JP2022502358A - がんに対するa*01拘束性ペプチドおよびペプチド組み合わせによる免疫療法 - Google Patents
がんに対するa*01拘束性ペプチドおよびペプチド組み合わせによる免疫療法 Download PDFInfo
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Abstract
Description
2012年には、1410万件の新規がん症例、3260万人のがん患者(診断の5年以内)、および820万件のがん死亡が世界的に推定された(Bray et al.,2013;Ferlay et al.,2013)。
a)がん精巣抗原:T細胞によって認識され得る初めて同定されたTAAはこのクラスに属し、元々はがん精巣(CT)抗原と称されたが、それは、そのメンバーが組織学的に異なるヒト腫瘍において発現され、正常組織では精巣の精母細胞/精原細胞のみに存在し、時として胎盤に存在するためであった。精巣の細胞は、クラスIおよびII HLA分子を発現しないので、これらの抗原は正常組織のT細胞によって認識され得ず、したがって免疫学的に腫瘍特異的と見なされる。CT抗原の周知の例は、MAGEファミリーメンバーおよびNY−ESO−1である。
b)分化抗原:これらのTAAは、腫瘍と、それから腫瘍が生じる正常組織との間で共有される。既知の分化抗原のほとんどは、黒色腫および正常メラノサイトに見いだされる。これらのメラノサイト系関連タンパク質の多くは、メラニン生合成に関与し、したがって腫瘍特異的でないが、それでもなおがん免疫療法のために広く利用されている。例としては、黒色腫に対するチロシナーゼおよびMelan−A/MART−1、または前立腺がんに対するPSAが挙げられるが、これに限定されるものではない。
c)過剰発現TAA:広範に発現されるTAAをエンコードする遺伝子は、組織学的に異なる型の腫瘍において検出され、多数の正常組織においても概してより低い発現レベルで検出されている。正常組織によってプロセスされて潜在的に提示されるエピトープの多くは、T細胞認識の閾値レベル未満であり得る一方で、腫瘍細胞におけるそれらの過剰発現は、以前確立された免疫寛容を破壊することにより、抗がん応答を始動し得る。このクラスのTAAの顕著な例は、Her−2/neu、サバイビン、テロメラーゼ、またはWT1である。
d)腫瘍特異的抗原:これらのユニークなTAAは、正常な遺伝子(β−カテニン、CDK4など)の変異から生じる。これらの分子変化のいくつかは、腫瘍性形質転換および/または進行に関連している。腫瘍特異的抗原は、通常、正常組織に対する自己免疫反応のリスクなしに、強力な免疫応答を誘導できる。他方、これらのTAAは、ほとんどの場合、その上でそれらが同定されたまさにその腫瘍のみと関係があり、通常は、多くの個々の腫瘍間で共有されない。腫瘍特異的(関連)イソ型を有するタンパク質では、ペプチドの腫瘍特異性(または関連性)はまた、ペプチドが腫瘍(関連)エクソンに由来する場合に生じてもよい。
e)異常な翻訳後修飾から生じるTAA:このようなTAAは、特異的でなく腫瘍において過剰発現もされないタンパク質から生じてもよいが、それでもなお、腫瘍において主に活性である翻訳後プロセスによって腫瘍関連になる。このクラスの例は、腫瘍でMUC1のような新規エピトープをもたらす改変グリコシル化パターンから、または腫瘍特異的であってもなくてもよい分解中のタンパク質スプライシング事象から生じる。
f)オンコウイルスタンパク質:これらのTAAはウイルスタンパク質であり、それらは発がん過程において重要な役割を果たしてもよく、外来性である(ヒト由来でない)ため、それらはT細胞応答を誘起し得る。このようなタンパク質の例は、子宮頸がんで発現される、ヒト乳頭腫16型ウイルスタンパク質E6およびE7である。
表1中において、
Table 1: Peptides according to the present invention は、表1:本発明に従ったペプチド
Seq ID Noは、配列番号、
Sequenceは、配列、
Gene(s)は、遺伝子、
HLA allotypeは、HLAアロタイプ
をそれぞれ意味する。
表2中において、
Table 2: Additional peptides according to the present invention with no prior known cancer association.は、表2:がん関連性が以前知られていない本発明による追加的なペプチド、
Seq ID Noは、配列番号、
Sequenceは、配列、
