JP2018512166A - 上皮増殖因子受容体変異型iii−メソテリン融合物及びこれを使用する方法 - Google Patents
上皮増殖因子受容体変異型iii−メソテリン融合物及びこれを使用する方法 Download PDFInfo
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Abstract
Description
本願は、2015年4月13日に出願された米国仮特許出願第62/146,559号明細書及び2015年10月19日に出願された米国仮特許出願第62/243,397号明細書の利益を主張する。上記出願の教示全体が参照により本明細書に組み込まれる。
本願は、本願と一緒に提出される下記ASCIIテキストファイルに含まれる配列表を参照により組み込むものとする:
a)ファイル名:53161000003Sequence.txt;2016年4月8日作成、サイズ45KB。
本明細書では、メソテリンポリペプチドに融合された上皮増殖因子受容体変異型III(EGFRvIII)ポリペプチドを含む融合タンパク質(EGFRvIII−メソテリン融合タンパク質)が開示される。
本明細書では、EGFRvIII−メソテリン融合タンパク質をコードする核酸分子が開示される。開示の核酸分子は、本明細書に開示されるEGFRvIII−メソテリン融合タンパク質のいずれをコードすることもできる。
本明細書で開示される核酸分子のいずれかを含む宿主細胞も提供される。
また、対象において免疫応答を誘発する方法も提供され、これは、宿主細胞を含む組成物を対象に投与するステップを含み、宿主細胞は、EGFRvIII−メソテリン融合タンパク質をコードする核酸分子を含む。
本明細書では、メソテリンポリペプチドの発現を増大させる方法が開示され、これは、宿主細胞において、EGFRvIIIポリヌクレオチドと、メソテリンポリペプチドをコードするメソテリンポリヌクレオチドとを含む核酸分子を発現させるステップを含む。
癌ワクチンの治療コンセプトは、悪性腫瘍細胞に対する特定の適応免疫応答を誘導し、増大させることを目的とする広範囲のプラットフォーム技術を包含する。関連する非臨床的癌モデルで初期に開発された複数のワクチン技術は、既存の疾患を有する患者の集団において、又は治癒切除後の補助薬物療法として臨床試験段階に入った。残念ながら、世界的に癌関連死亡の第1位の原因であるNSCLCでは、ワクチンによる積極的な免疫療法介入は、腫瘍応答、腫瘍再発又は進行の遅延、及び最終的に全生存期間(OS)の延長に関する有意な利益を実証することによるクリニカルプルーフオブコンセプトを依然として達成していない。臨床的有効性の不足は、主として特定の耐性機構によるものであり、これにより、NSCLC細胞は、免疫認識を忌避すると共に、治療用癌ワクチン接種後に誘導及び活性化される抗原指向性Tリンパ球による細胞傷害性破壊を回避することができる。開示の方法は、上記及び他の問題に取り組むものである。
細菌株
開示される試験で使用する細菌株を表2に列記する。
221塩基対(bp)actAプロモータ及び258bp修飾シグナル配列ActAN100*を、KpnI−BamHI断片としてpPL2組込みベクターの誘導体にクローニングした。EGFRvIIIネオアンチゲン結合領域の5つのコピー(EGFRvIIIx5)をコードする486bp配列を、BamHI−MfeI断片としてActAN100*と共にフレーム内にクローニングした。ヒトメソテリン(メソテリン35〜622)のアミノ酸35〜622をコードする1767bp配列を、MfeI−EagI断片としてフレーム内にクローニングした。Lauer,P.et al.,Construction,Characterization and Use of Two Listeria monocytogenes site−specific phage integration vectors.J.Bacteriology(2002)184(15):4177−4186)(参照により本明細書に組み込まれる)に記載されているように、発現カセット全体をLADDプラットフォーム株(Lm11、Lm ΔactAΔinlBとも称する)のtRNAArg遺伝子座に挿入した後、ベクター骨格配列を除去した。
ブロス培養物増殖ウエスタンブロットのため、リステリア(Listeria)属株を酵母培地中に2.0のOD600まで増殖させた。遠心分離により細菌を除去してから、上清を氷上でTCA沈殿させた。上清を遠心分離し、ペレットをアセトンで洗浄した後、還元LDSバッファー(Invitrogen)に再懸濁させた。サンプルを95℃に10分間加熱し、等量を4〜12%ポリアクリルアミドゲル上で泳動させた後、ウエスタンブロット分析のためにニトロセルロース膜に移した。ActAタンパク質の成熟N末端に対するポリクローナル抗体でブロットをプロービングした。検出を視覚化し、Licor Odyssey IR検出システムで定量した。
