JP2018526390A - 卵巣癌ワクチン - Google Patents
卵巣癌ワクチン Download PDFInfo
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- JP2018526390A JP2018526390A JP2018511702A JP2018511702A JP2018526390A JP 2018526390 A JP2018526390 A JP 2018526390A JP 2018511702 A JP2018511702 A JP 2018511702A JP 2018511702 A JP2018511702 A JP 2018511702A JP 2018526390 A JP2018526390 A JP 2018526390A
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- amhr2
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Abstract
【選択図】なし
Description
本願は、参照によりその全体が本明細書に組み込まれる、2015年9月2日に出願された米国仮特許出願第62/213,286号に対する優先権の利益を主張する。
一般
本願では、抗ミュラー管ホルモンII型受容体(AMHR2)に対する免疫応答の誘導を介した卵巣癌の治療および/または予防のための方法、キットおよび組成物が提供される。
便宜上、本明細書、実施例および添付の特許請求の範囲で使用される特定の用語をここに集める。
特定の態様において、AMHR2ポリペプチド(例えば、AMHR2−EDまたはその免疫原性フラグメント、またはAMHR2−CDまたはその免疫原性フラグメントを含有するポリペプチド)またはAMHR2ポリペプチドをコードする核酸の投与による、抗ミュラー管ホルモンII型受容体(AMHR2)に対する免疫応答の誘導を介した卵巣癌の治療および/または予防のための方法、キットおよび組成物が提供される。
特定の態様において、本明細書に記載のAMHR2ポリペプチドおよび/または本明細書に記載のAMHR2ポリペプチドをコードする核酸を含む医薬組成物(例えば、ワクチン組成物)が提供される。いくつかの実施形態において、該組成物は医薬的に許容される担体を含む。いくつかの実施形態では、組成物は、本明細書に記載の複数(例えば2つ以上の)のAMHR2ポリペプチドまたは核酸の組み合わせを含む。
アナログまたはヌクレオシドジホスフェートレダクターゼのアンタゴニストまたは阻害剤(例えばシタラビン、5−フルオロウラシル(5−FU)、ペメトレキセド、テガフール/ウラシル、ゲムシタビン、カペシタビン、メルカプトプリン、メトトレキサート)、抗癌剤(例えばパクリタキセル(taxol)またはドセタキセル)、ビンカアルカロイド(例えばナベルビン、ビンブラスチン、ビンクリスチン、ビンデシンまたはビノレルビン)、抗有糸分裂性ペプチド(例えばドラスタチン)、エピポドフィロトキシンまたはポドフィロトキシンの誘導体(例えばエトポシドまたはテニポシド)、非ステロイド性炎症性薬(例えばメロキシカム、セレコキシブ、ロフェコキシブ)、ガン細胞の表面分子を標的にする抗体(例えばアポリズマブまたはID09C3)、またはヒートショックタンパク質HSP90修飾薬ゲルダナマイシンおよびその誘導体17−アリルアミノゲルダナマイシンまたは17−AAGが挙げられる。
特定の態様において、卵巣癌を治療または予防する方法、および/または卵巣癌腫瘍またはAMHR2に対する免疫応答を誘導する方法が本明細書で提供される。特定の実施形態では、本方法は、本明細書に記載の医薬組成物を対象に投与することを含む。いくつかの実施形態では、卵巣癌腫瘍は原発性腫瘍である。いくつかの実施形態では、該卵巣癌腫瘍は転移性腫瘍である。いくつかの実施形態では、該卵巣癌腫瘍は、卵巣上皮癌(EOC)腫瘍である。いくつかの実施形態では、該卵巣癌腫瘍はAMHR2を発現する。
特定の態様では、本明細書に記載のAMHR2ポリペプチドまたは当該AMHR2ポリペプチドをコードする核酸は、AMHR2で刺激された抗原提示細胞および/またはこれらの抗原提示細胞で産生されたAMHR2特異的リンパ球を提供するための組成物および方法において使用されることができる。いくつかの実施形態において、このような抗原提示細胞および/またはリンパ球は、卵巣癌の治療または予防に使用される。
