JP5998370B2 - Egfrviiiに対する免疫応答を誘発する方法および組成物 - Google Patents
Egfrviiiに対する免疫応答を誘発する方法および組成物 Download PDFInfo
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 229940125575 vaccine candidate Drugs 0.000 description 1
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- 229960004854 viral vaccine Drugs 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は、全ての表、図および特許請求の範囲を含むその全体が参照することによって本明細書中に組み込まれる、2010年11月17付で出願された米国特許仮出願第61/414,850号からの優先権を主張する。
et al., Infect. Immun. 76: 3742-53, 2008;およびSinnathamby
et al., (J. Immunother. 32: 856-69, 2009を参照のこと。
flexneri)、大腸菌(Escherichia coli)、リステリア・モノサイトゲネス、エルシニア・エンテロコリチカ(Yersinia enterocolitica)、ネズミチフス菌(Salmonella
typhimurium)、腸チフス菌(Salmonella typhi)またはマイコバクテリウム(mycobacterium)種をはじめとする多くの細菌種がワクチンとしての使用のために開発され、本発明においてワクチンプラットフォームとして用いることができる。このリストは、限定するものではない。本発明は、弱毒化、片利共生的、および/または不活性化されているが、代謝的に活性な細菌株のワクチンプラットフォームとしての使用を想定する。好ましい実施形態において、細菌は、本発明のEGFRvIIIポリペプチド配列の細菌による発現のためにコード化する核酸配列を含むリステリア・モノサイトゲネスである。この核酸は、最も好ましくは、細菌のゲノム中に組み込まれる。リステリア・モノサイトゲネスの弱毒化および不活性化されているが、代謝的に活性な形態が特に好ましく、actAおよび/またはinlBに弱毒化突然変異を有するリステリア・モノサイトゲネスを本明細書中の好ましい実施形態で後述する。本発明を本明細書中で細菌ベクターに関して記載するが、標的抗原の送達のための好適な薬剤は、さらなる組換え型ベクター、例えば、ウイルス、および裸のDNAを含む。
(a)配列番号37、38および39からなる群から選択されるActA−N100配列、またはそのようなActA−N100配列に対して少なくとも90%の配列同一性を有するアミノ酸配列;
(b)その配列がそれぞれEEKKGNYV(配列番号3)を含む、複数(2、3、4、5コピーまたはそれ以上)のEGFRvIIIポリペプチド配列を含むアミノ酸配列;および
(c)少なくとも2つのEGFRvIIIポリペプチド配列間に配置されたリンカーアミノ酸配列であって、ここで、リンカーアミノ酸配列はプロテアソーム切断のために構成される、リンカーアミノ酸配列
を含む融合タンパク質を発現するリステリア・モノサイトゲネスを含み、ここで、融合タンパク質は、リステリア・モノサイトゲネスActAプロモータに機能的に連結された核酸配列から発現される。
(1)疎水性:ノルロイシン、Ile、Val、Leu、Phe、Cys、Met;
(2)中性親水性:Cys、Ser、Thr;
(3)酸性:Asp、Glu;
(4)塩基性:Asn、Gln、His、Lys、Arg;
(5)鎖配向に影響を及ぼす残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe;oyobi
(7)小アミノ酸:Gly、Ala、Ser。
Doolittle: “A Simple Method for Displaying the Hydropathic Character of a
Protein”. J. Mol. Biol. 157(1982)105-132の方法によるポリペプチド配列の分析を指す。この方法では、各アミノ酸は4.6から−4.6の間の疎水性スコアを与えられる。4.6のスコアは最も疎水性であり、−4.6のスコアは最も親水性である。次いでウインドウサイズを設定する。ウインドウサイズは、疎水性スコアが平均され、ウインドウ中の第1アミノ酸に帰属されるアミノ酸の数である。計算はアミノ酸の第1ウインドウから始め、そのウインドウ中の全ての疎水性スコアの平均を計算する。次に、ウインドウを1つ下のアミノ酸に移動し、第2ウインドウ中の全ての疎水性スコアの平均を計算する。このパターンを最後のタンパク質まで続け、各ウインドウの平均スコアを計算し、ウインドウ中の第1アミノ酸にそれを帰属する。平均を次いでグラフ上にプロットする。y軸は疎水性スコアを表し、x軸はウインドウ数を表す。20個の一般的なアミノ酸について以下の疎水性スコアを使用する。
Arg:−4.5 Ser:−0.8 Lys:−3.9
Thr:−0.7 Asn:−3.5 Gly:−0.4
Asp:−3.5 Ala:1.8 Gln:−3.5
Met:1.9 Glu:−3.5 Cys:2.5
His:−3.2 Phe:2.8 Pro:−1.6
Leu:3.8 Tyr:−1.3 Val:4.2
Trp:−0.9 Ile:4.5
(1998) Chem. Biol. 5:713-728を参照のこと)。
Bioinformatics 17:327-337を参照のこと)。
Biotechnol. 13:18-23を参照のこと)。
et al. (1980) Analyt. Biochem.