Gene(s)は、遺伝子、
HLA allotypeは、HLAアロタイプ
をそれぞれ意味する。
表3中において、
Table 3: Peptides useful for e.g. personalized cancer therapies. は、表3:例えば個別化がん治療のために有用なペプチド
Seq ID Noは、配列番号、
Sequenceは、配列、
Gene(s)は、遺伝子、
HLA allotypeは、HLAアロタイプ
をそれぞれ意味する。
表中、
Table 5: HLA alleles coverage in European Caucasian population (calculated from (Gragert et al., 2013)).は、表5:欧州の白人人口におけるHLA対立遺伝子のカバー範囲 ((Gragert et al., 2013)から計算された)、
coverage (at least one A-allele)は、カバー範囲 (少なくとも1つのA対立遺伝子)
combined with B*07は、B*07との組み合わせ
combined with B*44は、B*44との組み合わせ
combined with B*07 and B*44は、B*07およびB*44との組み合わせ
をそれぞれ意味する。
同一性百分率=100[1−(C/R)]
式中、Cは、参照配列と比較される配列との間のアライメント長にわたる、参照配列と比較配列の間の差異の数であり、
(i)比較配列中に対応する整列塩基またはアミノ酸を有しない、参照配列中の各塩基またはアミノ酸、および
(ii)参照配列中の各ギャップ、および
(iii)比較配列中の整列塩基またはアミノ酸と異なる参照配列中の各整列塩基またはアミノ酸が、差異を構成して、
(iiii)アライメントは、整合配列の1位から開始しなくてはならず;
Rは、比較配列とのアライメント長にわたる参照配列中の塩基またはアミノ酸の数であり、参照配列中に生じるあらゆるギャップも塩基またはアミノ酸として数えられる。
表中、
Conservative Amino Acid Substitutions は、保存的アミノ酸置換
Amino Acid は、アミノ酸
Substitutions (others are known in the art) は、置換(その他は技術分野で知られている)
を意味する。
表中、
Amino Acid Substitutions は、アミノ酸置換
Original Residue(naturally occurring amino acid) は、元の残基(天然アミノ酸)
Conservative Substitutions は、保存的置換
Exemplary Substitutions は、例示的な置換
Norleucine は、ノルロイシン
を意味する。
表中、
Table 6: Variants and motif of the peptides according to SEQ ID NO: 1, 4, 9, 10, and 12.は、表6:配列番号1、4、9、10、および12に記載のペプチドの変異型およびモチーフ、
Position は、位置、
Seq ID No は、配列番号、
Variant は、変異型
(a)溶液中のまたは凍結乾燥形態の上述の医薬組成物を含有する容器;
(b)任意選択的に、凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;および
(c)任意選択的に、(i)溶液の使用、または(ii)凍結乾燥製剤の再構成および/または使用のための取扱説明書
を含んでなるキットをさらに目的とする。
1.悪性物質からのHLAリガンドは、質量分析法によって同定された
2.ゲノム全域にわたるメッセンジャーリボ核酸(mRNA)発現解析を用いて、一連の正常な臓器および組織と比較して、悪性組織(急性骨髄性白血病、乳がん、胆管細胞がん、慢性リンパ球性白血病、結腸直腸がん、胆嚢がん、神経膠芽腫、胃がん、肝細胞がん、頭頸部扁上皮がん、黒色腫、非ホジキンリンパ腫、肺がん(非小細胞肺がん腺がん、扁平上皮細胞非小細胞肺がん、および小細胞肺がんを含めた)、卵巣がん、食道がん、膵臓がん、前立腺がん、腎細胞がん、膀胱がん、子宮および子宮内膜がん)で過剰発現される遺伝子が同定された。
3.同定されたHLAリガンドは、遺伝子発現データと比較された。好ましくは、ステップ2で検出されたような選択的に発現されまたは過剰発現される遺伝子によってコードされる、腫瘍組織上で過剰提示されまたは選択的に提示されるペプチドが、多重ペプチドワクチンのための適切なTUMAP候補と見なされた。