8週齢の雌C57BL/6マウスの卵巣からトータルmRNAを抽出した。AMHR2配列1−140または170−568を増幅するように設計されたプライマー対を使用して、RT−PCRによってマウスAMHR2の140アミノ酸細胞外ドメイン全体または399アミノ酸細胞質ドメイン全体のいずれかをコードするcDNAを生成した。タンパク質フォールディングを最適化し、全収率を高めるために、天然のコドン配列の置換(Dapcel、Cleveland、OH)を行い、当該最適化したcDNAをpET−3a(Novagen、Darmstadt、Germany)のNdeI−BamHI部位に挿入し、C末端6×His標識組換えタンパク質を得た(図1Aおよび10A)。大腸菌を、これらの挿入断片を含むプラスミドで形質転換した。高レベルの発現コロニーを、イソプロピルチオガラクトピロニダーゼ(IPTG;Amresco、Solon OH)による誘導後に選択し、適切な配向および整列を確認するために配列決定した。6xHis標識AMHR2ポリペプチドを、ニッケル−ニトリロ三酢酸(Ni−NTA)アフィニティークロマトグラフィー(Qiagen Sciences、Germantown、MD)を用いて変性条件下で精製した。精製したAMHR2ポリペプチドを変性SDS−PAGEゲル(Bio−Rad、Hercules、CA)で電気泳動し、免疫ブロットPVDF膜(Bio−Rad)上にブロットした。AMHR2ポリペプチドの免疫検出は、HRP結合His抗体(Qiagen)を用いた増強化学発光システム(Amersham Biosciences、Piscataway、NJ)を用いて行った。使用前に、6xHis標識AMHR2ポリペプチドを逆相HPLCによって精製し、エンドトキシンフリータンパク質を得た。エンドトキシンのレベルは、組換えタンパク質1mgあたり<0.05エンドトキシン単位(<5pg)であった。
雌のC57BL/6マウスを、ID8腫瘍のレシピエントとして使用した。マウスを6週齢で商業的に入手し(Jackson Laboratory、Bar Harbor、ME)、7−10週齢で、等量の水と400μgのマイコバクテリウム・ツベルクローシス(Mycobacteria tuberculosis)を含有する完全フロイントアジュバント(CFA;Difco、Detroit、MI)のエマルション200μL中に含まれる組換えマウスAMHR2−CDまたはAMHR2−ED100μgを、側腹部に皮下注射することにより免疫した。TgMlSIIR−TAg(DR26 line)トランスジェニックマウスは雄のTgMISIIR−TAg(H−2b)マウスを雌の野生型同系C57BL/6(Jackson Laboratory)と交配させることによって維持された。TgMlSIIR−TAgマウスを、6〜7週齢で、上記のようにCFA中の組換えマウスAMHR2−CDまたはAMHR2−ED100μgで免疫化した。妊孕性表現型(phenotype)を決定するために、年齢適合試験および対照ワクチン接種C57BL/6雌マウスを同じC57BL/6雄と交配させた。
ID8細胞を75または225cm2組織培養フラスコ(BD Biosciences、Franklin Lakes、NJ)中、4%ウシ胎仔血清(Thermo Scientific Hyclone、Logan、UT)、1%ペニシリン/ストレプトマイシン(Invitrogen、Carlsbad、CA)、およびインスリン−トランスフェリン−亜セレン酸ナトリウム培地補充物(Sigma−Aldrich、St. Louis、MO)を含有するDMEM(Mediatech Cellgro, Manassas, VA)中で、該細胞が70−80%コンフルエントになるまで培養した。トリプシン処理により細胞を回収し、PBSで2回洗浄した。メスC57BL/6マウスに、5x106個のID8細胞を左背側腹部に皮下接種した。ID8腫瘍の増殖は、長さx幅を測定するためにバーニアキャリパーを用いて定期的に評価した。腫瘍増殖のエンドポイントは、17mmの任意の方向の測定によって決定した。
雌トランスジェニックマウスにおける両側卵巣腫瘍増殖を、小動物用のVevo770高分解能in vivoマイクロイメージングシステム(VisualSonics、Toronto、Canada)を用いて超音波により毎月測定した。腹部から毛を除去した後、RMV704低周波プローブ/スキャンヘッドおよび水性導電性ゲルを用いて、腹部のリアルタイムイメージングを行った。30分間未満の画像取得時間中、1〜2%vol/volイソフルランの連続流を有するノーズコーンを用いて固定のための麻酔を施し、酸素供給を連続的に維持した。プローブ/スキャンヘッドを、水性導電性ゲルを塗布した後、腹部を非常に穏やかに移動させた。腫瘍領域の測定および計算を、関心設定の多角形領域(VisualSonics)を用いて、インビボでの卵巣腫瘍サイズの2−D評価を可能にするVevoソフトウェアBモード測定ツールを用いて行った。Bモード超音波検査による固形腫瘍の測定は組織病理学的測定と良好に相関することが示されている。
