JP5139530B2 - 前立腺癌(Pca)を治療するための組成物 - Google Patents
前立腺癌(Pca)を治療するための組成物 Download PDFInfo
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- JP5139530B2 JP5139530B2 JP2010528313A JP2010528313A JP5139530B2 JP 5139530 B2 JP5139530 B2 JP 5139530B2 JP 2010528313 A JP2010528313 A JP 2010528313A JP 2010528313 A JP2010528313 A JP 2010528313A JP 5139530 B2 JP5139530 B2 JP 5139530B2
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- rna
- immunostimulatory
- active
- antigen
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Images
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/00—Drugs for disorders of the urinary system
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- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
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- A61K39/001195—Prostate specific membrane antigen [PSMA]
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Description
本発明は、哺乳動物の(適応)免疫応答を誘発することが可能な少なくとも2つの抗原(好ましくは異なる抗原)をコードする、少なくとも1つのRNA(好ましくはmRNA)を有する活性(免疫賦活)組成物に関し、上記抗原は、PSA(前立腺特異抗原)、PSMA(前立腺特異膜抗原)、PSCA(前立腺肝細胞抗原)およびSTEAP(前立腺6膜貫通上皮抗原)からなる群から選択される。また、本発明は、上記活性(免疫賦活)組成物を含むワクチン、(ワクチン調製を目的とする)上記活性(免疫賦活)組成物の使用、ならびに、前立腺癌(PCa)の治療、好ましくは新規の補助療法(neoadjuvant)、および/またはホルモン抵抗性前立腺癌、それに関連する疾病または疾患の治療のための、(適応)免疫応答を引き起こすワクチンの使用に関する。さらに、本発明はキットに関し、特に上記活性(免疫賦活)組成物および/または上記ワクチンを含む、複数のパーツからなるキットに関する。
前立腺癌は、現在、世界の先進国における男性において、癌に関する診断数において2番目に多く、癌の死因としては4番目に多い。有効な治療措置の方法は弱体化させることであり、局部的な疾患にのみ利用されている。ホルモン抵抗性前立腺癌に関しては、実質的に1年以上の延命が認められる薬はない(例えばPavlenko,M.,A.K.Roosら, (2004).“A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer.”Br J Cancer 91(4):688-94.参照)。現在、米国などのいくつかの欧米主要先進国においては、男性において、前立腺癌は最も多く診断される悪性腫瘍であり、男性における癌死因としては、米国(例えばJemal,A.,R.Siegelら, (2006). “Cancer statistics,2006.”CA Cancer J Clin 56(2):106-30.参照)および欧州(例えばThomas-Kaskel,A.K.,C.F.Wallerら,(2007). “Immunotherapy with dendritic cells for prostate cancer.”Int J Cancer 121(3):467-73参照)それぞれにおいて、3番目に多い。診断される腫瘍の多くは腺癌であり、ホルモン依存性の態様で初期に増殖する。
・PSA(前立腺特異抗原)=KLK3(カリクレイン−3)
・PSMA(前立腺特異膜抗原)
・PSCA(前立腺幹細胞抗原)
・STEAP(前立腺6膜貫通上皮抗原)
からなる群から選択される少なくとも2つ、3つまたは4つの抗原(好ましくは異なる抗原)をコードしている、という本発明の特徴によって達成される。
・PSAおよびPSMA
・PSAおよびPSCA
・PSAおよびSTEAP
・PSMAおよびPSCA
・PSMAおよびSTEAP
・PSCAおよびSTEAP
または、
・PSA、PSMAおよびPSCA
・PSA、PSMAおよびSTEAP
・PSMA、PSCAおよびSTEAP
・PSA、PSCAおよびSTEAP
または、
・PSA、PSMA、PSCAおよびSTEAP
のうち(少なくとも)いずれか1つを含んでいる上記群の抗原のいずれかから選択される、少なくとも2つの(好ましくは異なる)抗原をコードしていてもよい。
