JP5391080B2 - ワクチン - Google Patents
ワクチン Download PDFInfo
- Publication number
- JP5391080B2 JP5391080B2 JP2009545186A JP2009545186A JP5391080B2 JP 5391080 B2 JP5391080 B2 JP 5391080B2 JP 2009545186 A JP2009545186 A JP 2009545186A JP 2009545186 A JP2009545186 A JP 2009545186A JP 5391080 B2 JP5391080 B2 JP 5391080B2
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- Prior art keywords
- protein
- prame
- fusion
- cancer
- fusion protein
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Images
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- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001189—PRAME
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
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- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
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Description
a)PRAMEまたはその免疫原性断片、および
b)Dタンパク質から誘導される異種融合パートナー、
を含む融合タンパク質であって、Dタンパク質の分泌配列(シグナル配列)を含まない前記融合タンパク質を提供する。
一態様においては、本発明の融合タンパク質は、本明細書に記載の融合パートナータンパク質およびPRAME抗原またはその免疫原性断片を含む。一般的には、PRAMEタンパク質は、509個のアミノ酸を有し、一実施形態においては、全部で509個のアミノ酸のPRAMEを用いることができる。いくつかの細胞傷害性Tリンパ球(CTL)エピトープ、例えば、
VLDGLDVLL (PRA100-108; 配列番号13);
SLYSFPEPEA (PRA142-151; 配列番号14);
ALYVDSLFFL (PRA300-309; 配列番号15);
LYVDSLFFL (PRA301-309; 配列番号16)および
SLLQHLIGL (PRA425-433; 配列番号17)
が、PRAME上で同定されている。
i)アスパラギン酸/アスパラギン/グルタミン酸/グルタミン
ii)セリン/トレオニン
iii)リジン/アルギニン
iv)フェニルアラニン/チロシン/トリプトファン
v)ロイシン/イソロイシン/バリン/メチオニン
vi)グリシン/アラニン
である。
VLDGLDVLL (PRA100-108; 配列番号13);
SLYSFPEPEA (PRA142-151; 配列番号14);
ALYVDSLFFL (PRA300-309; 配列番号15);
LYVDSLFFL (PRA301-309; 配列番号16)および
SLLQHLIGL (PRA425-433; 配列番号17)
を含む、からなる、または本質的にそれからなる。
本発明のさらなる実施形態においては、PRAME以外の腫瘍抗原またはPRAMEに加えた腫瘍抗原を、本明細書に記載の融合タンパク質中で用いることができる。一実施形態においては、本明細書に記載の融合パートナータンパク質と、前記抗原に対する免疫応答を指令することができる1種以上の以下の腫瘍抗原:MAGE抗原、例えば、MAGE1、MAGE2、MAGE3、MAGE4、MAGE5、MAGE6、MAGE7、MAGE8、MAGE9、MAGE10、MAGE11、MAGE12などのMAGE-A抗原または腫瘍抗原誘導体またはその免疫原性部分を含む融合タンパク質が提供される。これらの抗原は、時にはMAGE A1、MAGE A2、MAGE A3、MAGE A4、MAGE A5、MAGE A6、MAGE A7、MAGE A8、MAGE A9、MAGE A 10、MAGE A11および/またはMAGE A12(MAGE Aファミリー)として知られる。一実施形態においては、2種のさらなるMAGEファミリー:MAGE BおよびMAGE C群の一方に由来する抗原を用いることができる。MAGE Bファミリーは、MAGE B1(MAGE Xp1、およびDAM 10としても知られる)、MAGE B2(MAGE Xp2およびDAM 6としても知られる)、MAGE B3ならびにMAGE B4を含む。Mage Cファミリーは現在、MAGE C1およびMAGE C2を含む。
