上のT細胞受容体に結合する、請求項1または2記載の方法。
- スーパー抗原が、ブドウ球菌エンテロトキシンAまたはその免疫学的バリアントおよび/または断片を含む、請求項1〜3いずれか一項記載の方法。
- 第1の抗原が細胞表面抗原である、請求項1記載の方法。
- 細胞表面抗原が5T4癌抗原である、請求項5記載の方法。
- 標的化部分が抗体である、請求項1〜6いずれか一項記載の方法。
- 抗体が抗5T4抗体である、請求項7記載の方法。
- 抗5T4抗体が、5T4癌抗原に結合するFab断片を含む、請求項8記載の方法。
- スーパー抗原が、配列番号:7のアミノ酸残基226〜458またはその免疫学的に反応性のバリアントおよび/または断片を含む、請求項1〜9いずれか一項記載の方法。
- T細胞により発現されるプログラム細胞死-1タンパク質(PD-1)に結合するプログラム細胞死リガンド(PD-L)が、癌性細胞の表面に発現される、請求項1〜10いずれか一項記載の方法。
- 免疫増強物質が、T細胞の表面上に発現されるPD-1にPD-Lが結合することを防ぐ抗PD-1抗体である、請求項11記載の方法。
- 抗PD-1抗体が、ヒトIgG4アイソタイプを有するかまたはヒトIgG4アイソタイプに基づく、請求項12記載の方法。
- 抗PD-1抗体が、ニボルマブおよびペンブロリズマブからなる群より選択される、請求項12または13記載の方法。
- 癌が、乳癌、子宮頸癌、結腸直腸癌、胃癌、非小細胞肺癌、卵巣癌、膵臓癌、前立腺癌、腎臓細胞癌および皮膚癌からなる群より選択される、請求項1〜14いずれか一項記載の方法。
- 被験体において癌性細胞により発現される第1の抗原に結合する標的化部分に共有結合するスーパー抗原を含むスーパー抗原コンジュゲートの有効量、被験体において以下の活性(a) T細胞シグナル伝達の活性化の刺激、(b) 癌性細胞とT細胞の間のT細胞抑制性シグナル伝達の抑制、および/または(c)ヒトIgG4免疫グロブリン媒介性経路を介するT細胞の拡大、活性化および/または活性をもたらす抑制性シグナル伝達の抑制の1つ以上をなし得る免疫増強物質の有効量、ならびに薬学的に許容され得る賦形剤を含む、医薬組成物。
- スーパー抗原がT細胞の細胞表面に発現されるT細胞受容体に結合する、請求項16記載の組成物。
- スーパー抗原が、ブドウ球菌エンテロトキシンAまたはその免疫学的バリアントおよび/または断片を含む、請求項16または17記載の組成物。
- 第1の抗原が細胞表面抗原である、請求項16〜18いずれか一項記載の組成物。
- 該抗原が5T4癌抗原である、請求項16〜19いずれか一項記載の組成物。
- 標的化部分が抗体である、請求項16〜20いずれか一項記載の組成物。
- 該抗体が抗5T4抗体である、請求項20記載の組成物。
- 該抗体が5T4抗原に結合するFab断片を含む、請求項22記載の組成物。
- スーパー抗原が、配列番号:7のアミノ酸残基226〜458またはその免疫学的に反応性のバリアントおよび/または断片を含む、請求項16〜23いずれか一項記載の組成物。
- 免疫増強物質が、癌細胞において発現されるPD-LがT細胞により発現されるPD-1に結合することを防ぐ、請求項16〜24いずれか一項記載の組成物。
- 免疫増強物質が、抗PD-1抗体である、請求項25記載の組成物。
- 該抗体が、ヒトIgG4アイソタイプを有するかまたはヒトIgG4アイソタイプに基づく、請求項26記載の組成物。
- 抗PD-1抗体が、ニボルマブおよびペンブロリズマブからなる群より選択される、請求項26または27記載の組成物。
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JP7161938B2 (ja) | 2022-10-27 |
KR20180100412A (ko) | 2018-09-10 |
CN109195988A (zh) | 2019-01-11 |
AU2017206656B2 (en) | 2024-02-01 |
IL260423A (ja) | 2018-08-30 |
WO2017122098A2 (en) | 2017-07-20 |
CA3010678A1 (en) | 2017-07-20 |
US10314910B2 (en) | 2019-06-11 |
IL260423B2 (en) | 2023-07-01 |
US20240100156A1 (en) | 2024-03-28 |
EP3411409A2 (en) | 2018-12-12 |
IL260423B1 (en) | 2023-03-01 |
US11202829B2 (en) | 2021-12-21 |
US11607452B2 (en) | 2023-03-21 |
CN117679499A (zh) | 2024-03-12 |
EA201891601A1 (ru) | 2019-03-29 |
WO2017122098A9 (en) | 2017-12-07 |
ZA201804565B (en) | 2024-02-28 |
MX2018008383A (es) | 2019-05-30 |
US20200078457A1 (en) | 2020-03-12 |
US20200101160A1 (en) | 2020-04-02 |
US20170258905A1 (en) | 2017-09-14 |
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WO2017122098A3 (en) | 2017-09-28 |
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