JP5502253B2 - 新規化合物 - Google Patents
新規化合物 Download PDFInfo
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- JP5502253B2 JP5502253B2 JP2001562559A JP2001562559A JP5502253B2 JP 5502253 B2 JP5502253 B2 JP 5502253B2 JP 2001562559 A JP2001562559 A JP 2001562559A JP 2001562559 A JP2001562559 A JP 2001562559A JP 5502253 B2 JP5502253 B2 JP 5502253B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/82—Translation products from oncogenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
Description
i)該タンパク質また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、宿主細胞中で発現することができる複製能を有する発現ベクターまたは組込み発現ベクターを調製し、
ii)該ベクターで宿主細胞を形質転換し、
iii)該DNAポリマーが発現して該タンパク質を産生できる条件下で該形質転換宿主細胞を培養し、そして、
iv)該タンパク質を回収する。
(a)配列番号4および5の全長にわたって配列番号4および5のヌクレオチド配列に対して少なくとも70%の同一性、好ましくは少なくとも80%の同一性、より好ましくは少なくとも90%の同一性、さらに好ましくは少なくとも95%の同一性、最も好ましくは97〜99%の同一性を有するヌクレオチド配列を含んでなる単離されたポリヌクレオチド、
(b)配列番号4および5の全長にわたってそれぞれ配列番号1または6のヌクレオチド配列に対して少なくとも70%の同一性、好ましくは少なくとも80%の同一性、より好ましくは少なくとも90%の同一性、さらに好ましくは少なくとも95%の同一性、最も好ましくは97〜99%の同一性を有するヌクレオチド配列を有する単離されたポリヌクレオチド、
(c)配列番号4および5の単離されたポリヌクレオチド、または
(d)配列番号2および7の全長にわたってそれぞれ配列番号2および7のアミノ酸配列に対して少なくとも70%の同一性、好ましくは少なくとも80%の同一性、より好ましくは少なくとも90%の同一性、さらに好ましくは少なくとも95%の同一性、最も好ましくは少なくとも97〜99%の同一性を有するポリペプチドをコードするヌクレオチド配列を有する単離されたポリヌクレオチド、
ならびに配列番号4および5のポリヌクレオチド、を提供する。
(a)配列番号2または7の全長にわたって配列番号2または7のアミノ酸配列に対して少なくとも70%の同一性、好ましくは少なくとも80%の同一性、より好ましくは少なくとも90%の同一性、さらに好ましくは少なくとも95%の同一性、最も好ましくは少なくとも97〜99%の同一性を有するアミノ酸配列を含むポリペプチド、
(b)配列番号2または7の全長にわたって配列番号2または7のアミノ酸配列に対して少なくとも70%の同一性、好ましくは少なくとも80%の同一性、より好ましくは少なくとも90%の同一性、さらに好ましくは少なくとも95%の同一性、最も好ましくは少なくとも97〜99%の同一性を有するアミノ酸配列を有するポリペプチド、
(c)配列番号2または7のアミノ酸を含むポリペプチド、および
(d)配列番号7のポリペプチド、
ならびに、配列番号4および5の配列に含まれる配列を含むポリヌクレオチドによりコードされるポリペプチド。
好ましくは、該製剤はさらに水中油型乳剤およびトコフェロールを含む。
HO(CH2CH2O)n-A-R
[式中nは1〜50であり、Aは結合または-C(O)-であり、RはC1-50アルキルまたはフェニルC1-50アルキルである]
で表されるアジュバント分子が含まれる。
(b)(a)のヌクレオチド配列に相補的なヌクレオチド配列(好ましくは配列番号6のヌクレオチド配列)、
(c)本発明のポリペプチド(好ましくは、配列番号2もしくは3のポリペプチド)もしくはその断片、または