組織を切除し、RNA−Later(Life Technologies, Grand Island, NY)で凍結保存した。RNAは、TRIZOL試薬(Invitrogen)中でのホモジナイゼーションによって各組織から抽出するか、または市販品を購入した(OriGene Technologies, Rockville, MD;ILS Biotech, Chestertown, MD)。Superscript III(Invitrogen)を用いてバルクRNAからcDNAを生成した。遺伝子特異的プライマー(テーブル1)を用いてSYBR Green PCR mix(Applied Biosystems、Carlsbad、CA)を用いてqRT−PCRにより遺伝子発現を定量した。相対的遺伝子発現は、個々の組織におけるβ−アクチン発現レベルに対する各試験遺伝子発現レベルの標準化によって評価した。遺伝子発現は、AMHR2特異的プライマーおよびβアクチン特異的プライマー(テーブル1)を用いたConventional RT−PCRによって決定した。30サイクルの増幅後、PCR産物をアガロースゲル(1TBE緩衝液中2%)で分離し、臭化エチジウムで染色した後に紫外線下で可視化した。TgMlSIIR−TAgマウスの子孫における導入遺伝子発現は、先に記載したようなプライマー対(テーブル1)を用いたSV40−TAgの773bpフラグメントのPCR増幅によって決定した。マウスAMHR2の細胞外ドメインの全140アミノ酸配列のDNAを、AMHR2特異的プライマー対(テーブル1)を用いてマウス卵巣組織からRT−PCRにより増幅した。
50KUのDNase I(Sigma−Aldrich)および0.2mg/mlコラゲナーゼII(Life Technologies)を含むHBSS中37℃で30分間、刻んだ腫瘍を消化し、続いて不連続勾配遠心分離によってTILをID8腫瘍から単離した。当該部分的に精製されたTILを、0.5%BSAおよび0.05%アジ化ナトリウムを含むPBS中、FcγIII/II受容体抗体(BD Biosciences)で処理し、FITC結合抗マウスCD3とPE結合抗マウスCD4またはPE結合抗マウスCD8(BD Biosciences)の一方でニ重染色した。CD3+T細胞集団をゲーティングし、CD4+およびCD8+T細胞のパーセンテージについて分析した。30,000の総イベントで収集されたデータをFlowJoソフトウェア(BD Biosciences)を用いて分析した。
AMHR2ポリペプチドまたはコントロール免疫原(オボアルブミン;Sigma−Aldrich)を用いたメスC57BL/6マウスの免疫の10日後、5x106細胞/mlのLNCを、IL−12(10ng/ml)およびIL−18(10ng/ml;Peprotech、Rocky Hill、NJ)の存在下、24ウェル平底Falconプレート(BD Biosciences)中、上記のように補充したDMEM中、総量2.0 ml/ウェルで、20μg/mlの免疫原でin vitroで活性化した。再刺激の3日後、2×107個の活性化全LNCを、亜致死的にγ照射された(5Gy)ナイーブメスレシピエントに腹腔内注射した。あるいは、C57BL/6雌マウスをAMHR2ポリペプチドまたはOVAのいずれかで免疫化し、4週間後、上記のように免疫原、IL−12、およびIL−18で再活性化された7.5x107全脾細胞、磁気ビーズ分離で全脾細胞から精製され同様に再活性化された2x107のCD4+T細胞、および
磁気ビーズ分離で全脾細胞から精製された2x107の非再活性化B220+B細胞を含む、3グループの細胞を亜致死的にγ照射された(5Gy)ナイーブメスレシピエントに腹腔内注射した。すべての場合において、細胞移入の翌日に5x106個のID8細胞を宿主に皮下接種し、腫瘍増殖を上記のように定期的に評価した。濃縮された細胞の純度は、CellQuestソフトウェア(BD Biosciences)を用いたフローサイトメトリー分析によって決定され、一貫して>90%であった。
スチューデントのt検定を用いて、mRNA発現レベルと平均腫瘍重量の差違を比較した。腫瘍増殖曲線間の差異を、unweighted one−way ANOVAによって比較し、logrank検定を用いてマウス生存曲線の差を比較した。
全細胞質ドメインの399個のアミノ酸を含む170−568配列からなるマウスAMHR2の最も長い親水性ドメインが発現された(図1A)。Ni−NTAアフィニティー精製C末端6xHisタグタンパク質は、SDS−PAGEゲルのクマシーブルー染色(図1B)およびHRPコンジュゲートHis特異的抗体を用いたウエスタンブロットブロット免疫染色によって決定される(図1C)〜44kDタンパク質として移動した。
