JP6387156B2 - 乳癌再発の予防用ワクチン - Google Patents
乳癌再発の予防用ワクチン Download PDFInfo
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55522—Cytokines; Lymphokines; Interferons
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
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Description
本出願は、EFS-Webにより提出された配列表を含むものであり、参照によりその全体を本明細書に組み入れる。ASCIIのコピーは、2009年12月7日に作成され、HMJ106PCT.txtという名称で、サイズが11,473バイトである。
本発明の一部は政府の支援を受けてなされたものである。政府は本発明について一定の権利を有する。
本出願は、2008年12月10日出願の米国特許仮出願番号61/121,220(その全開示を参照により本明細書に組み入れることとする)の利益を主張し、その出願日に頼るものである。
QDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDPLNNTTPVTGA
SPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLALTLIDTNRSR
ACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQCAAGCTGPK
HSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACPYNYLST
DVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEF
AGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLPDL
SVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTV
PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQ
ECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFC
VARCPSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSI
ISAVVGILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQM
RILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDE
AYVMAGVGSPYVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQ
IAKGMSYLEDVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPI
KWMALESILRRRFTHQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQP
PICTIDVYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDS
TFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLT
LGLEPSEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTV
PLPSETDGYVAPLTCSPQPEYVNQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPG
KNGVVKDVFAFGGAVENPEYLTPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPP
STFKGTPTAENPEYLGLDVPV(配列番号1)
患者の特性及び臨床プロトコール:
これは、無病の乳癌患者におけるGM-CSF免疫アジュバントと一緒のHER2/neu由来GP2ペプチドの最初のフェーズI臨床試験である。試験は、施設内試験審査委員会(Institutional Review Boards)により承認され、試験新薬申請(BB-IND #11730)に基づいてWalter Reed Army Medical Centerにおいて実施された。全ての患者は、組織学的に確認されたリンパ節転移陰性の乳癌を有し、標準的な免疫組織化学によりHER2/neuのあらゆるレベルを発現していた(IHC 1〜3+)。患者は、登録前に手術、化学療法及び放射線療法(必要に応じて)の標準的なコースを完了しており、ホルモン化学的予防を受けている患者はその特定の治療計画を継続した。適格基準についてスクリーニングし、適切なカウンセリング及び同意の後、適格なHLA-A2+患者を本試験に登録した。ワクチン接種前に、患者を一連の想起(recall)抗原(マントゥー法)で皮膚検査した。患者が≧2の抗原と反応(>5mm)した場合には、該患者は免疫応答性とされた。