(a)ここで、少なくとも1つの抗原は、
・STEAP(前立腺6膜貫通上皮抗原)から選択され;
(b)残りの抗原は、以下の抗原もしくはこれらの特定の組み合わせ:
・PSA(前立腺特異抗原)、
・PSMA(前立腺特異膜抗原)、もしくは、
・PSCA(前立腺幹細胞抗原);
または、
・PSAおよびPSMA、
・PSAおよびPSCA、もしくは、
・PSMAおよびPSCA;
または、
・PSA、PSMAおよびPSCA;
のうちの少なくとも1つから選択される。
Argをコードするコドンは、CGU、CGA、AGAまたはAGGから、CGCまたはCGGに修飾され得;
Alaをコードするコドンは、GCUまたはGCAから、GCCまたはGCGに修飾され;
Glyをコードするコドンは、GGUまたはGGAから、GGCまたはGGGに修飾され得る。
Pheをコードするコドンは、UUUからUUCに修飾され得;
Leuをコードするコドンは、UUA、UUG、CUUまたはCUAから、CUCまたはCUGに修飾され得;
Serをコードするコドンは、UCU、UCAまたはAGUから、UCC、UCGまたはAGCに修飾され得;
Tyrをコードするコドンは、UAUからUACに修飾され得;
Cysをコードするコドンは、UGUからUGCに修飾され得;
Hisをコードするコドンは、CAUからCACに修飾され得;
Glnをコードするコドンは、CAAからCAGに修飾され得;
Ileをコードするコドンは、AUUまたはAUAから、AUCに修飾され得;
Thrをコードするコドンは、ACUまたはACAから、ACCまたはACGに修飾され得;
Asnをコードするコドンは、AAUからAACに修飾され得;
Lysをコードするコドンは、AAAからAAGに修飾され得;
Valをコードするコドンは、GUUまたはGUAから、GUCまたはGUGに修飾され得;
Aspをコードするコドンは、GAUからGACに修飾され得;
Gluをコードするコドンは、GAAからGAGに修飾され得;
終止コドンUAAは、UAGまたはUGAに修飾され得る。
元はSerをコードするすべてのコドンを、UCC(またはUCGまたはAGC)へと置換する;
元の配列においてIleをコードするすべてのコドンを、AUCへと置換し、
元はLysをコードするすべてのコドンを、AAGへと置換し、
元はTyrをコードするすべてのコドンを、UACへと置換する;
元の配列においてValをコードするすべてのコドンを、GUC(またはGUG)へと置換し、
元はGluをコードするすべてのコドンをGAGへと置換し、
元はAlaをコードするすべてのコドンをGCC(またはGCG)へと置換し、
元はArgをコードするすべてのコドンをCGC(またはCGG)へと置換する;
元の配列においてValをコードするすべてのコドンを、GUC(またはGUG)へと置換し、
元はGluをコードするすべてのコドンを、GAGへと置換し、
元はAlaをコードするすべてのコドンを、GCC(またはGCG)へと置換し、
元はGlyをコードするすべてのコドンを、GGC(またはGGG)へと置換し、
元はAsnをコードするすべてのコドンを、AACへと置換する;
元の配列においてValをコードするすべてのコドンを、GUC(またはGUG)へと置換し、
元はPheをコードするすべてのコドンを、UUCへと置換し、
元はCysをコードするすべてのコドンを、UGCへと置換し、
元はLeuをコードするすべてのコドンを、CUG(またはCUC)へと置換し、
元はGlnをコードするすべてのコドンを、CAGへと置換し、
元はProをコードするすべてのコドンを、CCC(またはCCG)へと置換する;等が挙げられる。
(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x・・・(I)
(式中、l+m+n+o+xは8〜15であり、l、m、nまたはoは互いに独立して、Arg、Lys、HisおよびOrnの総含有量がオリゴペプチドの全アミノ酸の少なくとも50%を示すように、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14または15から選択される任意の数であり;Xaaは、Arg、Lys、HisまたはOrnを除く、野生型(すなわち自然発生)または非天然アミノ酸から選択される任意のアミノ酸であればよく;xはXaaの総含有量がオリゴペプチドのすべてのアミノ酸の50%を超えない範囲で、0、1、2、3または4から選択される任意の数であればよい)を有するタンパク質またはペプチドから選択されることが好ましい。ここで、特に好ましいオリゴアルギニンとしては、例えばArg7、Arg8、Arg9、Arg7、H3R9、R9H3、H3R9H3、YSSR9SSY、(RKH)4、Y(RKH)2Rなどが挙げられる。
GlXmGn・・・(II)
(式中、Gはグアノシン、ウラシルあるいはグアノシンまたはウラシルの類似体であり、Xはグアノシン、ウラシル、アデノシン、チミジン、シトシンまたは上記ヌクレオチドの類似体であり;lは1から40までの整数であり、l=1のとき、Gはグアノシンまたはその類似体であり;l>1のとき、ヌクレオチドの少なくとも50%はグアノシンまたはその類似体であり;mは整数であり、少なくとも3であり;m=3のとき、Xはウラシルまたはその類似体であり、m>3のとき、少なくとも3つの連続するウラシルまたはウラシルの類似体があり;nは1から40までの整数であり、n=1のとき、Gはグアノシンまたはその類似体であり、n>1のとき、ヌクレオチドの少なくとも50%はグアノシンまたはその類似体である)を有する核酸から選択されてもよい。
