JP2021515774A - 制御性t細胞を枯渇する薬剤、及びチェックポイント阻害剤を使用してがんを治療、又は予防する方法 - Google Patents
制御性t細胞を枯渇する薬剤、及びチェックポイント阻害剤を使用してがんを治療、又は予防する方法 Download PDFInfo
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Abstract
Description
(政府の利害関係の表明)
本発明は、米国国立衛生研究所(National Institutes of Health)から授与された助成金番号 AI37856、HL133190、AI130595、及びCA006973は、国立衛生研究所によって授与された。 政府は、本発明に関して一定の権利を有する。
別段の定義がない限り、本明細書で使用されるすべての技術的、及び科学的用語は、本発明が属する技術に熟練した者によって一般的に理解される意味を有する。 以下の参考文献は、本発明で使用される多くの用語の一般的な定義を当業者に提供する:Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991)。 本明細書で使用される場合、以下の用語は、特に 明記されていない限り、それらに付随する意味を有する。
用語「DT」及び「s-DAB」は互換的に使用され、ジフテリア毒素フラグメントA、及びフラグメントBの一部の分泌形態を指す。
toxOは、中央のシトシン(C)塩基によって中断された2つの9bpの不完全な回文腕からなる19bpのオペレーター領域である。本発明者らによって発見された野生型toxO(図1b)、及び変異toxO(図1a)のオペレーターを図1に示す。SEQ ID NO:1は、本発明の変異toxOのDNA配列の一実施例を示すものであり、toxPは、SEQ ID NO:2のDNA配列を有するプロモーターであり、SEQ ID NO:2は、toxPのDNA配列がtoxOのDNA配列を含むことを示すものである。SEQ ID NO:3は、toxP、tox0、シグナルペプチド、及びタンパク質をコードするDNA配列を含むDNA配列を例示する。SEQ ID NO:3のアスタリスクは、変異体toxOを作製するために導入された変化を示す。
本発明のDNA発現ベクターは、toxP、変異toxO、タンパク質をコードするDNA配列、好ましくはシグナル配列を含む。SEQ ID NO:3は、本発明のDNA発現ベクターの一部であり得るこれらの遺伝的要素を含むDNA配列の一例である。前述のように、SEQ ID NO:3で観察されるアスタリスクは、変異体と野生型toxOとの間の塩基対の変化の上に配置されている。SEQ ID NO:3は、toxPが1塩基から30塩基まで延び、toxOが24塩基で始まり42塩基で終わるように番号が付けられている(下線付きDNA配列の前)。下線部のDNA配列は、塩基74から塩基148までを表し、25アミノ酸シグナル配列をコードするDNAの領域である(SEQ ID NO:4、SEQ ID NO:5、及び図2においても観察される)。本発明のDNA発現ベクターは、好ましくは、1つ以上のタンパク質がtoxP、変異toxOから発現され、N末端シグナル配列で翻訳されるように構築される。N末端シグナル配列は、分泌のために(ベクターから発現された)1つ以上のタンパク質を標的とし、N末端シグナルペプチドは後に切断されて成熟た活性タンパク質となる。SEQ ID NO:3には、分泌型デニロイキン・ディフティトックス、又はs-デニロイキン・ディフティトックスと呼ばれる新規なデニロイキン・ディフティトックスのようなタンパク質をコードするDNA配列が含まれる。s-デニロイキン・ディフティトックスには、未成熟分泌型デニロイキン・ディフティトックス(is-デニロイキン・ディフティトックス)と成熟分泌型デニロイキン・ディフティトックス(ms-デニレウキンdiftitox)と呼ばれる2つの形態がある。 SEQ ID NO:12は本発明のis-デニロイキン・ディフティトックスのものであり、SEQ ID NO:13は本発明のms-デニロイキン・ディフティトックスのものである。is-デニロイキン・ディフティトックスは、処理中に切断されてms-デニロイキン・ディフティトックスを形成するシグナル配列を含む。 さらに、SEQ ID NO:3は、タンパク質、具体的にはジフテリア毒素の機能部分とIL 2の機能部分とを含む融合タンパク質をコードする、塩基149で始まり1711 で終わるDNA配列を含む。