・インフルエンザウイルスに由来する非構造タンパク質、NS1(ヘマグルチニン)、典型的には、N末端の81アミノ酸を用いるが、それらがTヘルパーエピトープを含む条件で、異なる断片を用いることができる;
・例えば、残基188〜305などの残基178で開始するC末端に認められるLyta分子の反復部分などの、N-アセチル-L-アラニンアミダーゼ、アミダーゼLYTA(lytA遺伝子によりコードされる{Gene, 43 (1986) p.265-272})を合成する肺炎連鎖球菌(Streptococcus pneumoniae)から誘導されるLYTA;
が挙げられる。
i)宿主細胞中で、前記タンパク質もしくはその免疫原性誘導体をコードするヌクレオチド配列を含むDNAポリマーを発現することができる複製可能な、もしくは組込み発現ベクターを調製する工程;
ii)宿主細胞を前記ベクターで形質転換する工程;
iii)前記DNAポリマーの発現を可能にして前記タンパク質を産生する条件下で前記形質転換された宿主細胞を培養する工程;ならびに
iv)前記タンパク質を回収する工程、
を含んでもよい。
本発明の一実施形態においては、(a) PRAME抗原または本明細書に記載の融合タンパク質を含む抗原成分および(b) MAGE抗原または本明細書に記載の融合タンパク質を含む抗原成分を含む組成物が提供される。一実施形態においては、前記組成物は、本明細書に記載のアジュバントをさらに含んでもよい。
4種の融合構築物を調製し、本明細書では実施例/構築物1、2、3および4と言う。コドン最適化された構築物を実施例3から調製し、本明細書では実施例3aと命名する。コドン最適化された構築物を実施例4から調製し、本明細書では実施例4aと命名する。
プラスミドTCMP14中で提供される配列の増幅を、3段階のPCR戦略を用いて行った。Dタンパク質遺伝子全体をコードするDNA配列を含むベクターpHIC348を、Dr. A. Forsgren, Department of Medical Microbiology, University of Lund, Malmo General Hospital, Malmo, Swedenから得た。Dタンパク質のDNA配列は、Jansonら(1991) {Janson H, LO Heden, A Grubb, M Ruan, & A Forsgren. 1991. Infect Immun 59:119-125}により公開されている。発現ベクターpMG81は、外来挿入遺伝子の転写および翻訳のためにバクテリオファージλ由来制御エレメントが導入された、pBR322の誘導体である(Shatzmanら、1983) {Shatzman A, YS Ho, & M Rosenberg. 1983. Experimental Manipulation of Gene Expression. Inouya (編) pp 1-14. Academic NY}。さらに、アンピシリン耐性遺伝子をカナマイシン耐性遺伝子と交換した。NS1タンパク質の一部に関するコード配列(アミノ酸4〜81)を、複数クローニング部位に置換して、pMG81 MCSを得た。Dタンパク質の1/3のコード配列(アミノ酸20〜127)を、BamHIおよびNcoI制限部位を用いてpMG81 MCS中にクローニングして、pMG81-1/3PDを得た。第1に、Dタンパク質のアミノ酸20〜127に対応する断片のPCR増幅を、鋳型としてのpMF81-1/3PDベクターならびにオリゴヌクレオチドセンス:
5’ ATA TAA CAT ATG GAT CCA AGC AGC CAT TCA TCA AAT 3’ (CAN008; 配列番号18)およびアンチセンス:
5’ CCA CAA ACG CCT TCG TTC CAT GGT TTC AAA GTT TTC TGT C 3’ (CAN037; 配列番号19)
を用いて行った。
5’ GAC AGA AAA CTT TGA AAC CAT GGA ACG AAG GCG TTT GTG G 3’ (CAN036; 配列番号20)およびhis尾部を添加するか(CAN002)、または添加しない(CAN029)かどうかに応じて、アンチセンス:
5’ AGA GAG ACT AGT CTA GTT AGG CAT GAA ACA GGG GCA CAG 3’ (CAN029; 配列番号21)または