ワクチン:
GP2ペプチド(HER2/neu, 654-662)は、連邦ガイドラインに従って、適正製造基準(good manufacturing practices)(GMP)で、NeoMPS, Inc.(San Diego, CA)により商業的に製造された。ペプチド純度(>95%)は高速液体クロマトグラフィー及び質量分析により確認され、アミノ酸含量はアミノ酸分析により決定された。無菌性、エンドトキシン(リムルス変形細胞溶解物試験)及び一般安全性試験は上記製造業者により行われた。無菌生理食塩水中に以下の濃度の凍結乾燥ペプチド(100μg/0.5ml、500μg/0.5ml及び1mg/0.5ml)を再構成した。GP2ペプチドを、250μg/0.5mlのGM-CSF(Berlex, Seattle, WA)で混合し、その1.0mlの接種物を分割し、同じ四肢で5cm離れた2つの部位に皮内投与した。
アジュバントGM-CSFと組み合わせたGP2ペプチドの安全性、免疫原性及び最適な最良用量を決定するために、用量漸増安全性試験として試験を設計し実施した。最適な最良用量は、最良のin vivo及びex vivo免疫応答を示すワクチン及びアジュバントの最少用量と定義した。
患者をワクチン接種後1時間にわたって即時型過敏症に関して観察し、48〜72時間後に呼び戻して注射部位を測定し、毒性に関して質問した。毒性をNCI Common Terminology Criteria for Adverse Events, v3.0(CTCAE)によりグレード決定した。過敏性反応又はグレード3以上の毒性を示す用量群内2名の患者として定義される用量制限毒性がない場合に限り、1つの用量群から次の用量群へと進めた。
各ワクチン接種の前並びに一連のワクチン接種の完了の1ヶ月後(ワクチン後(post-vaccine))及び6ヶ月後(長期(long-term))に血液を採取した。50mlの血液を採取し、PBMCを単離した。PBMCを洗浄し、培養培地に再懸濁させ、リンパ球源として使用した。
患者からの新たに単離されたPBMCにおけるGP2特異的CD8+ T細胞の存在を、逐次ワクチン接種の各回の前並びに一連のワクチン接種完了の1ヶ月、6ヶ月及び12ヶ月後に、ベースラインにおける二量体アッセイにより直接的にex vivoでアッセイした(Woll MM et al., J Clin Immunol (2004) 24:449-461)。簡潔に説明すると、HLA-A2:免疫グロブリン(Ig)二量体(PharMingen, San Diego, CA)をGP2、E75又は対照ペプチド(E37, 葉酸結合性タンパク質(25-33)RIAWARTEL)と共に添加した。これは、1μgの二量体を過剰(5μg)のペプチド及び0.5μgのβ2-ミクログロブリン(Sigma , St. Louis, MO)と共に37℃で一晩インキュベートすることにより行った。ついでそれらを、使用するまで4℃で保存した。PBMCを洗浄し、PharMingen染色バッファー(Stain Buffer)(PharMingen)に再懸濁させ、5ml丸底ポリスチレンチューブ(Becton Dickinson, Mountain View, CA)内に5×105細胞/100μl/チューブで加え、添加された二量体及び抗体で染色した。各患者において、それぞれの逐次ワクチン接種に応答したGP2特異的及びE75特異的CD8+細胞のレベルを決定し、平均接種後レベルを接種前レベルと比較した。
GP2ペプチドに対するDTH反応は、一連のワクチン接種の前及び後に実施した。0.5mlの生理食塩水中の100μgのGP2(GM-CSFなし)を用いた背中又は四肢(ワクチン接種とは反対側)における皮内注射を、等量の生理食塩水接種対照と比較した。感受性ボールペン法を用いることにより、48〜72時間の時点で二次元で該DTH反応を測定し、直交平均(orthogonal mean)として記録した(Sokol JE, Measurement of delayed skin test responses. N Engl J Med (1975) 293:501-501)。
臨床病理学的因子についてのp値は、必要に応じてWilcoxon、Fisherの直接確率検定又はχ2を用いて算出した。ワクチン接種前及び後のDTHの比較並びに二量体アッセイのためのp値は、必要に応じて対応のある又は対応のないスチューデントt検定を用いて算出した。p<0.05の場合に差を有意とみなした。
GP2及びGM-CSFを含む組成物は、いずれも安全で免疫原性が高かった。免疫応答は、ex vivo及びin vivoの両方で、一連の接種の開始時におけるGP2特異的免疫の存在又は不在により、及び使用するGM-CSF用量により、影響を受けると考えられる。さらに、GP2ワクチン接種は、抗原内(intra-antigenic)エピトープスプレッディングを効率的に生じる。