ClXmCn・・・(III)
(式中、Cはシトシン、ウラシル、またはそれらの類似体であり;Xはグアノシン、ウラシル、アデノシン、チミジン、シトシンまたは上記ヌクレオチドの類似体であり;lは1から40までの整数であり、l=1のとき、Cはシトシンまたはその類似体であり、l>1のとき、ヌクレオチドの少なくとも50%はシトシンまたはその類似体であり;mは整数であり、少なくとも3であり;m=3のとき、Xはウラシルまたはその類似体であり、m>3のとき、少なくとも3つの連続するウラシルまたはその類似体があり;nは1から40までの整数であり、n=1のとき、Cはシトシンまたはその類似体であり、n>1のとき、ヌクレオチドの少なくとも50%はシトシンまたはその類似体である)を有する核酸から選択されるアジュバントが挙げられる。
本発明は前立腺癌(PCa)治療のための活性(免疫賦活)組成物を提供するものであって、哺乳動物における(適応)免疫応答を誘導することができる少なくとも2つの(好ましくは異なる)抗原をコードする少なくとも1つのRNA(好ましくはmRNA)を含んでおり、上記抗原はPSA(前立腺特異抗原)、PSMA(前立腺特異膜抗原)、PSCA(前立腺幹細胞抗原)およびSTEAP(前立腺6膜貫通上皮抗原)からなる群から選択されることを特徴とする、活性(免疫賦活)組成物を提供する。このような活性(免疫賦活)組成物は、前立腺癌(PCa)に対する効率的な治療を可能にする、または従来の治療法を使用において補助的治療を可能にする。さらに、本発明は治療法のための方法としてRNAを使用することによって、導入されたDNA配列が制御不能に増殖してしまうという問題を回避する。本発明の活性(免疫賦活)組成物において使用されるRNAは、DNA発現システム(例えば免疫応答、免疫付与またはワクチン接種において)において、さらなる顕著な利点を有している。利点として、特に、細胞に導入されたRNAがゲノムに組み込まれない点が挙げられる。これにより、遺伝子が突然変異してしまう危険性を回避する。この突然変異は完全、または部分的な不活性化、または誤った遺伝子情報を引き起こす可能性がある。さらに、本発明の活性(免疫賦活)組成物は、DNAを抗原として使用して免疫応答を誘導する際に付随する他のリスク(例えばワクチンとして使用した場合)、例えば外来DNAが導入された患者において病原性抗DNA抗体を誘導して、(至死的な場合もある)免疫応答を引き起こすというリスクを回避する。その一方で、抗RNA抗体は検出されていない。
以下の図面は本発明をさらに詳しく説明するためのものである。これらは本発明の対象を制限することを意図したものではない。
安定化およびより良いコドン処理のためのGC最適配列;
3’−末端に〜70×アデノシン(ポリ−A−尾部);
3’−末端に〜30×シトシンを(ポリ−C−尾部);
このDNAコンストラクトはコードmRNAに対応しており、インビトロ転写実験によって、対応するRNAコンストラクトを調製するためのベースとして供給される)。
安定化およびより良いコドン処理のためのGC最適配列;
3’−末端に〜70×アデノシン(ポリ−A−尾部);
3’−末端に30×シトシン(ポリ−C−尾部);
このDNAコンストラクトはコードmRNAに対応しており、インビトロ転写によって、対応するRNAコンストラクトを生成するためのベースとして供給される)。
安定化およびより良いコドン処理のためのGC最適配列;
3’−末端に〜70×アデノシン(ポリ−A−尾部);
3’−末端に30×シトシン(ポリ−C−尾部);
このDNAコンストラクトはコードmRNAに対応しており、インビトロ転写によって、対応するRNA構成を生成するためのベースとして供給される)。
安定化およびより良いコドン処理のためのGC最適配列;
3’−末端に〜70×アデノシン(ポリ−A−尾部);
3’−末端に30×シトシン(ポリ−C−尾部);
このDNA構成はコードmRNAに対応しており、インビトロ転写によって、対応するRNA構成を生成するベースとして供給される)。
コントロールのマウスは、バッファ(リンガー乳酸塩)、またはmRNAワクチンのプロタミン類似体によって調製した無関係のRNA(Pp Luc)のいずれかにより処理した。血清分析のため、グループ毎に5匹のマウスから血清を採取し、滴定した。エラーバーは、平均値から2回の繰り返しの平均偏差を示す。
以下の実施例は本発明をさらに説明するためのものである。これらは、本発明の対象を制限することを意図してはいない。
以下の実験では、下記の抗原をそれぞれ末端にコードするmRNA配列に対応するDNA配列を調整し、インビトロ転写およびトランスフェクション実験に使用した。
・PSA(前立腺特異抗原)
・PSMA(前立腺特異膜抗原)
・PSCA(前立腺幹細胞抗原)および、
・STEAP(前立腺6膜貫通上皮抗原)