(d)本発明のポリペプチド(好ましくは、配列番号2もしくは3のポリペプチド)に対する抗体、
を含んでなる、診断アッセイを実施するための診断用キットに関する。
(a)候補化合物と、上記ポリペプチド(または該ポリペプチドを担持している細胞もしくはその膜)またはその融合タンパク質との結合を、該候補化合物に直接または間接的に結合させた標識により測定すること、
(b)候補化合物と、上記ポリペプチド(または該ポリペプチドを担持している細胞もしくはその膜)またはその融合タンパク質との結合を、標識競合物質の存在下で測定すること、
(c)候補化合物が上記ポリペプチドの活性化または抑制により生ずるシグナルをもたらすか否かを、該ポリペプチドを担持している細胞または細胞膜に適した検出系を用いて調べること、
(d)候補化合物と、請求項1に記載のポリペプチドを含有する溶液とを一緒にして混合物を調製し、該混合物中の該ポリペプチドの活性を測定して、該混合物の活性をスタンダードと比較すること、または
(e)候補化合物が細胞における上記ポリペプチドをコードするmRNAおよび該ポリペプチドの産生に及ぼす効果を例えばELISAアッセイを用いて検出すること、
よりなる群から選択される方法を含んでなるスクリーニング法を提供する。
(a)本発明のポリペプチド、
(b)本発明のポリペプチドを発現している組換え細胞、
(c)本発明のポリペプチドを発現している細胞膜、または
(d)本発明のポリペプチドに対する抗体、
を含んでなり、前記ポリペプチドは好ましくは配列番号2または3のポリペプチドである。
当業者であれば、本発明のポリペプチドは、その構造に基づいて該ポリペプチドのアゴニスト、アンタゴニストまたはインヒビターを設計する方法にも使用できることが容易に理解されよう。この方法は、
(a)最初に該ポリペプチドの三次元構造を解析し、
(b)アゴニスト、アンタゴニストまたはインヒビターの確実と思われる反応部位または結合部位の三次元構造を想定し、
(c)想定された反応部位または結合部位と結合または反応すると予想される候補化合物を合成し、そして
(d)その候補化合物が実際にアゴニスト、アンタゴニストまたはインヒビターであるか否かを調べる、
ことを含んでなる。
ギャップペナルティー:12
ギャップ伸長ペナルティー:4
ワードサイズ:2、最大6
ポリペプチド配列をその他の方法で比較するための好ましいパラメーターは次のものを含む:
1)アルゴリズム:Needleman & Wunsch, J. Mol. Biol. 48: 443-453 (1970)
比較マトリックス:BLOSSUM62 、Hentikoff and Hentikoff, Proc. Natl. Acad. Sci. USA, 89: 10915-10919 (1992)
ギャップペナルティー:12
ギャップ長ペナルティー:4
これらのパラメーターを用いて有効なプログラムはGenetics Computer Group(Madison WI)から「gap」プログラムとして一般に入手可能である。前記のパラメーターはポリペプチド比較のためのデフォルトパラメーター(default parameter) である(末端ギャップのペナルティーは無し)。
1)アルゴリズム:Needleman & Wunsch, J. Mol. Biol. 48: 443-453 (1970); 比較マトリックス:マッチ=+10、ミスマッチ=0
ギャップペナルティー:50
ギャップ長ペナルティー:3
これらのパラメーターを用いて有用であるプログラムは Genetics Computer Group(Madison WI)から「gap」プログラムとして公に入手可能である。前記パラメーターはポリヌクレオチド比較のためのデフォルトパラメーターである。
nn ≦xn −(xn・y)
により求めることができる。式中、nnはヌクレオチド変異の数であり、xnは配列番号1のヌクレオチドの総数であり、yは例えば70%については0.70、80%については0.80、85%については0.85、90%については0.90、95%については0.95などであり、さらにxnとyの非整数の積は、その積をxnから引く前に、最も近似する整数に切り下げる。配列番号2のポリペプチドをコードするポリヌクレオチド配列の改変は、そのコード配列にナンセンス、ミスセンスまたはフレームシフト突然変異を生じさせ、それにより、こうした変異後に該ポリヌクレオチドによりコードされたポリペプチドを改変させることができる。