4.同定されたペプチドのTUMAPとしての妥当性を支持する追加的な証拠を同定するために、文献調査が実施された
5.mRNAレベルでの過剰発現の関連性は、ステップ3からの選択されたTUMAPの腫瘍組織上における再検出と、健常組織における検出の欠如(または稀な)検出によって確認された。
6.選択されたペプチドによる生体内T細胞応答の誘導が可能かどうかを評価するために、健常ドナーならびに急性骨髄性白血病、乳がん、胆管細胞がん、慢性リンパ球性白血病、結腸直腸がん、胆嚢がん、神経膠芽腫、胃がん、肝細胞がん、頭頸部扁上皮がん、黒色腫、非ホジキンリンパ腫、肺がん(非小細胞肺がん腺がん、扁平上皮細胞非小細胞肺がん、および小細胞肺がんを含めた)、卵巣がん、食道がん、膵臓がん、前立腺がん、腎細胞がん、膀胱がん、子宮および子宮内膜がん患者からのヒトT細胞を使用して、生体外免疫原性アッセイが実施された。
細胞表面に提示された腫瘍関連ペプチドの同定および定量
組織サンプル
患者の腫瘍組織は、Asterand(米国ミシガン州デトロイトおよび英国ハートフォードシャー州ロイストン)、Bio−Options Inc.(米国カリフォルニア州ブレア)、BioServe(米国メリーランド州ベルツビル)、Geneticist Inc.(米国カリフォルニア州グレンデール)、Leiden University Medical Center(LUMC)(オランダ国ライデン)、ProteoGenex Inc.(米国カリフォルニア州カルバーシティ)、Saint Savas Hospital (ギリシャ国アテネ)、Tissue Solutions Ltd(英国グラスゴー)、University Hospital Bonn(独国ボン)、University Hospital Geneva(スイス国ジュネーブ)、University Hospital Heidelberg(独国ハイデルベルク)、大阪市立大学(日本国大阪)、University Hospital Tuebingen(独国チュービンゲン)から入手された。正常組織は、Asterand(米国ミシガン州デトロイトおよび英国ハートフォードシャー州ロイストン)、BioServe(米国メリーランド州ベルツビル)、Capital BioScience Inc.(米国メリーランド州ロックビル)、Centre for Clinical Transfusion Medicine Tuebingen(独国チュービンゲン)、Geneticist Inc.(米国カリフォルニア州グレンデール)、ProteoGenex Inc.(米国カリフォルニア州カルバーシティ)、Tissue Solutions Ltd(英国グラスゴー)、University Hospital Heidelberg(独国ハイデルベルク)、University Hospital Tuebingen(独国チュービンゲン)から入手された。
衝撃凍結組織サンプルからのHLAペプチドプールは、HLA−A*02−特異的抗体BB7.2、HLA−A、−B、−C特異的抗体W6/32、HLA−DR特異的抗体L243およびHLA DP特異的抗体B7/21、CNBr活性化セファロース、酸処理、および限外濾過を用いて、わずかに修正されたプロトコル(Falk et al.,1991;Seeger et al.,1999)に従って固体組織からの免疫沈降によって得た。
得られたHLAペプチド貯留は、逆相クロマトグラフィー(nanoAcquity UPL C system,Waters)によってそれらの疎水性に従って分離し、ESI源を装着したLTQ−velosおよびfusion hybrid質量分光計(ThermoElectron)内で溶出ペプチドを分析した。ペプチド貯留は、毎分400nLの流速を適用して、1.7μm C18逆相材料(Waters)で充填された分析用融合シリカマイクロキャピラリーカラム(75μm内径×250mm)上に直接挿入した。引き続いて、毎分300nLの流速で10%から33%へのBの二段階180分間二成分勾配を用いて、ペプチドを分離した。勾配は、溶媒A(水中の0.1%ギ酸)および溶媒B(アセトニトリル中の0.1%ギ酸)から構成された。nanoESI源への導入には、金被覆ガラス毛管(PicoTip,New Objective)を使用した。LTQ−Orbitrap質量分光計は、TOP5ストラテジーを使用してデータ依存モードで操作した。手短に述べると、Orbitrap(R=30000)内の高質量精度の完全スキャンでスキャンサイクルを開始し、これもまたOrbitrap(R=7500)内の5種の最も豊富な前駆イオンのMS/MSスキャンがそれに続き、以前選択されたイオンを動的に排除した。タンデム質量スペクトルは、固定偽検出率(q≤0.05)および追加の手動制御で、またはSEQUESTによって解釈した。同定されたペプチド配列が不確実である場合には、生成された天然ペプチド断片化パターンと合成配列同一参照ペプチドの断片化パターンとの比較によって、それをさらに検証した。