雌C57BL/6マウスのAMHR2−CD免疫化の10日後、LNCは、AMHR2−CDに用量反応的に増殖したが、AMHR2−CDと同様の方法で生成および精製された組換えヒトコクリン(cochlin)、コントロールタンパク質では増殖しなかった(図2A)。LNCによるこの抗原特異的増殖は、精製CD4+T細胞から誘導されたが、精製CD8+T細胞からは誘導されず(図2B)、CD4特異的抗体(CD8特異的抗体でない)との培養の処理によって阻害された(図2C)。免疫化から4週間後、免疫原刺激された脾細胞からの上清のELISA分析は、IFNγの高産生およびIL−2、IL−4、およびIL−5の産生が比較的低いといった、AMHR2−CDに対する主要な炎症促進性応答を示した(図2D)。全脾細胞集団からのT細胞サブセットの精製は、CD4+T細胞(CD8+T細胞でなく)がAMHR2−CDに応答してIFNγを産生することを示した(図2E)。免疫化の2ヶ月後、AMHR2−CD特異的IgGの血清レベルは、1:50,000希釈を超える力価でも検出可能であった(図2F)。
次に、卵巣の自己免疫を誘導するAMHR2−CD免疫の可能性を調べた。C57BL/6雌マウスのAMHR2−CD免疫化の4週間後および8週間後、卵巣IFNγ遺伝子発現をqRT−PCRによって測定した。相対的な卵巣IFNγ遺伝子発現は、AMHR2−CD免疫化の4週間後には中程度に上昇したが、CFA単独の免疫化後ではそうではなかった(図3A)。免疫化の8週間後、相対的な卵巣IFNγ遺伝子発現は、免疫した両マウス群において同様であった。中でも注目すべきは、4週間でAMHR2−CD免疫化マウスで観察されたIFNγ遺伝子発現の一時的な上昇は、CFAコントロールマウスより3倍高いだけであった。AMHR2−CD免疫化の4、8および12週間後の免疫組織化学分析により、卵巣でCD3+T細胞浸潤は観察されなかった。4連続交配サイクル(この間、AMHR2−CDおよびCFA免疫化マウス間に同腹仔あたりの子の数に有意差は生じなかった(P>0.60)(図3C))にわたるマウス妊孕性により示されるとおり、AMHR2−CD免疫マウスの卵巣におけるIFNγの低い一過性発現は、卵巣機能への検出可能な影響と関連していなかった。AMHR2遺伝子の発現は、卵巣およびID8卵巣腫瘍細胞で直ちに検出され、正常なマウス子宮、胃、脾臓、心臓、肺、腎臓および肝臓ではいずれも感知可能なレベルで検出されなかった(図3C)。
AMHR2−CDによるワクチン接種が、C57BL/6雌マウスにおける移植可能なID8腫瘍の増殖を阻害するかどうかを次に試験した。ID8卵巣腫瘍細胞の接種の15日前(図4A;P<0.001)、7日前(図4V;P<0.001)または1日後(図4C;P<0.05)に予防ワクチン接種したマウスにおいて、ID8腫瘍増殖は阻害された。さらに、ID8接種の7日前(P<0.01)および1日前(P<0.05)にワクチン接種されたマウスにおける実験の終了時の最終ID8腫瘍重量によって測定されたとおり、AMHR2−CDワクチン接種は、全腫瘍量の有意な減少をもたらした(図4D)。AMHR2−CDワクチン接種は、EOCに対する治療としても有効であった。ID8腫瘍の接種60日後のAMHR2−CDによるワクチン接種は、確立された触診可能なID8腫瘍の増殖を有意に阻害した(P<0.05;図4E)。AMHR2−CDを用いたワクチン接種は、TgM1SIIR−TAgトランスジェニックマウスにおいて自然発症的に発生する自然発症EOCの増殖を有意に阻害した(P<0.0001;図4F)。さらに、CFAワクチン接種コントロールマウスと比較した場合、腫瘍増殖におけるこの阻害は、極めて有意に全生存期間(OS)の増加を伴った(P<0.0005;図4G)。CFAワクチン接種対照マウス(平均135日±13.89)と比較したAMHR2−CDワクチン接種マウスのこの拡大された寿命(平均191.25日±22.95)は、OSにおける41.7%の増大を表す。
全てのレシピエントマウスに、細胞移入の翌日にID8腫瘍細胞を接種した。OVA特異的LNCを投与されたマウスと比較した場合、AMHR2−CD特異的LNC(P=0.04;図6A)および脾細胞(P<0.01;図6B)を移入したマウスにおいて腫瘍増殖は有意に阻害された。初回刺激された脾細胞の移入および腫瘍接種の190日後、平均腫瘍重量は、OVA特異的脾細胞のレシピエントと比較して、AMHR2−CD特異的脾細胞のレシピエントにおいて有意に低かった(P<0.05;図6C)。4週間の初回刺激脾細胞から精製したAMHR2−CD特異的CD4+T細胞の移入は、精製OVA特異的CD4+T細胞の移入と比較してID8腫瘍増殖の有意な阻害をもたらした(P<0.0004;図6D)、一方、4週間初回刺激された脾臓細胞から精製されたAMHR2−CD−刺激B220+B細胞の移入は、OVA刺激B220+B細胞の移入と比較して、ID8腫瘍増殖を有意に阻害しなかった(P=0.07;図6D)。したがって、AMHR2−CD特異的炎症誘発性CD4+T細胞は、EOCの増殖に対する免疫防御を伝達するのに十分である。
ヒトタンパク質アトラスデータベースを調べて、30のヒト組織における相対的なAMHR2遺伝子発現を決定した。図7に見られるように、AMHR2遺伝子発現は、30個の組織のうちのわずか5個でバックグラウンドを上回ることが観察され、最高発現は卵巣で観察された。