式中、naはアミノ酸変異の数であり、xaは配列番号2中のアミノ酸の総数であり、yは例えば70%については0.70、80%については0.80、85%については0.85等であり、さらにxaとyの非整数の積は、その積をxaから引く前に、最も近似する整数に切り下げる。
実施例1
リアルタイムRT-PCR分析
リアルタイムRT-PCR(U.Gibson, 1996, Genome Research:6, 996)を用いて複数の患者由来の対応する腫瘍および正常大腸組織における候補抗原のmRNA転写産物存在度を比較する。さらに、正常組織のパネルにおける候補遺伝子のmRNAレベルを、この手法により評価する。
表1:CASB7439リアルタイムPCR発現結果:12患者のデータセット
[表2]
表2:CASB7439リアルタイムPCR発現結果:18患者のデータセット
[表3]
表3:CASB7439リアルタイムPCR発現結果:24患者のデータセット
また、リアルタイムPCR反応を、Taqmanプロトコル(上記の通り)を用いて、6患者のバイオプシーから得た腫瘍結腸および隣接正常結腸についても実施した。それぞれについて3つの重複測定を行い、さらなる計算には平均を使った。結果を図1に示す。さらに、異なる28組織(表5)を代表する36組織サンプルも同じ手順により試験した。結果を図2に示す。
表4:Taqmanプローブを用いたCASB7439リアルタイムPCR発現結果
結果は、CASB7439転写物が、隣接正常結腸および上記の正常組織の全てと比較して、結腸腫瘍に過剰発現することを明らかに示唆する。90%を超える患者が、隣接正常結腸と比較して、腫瘍においてCASB7439転写物を強く過剰発現する。腫瘍の平均過剰発現倍数は100以上である。さらに、90%を超える患者が、他の正常組織と比較して、結腸腫瘍にCASB7439転写物を過剰発現し、そしてそれらの60%超は10倍以上過剰発現する。
表5:CASB7439転写物発現分析に使用した正常組織の表
実施例2
cDNAアレイの示差スクリーニング
差引かれたcDNAライブラリー中の腫瘍関連遺伝子の同定を、示差スクリーニングにより実施する。
DNAマイクロアレイ
DNAマイクロアレイを用いて、複数サンプル中の遺伝子の大規模コレクションのmRNA発現プロファイルを調べる。この情報をリアルタイムPCRによって得られるデータを補完するために用いて、腫瘍と正常組織における遺伝子発現レベルの独立した測定を行う。
ノーザン−サザンブロット分析
限られた量の混合した腫瘍cDNAおよび対応する正常大腸cDNAをAdvantage PCRによって増幅する(上記参照)。また、複数の正常組織からのメッセンジャーRNAを、同じ手法を用いて増幅する。増幅したcDNA(1μg)を1.2%アガロースゲルで電気泳動し、ナイロンメンブレンにトランスファーする。該メンブレンは、候補TAA cDNAの断片を用いて調製したプローブとハイブリダイズさせる(AlkPhos Direct System)。ノーザン−サザン分析は、腫瘍組織および正常組織における転写物の大きさ、スプライス変異体の存在および転写物量についての情報を提供する。
ノーザンブロット分析
ノーザンブロットはポリA+mRNAを1μg用いて標準的プロトコールにしたがって行う。放射性プローブはReady-to-Goシステム(Pharmacia)を用いて調製する。
全長cDNA配列の実験による同定
結腸腫瘍cDNAライブラリーを、λZapIIシステム(Stratagene)を使って、5μgのpolyA+ mRNAから構築する。逆転写工程にSuperscriptII(Life Technologies)を用いることを除いて、供給されたプロトコルに従う。オリゴdTプライマーおよび無作為プライマーを用いたライブラリーを構築する。ライブラリーのそれぞれのスクリーニングのために、約1.5x106の独立したファージをプレーティングする。ファージプラークをナイロンフィルター上に移し、AlkPhos Directにより標識したcDNAプローブを用いてハイブリダイズする。化学発光によりポジティブファージを検出する。寒天プレートからポジティブファージを切取り、500μl SMバッファー中に溶出し、遺伝子特異的PCRにより確認する。溶出したファージを、in vivo切除によって一本鎖M13バクテリオファージに変換する。次にバクテリオファージを、大腸菌(E.coli)の感染によって二本鎖プラスミドDNAに変換する。感染した細菌をプレーティングし、cDNAプローブを用いて第2ラウンドのスクリーニングにかける。ポジティブ細菌クローンからプラスミドDNAを精製し、両方の鎖の配列を決定する。