この用量漸増試験では、漸増するGP2ペプチド用量(100μg、500μg、及び1000μg)を250μgのGM-CSFと共に使用し、最初の3つの用量群については6回毎月接種した(略:GP2ペプチド(μg):GM-CSF(μg):接種の回数(#)−100:250:6、500:250:6、及び1000:250:6)。GM-CSFは、100mmを超える局所反応測定又はグレード2を超える全身毒性を発症した場合には50%低減した。最初の9名の患者のうち8名(89%)は、大きな局所反応のためにGM-CSF用量の低減が必要であった。数回の用量低減が必要であったため、9名の患者の4番目及び最後の群についてはGM-CSFの開始用量を接種当たり250μgから125μgへ低減した(500:125:6)。最終用量群における9名の患者のうち2名のみ(22%)が、さらなるGM-CSF用量の低減を必要とした。一連のワクチン接種について、ペプチドの用量低減は必要ではなかった。図1は、各用量群についての平均局所反応 対 平均GM-CSF用量を示す。最終用量群における局所反応は、接種当たり125μgの開始用量のGM-CSFを用いた一連のワクチン接種全体で変動が少なかった。
合計180用量のGP2+GM-CSFを投与した18名の患者のうちグレード3〜5の毒性はなかった。全ての患者の中で、一連の接種全体の間に生じた最大局所毒性はグレード1(38.9%)又はグレード2(61.1%)であった。一連の接種の間に生じた最大全身毒性はグレード0(5.6%)、グレード1(61.1%)及びグレード2(33.3%)であった。最も一般的な局所反応には、紅斑及び硬結(患者の100%)、掻痒(25%)、及び炎症(23%)が含まれる。最も一般的な全身反応は、グレード1の倦怠(40%)及びグレード1の関節痛/筋肉痛(15%)が含まれる。全体的な局所及び全身毒性率のまとめを図2のaに示す。
以前に定義されているように、既存の免疫は、>0.3%のペプチド特異的二量体レベルである(Peoples GE et al., J Clin Oncol (2005) 23:7536-7545)。10名の患者(56%)は、GP2に対する既存の免疫と一致する二量体レベルを有し、8名の患者(44%)は既存の免疫を有しなかった。2つの群のワクチン前のGP2-二量体レベルには統計学的差があった(0.8+0.1% 対 0.06+0.02%、p=0.0007)。
2つの開始用量のGM-CSFによる患者の分析も実施した。局所毒性及び全身毒性の両方が125μg GM-CSFの最終用量群で低下したが、これは統計学的に有意ではなかった(図4a)。
以下の表2に示すように、HER2発現のレベル(IHC 1+、IHC 2+、又はIHC 3+)に従って分類した患者についてin vivo 免疫応答データを分析した。3つの群全てがワクチン後に実質的なDTH反応が増大した。驚くべきことに、低度から中度のHER2/neu発現を示す患者は、IHC 3+患者において観察されたワクチン後のDTH反応と同程度のin vivo免疫応答を示した。低度から中度のHER2/neuを発現する患者はまた、IHC 3+患者と比較した場合に、ワクチン前及び後のDTH反応の間により統計学的に有意な差がある傾向を示した。具体的には、IHC 2+患者は、ワクチン前 対 後の測定を比較した場合に、DTH反応に統計学的に有意な増大があった(2.3±2.3mmから32.5±6.6mm、p=0.02)。IHC 1+及びIHC 3+の患者は、より強力なワクチン後のDTH反応の傾向があり、IHC 1+患者はIHC 3+患者よりも統計学的有意性に近かった(IHC 1+=2.1±2.1mmから33.0±12.8mm、p=0.06、及びIHC 3+=3.9±3.9mmから44.0±17.9mm、p=0.1)。低度から中度の発現を示す患者のDTHデータをまとめた場合(「LE」)、そしてIHC 3+患者からのDTHデータと比較した場合(「OE」)、LE患者は、予想外にも、OE患者(3.9±3.9mmから44.0±17.9mm、p=0.1)と比較して、ワクチン前 対 後の測定で比較したDTH反応の統計学的に有意な増大を有することが観察された(2.0±1.4mmから31.7±7.1mm、p=0.002)。
最後に、GP2+GM-CSFによるワクチン接種に応答した抗原内エピトープスプレッディングの証拠を評価した。ワクチン接種の前、その間及びその後のGP2特異的及びE75特異的CTLの両方の測定を行った。E75特異的CTLの割合(%)は、GP2ペプチドによるワクチン接種に応答して、前 対 最大レベルを比較した場合に有意に上昇し(0.8±0.2% 対 2.0±0.2%、p=0.0001)、そして有意ではないが、ワクチン前 対 後(0.8±0.2% 対 1.2±0.2%; p=0.1)及び前 対 長期(0.8±0.2% 対 1.0±0.2%; p=0.6)で増大したことが観察された(図5)。注目すべき点は、E75特異的CTLのこれらのレベルはE75による一次ワクチン接種と同程度であり、GP2と比較してE75最大二量体応答が大きくなる傾向があるというわずかな違いしかなかった(2.0±0.2% 対 1.4±0.2%、p=0.07)。
方法
標準的な補助療法を完了した無病の高リスク乳癌患者を、複数の施設で登録し、無作為に500μgのGP2と125μgのGM-CSF(ペプチド群;PG)又は125μgのGM-CSF単独(アジュバント群;AG)のいずれかを6回の毎月接種を行った。毒性を各接種後に評価した。免疫応答は、遅延型過敏反応(DTH)の測定、及びGP2特異的CD8+ Tリンパ球を検出するためのHLA-A2:免疫グロブリン二量体アッセイによりモニターした、患者は、再発について、臨床的、X線写真により及び病理学的にモニターした。
Claims (19)