5’ GGA GGA ACT AGT GTT AGG CAT GAA ACA GGG GCA CAG 3’ (CAN002; 配列番号22)
を用いて行った。TCMP14プラスミド中に挿入される最終的なPRAME配列を、鋳型ならびにオリゴヌクレオチドセンス:CAN008、およびhis尾部が存在するか(CAN002)、もしくは存在しないか(CAN029)に応じて、アンチセンス:CAN029もしくはCAN002のために予備工程において作製された1/3PDおよびPRAME遺伝子鋳型を用いるPCR増幅後に得た。また、TCMP14ベクターへの前記断片のクローニングのために、5'末端にNdeI部位および3'末端にSpeI部位を加えた。
PRAME遺伝子のコード配列を含有するpcDNA1-PRAMEと呼ばれる組換えcDNAプラスミド(以前の戦略に記載)と、Dタンパク質コード配列のN末端部分を含有するベクターPMG81-1/3PD(以前の戦略に記載)とを用いた。このクローニング戦略は、以下の工程を含んでいた。
PRAME遺伝子をコドン最適化し、最適化された遺伝子の、それぞれ5'末端および3'末端中にNotIおよびXhoI部位を付加したpGA4骨格中にクローニングした。
大腸菌株AR58(Mottら、Proc. Natl. Acad. Sci. USA, vol 82, pp 88-92, January 1985, Biochemistry)に由来する宿主を、実施例/構築物1および2のためにプラスミドDNAを用いて形質転換した。
・培養
20 mlのLuria-Bertani(LB)培地(BD) + 1%(w/v)グルコース(Laboratoire MAT、カタログ番号GR-0101) + 抗生物質(pET21bについてはカルベニシリン100μg/ml、TCMP14についてはカナマイシン40μg/ml)上で細菌を増殖させた。培養物を、AR58細胞については33℃で、BLR(DE3)細胞については37℃で、O.D.600nmが約0.8になるまでインキュベートした。
約0.8のO.D.600nmで、培養物BLR(DE3)を、1 mMイソプロピルβ-D-1-チオガラクトピラノシド(IPTG;EMD Chemicals Inc.、カタログ番号5815)で誘導し、37℃で2時間または3時間インキュベートしたが、より低い温度を用いる場合、溶解度を増加させることができる。
培養物中での前記ポリペプチドの発現の際に、典型的には細胞を遠心分離により収穫した後、物理的または化学的手段(発現されたポリペプチドが培地中に分泌されない場合)により破壊し、得られる粗抽出物を保持して目的のポリペプチドを単離する。BugBuster(商標)Protein Extraction Reagentを、供給業者(Novagen)により推奨される条件下で用いる。
大腸菌細胞ペーストを、20 mM TrisバッファーpH 8.5中に再懸濁した後、ホモジェナイザー系(Niro Soavi S.p.A.社製Panda、2回通過、750バール)を通過させた。2 mM MgCl2およびBenzonase (50 U/ml)を添加した後、ホモジェネートを緩やかな攪拌下、室温(RT)で1時間インキュベートした後、15900 gかつRTで30分間遠心分離した。得られるペレットを、1%ドデシル硫酸ナトリウム(SDS)および60 mMグルタチオンを含む20 mM Tris
バッファーpH 8.5中に再懸濁し、緩やかな攪拌下、RTで30分間インキュベートした。15900 gかつRTで30分間遠心分離した後、ペレットを廃棄した。
・ベンゾナーゼ処理を行わない、
・IMACカラム上でSDSからサルコシルへのシフトを行わない(抽出からHA工程までSDS)、
・ダイアフィルトレーションに用いるバッファーが5 mM TrisバッファーpH 8.5-0.5 Mアルギニンであった、
において上記プロセスとは異なる、代替的な精製プロセスも用いた。この代替的な精製プロセスにより、約0.05および0.085%の残留値を有する不完全なSDS除去が得られた。
発現された組換えタンパク質を、樹脂の製造業者からの指示書に従って、His-Bind金属キレート化樹脂(QIAgen, Chatsworth, CA)を用いて誘導された大腸菌を遠心分離した後に得られた上清画分から精製した。
SDS-Page:
ゲル:NuPAGE 4-12%Bis-Tris Gel 1.0 mm 15または26ウェル(Invitrogenカタログ番号NP0323BOX)。