AML:急性骨髄性白血病;BRCA:乳がん;CCC:胆管細胞がん;CLL:慢性リンパ球性白血病;CRC:結腸直腸がん;GBC:胆嚢がん;GBM:神経膠芽腫;GC:胃がん;HCC:肝細胞がん;HNSCC:頭頸部扁上皮がん;MEL:黒色腫;NHL:非ホジキンリンパ腫;NSCLCadeno:非小細胞肺がん 腺がん;NSCLCother:NSCLCadenoまたはNSCLCsquamに明確に割り当てることができなかったNSCLCサンプル;NSCLCsquam:扁平上皮細胞 非小細胞肺がん;OC:卵巣がん;OSCAR:食道がん;PACA:膵臓がん;PRCA:前立腺がん;RCC:腎細胞がん;SCLC:小細胞肺がん;UBC:膀胱がん;UEC:子宮および子宮内膜がん。
表中、
SEQ ID No.は、配列番号、
Sequenceは、配列、
Peptide Presentation on cancer entitiesは、がん実体上のペプチド提示、
を意味する。
本発明のペプチドをコードする遺伝子発現プロファイリング
正常細胞と比較した腫瘍細胞上のペプチドの過剰提示または特異的提示は、免疫療法におけるその有用性にとって十分であり、いくつかのペプチドは、それらの起源タンパク質が正常組織にもまた存在するにもかかわらず、腫瘍特異的である。それでもなお、mRNA発現プロファイリングは、免疫療法のためのペプチド標的の選択において、安全性のレベルを高めることができる。特に、アフィニティ成熟TCRなどの安全性リスクが高い治療選択肢では、理想的な標的ペプチドは、腫瘍に特有で正常組織上には見いだされないタンパク質に由来するであろう。
外科的に除去された組織標本は、告知に基づく同意書が各患者から入手された後に、上述の通り提供された(実施例1を参照されたい)。腫瘍組織標本を手術直後にスナップ凍結し、その後、液体窒素下で乳鉢と乳棒を用いて均質化した。TRI試薬(独国ダルムシュタットのAmbion)を使用して、これらのサンプルから全RNAを調製し、RNeasy(独国ヒルデンのQIAGEN)による精製がそれに続き;どちらの方法も製造業者のプロトコルに従って実施した。
腫瘍および正常組織RNAサンプルの遺伝子発現解析は、CeGaT(独国チュービンゲン)によって、次世代配列決定(RNAseq)によって実施した。簡単に述べると、RNA断片化、cDNA転換、および配列決定アダプターの付加を含むIllumina HiSeq v4試薬キットを使用して、販売業者(米国カリフォルニア州サンディエゴのIllumina Inc.)のプロトコルに従って、配列決定ライブラリーを作成する。複数のサンプルに由来するライブラリーを等モル混合し、Illumina HiSeq 2500配列決定装置上で製造会社の使用説明書に従って配列決定し、50bpのシングルエンドリードを生成する。処理された読み取りをSTARソフトウェアを使用して、ヒトゲノム(GRCh38)にマッピングする。発現データは、ensembl配列データベース(Ensembl77)の注釈に基づいて、RPKM(Reads Per Kilobase per Million mapped reads:100万個のマッピングされた読み取り当たりキロベース当たり読み取り、ソフトウェアCufflinksによって作成される)として転写物レベルで、そしてエクソンレベルで(全読み取り、ソフトウェアBedtoolsによって作成される)提供される。エクソン読み取りをエクソン長さおよびアライメントサイズについて正規化し、RPKM値を得る。
表中、
SEQ ID Noは、配列番号、
Sequenceは、配列、
Gene Expression in tumor samplesは、腫瘍サンプル中の遺伝子発現、
over-expressed (+)は、過剰発現 (+)、
Highly over-expressed (++)は、高度に過剰発現 (++)
very highly over-expressed (+++)は、非常に高度に過剰発現 (+++)、
を意味する。
MHCクラスI提示ペプチドの生体外免疫原性