これにより、野生型抗原をコードするmRNA(図2、5、8および11(すなわち、配列番号2、5、8および11)に示されるコード配列を含んでなる配列)に対応するDNA配列を、より良いコドン使用のためにGC最適化し、図3、6、9および12(配列番号3、6、9および12)に示されるコード配列からなる配列を得た。その後、ポリ−A−タグおよびポリ−C−タグ(A70−C30)を用いて修飾したGC最適化コンストラクト(CureVac GmbH,Tubingen,ドイツ)に、コード配列を転写した。最終的なコンストラクトは、それぞれ以下のようになった:
RNActive CAP−KLK3(GC)−muag−A70−C30(配列番号1)、
RNActive CAP−FOLH1(GC)−muag−A70−C30(配列番号4)、
RNActive CAP−PSCA(GC)−muag−A70−C30(配列番号7)および、
RNActive CAP−STEAP(GC)−muag−A70−C30(配列番号10)と称する。
最終的なコンストラクトはそれぞれ、図1、4、7および10(配列番号1、4、7および10)に示される配列による配列を含んでおり、以下の配列要素を含む:
安定化およびより良いコドン使用のためのGC最適配列、
3’−末端に〜70個のアデノシン(ポリ−A−尾部)
3’−末端に30個のシトシン(ポリ−C−尾部)
実施例1において得られた組換えプラスミドDNAを基に、インビトロ転写によってRNA配列を調製した。その結果線形化した組換えプラスミドDNAを、続いてT7RNAポリメラーゼを用いて、インビトロ転写した。その後、DNAテンプレートをDNase I消化によって分解し、RNAをLiCl沈殿によって再生し、さらにHPLC抽出によって洗浄した(PUREMessenger(商標登録),CureVac GmbH,Tubingen,ドイツ)。
RNAを細胞および生体に導入するために、インビトロ転写によって得られたRNAを好ましくは複合させ、より好ましくはRNAをプロタミンに混合することで、プロタミンと複合させた。
免疫付与のため、上述したインビトロ転写実験(実施例2参照)によって得られたRNA、好ましくはプロタミンと複合しているRNAを、マウス(Mice:C57 BL/6)に導入した。異なるグループにワクチンを接種し、1つのグループ(コントロールグループ)に属するマウスにはコントロール(対称)として、バッファを注入した。グループごとに4匹のマウスに、プロタミンと複合した20μgのmRNA(遺伝子ごとに5μg)を4回経皮投与して免疫を与えた。ここで、RNAはPSA、PSMA、PSCAおよびSTEAPをコードしていた。
抗原特異的抗体を検出することによって、抗原特異的免疫応答(B細胞免疫応答)を検出した。その結果、ワクチン接種したマウスから、最後にワクチンを投与してから1週間経過した後、血液サンプルを採取し、血清を調製した。MaxiSorbプレート(Nalgene Nunc International)をヒトPSAタンパク質(0.5μg/well)を用いてコートした。1×PBS含有0.05%Tween−20および1%BSAを用いてブロックした後、プレートを希釈したマウス血清(1:30、1:90、1:270、1:810)とともに培養した。その後、ビオチン結合した第2抗体(抗マウスIgG2a Pharmingen)を加えた。洗浄後、プレートをセイヨウワサビペルオキシダーゼ−ストレプトアビジン(Horseradish peroxidase-streptavidi)とともに培養し、その後、ABTS基質((2,2’−アジノ−bis(3−エチル−ベンズチアゾリン−6−スルホン酸)の転換を測定した。
最後にワクチンを接種してから2ヵ月経過したマウスを殺傷し、脾臓を摘出し、脾細胞を分離した。脾細胞を、IL−4の存在下において7日間培養し、樹状細胞を選択した。抗原特異的細胞免疫応答を検出するために再び刺激した後、INFガンマ分泌を測定した。標的細胞として、野生型マウスから採取した脾細胞を使用した。脾細胞はPCa−mRNA−カクテル(Mix)、またはPSA、PSMA、PSCAもしくはSTEAPをコードするmRNA(図1、4、7および10(配列番号1、4、7および10)それぞれに示される配列)を用いて電気穿孔した。
(a)免疫付与
mRNA(PSA、PSMA、PSCAおよびSTEAPをそれぞれコードするmRNAを5μgずつ含むPCa−RNAカクテル、例えばRNActive CAP−KLK3(GC)−muag−A70−C30、RNActive CAP−FOLH1(GC)−muag−A70−C30、RNActive CAP−PSCA(GC)−muag−A70−C30およびRNActive CAP−STEAP(GC)−muag−A70−C30(図1、4、7および10(すなわち配列番号1、4、7および10)に示される配列)をそれぞれ構成するmRNA)を20μg、筋肉内経路にてマウスに注入した。7週間にわたって、免疫付与を1回または3回繰り返した。最後に免疫付与してから40日後、MioTramp−C1腫瘍細胞を皮下経路にてマウスに注入した。50日間、腫瘍体積を測定した。
図15に示すように、腫瘍体積は、(a)PSA、PSMA、PSCAおよびSTEAPをそれぞれコードするmRNAを含むPca−RNAカクテルによって、をi.m(筋肉内経路)にて2回使用した免疫付与において、著しく減少した。腫瘍体積は、上記(a)によるPCa−RNA カクテルを筋肉内経路にて4回投与したとき、さらに著しく減少した。
(8.1.mRNAワクチン調製)