3%ミルク/PBS 1Xの新鮮な溶液を用いて、37℃、60RPMで30分間、膜をブロックした。ブロッキングインキュベーションの後、1:5000の希釈率で一次抗体(ウサギ抗PRAME;GSK Biologicals SA)または1:3000の希釈率でα-6X Hisタグ(AbCam)を、3%ミルク/PBS 1Xの新鮮な溶液中、37℃、60RPMで1時間添加した。その後、0.02%Tween20/PBS 1Xを用いて室温で5分間、3回膜を洗浄した。3%ミルク/PBS 1Xの新鮮な溶液を用いて、1:20000の希釈率で二次抗体(ペルオキシダーゼ結合ロバ抗IgG(H+L)ウサギ抗体(Jackson laboratory))を添加した。膜を37℃、60RPMで1時間インキュベートした。その後、膜を0.02%Tween20/PBS 1Xを用いて室温で5分間、3回洗浄した後、供給業者の推奨に従って、膜をペルオキシダーゼ基質(KH2PO4、10 mM;(NH4)2SO4、10 mM;O-ジアニシジン、0.01%および過酸化水素0.045%)またはアルカリホスファターゼ基質(Sigma Fast)に曝露した。
目的:前臨床試験において用いるのに最も良い用量を選択するための抗原の用量範囲の決定。
1. PBS
2. AS01BまたはAS15中のPRAME(50*μg)
3. AS01BまたはAS15中のPRAME(10μg)
4. AS01BまたはAS15中のPRAME(2μg)
5. AS01BまたはAS15中のPRAME(0.4μg)
6. AS01BまたはAS15中のPRAME(0.08μg)
*50μgの意図される用量の代わりに、実際に投与されたのは44.7μgであった。
・1μg/ml/ペプチド(15マー)でペプチドPRAMEのプールを用いるin vitroでの脾臓細胞の再刺激(1群あたり3匹のマウスの4つのプール)後、2回の注入の14日後の細胞内サイトカイン染色(ICS)。
AS01Bアジュバントに関するCD4サイトカインのICSの結果を図3に示す。この実験で、これらの条件下でAS01BにおけるCD4応答を誘導するためのPRAME抗原の最良の用量は2μgであると結論付けることができる。
AS01Bアジュバントに関するCD8サイトカインのICSの結果を図4に示す。このデータは、非常に低いCD8応答および群内応答の不均質性を示すようである。
AS15アジュバントに関するCD4サイトカインのICSの結果を図5に示す。これらのデータは、AS15中で製剤化された44μg、10μg、2μgおよび0.4μgのPRAMEに関して類似するCD4応答が誘導され、0.08μgのPRAMEの場合、応答の誘導が低下したことを示すようである。
AS15アジュバントに関するCD8サイトカインのICSの結果を図6に示す。これらのデータは、CD8応答がないことを示すようである(PBS群におけるバックグラウンド)。
まとめると、本明細書に記載の本発明について、以下の概要を用いて、今までのところ作製されたPD1/3-PRAMEの特定の構築物を説明することができる。
Dタンパク質のシグナル配列は含まれない(Dタンパク質のアミノ酸2〜19)。
・TCMP14プラスミド中でのクローニングのための3個の非関連アミノ酸(Thr、SerおよびGly)+6個のHis残基;または
・pET21プラスミド中でのクローニングのための2個の非関連アミノ酸(LeuおよびGlu)+6個のHis残基;または
・pET26プラスミド中でのクローニングのための6個のHis残基、
のうちの1つから構成されるHis尾部を含むか、または含まない。
LipoD-MAGE3-HisとD1/3-PRAME-Hisとのアラインメント(図8)、
インフルエンザ菌に由来する元のDタンパク質とLipoD-MAGE3-Hisとの共有配列間のアラインメント(図9)、
インフルエンザ菌に由来する元のDタンパク質、LipoD-MAGE3-HisおよびpD1/3-PRAME-Hisの共有配列間のアラインメント(図10)。
本発明の融合タンパク質を、アジュバント化されているか、またはされていないワクチン中で製剤化することができる。一実施形態においては、アジュバントとして、前記製剤は油/水乳濁液中に3-脱-O-アシル化モノホスホリルリピドA(3D-MPL)およびQS21の混合物を含んでもよい。アジュバント系SBAS2は、WO 95/17210に以前に記載されている。あるいは、本発明における使用のためのアジュバントは、水中油製剤またはリポソーム製剤中に3-脱-O-アシル化モノホスホリルリピドA(3D-MPL)、QS21およびCpGを含んでもよい。
TCC ATG ACG TTC CTG ACG TT (CpG 1826; 配列番号36)
TCT CCC AGC GTG CGC CAT (CpG 1758; 配列番号37)
ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG TCG TCG TTT TGT CGT TTT GTC GTT (CpG 2006; 配列番号38)