- 被験体における乳癌再発を予防するための医薬組成物であって、該被験体が標準的な治療コースによる治療後の寛解期にあり、かつ寛解前にHER2/neuの過剰発現を有する癌細胞を有していた被験体であって、HER2/neuの過剰発現がタンパク質発現3+の免疫組織化学(IHC)評価、又はHER2/neu遺伝子発現に関して2.0以上の蛍光in situハイブリダイゼーション(FISH)評価を有し、該組成物が製薬上有効な担体、配列番号2のアミノ酸配列からなるペプチド(GP2ペプチド)、及び顆粒球マクロファージコロニー刺激因子を含み、かつ該組成物が配列番号3のアミノ酸配列を有するE75ペプチドを含まない、上記組成物。
- 注射又は接種により投与される、請求項1に記載の医薬組成物。
- 該注射が皮内注射である、請求項2に記載の医薬組成物。
- 該注射が1以上の分割用量として注射される、請求項2に記載の医薬組成物。
- 該被験体上の複数の注射部位が互いに約5cm離れて位置する、請求項2に記載の医薬組成物。
- 6ヶ月にわたって毎月投与される、請求項1に記載の医薬組成物。
- 製薬上有効な担体と配列番号2のアミノ酸配列からなるペプチドとを含むワクチンブースター組成物の有効量を含むブースターと組み合わせて該被験体に投与される、請求項1に記載の医薬組成物。
- 一次免疫スケジュールが完了した後、6ヶ月又は12ヶ月ごとに該ブースターが投与される、請求項7に記載の医薬組成物。
- 該被験体がヒトである、請求項1に記載の医薬組成物。
- 該ヒトがヒト白血球抗原A2を発現する、請求項9に記載の医薬組成物。
- 顆粒球マクロファージコロニー刺激因子が組換えヒト顆粒球マクロファージコロニー刺激因子である、請求項1に記載の医薬組成物。
- 該ワクチンブースター組成物がアジュバントを更に含む、請求項7に記載の医薬組成物。
- 該アジュバントが顆粒球マクロファージコロニー刺激因子である、請求項12に記載の医薬組成物。
- 該組成物の投与が、配列番号2のアミノ酸配列からなるペプチドに対する細胞傷害性Tリンパ球応答を誘導する、請求項1に記載の医薬組成物。
- 被験体が、配列番号2のアミノ酸配列からなるペプチドに対して既存の免疫を有しない、請求項1に記載の医薬組成物。
- 該ヒトがヒト白血球抗原A3を発現する、請求項9に記載の医薬組成物。
- 標準的な治療コースがトラスツズマブによる治療を含む、請求項1に記載の医薬組成物。
- 該被験体がトラスツズマブによって同時に(concurrently)治療されている、請求項1に記載の医薬組成物。
- トラスツズマブが投与された後に投与される、請求項18に記載の医薬組成物。
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US12122008P | 2008-12-10 | 2008-12-10 | |
US61/121,220 | 2008-12-10 |
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JP2011540853A Division JP6220111B2 (ja) | 2008-12-10 | 2009-12-09 | 乳癌再発の予防用ワクチン |
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US8945573B2 (en) | 2005-09-08 | 2015-02-03 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Targeted identification of immunogenic peptides |
WO2010068647A1 (en) * | 2008-12-10 | 2010-06-17 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Vaccine for the prevention of breast cancer recurrence |
BR112013033974A2 (pt) | 2011-07-01 | 2017-02-14 | Biosceptre Int Ltd | terapia de combinação |
CN102532268B (zh) * | 2012-03-12 | 2013-12-18 | 胡海波 | 具有抗乳腺癌活性的寡肽及其应用 |
JP2016514291A (ja) * | 2013-01-29 | 2016-05-19 | モレキュラー ヘルス ゲーエムベーハー | 臨床判断支援のためのシステムおよび方法 |
US20160258951A1 (en) * | 2013-10-28 | 2016-09-08 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Methods of monitoring immune responses |
CN105037495A (zh) * | 2014-04-25 | 2015-11-11 | 杨甫进 | 一种具有抗乳腺癌活性的寡肽 |
CN107141351A (zh) * | 2017-05-15 | 2017-09-08 | 广州领晟医疗科技有限公司 | 一种e75肽的液相合成方法 |