ESTプロフィール
実験による抗原組織発現特性決定を補完するアプローチの1つは、ヒトESTデータベースを探索することである。EST(Expressed Sequence Tag)は、特定の組織または細胞系から抽出したmRNAのコレクションから作ったcDNAの小断片である。そのようなデータベースは現在、数千のcDNA組織ライブラリーからの大量のヒトEST(2 106)を提供し、疾患の様々なタイプと状態に由来する腫瘍組織が挙げられる。情報学ツール(Blast)を使って、組織発現についてさらなる知見を得るために、CASB7439配列の比較検索を実施する。
これらのESTはCASB7439と完全に対合する。表は4つの異なる腫瘍結腸ライブラリー由来の9つのEST、1つの正常結腸ライブラリー由来の1つのEST、1つの腫瘍生殖細胞ライブラリー由来の3つのEST、1つの慢性リンパ球白血病細胞ライブラリー由来の1つのEST、2つの混合腫瘍ライブラリー由来の2つのEST、未知のタイプのライブラリー由来の2つのESTを含有する。これは予想通り、CASB7439が、正常組織と比較して、腫瘍組織において、特に大腸腫瘍組織において過剰発現することを明らかに示す。
9.1 腫瘍特異的抗原の発現および精製
ワクチン用途のために本発明の抗原を産生させるため、そして天然発現のタンパク質の免疫組織化学による特性評価に必要な抗体の迅速な精製および作製、または精製の追跡用のタンパク質断片またはタンパク質全体を産生させるために、微生物宿主における発現、またはその代わりにin vitroでの転写/翻訳を用いる。
構築物1:EFPとしてNS1 cDNAおよびAFPとしてヒスチジン尾部をコードするcDNAと融合した全長野生型CASB7439 cDNA(配列番号8)。コードされる融合タンパク質は配列番号10である。
名前:TCM 281 pRIT..15143
レプリコン:pMB1
選択:Kan
プロモーター:PLロング
インサート:NS1-C74-39-His
構築物1からの組換えタンパク質の発現:
細菌をLB培地+50μg/ml Kan中で30℃にて増殖した。培養がOD=0.5(620nm)に到達したとき、培養を39℃まで加熱し、時間の誘導後、細胞を収穫した。
細胞濃度: PBSバッファー+完全培地中で、50X
破砕: フレンチプレスで、3X
遠心分離: 14000tにて、30分間
備考: 細胞抽出物の上清の>90%
細胞抽出物を12.5% SDS PAGEで泳動し、次いでクーマシーブルーを用いて染色した。また市販のポリヒスチジン尾部に対するモノクローナル抗体(Quiagen)によって、ウェスタンブロットも実施した。得られたゲル(図3および4)は、タンパク質が発現されかつ細胞抽出上清中に認識できることを示す。
平衡バッファー:NaH2PO4 100mM PH 8
Tris 10mM
Urea 6M
サンプル:尿素6M、100mM NaH2PO4、10mM Tris中の上清
洗浄バッファー:1)NaH2PO4 100mM、PH 8
Tris 10mM
尿素 6M
イミダゾール 25mM
:2)NaH2PO4 100mM、PH 8
Tris 10mM
尿素 6mM
イミダゾール 50mM
溶出バッファー: NaH2PO4 100mM、PH 5.5
Tris 10mM
尿素 6M
イミダゾール 500mM
500mMイミダゾール+6M尿素中の溶出タンパク質を、次の条件下で透析する:
- PBS PH 7.2 + サルコシル0.5% + 4M尿素
- 同上、2M尿素にて2時間
- 同上、0M尿素にて2時間
最終物質は凍結して保存する。タンパク質含量をローリー(Lowry)タンパク質アッセイを用いて定量した(0.9mg/1.2ml)。純度をクーマシーブルーを用いて染色した12.5% PAGE SDSにより評価し(図5)、そして組換えタンパク質の存在をウェスタンブロットにより抗ポリヒスチジンモノクローナル抗体を用いて確認した(図6)。