mRNAワクチンは、ヒト前立腺分化抗原PSMA、STEAP、PSAおよびPSCAをコードするGC最適mRNA(配列番号3、6、9および12に示される)からなり、それぞれの抗原は80%(v/v)リンガー乳酸塩溶液に、カチオン性ペプチドプロタミンを4:1の質量比(RNA:プロタミン)にて溶解して調製される。
上記8.1に記載したmRNAワクチンを64μg(各抗原を16μg)、C57BL/6のマウスに皮内経路にてワクチン接種した。コントロールのマウスにはバッファ(リンガー乳酸塩)、mRNAワクチンに対するプロタミン類似体を使用して調整した無関係のRNA(フォチナスフィラリスルシフェラーゼ(Photinus pyralis luciferase)をコードする、高GCmRNA)どちらかを使用した。ワクチン接種は第1週、第3週(および第7週)において、2回または3回の免疫付与サイクルにて行った。それぞれのサイクルにおいて、4回(週の1日目、2日目、3日目および4日目)注入した。
ワクチン接種完了から15日後、各マウスに、1×106TRAMP−C1細胞(ヒトPSMA、PSCAおよびSTEAPに対するマウスホモログを発現している、マウス前立腺細胞株1における遺伝子組換え腺癌)を皮下経路にて移植した。腫瘍は、腫瘍細胞移植から4週間後には明確となった。キャリパーを使用して腫瘍サイズを測定し、腫瘍成長を観察した。
ワクチン接種から14日後、血液サンプル(200μl)を眼窩後方から採取し、血清を下記のELISAプロトコルを使用して、抗原特異的抗体サブタイプIgG1およびIgG2aの存在から分析した。96ウェルのELISAプレートを組み替えタンパク質PSCAまたはヒト精製PSA(どちらもコートバッファにおいて10μg/ml)によってコートし、(ブロックし、洗浄した後に)血清とともに37℃にて4時間培養した。マウスIgG1またはマウスIgG2aに対するビオチン標識抗体とともに培養し、HRP−ストレプトアビジンとともに培養した後、TMB基質を加えた。比色反応を、Tecan ELISAリーダーを使用して、450nmにて測定した。
CTL(細胞傷害性T細胞)反応を検出するにあたって、エリスポット法によって、特定の刺激に対するIFN−γ分泌の分析を、単一細胞レベルにて視覚化することができる。上記8.1において記載したmRNAワクチンを接種したマウス、およびコントロールマウスの脾細胞を、3番目のワクチン接種サイクルにおいて最後にワクチンを接種してから6日後に分離し、その後、α−IFN−γ捕獲抗体によってコートされた96ウェルのエリスポットプレートへと移した。その後、PSMA由来ペプチドライブラリー、またはコントロール(対象)としてHIV由来ライブラリーどちらかを使用し、細胞を37℃にて24時間刺激した。どちらのライブラリーも、1μg/ペプチド/ml濃度にて使用した。培養期間経過後、細胞をプレートから洗浄し、細胞から分泌されたIFN−γを、マウスのIFN−γに対するビオニチル化二次抗体、その後ストレプトアビジン−AKPを使用して検出した。BCIP/NBT基質を使用してスポットを視覚化し、自動エリスポットリーダー(Immunospot Analyzer,CTL Analyzers LLC)を使用してカウントした。
インビボにおける細胞傷害性T細胞の活性を検出するために、ワクチンを接種したマウスおよびコントロールのマウスにおける、特定の標的細胞の溶解を分析した。記憶細胞傷害性Tリンパ球の誘導を検出するために、分析は最後に免疫付与してから1週間後および10週間後に行った。
残存特定標的の割合=コントロールマウスにおける(観察された)特定標的/コントロールマウスにおける(観察された)コントロール標的
残存特定標的の割合×ワクチン接種マウスにおいて観察されたコントロール標的の数=ワクチン接種マウスにおける予想された特定標的の数
死滅%=(1−(観察された特定標的/予想された特定標的)
(8.7.統計分析)
グラフパッド(GraphPad Prism)Software Version 5.01を使用して、統計分析を行なった。サンプル個体群の正規分布が欠如しており、サンプルサイズが小さいため、非パラメトリックマンホイットニー検定(non-parametric Mann Whitney tests)を5%の危険率有意水準にて使用して、テストグループ間の差分を分析した。
ヒト前立腺分化抗原PSMA、STEAP、PSAおよびPSCAをコードするGC最適mRNAからなるmRNAワクチンをマウスに接種した。それぞれの抗原は、別々に、質量比4:1(RNA:プロタミン)にて、カチオン性ペプチドプロタミンを使用して調製した。コントロールマウスにはバッファ(リンガー乳酸塩)またはmRNAワクチンに対するプロタミン類似体によって調製した無関係のRNA(PpLuc)を使用した。
抗体を検出するために必要な組換えタンパク質の可用性に制限があり、4つのうち2つの抗原に対する特定の抗体の誘導を試験した。分析したどちらのタンパク質においても、PSA抗原特異的抗体およびPSCA抗原特異的抗体が、mRNAワクチンを接種したマウスの血清において検出され、どちらのmRNAもインビボにおいて機能性および免疫原性を有することが証明された(図16〜図18参照)。