メソテリン特異的免疫原性について、Balb/cマウス(n=5)に2×106cfuのADU−214で静脈内に(IV)ワクチン接種した。7日後、脾臓を採取し、メソテリンのオーバーラップペプチドライブラリー(11アミノ酸による153の15量体ペプチドオーバーラップ)又は非刺激培地対照を用いたIFNγELIspotアッセイにより、免疫応答を測定した。EGFRvIII特異的免疫原性について、C3H/HeNマウス(n=4)に5×106cfuのADU−214IVでワクチン接種した。7日後、脾臓を採取して、EGFRvIII26〜33−Kk結合ペプチドEEKKGNYVを用いたIFNγELIspotアッセイにより、免疫応答を測定した。
2×106cfuの各Lm株IVでBalb/cマウスに1回ワクチン接種した。40日後、5×104cfu(2回のLD50用量)の野生型(WT)Lm株DP−L4056でマウスをIV攻撃した(参照により本明細書に組み込まれるLauer,P.et al.,Construction,Characterization and Use of Two Listeria monocytogenes site−specific phage integration vectors.J.Bacteriology(2002)184(15):4177−4186)に記載されている通り)。3日後、脾臓を採取し、ホモジナイズした。200μg/mLのストレプトマイシンを含有するBHIプレート上で希釈液を平板培養して、cfu/臓器を決定した。このアッセイの検出限界(LOD)は50CFUであった。
CT26腫瘍細胞を、ヒトメソテリンを発現するDNAプラスミドでトランスフェクトして、安定した細胞株CT26−hMesoクローン3を産生した。内移植の直前に、凍結した腫瘍細胞のアリコートを解凍し、T細胞培地中で密集まで増殖させた。密集に達したら細胞を採取し、2×105細胞/200μL用量/マウスの内移植のために1×106細胞/mLの濃度までHBSS中に再懸濁させた。第0日に、Balb/cマウス(群毎に10匹)に2×105CT26−hMeso細胞を静脈内(IV)で内移植した。腫瘍の内移植から3日後、IVによりHBSS;5×106cfu、1×105cfu、若しくは5×103cfuのADU−214;又は5×106cfuのLm11(空のプラットフォーム株)をマウスに投与した。生存についてマウスをモニターした。
標準療法に失敗し、スクリーニングで増悪している進行(IIIb期)又は転移(IV期)NSCLC(腺癌)を有する対象における単剤ADU−214の安全性を評価し、推奨される第2相用量(RP2D)を確立し、予備臨床有効性を評価し、免疫応答を決定するため、ファーストインヒューマン(FiH)、第I相、オープンラベル、多施設試験、2部試験を実施した。治療薬は、放射線写真による疾患進行の確認、許容できない毒性、同意の撤回、治験責任医師による治療停止の決定、後の抗癌療法の開始、又はスポンサーによる試験の終了まで投与される。
ブロス培養物におけるADU−214の発現
図2に示すように、EGFRvIIIとメソテリン35〜622との融合は、ブロス培養物中のCRS−207に比べて約50倍のタンパク質増加をもたらした。ADU−214融合タンパク質は、約88kDaであることが予測される(EGFRvIII−Mesoと称する)。CRS−207タンパク質は、約72kDaであることが予測される(Mesoと称する)。負の対照プラットフォーム株であるLm11について、バンドは検出されなかった。
図2に示すように、EGFRvIIIとメソテリン35〜622との融合は、CRS−207に比べて約42倍の細胞内タンパク質発現増加をもたらした。ADU−214融合タンパク質は、約88kDaであることが予測される。CRS−207タンパク質は、約72kDaであることが予測される。p60は、感染細胞中の細菌数と相関する構成的Lmタンパク質であり、約60kDaである。上のパネルは、ActAポリクローナル抗体を用いて検出された融合タンパク質の発現を示す。下のパネルは、モノクローナル抗体を用いて検出されたp60発現を示す。負の対照プラットフォーム株であるLm11について、バンドは検出されなかった。
ADU−214は、Balb/cマウスにおける頑健なメソテリン特異的T細胞免疫応答を誘導した(図4A)。ADU−214は、C3H/HeNマウスにおいて頑健なEGFRvIII特異的CD8+T細胞免疫応答を誘導した(図3A及び図3B)。
ADU−214による1回のワクチン接種は、ワクチンプラットフォーム株Lm11と同等のレベルまで、WTリステリア(Listeria)攻撃に対する十分に防御的な長期免疫を誘導した(図4)。ADU−214によるワクチン接種は、WT−Lm攻撃後、6log超のcfu減少をもたらした。機能免疫は、抗原特異的免疫応答の大きさと、将来の攻撃から防御する免疫応答の能力との組合せである。この場合、機能性は、十分に毒性の野生型リステリア(Listeria)属攻撃を用いて試験した。