AMHR2タンパク質のN末端140アミノ酸で構成されるマウスAMHR2細胞外ドメインを発現させた(図10A)。Ni−NTAアフィニティー精製C末端6xHisタグタンパク質は、SDS−PAGEゲルのクマシーブルー染色およびHRP結合His特異的抗体を用いたウエスタンブロット免疫染色によって決定される〜17kDタンパク質として移動した(図10B)。6週齢の若いC57BL/6雌マウスのAMHR2−EDワクチン接種の1ヶ月後、ELISPOT分析は、IFNγ産生抗原特異的T細胞の脾細胞頻度(平均で3,831脾臓細胞あたり1)、IL−17の脾細胞頻度(平均で21,739脾細胞あたり1個)の上昇を示したがIL−5ではなかった(図10C)。
AMHR2−EDの免疫原性は、TgM1SIIR−TAg(DR26系)トランスジェニック雌マウスのCFA中AMHR2−EDによる免疫化によって決定した。免疫化の4週間後、AMHR2−ED由来の脾細胞は、AMHR2−EDに対する抗原特異的リコール増殖応答を示したが、組換えマウスβ−カゼイン(AMHR2−EDと同様の様式で生成および精製された無関係なコントロール抗原)では見られなかった(図11A)。対照的に、CFA免疫化マウス由来の脾細胞は、AMHR2−EDおよびβ−カゼインの両方に対して応答しなかった(図11B)。培養上清のELISA分析により、高レベルの炎症誘発性サイトカインサイトカイン、IFNγおよびIL−17のAMHR2−ED活性化産生が示され、および第2型制御性サイトカインIL−5の産生は最小であることが示された(図11C)。AMHR2−EDで免疫したマウスの脾細胞は、1型(〜1/4,000リンパ球;p<0.0001)および17型(〜1/20,000リンパ球;p<0.02)炎症誘発性T細胞の有意に高い頻度を示したが、IL−5を発現する2型制御性T細胞は最小の頻度であった(図11D)。AMHR2−EDによる免疫化の4ヶ月後、AMHR2−ED特異的IgGの血清力価は、1/50,000希釈を超える力価で依然として検出可能であった(p<0.001、図11E)。これらの結果は、AMHR2−EDが高度に免疫原性であることを示している。
AMHR2−EDによる免疫後の卵巣炎症のレベルを調べた。マウスの卵巣を、AMHR2−EDによる免疫化の4週間後および8週間後に採取し、RT−PCRによって分析した。図13に見られるように、採取された卵巣は、免疫後4週間で炎症性サイトカインIL−1βの発現を示したが、8週間では示さなかった。IFNγ発現は、免疫後のいずれの時点でも上昇しなかった。対照的に、AMHR2−EDワクチン接種の4週間後、9ヶ月齢のC57BL/6雌マウスの卵巣中のIL−1βについてもIFNγについては遺伝子発現の上昇は起こらなかった(図13C)。
自発性かつ移植可能な卵巣腫瘍の増殖を阻害するAMHR2−EDワクチン接種の能力を試験した。図15A〜Bに見られるように、6〜7週齢の雌TgM1SIIR−TAgトランスジェニックマウスの予防的AMHR2−ECワクチン接種は、自然発症EOCの増殖において高度に有意な阻害をもたらし(p<0.0001)、CFA単独でワクチン接種したコントロールマウスと比較して、全生存が42%増加した(平均193.7±34.5日対平均135±13.89日)。移植可能なTgMISIIR EOC腫瘍の増殖における同様の有意な阻害は、3x106マウス卵巣癌(MOVCAR)細胞を接種する7日前または15日前のいずれかにワクチン接種されたマウスで生じた(p<0.001;図15C〜D)。
EOC腫瘍増殖に対するAMHR2−ED刺激CD4+T細胞およびB220+B細胞の移入の効果を試験した。図16に見られるように、AMHR2−EDで免疫化したマウスからのCD4+T細胞またはB220+B細胞の移入後に、MOVCAR EOCの増殖の阻害が生じた。さらに、図17に見られるように、AMHR2−ED免疫化マウスからのCD4+T細胞またはB220+B細胞の移入もまた、細胞を受けたMOVCAR腫瘍を有するマウスにおいて全生存を増加させた。ナイーブレシピエントへの細胞の移入およびMOVCAR EOCの接種は、互いに1日以内に行われた。さらに、図18に見られるように、ID8−VEGF EOC腫瘍の増殖阻害は、AMHR2−EDで免疫化したマウスからのCD4+T細胞(左上パネル)または血清(左下パネル)を受けたマウスで生じた。全生存の増大は、AMHR2−EDで免疫化したマウスのCD4+T細胞(右上のパネル)または血清(右下のパネル)を受けたマウスで生じた。ナイーブレシピエントへの細胞の移入およびID8−VEGF EOCの接種は、互いに1日以内に行われた。アスタリスクは有意性を示す。