さらに、mRNAワクチン投与に対する細胞傷害性T細胞の活性化を、2つの独立した機能性分析を適用して分析した。すなわち、IFN−γの分泌、およびインビボ細胞傷害性分析である。IFN−γはThl反応の主要なメディエーターであり、活性化されたCTLによって分泌される。それゆえ、ワクチン接種マウスの脾細胞における抗原特異的細胞傷害性T細胞の存在を、エリスポット技術を使用して調査した。脾細胞用抗原促進剤として、制限PSMA由来ペプチドラブラリーを使用した。このライブラリーによる刺激は、高いIFN−γ分泌を引き起こしたが、上記mRNAワクチンを用いてワクチンを接種したマウスの脾細胞においてのみであり、関連のないタンパク質ルシフェラーゼ(Pp Luc)をコードするmRNAを用いてワクチンを接種したコントロールマウスには現れなかった。HIV由来コントロールペプチドライブラリーに反応した脾細胞は1つもなかった(図19参照)。
Claims (43)
- 互いに異なる抗原をコードする、4つのRNAを含んでいる活性(免疫賦活)組成物であって、上記抗原は、
・STEAP(前立腺6膜貫通上皮抗原)、
・PSA(前立腺特異抗原)、
・PSMA(前立腺特異膜抗原)、および
・PSCA(前立腺幹細胞抗原)
から選択される、活性(免疫賦活)組成物。 - 少なくとも1つの上記RNAは、250〜20000ヌクレオチドの長さである、請求項1に記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAはmRNAである、請求項1または2に記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAは、モノシストロン性RNA、ビシストロン性RNAまたはマルチシストロン性RNAである、請求1または2に記載の活性(免疫賦活)組成物。
- 少なくとも2つの上記抗原は、それぞれモノシストロン性RNAによってコードされている、請求項4に記載の活性(免疫賦活)組成物。
- 少なくとも2つの上記抗原は、ビシストロン性RNAまたはマルチシストロン性RNAによってコードされている、請求項4に記載の活性(免疫賦活)組成物。
- 少なくとも2つの上記抗原は、モノシストロン性RNA、ビシストロン性RNAおよび/またはマルチシストロン性RNAの混合物によってコードされている、請求項4に記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAは、請求項1または2に記載の抗原の断片、変異体またはエピトープをコードするRNA配列を含む、請求項1または2のいずれかに記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAは、配列番号2、5、8または11に示されるRNA配列と同一、または少なくとも5%、10%、20%、30%、40%、50%、60%、70%もしくは80%同一であるRNAから選択されるRNAを含む、請求項1から8のいずれか1項に記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAは、修飾されたRNAである、請求項1または2のいずれに記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのRNAは、安定化されたmRNAである、請求項10に記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAのコード領域のG/C含有量は、野生型RNAのコード領域のG/C含有量と比較して増加している、請求項10に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのRNAをコードするアミノ酸配列は、野生型RNAをコードするアミノ酸配列と比較して修飾されていない、請求項12に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのRNAのリボソーム結合部位の周囲におけるA/U含有量は、野生型RNAのリボソーム結合部位の周囲におけるA/U含有量と比較して増加している、請求項10に記載の活性(免疫賦活)組成物。
- 上記修飾されたmRNAのコード領域、ならびに/または、5’非翻訳領域および/もしくは3’非翻訳領域は、野生型RNAと比較して不安定化配列要素を含まないように修飾されている、請求項10に記載の活性(免疫賦活)組成物。
- 上記修飾されたmRNAをコードするアミノ酸配列は、野生型RNAと比較して修飾されていない、請求項15に記載の活性(免疫賦活)組成物。
- 上記修飾されたmRNAは、5’キャップ構造および/またはポリ(A)尾部、および/またはポリC尾部、および/または少なくとも1つのIRES、および/または少なくとも1つの5’安定化配列および/もしくは3’安定化配列を含む、請求項10に記載の活性(免疫賦活)組成物。
- 上記修飾されたmRNAは、5’キャップ構造および/または10〜200アデノシンヌクレオチドのポリ(A)尾部、および/または10〜200シトシンヌクレオチドのポリC尾部を含む、請求項17に記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAは、配列番号1、3、4、6、7、9、10または12に示されるRNA配列と同一、または少なくとも5%、10%、20%、30%、40%、50%、60%、70%または80%同一であるRNAから選択されるRNAを含む、請求項1または2のいずれかに記載の活性(免疫賦活)組成物。