治療用CT26−hMeso肺転移モデルにおいて、ADU−214の抗腫瘍効果をBALB/cマウスにおいて決定した(図5)。様々な用量のADU−214、空のLm ΔactAΔinlBプラットフォーム株(ANZ−100)又はハンクス平衡塩類溶液(HBSS)でマウスをIVワクチン接種した。ワクチンの強力な免疫原性と一致して、ADU−214を受けた動物は、ANZ−100(Lm11と称する)又はHBSSのいずれかを受けた動物と比較して生存期間が向上した。ADU−214投与後の生存期間延長は用量依存的であり、長期生存動物の70%が最高用量(5×106CFU)を、60%が中間用量(1×105CFU)を、20%が最低用量(5×103CFU)を受けた群であった。
Claims (18)
- メソテリンポリペプチドと融合された上皮増殖因子受容体変異型III(EGFRvIII)ポリペプチドを含む融合タンパク質ポリペプチドであって、配列番号8のアミノ酸配列を含む融合タンパク質ポリペプチド。
- 細菌によって発現される、請求項1に記載の融合タンパク質。
- 前記細菌がリステリア・モノサイトゲネス(Listeria monocytogenes)である、請求項2に記載の融合タンパク質。
- 請求項1に記載の融合タンパク質をコードする核酸分子。
- 発現カセットの一部である、請求項4に記載の核酸分子。
- 請求項5に記載の核酸分子を含む宿主細胞。
- リステリア・モノサイトゲネス(Listeria monocytogenes)がΔactA/ΔinlB突然変異体である、請求項6に記載の宿主細胞。
- 請求項5に記載の核酸分子を含むベクター。
- 請求項6に記載の宿主細胞と、薬学的に許容される賦形剤とを含むワクチン。
- 対象において免疫応答を誘発する方法であって、宿主細胞を含む組成物を前記対象に投与するステップを含み、前記宿主細胞が、配列番号8のポリペプチドをコードする核酸分子を含む、方法。
- 前記宿主細胞がリステリア・モノサイトゲネス(Listeria monocytogenes)ΔactA/ΔinlB突然変異体である、請求項10に記載の方法。
- メソテリンポリペプチドの発現を増大させる方法であって、宿主細胞において、配列番号8の配列を含むポリペプチドをコードする核酸分子を発現させるステップを含む方法。
- 癌の治療を、それを必要とする対象において行う方法であって、治療有効量の、宿主細胞を含む組成物を前記対象に投与するステップを含み、前記宿主細胞が、配列番号8を含むポリペプチドをコードする核酸分子を含む、方法。
- 前記癌がメソテリン発現癌、EGFRvIII発現癌、又はその両方である、請求項13に記載の方法。
- 前記癌が高レベルのメソテリン発現を有する、請求項13に記載の方法。
- 前記癌が肺癌である、請求項13に記載の方法。
- 前記肺癌が非小細胞肺癌(NSCLC)腺癌、NSCLC扁平上皮癌、大細胞癌、又はこれらの任意の組合せである、請求項16に記載の方法。
- 前記肺癌が進行NSCLC腺癌又は転移性NSCLC腺癌である、請求項17に記載の方法。
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EA201792274A1 (ru) | 2018-02-28 |
IL254957A0 (en) | 2017-12-31 |
BR112017022076A2 (pt) | 2018-08-14 |
HK1250992A1 (zh) | 2019-01-18 |
TW201710285A (zh) | 2017-03-16 |
UY36616A (es) | 2016-10-31 |
US20160346369A1 (en) | 2016-12-01 |
WO2016168198A1 (en) | 2016-10-20 |
ECSP17075380A (es) | 2018-02-28 |
PH12017502080A1 (en) | 2018-05-07 |
CO2017011431A2 (es) | 2018-01-16 |
CR20170507A (es) | 2018-02-13 |
HK1250730A1 (zh) | 2019-01-11 |
EP3283509A1 (en) | 2018-02-21 |
SG11201708360TA (en) | 2017-11-29 |
CA2982533A1 (en) | 2016-10-20 |
MX2017013174A (es) | 2018-04-11 |
JP6782253B2 (ja) | 2020-11-11 |
KR20180002640A (ko) | 2018-01-08 |
MA44379A (fr) | 2019-01-23 |
US10105427B2 (en) | 2018-10-23 |
SV2017005545A (es) | 2018-05-11 |
CN107750256A (zh) | 2018-03-02 |
AU2016247887A1 (en) | 2017-11-02 |
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