TCC ATG ACG TTC CTG ATG CT (CpG 1668; 配列番号39)
TCG ACG TTT TCG GCG CGC GCC G (CpG 5456; 配列番号40)、
であり、これらの配列はホスホロチオエート改変ヌクレオチド間結合を含んでもよい。
1. A. Roca (U. of Wisconsin), personal communication、
2. Studier, F.W. (1991) J. Mol. Biol. 219, 37-44、
3. Jan H. Kessleraら、The Journal of Experimental Medicine, Volume 193, Number 1, January 1, 2001 73-88、
4. Ikeda Hら、Immunity, Feb; 6(2): 1997, 199-208。
Claims (18)
- (a)癌精巣抗原PRAME、
(b)Dタンパク質から誘導された異種融合パートナータンパク質であって、Dタンパク質のアミノ酸20〜127を含む、前記融合パートナータンパク質、及び、
(c)融合タンパク質配列のN末端における追加アミノ酸Met-Asp-Pro、
を含む融合タンパク質であって、前記Dタンパク質から誘導された異種融合パートナータンパク質(b)がPRAMEのN末端に融合される、前記融合タンパク質。 - アフィニティタグをさらに含む、請求項1記載の融合タンパク質。
- アフィニティタグがヒスチジン尾部である、請求項2記載の融合タンパク質。
- 融合パートナータンパク質とPRAMEとの間;又は融合パートナータンパク質とアフィニティタグとの間;又はPRAMEとアフィニティタグとの間に1以上のリンカー配列をさらに含む、請求項1〜3のいずれか1項記載の融合タンパク質。
- 請求項1〜4のいずれか1項記載の融合タンパク質をコードする核酸。
- 請求項5記載の核酸を含むベクター。
- 請求項6記載のベクターで形質転換された単離された宿主細胞。
- 請求項1〜4のいずれか1項記載の融合タンパク質又は請求項5記載の核酸又は請求項6記載のベクターを含むワクチン。
- アジュバント、及び/又は免疫刺激性サイトカイン若しくはケモカインをさらに含む、請求項8記載のワクチン。
- アジュバントが3D-MPL、QS21及び/又はCpGオリゴヌクレオチドを含む、請求項9記載のワクチン。
- 医療における使用のための請求項8〜10のいずれか1項記載のワクチン。
- 癌に罹患する患者を免疫療法的に治療するためのワクチンの製造における請求項1〜6のいずれか1項記載のタンパク質又は核酸又はベクターの使用。
- 請求項1〜4のいずれか1項記載の融合タンパク質を単離された細胞中で発現させる工程を含む、融合タンパク質を製造する方法。
- 細胞が細菌である、請求項13記載の方法。
- 細菌が大腸菌である、請求項14記載の方法。
- 前記細胞を溶解し、溶解された細胞から発現された融合タンパク質を精製する工程をさらに含む、請求項13〜15のいずれか1項記載の方法。
- 請求項13〜16のいずれか1項記載の方法により得られたか、又は得られる融合タンパク質。
- 癌が、メラノーマ、乳癌、膀胱癌、NSCLCなどの肺癌、肉腫、卵巣癌、頭部及び頸部癌、腎臓癌、結腸直腸癌、多発性ミエローマ、急性白血病を含む白血病及び食道癌から選択される、請求項12記載の使用。
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EP3053592A4 (en) | 2013-10-01 | 2017-09-06 | Mie University | T cell-inducing vaccine containing interepitope sequence promoting antigen presentation |
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SG10202105561PA (en) | 2016-11-30 | 2021-07-29 | Advaxis Inc | Immunogenic compositions targeting recurrent cancer mutations and methods of use thereof |
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CN108948184B (zh) * | 2017-05-22 | 2021-04-23 | 香雪生命科学技术(广东)有限公司 | 一种识别衍生自prame抗原短肽的t细胞受体 |
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