107:220-239)によって測定すると、約109リットル/モルを越える親和性を有するであろう。いくつかの結合化合物は複数の標的と特異的に結合することができ、例えば抗体はその抗原と、抗体のオリゴ糖によりレクチンと、および/または抗体のFc領域によりFc受容体と、特異的に結合することは、当業者には認識される。
and Thorpe (2002) Mol. Microbiol. 44:299-307; Groth and Calos (2004) J. Mol.
Biol. 335:667-678; Nunes-Duby, et al. (1998) Nucleic Acids Res. 26:391-406を参照のこと)。
Saunders, Co., Phila., PA.; Sikora, et al. (eds.) (1996) Tumor Immunology
Cambridge University Press, Cambridge, UK; Hackett and Harn (eds.) Vaccine
Adjuvants, Humana Press, Totowa, NJ; Isaacson (eds.) (1992) Recombinant DNA
Vaccines, Marcel Dekker, NY, NY; Morse, et al. (eds.) (2004) Handbook of Cancer
Vaccines, Humana Press, Totowa, NJ), Liao, et al. (2005) Cancer Res.
65:9089-9098; Dean (2005) Expert Opin. Drug Deliv. 2:227-236; Arlen, et al.
(2003) Expert Rev. Vaccines 2:483-493; Dela Cruz, et al. (2003) Vaccine
21:1317-1326; Johansen, et al. (2000) Eur. J. Pharm. Biopharm. 50:413-417;
Excler (1998) Vaccine 16:1439-1443; Disis, et al. (1996) J. Immunol.
156:3151-3158)を参照のこと。ペプチドワクチンは記載されている(例えば、McCabe, et
al. (1995) Cancer Res. 55:1741-1747; Minev, et al. (1994) Cancer Res.
54:4155-4161; Snyder, et al. (2004) J. Virology 78:7052-7060を参照のこと。
441:161-162; Roberts, et al. (2006) Nature 441:239-243を参照のこと)。以下の表は、本発明で使用するためのウイルス由来の例示的ワクチンベクターを記載する:
Parmiani, et al. (2002) J. Natl.
Cancer Inst. 94:805-818; Kao, et al.
(2005) Immunol. Lett. 101:154-159; Geiger, et
al. (2005) J. Transl. Med. 3:29; Osada, et
al. (2005) Cancer Immunol. Immunother. Nov.5,1-10 [epub ahead of print];
Malowany, et al. (2005) Mol. Ther.
13:766-775; Morse and Lyerly (2002) World J. Surg. 26:819-825; Gabrilovich
(2002) Curr. Opin. Mol. Ther. 4:454-458; Morse, et al. (2003) Clin. Breast Cancer 3 Suppl.4:S164-S172; Morse, et al. (2002) Cancer Chemother. Biol.
Response Modif. 20:385-390; Arlen, et al.
(2003) Expert Rev. Vaccines 2:483-493; Morse and Lyerly (1998) Expert Opin.