- 少なくとも1つの上記RNAは、1つまたはそれ以上のポリカチオンと複合している、請求項1または2のいずれかに記載の活性(免疫賦活)組成物。
- 上記ポリカチオンは、プロタミンまたはオリゴフェクタミンである、請求項20に記載の活性(免疫賦活)組成物。
- 少なくとも1つのアジュバントを含んでいる、請求項1から16のいずれか1項に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、カチオン性もしくはポリカチオン性の化合物からなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、カチオン性もしくはポリカチオン性のペプチド、もしくはタンパク質、カチオン性多糖類、カチオン性脂質、またはカチオン性もしくはポリカチオン性ポリマーからなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、プロタミン、ヌクレオリン、スペルミン、またはスペルミジン、ポリ−L−リジン、ポリ−アルギニン、塩基性ポリペプチドおよび細胞透過性ペプチドからなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、HIV結合ペプチド、Tat、HIV−1 Tat(HIV)、Tat由来ぺプチド、ペネトラチン、VP22由来または類似ペプチド、HSV VP22、MAP、KALAまたはタンパク質形質導入ドメイン、PpT620、高プロリンペプチド、高アルギニンペプチド、高リジンペプチド、MPG−ペプチド、Pep−1、L−オリゴマー、カルシトニンペプチド、アンテナペディア由来ペプチド、pAntp、pIsl、FGF、ラクトフェリン、トランスポータン、ブホリン−2、Bac715−24、SynB、SynB(1)、pVEC、hCT由来ペプチド、SAP、プロタミン、スペルミン、スペルミジン、またはヒストンからなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、キトサン、ポリブレンおよびポリエチレンイミン(PEI)からなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、DOTMA:[1−(2,3−シオレイルオキシ(sioleyloxy))プロピル)]−N,N,N−トリメチルアンモニウムクロリド、DMRIE、di−C14−アミジン、DOTIM、SAINT、DC−Chol、BGTC、CTAP、DOPC、DODAP、DOPE:ジオレイルホスファチジルエタノールアミン、DOSPA、DODAB、DOIC、DMEPC、DOGS:ジオクタデシルアミドグリシルスペルミン、DIMRI:ジミリスト−オキシプロピルジメチルヒドロキシエチルアンモニウムブロミド、DOTAP:ジオレイルオキシ−3−(トリメチルアンモニオ)プロパン、DC−6−14:O,O−ジテトラデカノイル−N−(α−トリメチルアンモニオアセチル)ジエタノールアミンクロリド、CLIP1:rac−[(2,3−ジオクタデシルオキシプロピル)(2−ヒドロキシエチル)]−ジメチルアンモニウムクロリド、CLIP6:rac−[2(2,3−ジヘキサデシルオキシプロピル−オキシメチルオキシ)エチル]トリメチルアンモニウム、CLIP9:rac−[2(2,3−ジヘキサデシルオキシプロピル−オキシスクニシルオキシ)エチル]−トリメチルアンモニウム、オリゴフェクタミンからなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、修飾ポリアミノ酸、修飾ポリエチレン、修飾アクリレート、修飾アミドアミン、修飾ポリベータアミノエステル(PBAE)、デンドリマー、ポリイミン、ポリアリルアミン、糖骨格ベースポリマー、シラン骨格ベースポリマーおよび前述のカチオン性ポリマーから選択される1つまたはそれ以上のカチオン性ブロックと、1つまたはそれ以上の親水性または疎水性ブロックとの組み合わせからなるブロック重合体からなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、β−アミノ酸−ポリマー、逆ポリアミド、PVP(ポリ(N−エチル−4−ビニルピリジニウムブロミド))、pDMAEMA(ポリ(ジメチルアミノエチルメチルアクリレート))、pAMAM(ポリ(アミドアミン))、ジアミン末端修飾1,4ブタンジオルジアクリレート−co−5−アミノ−1−ペンタノールポリマー)、ポリプロピルアミンデンドリマー、またはpAMAMベースデンドリマー、PEI:ポリ(エチレンイミン)、ポリ(プロピレンイミン))、シクロデキストリンベースポリマー、デキストランベースポリマー、キトサン、PMOXA−PDMS共重合体、およびポリエチレングリコールからなる群より選択される請求項22に記載の活性(免疫賦活)組成物。
- 上記少なくとも1つのアジュバントは、
一般式(I):
(Arg) l ;(Lys) m ;(His) n ;(Orn) o ;(Xaa) x ・・・(I)