シグナル配列を切断した結果、520アミノ酸ポリペプチドになる、ジフテリア毒素フラグメントA、及びフラグメントBの一部(Gly1-His387)のアミノ酸配列とヒトインターロイキン-2の配列とからなる、ms-デニロイキン・ディフティトックスと呼ばれる新しいデニロイキン・ディフティトックス融合タンパク質配列が形成される。本発明のms-デニロイキン・ディフティトックスは、クラシック-デニロイキン・ディフティトックス(c-デニロイキン・ディフティトックス)に存在する第1のメチオニンを欠いており、それによってOntak(商標)として知られるクラシック-デニロイキン・ディフティトックスタンパク質のアミノ酸配列よりも1つ短いアミノ酸を有している。SEQ ID NO:13は、新規なデニロイキン・ディフティトックスタンパク質、ms-デニロイキン・ディフティトックスのタンパク質配列で、Ontak(商標)として知られているクラシック-デニロイキン・ディフティトックス(c-デニロイキン・ディフティトックス)のタンパク質配列を含むSEQ ID NO:10と比較され得る。
すべての細菌や植物の毒素と同様に、デニロイキン・ディフティトックスは、血管漏出症候群(VLS)を誘発する可能性のあるアミノ酸モチーフを持っている。Ontak(商標)の治療を受けた患者の約30%が、末梢性浮腫を伴う急激な体重増加から低アルブミン血症、肺水腫に至るまでの血管漏出症候群を発症する。Ontak(商標)のDNA配列には、米国特許第8,865,866号に記載されているような変異作成した。SEQ ID NO:10の7残基目のバリン(GTT)がSEQ ID NO:16に示されるようにアラニンに置換されるようにDNA配列を変異させることにより、融合毒素は血管漏出症候群の副作用をほとんど、又は全く示さないことが明らかになった。これらの変異体は、「血管漏出変異」(VLM)と呼ばれている。血管漏出変異、すなわちデニロイキン・ディフティトックス-VLMSは、図3のc-デニロイキン・ディフティトックスと同等の効力を有し、図4の血管漏出を起こさず、図5のc-デニロイキン・ディフティトックスよりも生体内での急性毒性が有意に少ないことが示されている。s-デニロイキン・ディフティトックス-VLMは、SEQ ID NO:14、及び15に示される第6残基でバリンを置換するアラニンを有しており、s-デニロイキン・ディフティトックス-VLMタンパク質は、c-デニロイキン・ディフティトックス-VLMタンパク質で見出されたのと同様の毒性の低下を有するはずである。
WTジフテリア毒素:
末端Hisタグ(SEQ ID:43)によって作られた上記バージョンのVLM s-Ontakの最終ポリペプチド配列中にHis6配列(SEQ ID:23)を有することを避けるために、Hisタグ配列の除去を可能にするために、C末端にTEV認識配列を挿入することが可能である。このバージョンでは、配列ENLYFQGHHHHHHHHHHHH(SEQ ID NO:54)は、VLM s-Ontak(....IISTLT(SEQ ID NO:53))のC末端スレオニンの直後に現れる。 ニッケル親和性結合は6アミノ酸よりもさらに長いポリHis配列によって増強されるので、9個のHis残基を含むことが可能である。このTEV開裂部位を有するC末端Hisタグ付きVLM s-Ontakのアミノ酸配列をSEQ ID:45(VLM s-OntakへのC末端TEV His9タグ(SEQ ID NO:48)のタンパク質配列)に示す。TEV開裂部位を有するこのC末端TEV Hisタグ付きVLM s-Ontakの成熟分泌されたタンパク質配列をSEQ ID:46(シグナル配列が切断された後のVLM s-OntakへのC末端TEV His9タグ(SEQ ID NO:48)のタンパク質配列)を示す。His9タグ(SEQ ID NO:48)を有するのでニッケルカラムアフィニティー精製に好適な候補である。親和性精製されたVLM s-Ontakは、その後、少量の純粋なTEVプロテアーゼに曝され、10個のC末端残基GHHHHHHHHH(SEQ ID NO: 55)を除去する酵素的タンパク質分解をもたらし、SEQ ID NO:30に示されるように、成熟した、タグ付けされていないVLM s-Ontakが出来上がる。注目すべきことに、精製されたVLM s-Ontak(SEQ ID:30)のこのバージョンは、VLM s-Ontakの通常のC末端スレオニン(....IISTLT(SEQ ID:53))に融合したTEVプロテアーゼ認識配列(ENLYFQ(SEQ ID:56))の6つの追加アミノ酸を含むため、520アミノ酸(SEQ ID:15)よりもむしろ526アミノ酸の長さである。TEV開裂部位(SEQ ID:30)を有するC末端Hisタグ付きVLM s-Ontakのこのバージョンの最終産物は、C末端配列....IISTLTENLYFQ(SEQ ID NO:57)である。