Investig. Drugs 7:1617-1627; Hirschowitz, et
al. (2004) J. Clin. Oncol. 22:2808-2815; Vasir, et al. (2005) Br. J. Haematol. 129:687-700; Koido, et al. (2005) Gynecol. Oncol. 99:462-471を参照のこと。
188:147-154; Jain, et al. (2003) Ann.
Surg. Oncol. 10:810-820; Borrello and Pardoll (2002) Cytokine Growth Factor
Rev. 13:185-193; Chen, et al. (2005)
Cancer Immunol. Immunother. 27:1-11; Kjaergaard, et al. (2005) J. Neurosurg. 103:156-164; Tai, et al. (2004) J. Biomed. Sci. 11:228-238; Schwaab, et al. (2004) J. Urol. 171:1036-1042;
Friese, et al. (2003) Cancer Res.
63:8996-9006; Briones, et al. (2002)
Cancer Res. 62:3195-3199; Vieweg and Dannull (2003) Urol. Clin. North Am.
30:633-643; Mincheff, et al. (2001)
Crit. Rev. Oncol. Hematol. 39:125-132を参照のこと)。
Ann. Rev. Immunol. 15:617-648; Mincheff, et
al. (2001) Crit. Rev. Oncol. Hematol. 39:125-132; Song, et al. (2005) J. Virol. 79:9854-9861;
Estcourt, et al. (2004) Immunol. Rev.
199:144-155を参照のこと)。裸の核酸の投与のための試薬および方法、例えば、遺伝子銃、皮内、筋肉内、およびエレクトロポレーション法によるものが利用可能である。核酸ワクチンは、ロックト核酸(LNA)を含んでもよく、この場合、LNAは機能的部分のプラスミドDNAへの付着を可能にし、機能的部分はアジュバントであり得る(例えば、Fensterle, et al. (1999) J. Immunol. 163:4510-4518; Strugnell, et al. (1997) Immunol. Cell Biol.
75:364-369; Hertoughs, et al. (2003)
Nucleic Acids Res. 31:5817-5830; Trimble, et
al. (2003) Vaccine 21:4036-4042; Nishitani, et al. (2000) Mol. Urol. 4:47-50; Tuting (1999) Curr. Opin. Mol.
Ther. 1:216-225を参照のこと)。核酸ワクチンは、未成熟の樹状細胞のワクチンへの移動を促進する試薬、および成プライミングが起こり得る流入領域リンパ節への熟DCの移動を促進する試薬と組み合わせて用いることができ、この場合、これらの試薬はMIP−1アルファおよびFlt3Lを含む(例えば、Kutzler and Weiner (2004) J. Clin.
Invest. 114:1241-1244; Sumida, et al.
(2004) J. Clin. Invest. 114:1334-1342を参照のこと)。
Cancer Research, 62: 2287-2293 (2002);米国特許第6,099,848号;WO99/25376;WO96/14087;および米国特許第5,830,702号)(そのそれぞれは、全ての表、図および特許請求の範囲を含むその全体として参照することによって本明細書中に組み込まれる)を参照のこと。リンパ球性脈絡髄膜炎ウイルス(LCMV)抗原を発現する組換え型エル・モノサイトゲネスワクチンも、抗原に対する保護細胞媒介性免疫を誘発することが証明されている(Shen et al., Proc. Natl. Acad. Sci. USA, 92: 3987-3991 (1995)。
Shetron-Rama, et al. (2003) Mol. Microbiol. 48:1537-1551; Luo, et al. (2004)
Mol. Microbiol. 52:39-52を参照のこと)。PrfAは、Gly145Ser突然変異、Gly155Ser突然変異、またはGlu77Lys突然変異によって構成的に活性にすることができる(例えば、Mueller and Freitag (2005) Infect. Immun. 73:1917-1926; Wong and
Freitag (2004) J. Bacteriol. 186:6265-6276; Ripio, et al. (1997) J. Bacteriol.