本発明のTUMAPの免疫原性に関する情報を得るために、本発明者らは、ペプチド/MHC複合体および抗CD28抗体を負荷した人工抗原提示細胞(aAPC)によるCD8+T細胞の反復刺激に基づく、生体外T細胞プライミングアッセイを用いて研究を実施した。このようにして、本発明者らは、本発明のHLA−A*01拘束性TUMAPの免疫原性を示し得て、これらのペプチドが、それに対するCD8+前駆T細胞がヒトに存在する、T細胞エピトープであることを実証した(表10)。
ペプチドMHC複合体(pMHC)および抗CD28抗体を負荷した、人工抗原提示細胞による生体外刺激を実施するために、本発明者らは、最初に、告知に基づく同意後に、独国のUniversity clinics Mannheimから得られた健常ドナーのCD8ミクロビーズ(独国ベルギッシュ・グラートバッハのMiltenyi Biotec)を使用した正の選択を通じて、新鮮HLA−A*02白血球除去生成物からCD8+T細胞を単離した。
急性骨髄性白血病、乳がん、胆管細胞がん、慢性リンパ球性白血病、結腸直腸がん、胆嚢がん、神経膠芽腫、胃がん、肝細胞がん、頭頸部扁上皮がん、黒色腫、非ホジキンリンパ腫、肺がん(非小細胞肺がん腺がん、扁平上皮細胞非小細胞肺がん、および小細胞肺がんを含めた)、卵巣がん、食道がん、膵臓がん、前立腺がん、腎細胞がん、膀胱がん、子宮および子宮内膜がんペプチドの生体外免疫原性を試験した。試験されたHLAクラスIペプチドでは、ペプチド特異的T細胞株の生成によって、生体外免疫原性を実証し得た。本発明の2つのペプチドに対するTUMAP特異的多量体染色後の例示的なフローサイトメトリー結果は、対応する陰性対照と共に図2および3に示される。本発明からの13個のペプチドに関する結果は、表10aに要約され、本発明のペプチド28のさらなる結果は、表10bに要約される。
出願人によって実施された本発明のペプチドの生体外免疫原性実験の例示的結果。 <20 % = +; 20 % - 49 % = ++; 50 % - 69 %= +++; >= 70 % = ++++
表中、
Seq ID Noは、配列番号、
Sequenceは、配列、
Wells positive[%]は、ウェル陽性 [%]、
を意味する。
出願人によって実施された本発明のペプチドの生体外免疫原性実験の例示的結果。 <20 % = +; 20 % - 49 % = ++; 50 % - 69 %= +++; >= 70 % = ++++
表中、
Seq ID Noは、配列番号、
Sequenceは、配列、
Wells positive[%]は、ウェル陽性 [%]、
を意味する。
ペプチドの合成
Fmocストラテジーを使用した標準的な十分に確立された固相ペプチド合成を使用して、全てのペプチドを合成した。個々のペプチドのアイデンティティーおよび純度は、質量分析および分析用RP−HPLCによって判定された。ペプチドは、純度>50%の白色から灰白色の凍結乾燥物(トリフルオロ酢酸塩)として得た。全てのTUMAPは、好ましくはトリフルオロ酢酸塩または酢酸塩として投与され、その他の塩形態もまた可能である。
MHC結合アッセイ
本発明によるT細胞ベースの治療法のための候補ペプチドをそれらのMHC結合能力(親和性)についてさらに試験した。個々のペプチドMHC複合体をUVリガンド交換によって生成し、UV感受性ペプチドはUV照射に際して切断されて、分析される目的ペプチドで交換された。ペプチド受容性MHC分子と効果的に結合して安定化し得るペプチド候補のみが、MHC複合体の分離を防止する。交換反応の収率を判定するために、安定化MHC複合体の軽鎖(β2m)の検出に基づくELISAを実施した。アッセイは、Rodenko et al.(Rodenko et al.,2006)に一般的に記載されるようにして実施した。
表11:MHCクラスI結合スコア。HLAクラスI拘束性ペプチドと HLA-A*01:01との結合は、ペプチド交換収率によって変動した: >10% = +; >20% = ++; >50 = +++; > 75% = ++++
表中、
Seq ID Noは、配列番号、
Sequenceは、配列、
Peptide exchangeは、ペプチド交換、
を意味する。
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Claims (39)
- 配列番号1〜配列番号398からなる群から選択されるアミノ酸配列を含んでなるペプチド、および配列番号1〜配列番号398と少なくとも88%相同的なその変異型配列であって、前記変異型が、主要組織適合性複合体(MHC)の分子と結合し、および/またはT細胞を前記変異型ペプチドと交差反応させる、完全長ポリペプチドではないペプチド、およびその薬学的に許容可能な塩。