少量の比較的精製されたタンパク質を用いて、
a) 正常または癌組織切片における免疫組織化学による発現を検出するため、
b) 発現を検出し、精製プロセス中のタンパク質を追跡するため(ELISA/ウェスタンブロット)、または
c) 精製タンパク質を特性評価/定量するため(ELISA)
に、免疫学的ツールを作成することができる。
免疫感作
2〜3羽のウサギを、アジュバント3D-MPL/QS21中で処方した100μgのタンパク質にて、3週間間隔で3回筋内投与(I.M.)により免疫感作する。各免疫感作の3週間後、血液サンプルを採取し、抗体力価を、標準プロトコルにしたがってコーティング抗原としてタンパク質を用いて血清中でELISAによって評価する。
96ウェルマイクロプレート(maxisorb Nunc)を5μgのタンパク質で4℃にて一晩かけて被覆する。PBS NCS1%で37℃にて1時間飽和させた後、ウサギ血清の連続希釈液を37℃で1時間30分かけて加える(1/10から出発)。PBS Tween中で3回洗浄した後、抗ウサギビオチニル化抗血清(Amersham)を加える(1//5000)。プレートを洗浄し、ペルオキシダーゼ結合ストレプトアビジン(1/5000)を37℃で30分かけて加える。洗浄後、50μlのTMB(BioRad)を7分かけて加え、次いで反応を0.2MのH2SO4で停止させる。ODを450nmで測定し、SoftmaxProで中点希釈度を計算し得る。
免疫感作
5匹のBALB/cマウスを5μgの精製タンパク質にて3週間間隔で3回免疫感作する。II後14日目、3後1週間目にブリージングを行う。この血清を、被覆抗原として用いられる精製タンパク質についてElisaによって試験する。これらの結果(中点希釈度>10000)に基づいて、融合のために1匹のマウスを選別する。
標準プロトコルにしたがってPEG40%およびDMSO5%を用いて、脾臓細胞をSP2/0骨髄腫と融合する。次いで、細胞を96ウェルプレートに2.5×104〜105細胞/ウェルで接種して、耐性クローンをHAT培地中で選択する。これらのハイブリドーマの上清を特異的抗体のその含量について試験し、陽性の場合、限界希釈法を2サイクル行う。スクリーニングを2ラウンド行った後、3種のハイブリドーマを腹水(ascitis)産生用に選択する。
抗体が入手可能な場合、
・正常組織に対する癌における本発明の抗原の発現のレベル、または
・その抗原を発現している一定のタイプの癌の割合、
・その他の癌のタイプもその抗原を発現するかどうか、
・癌組織においてその抗原を発現している細胞の割合、
を測定するために、免疫染色を正常または癌組織切片で行う。
切開後、組織サンプルをOCT化合物中でコルクディスク上にのせ、液体窒素(-160℃)中で予め過冷却したイソペンタン中で急速に凍結させる。次いで、ブロックを使用するまで-70℃で保存する。7〜10μmの切片はクライオスタットチャンバー(-20、-30℃)中で作製される。
組織切片を室温(RT)で5分間乾燥し、アセトン中にRTにて10分間固定し、再び乾燥し、PBS0.5%BSA5%血清で飽和する。RTで30分間置いた後、直接または間接染色を抗原特異的抗体を用いて行う。直接染色は良好な特異性をもたらすが、染色の強さは小さく、一方間接染色は染色の強さは大きいが染色の特異性が低い。
本発明の抗原の免疫学的な適切性はヒトT細胞のin vitro初回抗原刺激によって評価することができる。全てのT細胞リンパ球系および樹状細胞を健康なドナーのPBMC(末梢血単核細胞)(好ましくはHLA-A2サブタイプ)から誘導する。またHLA-A2.1/KbトランスジェニックマウスをHLA-A2.1ペプチドのスクリーニングに用いる。
簡単に述べると、トランスジェニックマウスをアジュバントを加えたHLA-A2ペプチドで免疫感作し、CD8応答(ペプチドでパルスした自己脾臓細胞の効率的な溶解により定義される)を誘導できないものをヒト系においてさらに分析する。
CD8 +T細胞系を、遺伝子銃でトランスフェクトした樹状細胞、レトロウイルスにより形質導入されたB7.1-トランスフェクト線維芽細胞、組換えポックスウイルス(Kimら)またはアデノウイルス(Butterfieldら)を感染させた樹状細胞のいずれかで抗原刺激する。ウイルス感染細胞は、抗原が高レベルで発現されるので抗原ペプチドを提示するのに非常に効率的であるが、ウイルスT細胞系の過剰増殖を回避するために1回使用できるにすぎない。