EOC腫瘍増殖の阻害を説明する免疫集団の同一性を試験した。MOVCAR接種の1日前にAMHR2−ED刺激CD4+T細胞をTgMISIIR−TAg(低)雌マウスに移入すると、オボアルブミン刺激CD4+T細胞を受けたマウスと比較して、腫瘍増殖の極めて有意な阻害がもたらされ(P<0.0001;図20A)、全生存が増大することが見出された(P<0.006;図20B)。さらに、MOVCAR接種の1日前にTgMISIIR−TAg(低)雌マウスにAMHR2−ED刺激B220+B細胞を移入することにより、オボアルブミン免疫化マウスからのB220+B細胞を受けたマウスと比較して、有意な腫瘍増殖の阻害(P<0.0001;図20C)および全生存の増大(P<0.009;図20D)が媒介された。MOVCAR接種の1日前にTgMISIIR−TAg(低)雌マウスへのAMHR2−ED免疫化マウス由来のアフィニティー精製IgGの移入は、オボアルブミン免疫化マウス由来のアフィニティー精製IgGを受けたマウスと比較して、腫瘍増殖の有意な阻害をもたらし(P<0.0001;図20E)、全生存を増大した(P<0.002;図20F)。
本明細書で言及されるすべての刊行物、特許および特許出願は、各々の刊行物、特許または特許出願が具体的に参照され、個々に示されているかのように、参照によりその全体が本明細書に組み込まれる。コンフリクトの場合には、本明細書中の定義を含む本出願は、コントロールする。
当業者であれば、本明細書に記載された特定の実施形態に対する多くの同等物(均等物)を認識するであろうし、あるいは通常の実験を用いて確認することができるであろう。
そのような同等物(均等物)は、下記の請求の範囲に記載されたものに包含されることが意図される。
Claims (83)
- ヒト女性対象における卵巣癌腫瘍を治療する方法であって、該方法は抗ミュラー管ホルモンII型受容体(AMHR2)ポリペプチドを含む免疫原性組成物を該対象に投与することを含み、該AMHR2ポリペプチドは配列番号1の少なくとも8個の連続するアミノ酸を含むアミノ酸配列を有する、方法。
- 該少なくとも8個の連続するアミノ酸がAMHR2の細胞質ドメイン中のアミノ酸配列と同一である、請求項1に記載の方法。
- 該ポリペプチドがAMHR2の細胞質ドメイン中のアミノ酸配列と少なくとも80%の同一性である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項2に記載の方法。
- 該ポリペプチドがAMHR2の細胞質ドメイン中のアミノ酸配列と同一である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項3に記載の方法。
- 該ポリペプチドがAMHR2の細胞質ドメインのアミノ酸配列と同一であるアミノ酸配列を有する、請求項4に記載の方法。
- 該ポリペプチドがAMHR2の細胞外ドメインと同一のアミノ酸配列を含まない、請求項2〜5のいずれか1項に記載の方法。
- 該ポリペプチドがAMHR2の膜貫通ドメインと同一のアミノ酸配列を含まない、請求項2〜6のいずれか1項に記載の方法。
- 該少なくとも8個の連続するアミノ酸がAMHR2の細胞外ドメイン中のアミノ酸配列と同一である、請求項1に記載の方法。
- 該ポリペプチドはAMHR2の細胞外ドメイン中のアミノ酸配列と少なくとも80%の同一性である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項8に記載の方法。
- 該ポリペプチドはAMHR2の細胞外ドメイン中のアミノ酸配列と同一である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項9に記載の方法。
- 該ポリペプチドはAMHR2の細胞外ドメインのアミノ酸配列と同一であるアミノ酸配列を有する、請求項10に記載の方法。
- 該ポリペプチドがAMHR2の膜貫通ドメインと同一のアミノ酸配列を含まない、請求項8〜11のいずれか1項に記載の方法。
- 該ポリペプチドがAMHR2の細胞質ドメインと同一であるアミノ酸配列を含まない、請求項8〜12のいずれか1項に記載の方法。
- 該免疫原性組成物がアジュバントを含む、請求項1〜13のいずれか1項に記載の方法。
- 該アジュバントがアジュバント65、α−GalCer、リン酸アルミニウム、水酸化アルミニウム、リン酸カルシウム、β−グルカンペプチド、CpG DNA、GM−CSF、GPI−0100、IFA、IFN−γ、IL−17、リピドA、リポ多糖、リポバント(Lipovant)、モンタナイド(Montanide)、N−アセチル−ムラミル−L−アラニル−D−イソグルタミン、Pam3CSK4、ポリ−IC、クイルA(quil A)、トレハロースジミコレートおよびザイモサンからなる群から選択される、請求項14に記載の方法。
- 該アジュバントが1型/17型混合型免疫応答を誘導するものである、請求項14または15に記載の方法。
- 該卵巣癌腫瘍が原発性卵巣癌腫瘍である、請求項1〜16のいずれか1項に記載の方法。
- 該卵巣癌腫瘍が転移性腫瘍である、請求項1〜16のいずれか1項に記載の方法。