- 請求項1に記載のペプチドであって、前記ペプチドがMHCクラスIまたはII分子に結合する能力を有し、前記ペプチドが前記MHCに結合した際に、CD4および/またはCD8T細胞によって認識されることができるようになる、ペプチド。
- 請求項1または2に記載のペプチドまたはその変異型であって、そのアミノ酸配列が、配列番号1〜配列番号398のいずれか1つに記載の一続きのアミノ酸を含んでなる、ペプチドまたはその変異型。
- 請求項1〜3のいずれか一項に記載のペプチドまたはその変異型であって、前記ペプチドまたはその変異型が8〜100、好ましくは8〜30、より好ましくは8〜16アミノ酸の全長を有し、最も好ましくは、前記ペプチドが配列番号1〜配列番号398のいずれかに記載のアミノ酸配列からなり、またはそれから本質的になる、ペプチドまたはその変異型。
- 請求項1〜4のいずれか一項に記載のペプチドまたはその変異型であって、前記ペプチドが修飾されており、および/または非ペプチド結合を含む、ペプチドまたはその変異型。
- 請求項1〜5のいずれか一項に記載のペプチドまたはその変異型であって、前記ペプチドが、特にHLA−DR抗原関連不変鎖(Ii)のN末端アミノ酸を含んでなる融合タンパク質の一部である、ペプチドまたはその変異型。
- 請求項1〜5のいずれか一項に記載のペプチドまたはその変異型を特異的に認識する抗体、特に可溶性または膜結合抗体、好ましくはモノクローナル抗体またはその断片であって、好ましくはMHC分子に結合した際に、請求項1〜5のいずれか一項に記載のペプチドまたはその変異型を特異的に認識する、抗体。
- HLAリガンドと反応性である、好ましくはMHC分子と結合した際に、請求項1〜5のいずれか一項に記載のペプチドまたはその変異型と反応性である、好ましくは可溶性または膜結合型のT細胞受容体またはその断片であって、前記リガンドが請求項1〜5のいずれか一項に記載のペプチドまたはその変異型である、T細胞受容体またはその断片。
- 請求項8に記載のT細胞受容体であって、前記リガンドアミノ酸配列が、配列番号1〜配列番号398のいずれか1つと少なくとも88%同一であり、または前記リガンドアミノ酸配列が、配列番号1〜配列番号398のいずれか1つからなる、T細胞受容体。
- 請求項8または9に記載のT細胞受容体であって、前記T細胞受容体が可溶性分子として提供され、任意選択的に、免疫刺激ドメインまたは毒素などのさらなるエフェクター機能を保有する、T細胞受容体。
- 請求項1〜5のいずれか一項に記載のペプチドまたはその変異型、好ましくはMHC分子に結合している請求項1〜5のいずれか一項に記載のペプチドまたはその変異型を特異的に認識する、アプタマー。
- 請求項1〜5のいずれか一項に記載のペプチドまたはその変異型、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片をコードする核酸であって、任意選択的に異種プロモーター配列または前記核酸を発現する発現ベクターに連結している、核酸。
- 請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、または請求項12に記載の核酸または発現ベクターを含んでなる組換え宿主細胞であって、好ましくは前記組換え宿主細胞が、樹状細胞、T細胞またはNK細胞などの抗原提示細胞から選択される、組換え宿主細胞。
- 前記T細胞を抗原特異的様式で活性化するのに十分な時間にわたり、適切な抗原提示細胞の表面または抗原提示細胞を模倣する人工コンストラクトの表面に発現される抗原負荷ヒトクラスIまたはII MHC分子に、T細胞を生体外で接触させるステップを含んでなり、前記抗原が、請求項1〜4のいずれか一項に記載のペプチドである、活性化Tリンパ球を製造するインビトロ法。
- 請求項1〜4のいずれか一項に記載のアミノ酸配列を含んでなるポリペプチドを提示する細胞を選択的に認識する、請求項14に記載の方法によって製造される、活性化Tリンパ球。
- 請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球、またはコンジュゲートされまたは標識された活性成分からなる群から選択される、少なくとも1つの活性成分と、薬学的に許容可能な担体、および任意選択的に、薬学的に許容可能な賦形剤および/または安定剤を含んでなる医薬組成物。