2008;6(12). PMID: 18334033)。本発明者らは、C. diphtheriae(ジフテリア菌)由来SEQ ID NO: 43、及びC. diphtheriae(ジフテリア菌)由来SEQ ID NO: 58によるTregsの枯渇が、メラノーマのマウスモデルで腫瘍増殖を抑制するかどうかを検討した。 さらに、本発明者らは、C. diphtheriae(ジフテリア菌)由来SEQ ID NO: 43、及びC. diphtheriae(ジフテリア菌)由来SEQ ID NO:58が、免疫チェックポイント遮断、特に抗PD-1抗体を増強し得るかどうかを評価した。本発明者らは、抗PD-1抗体が主にエフェクターT細胞(Teff)の枯渇を逆転させるように作用するので、C. diphtheriae(ジフテリア菌)由来SEQ ID NO: 15、又はC. diphtheriae(ジフテリア菌)由来SEQ ID NO: 43(又はC. diphtheriae(ジフテリア菌)由来SEQ ID NO 13、又はC. diphtheriae(ジフテリア菌)由来SEQ ID NO: 58)によるTregsの枯渇が、免疫抑制の別のモードを除去し、抗PD-1抗体抗腫瘍活性を向上させるという仮説を立てた。
Claims (13)
- 被験者のがんを治療、又は予防する方法であって、以下からなる方法:
がんに罹患している、又は罹患しやすい被験者に、被験者の制御性T細胞(Tregs)を枯渇させる第1剤を投与すること;次に
チェックポイント阻害剤からなる第2剤を被験者に投与すること;及び
被験者のがんを治療、又は予防すること。 - 請求項1に記載の方法、ここで、がんはメラノーマである。
- 請求項1に記載の方法で、ここで、前記第1剤は、ジフテリア毒素融合タンパク質である。
- 請求項3に記載の方法で、ここで、前記ジフテリア毒素融合タンパク質は、ジフテリア毒素フラグメントA、又はその機能部分;ジフテリア毒素フラグメントB、又はその機能部分;又はそれらの組合わせからなる。
- 請求項4に記載の方法で、ここで、前記ジフテリア毒素融合タンパク質は、ヒトインターロイキン配列からなる。
- 請求項5に記載の方法で、ここで、前記ヒトインターロイキン配列はヒトIL-2タンパク質、又はその機能部分からなる。
- 請求項5に記載の方法で、ここで、前記ジフテリア毒素融合タンパク質は、デニロイキン・ディフティトックを投与した対照被験者と比較した時、血管漏出を低下させる。
- 請求項1に記載の方法で、ここで、前記第1剤は、SEQ ID NO:13、又はその機能部分;SEQ ID NO:58、又はその機能部分;SEQ ID NO:15、又はその機能部分;SEQ ID NO:42、又はその機能部分;又それらの組み合わせからなる。
- 請求項1に記載の方法で、ここで前記チェックポイント阻害剤は、抗CTLA-4抗体;抗PD-1抗体;抗PD-L1抗体;又はそれらの組み合わせからなる。
- 請求項1に記載の方法で、ここで、前記チェックポイント阻害は、イピリムマブ(抗CTLA-4)、ニボルマブ(抗PD-1)、ペンブロリズマブ(抗PD-1)、アテゾリズマブ(抗PD-L1)、アベルマブ(抗PD-L1)、及びデュルバルマブ(抗PD-L1)、又はそれらの組み合わせ含むグループから選択される。
- 請求項1に記載の方法で、ここで、第2剤は、抗PD-1抗体である。
- 請求項1に記載の方法で、ここで、第1剤は、SEQ ID NO:13、又はその機能部分、SEQ ID NO:58、又はその機能部分;SEQ ID NO:15、又はその機能部分、SEQ ID NO:43、又はその機能部分、;又はそれらの組み合わせからなるタンパク質配列をコードしている発現ベクターを含む。
- 被験者のがんを治療、又は予防する方法であって、以下からなる方法:
がん、又はがんになりやすい被験者に、被験者のTregを枯渇させる第1剤からなる医薬組成物の有効量を投与すること;次に
被験者にチェックポイント阻害剤からなる第2剤からなる医薬組成物の有効量を投与すること;及び
被験者者のがんの治療、又は予防すること。
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