- 該卵巣癌腫瘍が卵巣上皮癌(EOC)腫瘍である、請求項1〜18のいずれか1項に記載の方法。
- 該卵巣癌腫瘍がAMHR2を発現する請求項1〜19に記載の方法、。
- 該免疫原性組成物の投与が該対象において卵巣癌腫瘍に対する免疫応答を誘導する、請求項1〜20のいずれか1項に記載の方法。
- 該卵巣癌腫瘍がAMHR2を発現するかどうかを決定する工程をさらに含む、請求項1〜21のいずれか1項に記載の方法。
- 該免疫原性組成物の投与が該対象において卵巣癌腫瘍に対する免疫応答を誘導するかどうかを決定する工程をさらに含む、請求項1〜22のいずれか1項に記載の方法。
- 該対象が該免疫原性組成物を複数用量投与される、請求項1〜23のいずれか1項に記載の方法。
- 該免疫原性組成物の投与が該対象においてAMHR2に対するT細胞免疫応答を誘導する、請求項1〜24のいずれか1項に記載の方法。
- 該免疫原性組成物の投与が該対象においてAMHR2に対するB細胞免疫応答を誘導する、請求項1〜25のいずれか1項に記載の方法。
- 該免疫原性組成物の投与が該対象による抗AMHR2IgG抗体の発現を誘導する、請求項26に記載の方法。
- 該対象に更なる抗癌剤を投与する工程をさらに含む、請求項1〜27のいずれか1項に記載の方法。
- 該更なる抗癌剤がパクリタキセル、シスプラチン、トポテカン、ゲムシタビン、ブレオマイシン、エトポシド、カルボプラチン、ドセタキセル、ドキソルビシン、トポテカン、シクロホスファミド、トラベクテジン、オラパリブ、タモキシフェン、レトロゾール、ベバシズマブ、抗CTLA4抗体、抗PD−1抗体および抗PD−L1抗体からなる群から選択される、請求項28に記載の方法。
- 該対象が卵巣癌腫瘍の少なくとも一部を除去するための外科手術を受けたことがある、請求項1〜29のいずれか1項に記載の方法。
- ヒト女性対象における卵巣癌を予防する方法であって、該方法は該対象に抗ミュラー管ホルモンII型受容体(AMHR2)ポリペプチドを含む免疫原性組成物を投与することを含み、該AMHR2ポリペプチドは配列番号1の少なくとも8個の連続するアミノ酸を含むアミノ酸配列を有する、該方法。
- 該少なくとも8個の連続するアミノ酸がAMHR2の細胞質ドメイン中のアミノ酸配列と同一である、請求項31に記載の方法。
- 該ポリペプチドがAMHR2の細胞質ドメイン中のアミノ酸配列と少なくとも80%の同一性である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項32に記載の方法。
- 該ポリペプチドがAMHR2の細胞質ドメイン中のアミノ酸配列と同一である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項33に記載の方法。
- 該ポリペプチドがAMHR2の細胞質ドメインのアミノ酸配列と同一であるアミノ酸配列を有する、請求項34に記載の方法。
- 該ポリペプチドがAMHR2の細胞外ドメインと同一のアミノ酸配列を含まない、請求項32〜35のいずれか1項に記載の方法。
- 該ポリペプチドがAMHR2の膜貫通ドメインと同一のアミノ酸配列を含まない、請求項32〜36のいずれか1項に記載の方法。
- 該少なくとも8個の連続するアミノ酸がAMHR2の細胞外ドメイン中のアミノ酸配列と同一である、請求項31に記載の方法。
- 該ポリペプチドがAMHR2の細胞外ドメイン中のアミノ酸配列と少なくとも80%の同一性である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項38に記載の方法。
- 該ポリペプチドがAMHR2の細胞外ドメイン中のアミノ酸配列と同一である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項39に記載の方法。
- 該ポリペプチドはAMHR2の細胞外ドメインのアミノ酸配列と同一であるアミノ酸配列を有する、請求項40に記載の方法。
- 該ポリペプチドがAMHR2の膜貫通ドメインと同一のアミノ酸配列を含まない、請求項38〜41のいずれか1項に記載の方法。
- 該ポリペプチドはAMHR2の細胞質ドメインと同一であるアミノ酸配列を含まない、 請求項38〜42のいずれか1項に記載の方法。
- 該免疫原性組成物がアジュバントを含む、請求項31〜43のいずれか1項に記載の方法。
- 該アジュバントがアジュバント65、α−GalCer、リン酸アルミニウム、水酸化アルミニウム、リン酸カルシウム、β−グルカンペプチド、CpG DNA、GM−CSF、GPI−0100、IFA、IFN−γ、IL−17、リピドA、リポ多糖、リポバント(Lipovant)、モンタナイド(Montanide)、N−アセチル−ムラミル−L−アラニル−D−イソグルタミン、Pam3CSK4、ポリ−IC、クイルA(quil A)、トレハロースジミコレートおよびザイモサンからなる群から選択される、請求項44に記載の方法。.