- 請求項13に記載の宿主細胞を培養するステップと、前記宿主細胞および/またはその培養液から、ペプチドまたはその変異型、抗体またはその断片、またはT細胞受容体またはその断片を単離するステップとを含んでなる、請求項1〜6のいずれか一項に記載のペプチドまたはその変異型、請求7項に記載の抗体またはその断片、または請求項8または9に記載のT細胞受容体またはその断片を製造する方法。
- 医薬品で使用するための、請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球。
- 請求項15で定義される活性T細胞の有効数を患者に投与するステップを含んでなる、その標的細胞が、請求項1〜4のいずれか一項に記載のアミノ酸配列を含んでなるポリペプチドを提示する患者において、標的細胞を殺滅する方法。
- がんの診断および/または治療で使用するための、またはがんに対する薬剤の製造で使用するための、請求項1〜6のいずれか一項に記載のペプチド、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球。
- 請求項20に記載の使用であって、前記がんが、配列番号1〜配列番号398のペプチドがそれに由来する、タンパク質の過剰発現を示す、急性骨髄性白血病、乳がん、胆管細胞がん、慢性リンパ球性白血病、結腸直腸がん、胆嚢がん、神経膠芽腫、胃がん、肝細胞がん、頭頸部扁上皮がん、黒色腫、非ホジキンリンパ腫、肺がん(非小細胞肺がん腺がん、扁平上皮細胞非小細胞肺がん、および小細胞肺がんを含めた)、卵巣がん、食道がん、膵臓がん、前立腺がん、腎細胞がん、膀胱がん、子宮および子宮内膜がんサンプルの群から選択される、使用。
- (a)溶液または凍結乾燥形態にある、請求項1〜6のいずれか一項に記載のペプチドまたは変異型、請求項7に記載の抗体またはその断片、請求項8または9に記載のT細胞受容体またはその断片、請求項11に記載のアプタマー、請求項12に記載の核酸または発現ベクター、請求項13に記載の宿主細胞、または請求項15に記載の活性化Tリンパ球を含有する医薬組成物を含んでなる容器;
(b)任意選択的に、前記凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;
(c)任意選択的に、配列番号1〜配列番号432からなる群から選択される少なくとももう1つのペプチド、および
(d)任意選択的に、(i)溶液の使用、または(ii)凍結乾燥製剤の再構成および/または使用のための取扱説明書
を含んでなるキット。 - 請求項22に記載のキットであって、(iii)緩衝液、(iv)希釈剤、(v)フィルター、(vi)針、または(v)シリンジの1つまたは複数をさらに含んでなる、キット。
- a)個々の患者からの腫瘍サンプルによって提示される腫瘍関連ペプチド(TUMAP)を同定するステップと;
b)a)で同定された前記ペプチドを正常組織との比較で、腫瘍における免疫原性および/または過剰提示について予備選別されたペプチド貯蔵庫と比較するステップと;
c)少なくとも1つのペプチドを前記患者において同定されたTUMAPと一致する前記貯蔵庫から選択するステップと;
d)ステップc)に基づいて、個別化ワクチンまたは化合物ベース療法または細胞療法を作成および/または処方するステップと
を含んでなる、個々の患者のための化合物ベースのおよび/または細胞療法のための個別化抗がんワクチンを生産する方法。 - 請求項24に記載の方法であって、前記TUMAPが、
a1)前記腫瘍サンプルからの発現データを前記腫瘍サンプルの組織型に対応する正常組織サンプルからの発現データと比較して、前記腫瘍サンプルにおいて過剰発現されまたは異常に発現されるタンパク質を同定するステップと;
a2)前記発現データを前記腫瘍サンプル中のMHCクラスI/またはクラスII分子に結合しているMHCリガンドの配列と相関させて、前記腫瘍によって過剰発現されまたは異常に発現されるタンパク質に由来するMHCリガンドを同定するステップと
によって同定される、方法。 - 請求項24または25に記載の方法であって、結合ペプチドを前記腫瘍サンプルから単離されたMHC分子から溶出させて、前記溶出したリガンドを配列決定することで、MHCリガンドの配列が同定される、方法。
- 請求項24〜26のいずれか一項に記載の方法であって、前記腫瘍サンプルの前記組織型に対応する前記正常組織が、前記同一患者から得られる、方法。
- 請求項24〜27のいずれか一項に記載の方法であって、前記貯蔵庫に包含される前記ペプチドが、
aa.正常組織または組織群と比較して悪性組織で過剰発現される遺伝子を同定するステップを含んでなる、マイクロアレイまたは配列決定ベース発現プロファイリングなどの高度並列法によって、ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を実施するステップと;
ab.ステップaaで検出された、選択的に発現されまたは過剰発現される遺伝子によってコードされる、ペプチドを選択するステップと;
ac.健常ドナーまたは前記患者からのヒトT細胞を使用した生体外免疫原性アッセイを含んでなる、前記選択されたペプチドによる生体内T細胞応答の誘導を判定するステップ;または
ba.質量分析を使用して、前記腫瘍サンプルからHLAリガンドを同定するステップと;
bb.正常組織または組織群と比較して悪性組織で過剰発現される遺伝子を同定するステップを含んでなる、マイクロアレイまたは配列決定ベース発現プロファイリングなどの高度並列法によって、ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を実施するステップと;
bc.前記同定されたHLAリガンドを前記遺伝子発現データと比較するステップと;
bd.ステップbcで検出された、選択的に発現されまたは過剰発現される遺伝子によってコードされるペプチドを選択するステップと;
be.ステップbdから選択されたTUMAPを腫瘍組織上で再検出し、健常組織上の検出の欠如または希な検出が、mRNAレベルにおける過剰発現の関連性を裏付けるステップと;
bf.健常ドナーまたは前記患者からのヒトT細胞を使用した生体外免疫原性アッセイを含んでなる、前記選択されたペプチドによる生体内T細胞応答の誘導を判定するステップと
に基づいて同定される、方法。 - 請求項24〜28のいずれか一項に記載の方法であって、前記貯蔵庫に包含される前記ペプチドの前記免疫原性が、生体外免疫原性アッセイ、個々のHLA結合についての患者免疫モニタリング、MHC多量体染色、ELISPOTアッセイおよび/または細胞内サイトカイン染色を含んでなる方法によって判定される、方法。
- 請求項24〜29のいずれか一項に記載の方法であって、前記貯蔵庫が、配列番号1〜配列番号432からなる群から選択される複数のペプチドを含んでなる、方法。
- 請求項24〜30のいずれか一項に記載の方法であって、前記個々の患者からの正常な対応する組織と比較して前記腫瘍サンプルに特有の少なくとも1つの変異を同定するステップと、前記ワクチンに包含するために、または細胞療法を作成するために、前記変異に関連があるペプチドを選択するステップとをさらに含んでなる、方法。
- 請求項31に記載の方法であって前記少なくとも1つの変異が、全ゲノム配列決定によって同定される、請求項31に記載の方法。
- 請求項1〜6のいずれか一項に記載のペプチドを発現する、患者のがん細胞を殺滅する活性化T細胞の集団を含んでなる組成物を前記患者に投与することを含んでなる、がんを有する患者を治療する方法であって、前記がんが、急性骨髄性白血病、乳がん、胆管細胞がん、慢性リンパ球性白血病、結腸直腸がん、胆嚢がん、神経膠芽細胞腫、胃がん、肝細胞がん、頭頸部扁平上皮がん、黒色腫、非ホジキンリンパ腫、非小細胞肺がん腺がん、扁平上皮細胞非小細胞肺がん、小細胞肺がん、卵巣がん、食道がん、膵臓がん、前立腺がん、腎細胞がん、膀胱がん、子宮がん、子宮内膜がんから選択される、方法。
- 請求項1〜6のいずれか一項に記載のペプチドを発現する、患者のがん細胞を殺滅する活性化T細胞の集団を含んでなる組成物を前記患者に投与することを含んでなる、がんを有する患者において免疫応答を誘発する方法であって、前記がんが、急性骨髄性白血病、乳がん、胆管細胞がん、慢性リンパ性白血病、結腸直腸がん、胆嚢がん、神経膠芽細胞腫、胃がん、肝細胞がん、頭頸部扁平上皮がん、黒色腫、非ホジキンリンパ腫、肺がん、卵巣がん、食道がん、膵臓がん、前立腺がん、腎細胞がん、膀胱がん、子宮がん、子宮内膜がんから選択される、方法。
- T細胞が患者に対して自己由来である、請求項33または34に記載の方法。
- T細胞が健常ドナーから得られる、請求項33または34に記載の方法。
- T細胞が腫瘍浸潤リンパ球または末梢血単核細胞に由来する、請求項33または34に記載の方法。
- T細胞を活性化するのに十分な時間にわたり、前記T細胞と、前記抗原提示細胞の表面上のMHCクラスI分子との複合体中でペプチドを発現する抗原提示細胞とを生体外で接触させることによって、前記活性化T細胞が生成される、請求項33〜37のいずれか一項に記載の方法。
- 免疫原性増強量のアジュバントをさらに含んでなる、請求項16に記載の医薬組成物。
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