179:1533-1540を参照のこと)。
MNAQAEEFKK YLETNGIKPK QFHKKELIFN QWDPQEYCIF LYDGITKLTS 50
ISENGTIMNL QYYKGAFVIM SGFIDTETSV GYYNLEVISE QATAYVIKIN 100
ELKELLSKNL THFFYVFQTL QKQVSYSLAK FNDFSINGKL GSICGQLLIL 150
TYVYGKETPD GIKITLDNLT MQELGYSSGI AHSSAVSRII SKLKQEKVIV 200
YKNSCFYVQN LDYLKRYAPK LDEWFYLACP ATWGKLN 237
MNAQAEEFKK YLETNGIKPK QFHKKELIFN QWDPQEYCIF LYDGITKLTS 50
ISENGTIMNL QYYKGAFVIM SGFIDTETSV GYYNLEVISE QATAYVIKIN 100
ELKELLSKNL THFFYVFQTL QKQVSYSLAK FNDFSINGKL GSICGQLLIL 150
TYVYSKETPD GIKITLDNLT MQELGYSSGI AHSSAVSRII SKLKQEKVIV 200
YKNSCFYVQN LDYLKRYAPK LDEWFYLACP ATWGKLN 237
本発明のワクチン株によって発現される抗原構築物は、最低でも、分泌を支持するワクチンプラットフォーム内で機能的であり、発現されるEGFRvIII由来抗原(複数可)と融合した、分泌配列をコード化する核酸を含む。細菌プラットフォームの場合、結果として得られる融合タンパク質は、細菌ワクチンプラットフォームによる融合タンパク質の発現に必要な調節配列(例えば、プロモータ)に機能的に連結される。本発明は、分泌されるポリペプチドおよびペプチド抗原に限定されるものではないが、リステリアもしくは他の細菌から分泌されないかまたは分泌される可能性がないポリペプチドおよびペプチドも含む。しかし、好ましくは、EGFRvIII由来抗原(複数可)は、株がレシピエントに接種された場合、細菌ワクチン株によって可溶性の分泌された形態で発現される。
VGLNRFMRAM MVVFITANCI TINPDIIFAA TDSEDSSLNT DEWEEEKTEE 50
QPSEVNTGPR YETAREVSSR DIEELEKSNK VKNTNKADLI AMLKAKAEKG 100
MGLNRFMRAM MVVFITANCI TINPDIIFAA TDSEDSSLNT DEWEEEKTEE 50
QPSEVNTGPR YETAREVSSR DIEELEKSNK VKNTNKADLI AMLKAKAEKG 100
VGLNRFMRAM MVVFITANCI TINPDIIFAA TDSEDSSLNT DEWEEEKTEE 50
QPSEVNTGPR YETAREVSSR DIEELEKSNK VKNTNKADLI AMLKAKAEKG 100
GS(配列番号30)
これは、最初の残基メチオニンを有するように合成された場合に、配列:
MGLNRFMRAM MVVFITANCI TINPDIIFAA TDSEDSSLNT DEWEEEKTEE 50
QPSEVNTGPR YETAREVSSR DIEELEKSNK VKNTNKADLI AMLKAKAEKG 100
GS(配列番号31)を有する。
vglnrfmram mvvfitanci tinpdiifaa tdsedsslnt deweeektee 50
qpsevntgpr yetarevssr dieeleksnk vkntnkadli amlkakaekg 100
gsASKVLPAS
RALEEKKGNY VVTDHGSCAD GSVKTSASKV APASRALEEK 150
KGNYVVTDHG SCGDGSIKLS KVLPASRALE EKKGNYVVTD HGSCADGSVK 200
ASKVAPASRA
LEEKKGNYVV TDHGSCGDGS IKLSKVLPAS RALEEKKGNY 250
VVTDHGSCAD
GSVKTS(配列番号32)。この配列では、ActA−N100配列は小文字であり、EGFRvIII由来の抗原配列に下線を引き、そしてリンカー「切断可能な」配列には下線を引いていない。対応するDNA配列は次のとおりである:
gtgggattaaatagatttatgcgtgcgatgatggtagttttcattactgccaactgcattacgattaaccccgacataatatttgcagcgacagatagcgaagattccagtctaaacacagatgaatgggaagaagaaaaaacagaagagcagccaagcgaggtaaatacgggaccaagatacgaaactgcacgtgaagtaagttcacgtgatattgaggaactagaaaaatcgaataaagtgaaaaatacgaacaaagcagacctaatagcaatgttgaaagcaaaagcagagaaaggtggatccgcaagcaaagtattgccagctagtcgtgcattagaggagaaaaaggggaattacgtggtgacggatcatggatcgtgtgccgatggctcagtaaagactagtgcgagcaaagtggcccctgcatcacgagcacttgaagagaaaaaaggaaactatgttgtgaccgatcatggtagctgcggagatggttcaattaaattatcaaaagtcttaccagcatctagagctttagaggaaaagaagggtaactatgtcgtaacagatcatggaagttgtgctgacggaagtgttaaagcgtcgaaagtagctccagcttctcgcgcattagaagaaaagaaaggcaattatgttgtaacagaccatggtagttgtggtgatggctcgatcaaattgtcaaaagttctaccggcttctcgtgcgctagaagagaagaaaggaaattacgtagttacagaccacggctcttgcgcggatggttccgttaaaactagt(配列番号33)。この配列では、ActA−N100配列は小文字であり、BamHIクローニング部位に下線を引き、そしてEGFRvIII由来の抗原およびリンカー「切断可能な」配列には下線を引かない。この配列の前にActAプロモータ配列があってもよい。例えば、
gggaagcagttggggttaactgattaacaaatgttagagaaaaattaattctccaagtgatattcttaaaataattcatgaatattttttcttatattagctaattaagaagataattaactgctaatccaatttttaacggaataaattagtgaaaatgaaggccgaattttccttgttctaaaaaggttgtattagcgtatcacgaggagggagtataa(配列番号34)。
Practice, Interpharm Press, Boca Raton, FL; Dent (2001) Good Laboratory and
Good Clinical Practice, Urch Publ., London, UKを参照のこと)。
and Gilman’s The Pharmacological Basis of Therapeutics, 10th
ed., McGraw-Hill, New York, NY; Poole and Peterson (eds.) (2001)
Pharmacotherapeutics for Advanced Practice:A Practical Approach, Lippincott,
Williams & Wilkins, Phila., PA; Chabner and Longo (eds.) (2001) Cancer
Chemotherapy and Biotherapy, Lippincott, Williams & Wilkins, Phila., PA)。
parvum)から精製された均一サポニンを含む合成アジュバントQS−21が含まれる(McCune et
al., Cancer, 1979; 43:1619)。アジュバントは最適化を受けると理解されるであろう。換言すれば、当業者は、通常の実験を行って、使用するのに最良のアジュバントを決定することができる。
Immunol.Cell Biol. 75:382-388; Gherardi, et al. (2001) Histol. Histopathol.
16:655-667; Leroux-Roels, et al. (2001) ActA Clin. Belg. 56:209-219; Greiner,
et al. (2002) Cancer Res. 62:6944-6951; Smith, et al. (2003) J. Med. Virol.
70:Suppl.1:S38-S41; Sepulveda-Amor, et al. (2002) Vaccine 20:2790-2795)を参照のこと。
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Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott,
Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical
Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al.
(eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY;
Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems,
Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety,
Marcel Dekker, Inc., New York, NYを参照のこと)。
Peptide induction of surface expression of class I MHC, p. 18.11.1-18.11.8 in J. E. Colgan, A. M. Kruisbeer, D. H.