- 該アジュバントが1型/17型混合型免疫応答を誘導するものである、請求項44または45に記載の方法。
- 該対象が卵巣癌腫瘍の少なくとも一部を除去するための外科手術を受けたことがある、請求項31〜46のいずれか1項に記載の方法。
- 該対象に更なる抗癌剤を投与する工程をさらに含む、請求項47に記載の方法。
- 該更なる抗癌剤がパクリタキセル、シスプラチン、トポテカン、ゲムシタビン、ブレオマイシン、エトポシド、カルボプラチン、ドセタキセル、ドキソルビシン、トポテカン、シクロホスファミド、トラベクテジン、オラパリブ、タモキシフェン、レトロゾール、ベバシズマブ、抗CTLA4抗体、抗PD−1抗体および抗PD−L1抗体からなる群から選択される、請求項48に記載の方法。
- 該卵巣癌腫瘍が原発性卵巣癌腫瘍である、請求項47〜49のいずれか1項に記載の方法。
- 該卵巣癌腫瘍が転移性腫瘍である、請求項47〜49のいずれか1項に記載の方法。
- 該卵巣癌腫瘍が卵巣上皮癌(EOC)腫瘍である、請求項47〜51のいずれか1項に記載の方法。
- 該卵巣癌腫瘍がAMHR2を発現する、請求項47〜52に記載の方法。
- 該卵巣癌腫瘍がAMHR2を発現するかどうかを決定する工程をさらに含む、請求項47〜53のいずれか1項に記載の方法。
- 該免疫原性組成物の投与が該対象においてAMHR2に対する免疫応答を誘導する、請求項31〜54のいずれか1項に記載の方法。
- 該免疫応答がAMHR2に対するT細胞免疫応答を含む、請求項55に記載の方法。
- 該免疫応答が該対象におけるAMHR2に対するB細胞免疫応答を含む、請求項55または56に記載の方法。
- 該免疫原性組成物の投与がAMHR2に対する免疫応答を誘導するかどうかを決定する工程を更に含む、請求項31〜57のいずれか1項に記載の方法。
- 該対象が該免疫原性組成物を複数用量投与される、請求項31〜58のいずれか1項に記載の方法。
- 該対象が卵巣癌になりやすい素因を持っている、請求項1〜59のいずれか1項に記載の方法。
- 該対象のゲノムが対象を卵巣癌になりやすくするBRCA1またはBRCA2変異を含む、請求項60に記載の方法。
- 該対象が卵巣癌の家族歴を有する、請求項60または61に記載の方法。
- 該対象が閉経後のヒト女性である、請求項1〜62のいずれか1項に記載の方法。
- ヒト女性対象における卵巣癌を予防または治療するためのキットであって、該キットは
抗ミュラー管ホルモンII型受容体(AMHR2)ポリペプチドを含み、該AMHR2ポリペプチドは配列番号1の少なくとも8個の連続するアミノ酸を含むアミノ酸配列を有する、キット。 - 該少なくとも8個の連続するアミノ酸がAMHR2の細胞質ドメイン中のアミノ酸配列と同一である、請求項64に記載のキット。
- 該ポリペプチドがAMHR2の細胞質ドメイン中のアミノ酸配列と少なくとも80%の同一性である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項65に記載のキット。
- 該ポリペプチドがAMHR2の細胞質ドメイン中のアミノ酸配列と同一である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項66に記載のキット。
- 該ポリペプチドがAMHR2の細胞質ドメインのアミノ酸配列と同一であるアミノ酸配列を有する、請求項67に記載のキット。
- 該ポリペプチドがAMHR2の細胞外ドメインと同一のアミノ酸配列を含まない、請求項65〜68のいずれか1項に記載のキット。
- 該ポリペプチドがAMHR2の膜貫通ドメインと同一のアミノ酸配列を含まない、請求項65〜69のいずれか1項に記載のキット。
- 該少なくとも8個の連続するアミノ酸がAMHR2の細胞外ドメイン中のアミノ酸配列と同一である、請求項64に記載のキット。
- 該ポリペプチドがAMHR2の細胞外ドメイン中のアミノ酸配列と少なくとも80%の同一性である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項71に記載のキット。
- 該ポリペプチドがAMHR2の細胞外ドメイン中のアミノ酸配列と同一である100個の連続するアミノ酸を含むアミノ酸配列を有する、請求項72に記載のキット。
- 該ポリペプチドはAMHR2の細胞外ドメインのアミノ酸配列と同一であるアミノ酸配列を有する、請求項73に記載のキット。
- 該ポリペプチドがAMHR2の膜貫通ドメインと同一のアミノ酸配列を含まない、請求項71〜74のいずれか1項に記載のキット。
- 該ポリペプチドはAMHR2の細胞質ドメインと同一であるアミノ酸配列を含まない、請求項71〜75のいずれか1項に記載のキット。
- さらにアジュバントを含む、請求項64〜76のいずれか1項に記載のキット。
- 該アジュバントがアジュバント65、α−GalCer、リン酸アルミニウム、水酸化アルミニウム、リン酸カルシウム、β−グルカンペプチド、CpG DNA、GM−CSF、GPI−0100、IFA、IFN−γ、IL−17、リピドA、リポ多糖、リポバント(Lipovant)、モンタナイド(Montanide)、N−アセチル−ムラミル−L−アラニル−D−イソグルタミン、Pam3CSK4、ポリ−IC、クイルA(quil A)、トレハロースジミコレートおよびザイモサンからなる群から選択される、請求項77に記載のキット。
- 該アジュバントが1型/17型混合型免疫応答を誘導するものである、請求項77または78に記載のキット。
- さらなる抗癌剤をさらに含む、請求項64〜79のいずれか1項に記載のキット。
- 該更なる抗癌剤がパクリタキセル、シスプラチン、トポテカン、ゲムシタビン、ブレオマイシン、エトポシド、カルボプラチン、ドセタキセル、ドキソルビシン、トポテカン、シクロホスファミド、トラベクテジン、オラパリブ、タモキシフェン、レトロゾール、ベバシズマブ、抗CTLA4抗体、抗PD−1抗体および抗PD−L1抗体からなる群から選択される、請求項80に記載のキット。
- 該キットが複数用量の該ポリペプチドを含む、請求項64〜81のいずれか1項に記載のキット。
- 使用説明をさらに含む、請求項64〜82のいずれか1項に記載のキット。
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