(式中、l+m+n+o+xは8〜15であり、l、m、nまたはoは互いに独立して、Arg、Lys、HisおよびOrnの総含有量がオリゴペプチドの全アミノ酸の少なくとも50%を示すように、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14または15から選択される任意の数であり;Xaaは、Arg、Lys、HisまたはOrnを除く、野生型(すなわち自然発生)または非天然アミノ酸から選択される任意のアミノ酸であればよく;xはXaaの総含有量がオリゴペプチドのすべてのアミノ酸の50%を超えない範囲で、0、1、2、3または4から選択される任意の数であり得る);を有するタンパク質またはペプチドから選択されるカチオン性もしくはポリカチオン性のペプチド、またはタンパク質からなる群より選択される請求項22に記載の活性(免疫賦活)組成物。 - 上記少なくとも1つのアジュバントは、
以下の一般式(II):
G l X m G n ・・・(II)
(式中、Gはグアノシン、ウラシルあるいはグアノシンまたはウラシルの類似体であり、Xはグアノシン、ウラシル、アデノシン、チミジン、シトシンまたは上記ヌクレオチドの類似体であり;lは1から40までの整数であり、l=1のとき、Gはグアノシンまたはその類似体であり;l>1のとき、ヌクレオチドの少なくとも50%はグアノシンまたはその類似体であり;mは整数であり、少なくとも3であり;m=3のとき、Xはウラシルまたはその類似体であり、m>3のとき、少なくとも3つの連続するウラシルまたはウラシルの類似体があり;nは1から40までの整数であり、n=1のとき、Gはグアノシンまたはその類似体であり、n>1のとき、ヌクレオチドの少なくとも50%はグアノシンまたはその類似体である);を有する核酸からなる群より選択される請求項22に記載の活性(免疫賦活)組成物。 - 上記少なくとも1つのアジュバントは、
以下の一般式(III):
C l X m C n ・・・(III)
(式中、Cはシトシン、ウラシル、またはそれらの類似体であり;Xはグアノシン、ウラシル、アデノシン、チミジン、シトシンまたは上記ヌクレオチドの類似体であり;lは1から40までの整数であり、l=1のとき、Cはシトシンまたはその類似体であり、l>1のとき、ヌクレオチドの少なくとも50%はシトシンまたはその類似体であり;mは整数であり、少なくとも3であり;m=3のとき、Xはウラシルまたはその類似体であり、m>3のとき、少なくとも3つの連続するウラシルまたはその類似体があり;nは1から40までの整数であり、n=1のとき、Cはシトシンまたはその類似体であり、n>1のとき、ヌクレオチドの少なくとも50%はシトシンまたはその類似体である);を有する核酸から選択される、請求項22に記載の活性(免疫賦活)組成物。 - 請求項1から33のいずれか1項に記載の活性(免疫賦活)組成物を含むワクチン。
- 請求項1から33のいずれか1項に記載の活性(免疫賦活)組成物は、適応免疫応答を引き起こす、請求項34に記載のワクチン。
- 上記ワクチンはさらに、薬学的に使用可能なキャリアを含んでいる、請求項34または35のいずれかに記載のワクチン。
- 前立腺癌(PCa)、およびそれに関連する疾病または疾患を治療するためのワクチンを調製するための、請求項1から33のいずれか1項に記載の活性(免疫賦活)組成物の使用。
- 新規の補助療法、および/またはホルモン抵抗性前立腺癌を治療するためのワクチンを調製するための、請求項1から33のいずれか1項に記載の活性(免疫賦活)組成物の使用。
- 請求項1から33のいずれか1項に記載の活性(免疫賦活)組成物、および/または請求項34から36のいずれか1項に記載のワクチンを備えているキット。
- 上記活性組成物および/またはワクチンの投与および投与量についての情報を有する技術指示書をさらに備えている、請求項39に記載のキット。
- 互いに異なる抗原をコードする、4つのRNAを含んでいるキットであって、上記抗原は、
・STEAP(前立腺6膜貫通上皮抗原)、
・PSA(前立腺特異抗原)、
・PSMA(前立腺特異膜抗原)、および
・PSCA(前立腺幹細胞抗原)
から選択される、キット。 - 少なくとも1つの上記RNAは、mRNAである請求項41に記載のキット。
- 少なくとも1つの上記RNAは、請求項41に記載の抗原の断片、変異体またはエピトープをコードするRNA配列を含む、請求項41または42に記載のキット。
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DK2195015T3 (da) | 2017-06-19 |
ES2633246T3 (es) | 2017-09-20 |
RU2508125C2 (ru) | 2014-02-27 |
US10434154B2 (en) | 2019-10-08 |
CN101820900A (zh) | 2010-09-01 |
US9402887B2 (en) | 2016-08-02 |
RU2010118013A (ru) | 2011-11-20 |
US20130251742A1 (en) | 2013-09-26 |
JP2010540673A (ja) | 2010-12-24 |
CN104840953A (zh) | 2015-08-19 |
US20100305196A1 (en) | 2010-12-02 |
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