Marguiles, and W. Strober (ed.), Current Protocols in Immunology, vol. 4. John
Wiley & Sons, New York, N.Yで記載されているようにして使用した。Kk発現T2細胞を図6で示すような濃度各EGFRvIIIペプチドとともに一晩インキュベートした。細胞を洗浄し、クラスI特異的抗体を使用して表面Kk発現について染色した。データは、EEKKGNYVがKkと結合し、also同様にこの配列を含む大きなペプチドと比較して最適であることを示す。これらのデータは、そのKkと結合する能力に基づいたエクスビボ細胞アッセイのために所定のEEKKGNYVペプチドを使用することを支持し、CD8+T細胞によって認識され得るMHC−ペプチド複合体を提供する。
Claims (20)
- そのアミノ酸配列が複数のEGFRvIIIポリペプチド配列を含み、その配列がそれぞれEEKKGNYV(配列番号3)を含む、免疫原性ポリペプチドであって、各EGFRvIIIポリペプチド配列に、プロテアソームによって切断されるような構成の配列が隣接している、免疫原性ポリペプチド。
- 前記複数のEGFRvIIIポリペプチド配列が、LEEKKGNYV(配列番号4)、LEEKKGNYVVTDH(配列番号2)、およびPASRALEEKKGNYVVTDHGSC(配列番号5)からなる群から選択される1以上のアミノ酸配列を含む、請求項1記載のポリペプチド。
- 前記複数のEGFRvIIIポリペプチド配列が、少なくとも3コピーのPASRALEEKKGNYVVTDHGSC(配列番号5)を含む、請求項1または2記載のポリペプチド。
- 前記複数のEGFRvIIIポリペプチド配列が、少なくとも5コピーのPASRALEEKKGNYVVTDHGSC(配列番号5)を含む、請求項1または2記載のポリペプチド。
- 前記ポリペプチドに抗原提示細胞の細胞表面受容体を標的とさせるような構成の部分をさらに含む、請求項1〜4のいずれか1項に記載のポリペプチド。
- 請求項1〜5のいずれか1項に記載のポリペプチドをコードする単離された核酸分子。
- 前記核酸分子が、リステリア・モノサイトゲネスによる発現用に最適化されているコドンである、請求項6記載の単離された核酸分子。
- 前記核酸分子が、分泌シグナル配列を含む融合タンパク質として前記免疫原性ポリペプチドをコードする、請求項6または7記載の単離された核酸分子。
- 前記分泌シグナル配列が、リステリア・モノサイトゲネスActAシグナル配列、または配列番号28、配列番号29、配列番号30、および配列番号31からなる群から選択されるインフレームActA−N100配列、または前記ActA−N100配列と少なくとも90%の配列同一性を有するアミノ酸配列である、請求項8記載の単離された核酸分子。
- 請求項6〜9のいずれか1項に記載の核酸を含む細菌またはウイルスを含む組成物。
- 前記細菌が、前記細菌のゲノム中に組み込まれた前記核酸を含むリステリア・モノサイトゲネス細菌である、請求項10記載の組成物。
- 前記リステリア・モノサイトゲネス細菌が、弱毒化されているリステリア・モノサイトゲネス細菌、または不活性化されているが代謝的に活性がある(KBMA)リステリア・モノサイトゲネス細菌である、請求項11記載の組成物。
- 前記核酸が前記細菌の病原性遺伝子に組み込まれ、前記核酸の配列の組込みが、前記病原性遺伝子の発現を妨害するか、または前記病原性遺伝子のコード配列を妨害する、請求項11または12記載の組成物。
- 前記病原性遺伝子がactAまたはinlBである、請求項13に記載の組成物。
- 前記細菌がリステリア・モノサイトゲネス ΔactA/ΔinlBである、請求項14記載の組成物。
- 前記細菌が、核酸を修復する前記細菌の能力を減弱する遺伝子突然変異をさらに含む、請求項10〜15のいずれか1項に記載の組成物。
- 前記遺伝子突然変異が、phrB、uvrA、uvrB、uvrC、uvrDおよびrecAから選択される1以上の遺伝子にある、請求項16に記載の組成物。
- 請求項10〜17のいずれか1項に記載の組成物、または請求項6〜9のいずれか1項に記載の核酸を含む、医薬組成物。
- 対象においてEGFRvIIIに対するT細胞応答を誘導する方法であって、前記対象において前記T細胞応答を誘導するために選択された条件下で前記対象において請求項6〜9のいずれか1項に記載の核酸を発現することを含む方法における使用のための、請求項18記載の医薬組成物。
- 前記対象が、グリオーマなどのEGFRvIIIを発現する悪性腫瘍を有する、請求項19に係る使用のための医薬組成物。
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