同様に、CD4+ T細胞免疫も評価することができる。特異的CD4+ T細胞の作製は、T細胞を刺激する組換え精製タンパク質またはペプチドを加えた樹状細胞を利用して行う。
HLAクラスI結合ペプチド配列は、パーカー(Parker)のアルゴリズム(Parker,K.C., M.A.Bednarek,およびJ.E.Coligan. 1994. 「個々のペプチド側鎖の独立結合に基づく、HLA-A2結合ペプチドの能力格付けスキーム(Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains)」 J. Immunol. 152:163、およびhttp://bimas.dcrt.nih.gov/molbio/hla_bind/)、またはラメンジー(Rammensee)の方法(Rammensee,Friede,Stevanovic,「MHCリガンドとペプチドモチーフ:第1リスティング(MHC ligands and peptide motifs: 1st listing)」, Immmogenetics 41, 178-228, 1995;Rammemsee,Bachmann,Stevanovic,「MHCリガンドとペプチドモチーフ(MHC ligands and peptide motifs)」. Landes Bioscience 1997、およびhttp://134.2.96.221/scripts/hlaserver.dll/home.htm)により予測する。次に、ペプチドをHLA-A2.1/Kbトランスジェニックマウスモデルでスクリーニングする(Vitielloら)。
配列情報
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配列番号2
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配列番号5
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Claims (8)
- 配列番号2または配列番号10の全長にわたって配列番号2または配列番号10のアミノ酸配列に対して少なくとも90%の同一性を有するCASB7439ポリペプチドおよび薬学的に許容される担体を含む免疫原性応答を誘導するための免疫原性組成物。
- 請求項1に記載のCASB7439ポリペプチドをin vitroで負荷することにより改変した抗原提示細胞の有効量と、薬学的に有効な担体とを含む免疫原性応答を誘導するための免疫原性組成物。
- 配列番号2または配列番号10の全長にわたって配列番号2または配列番号10のアミノ酸配列に対して少なくとも90%の同一性を有するCASB7439ポリペプチドおよび薬学的に許容される担体を含む免疫原性応答を誘導するための医薬組成物。
- 請求項3に記載のCASB7439ポリペプチドをin vitroで負荷することにより改変した抗原提示細胞の有効量と、薬学的に有効な担体とを含む免疫原性応答を誘導するための医薬組成物。
- さらにTH-1誘導性アジュバントを含む、請求項1または3に記載の免疫原性組成物または医薬組成物。
- TH-1誘導性アジュバントが3D-MPL、QS21、QS21とコレステロールとの混合物およびCpGオリゴヌクレオチドからなるアジュバントの群より選択されるか、または該アジュバントのうちの2種以上の混合物である、請求項5に記載の免疫原性組成物または医薬組成物。
- 請求項1または3に記載の免疫原性組成物または医薬組成物を生産する方法であって、請求項1もしくは3に記載のCASB7439ポリペプチドと、好適なアジュバント、希釈剤またはその他の薬学的に許容される担体とを混合することを含む該方法。
- 癌に罹患した患者または癌に罹りやすい患者を免疫治療により処置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項に記載の免疫原性組成物または医薬組成物の使用であって、該癌が、大腸癌またはその他の大腸に関連した腫瘍もしくは疾患である上記使用。
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