WO2023172625A1 (en) * | 2022-03-08 | 2023-09-14 | Greenwich Lifesciences, Inc. | Methods for reversing a suppressed immune state to increase survival in a subject |
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US4744984A (en) | 1985-10-08 | 1988-05-17 | Vetrepharm Research, Inc. | Antiviral immunotherapeutic agent and preparation thereof |
US5801005A (en) | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
US5869445A (en) | 1993-03-17 | 1999-02-09 | University Of Washington | Methods for eliciting or enhancing reactivity to HER-2/neu protein |
US5550214A (en) | 1994-02-10 | 1996-08-27 | Brigham And Women's Hospital | Isolated antigenic oncogene peptide fragments and uses |
US6514942B1 (en) | 1995-03-14 | 2003-02-04 | The Board Of Regents, The University Of Texas System | Methods and compositions for stimulating T-lymphocytes |
US5891432A (en) * | 1997-07-29 | 1999-04-06 | The Immune Response Corporation | Membrane-bound cytokine compositions comprising GM=CSF and methods of modulating an immune response using same |
US6969609B1 (en) * | 1998-12-09 | 2005-11-29 | The United States Of America As Represented By The Department Of Health And Human Serivces | Recombinant vector expressing multiple costimulatory molecules and uses thereof |
US20040121946A9 (en) | 2000-12-11 | 2004-06-24 | John Fikes | Inducing cellular immune responses to her2/neu using peptide and nucleic acid compositions |
WO2003055439A2 (en) | 2001-07-18 | 2003-07-10 | The Regents Of The University Of California | Her2/neu target antigen and use of same to stimulate an immune response |
WO2003076585A2 (en) | 2002-03-08 | 2003-09-18 | Board Of Regents, The University Of Texas System | Controlled modulation of amino acid side chain length of peptide antigens |
CN1288166C (zh) * | 2004-07-14 | 2006-12-06 | 吉林圣元科技有限责任公司 | 修饰的肿瘤抗原肽及其应用 |
US8945573B2 (en) * | 2005-09-08 | 2015-02-03 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Targeted identification of immunogenic peptides |
MX2009012858A (es) | 2007-06-01 | 2010-02-03 | Jackson H M Found Military Med | Vacuna para la prevencion de recaidas de cancer de seno. |
WO2010068647A1 (en) * | 2008-12-10 | 2010-06-17 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Vaccine for the prevention of breast cancer recurrence |
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JP2018008960A (ja) | 2018-01-18 |
EP3238740A1 (en) | 2017-11-01 |
US20110256164A1 (en) | 2011-10-20 |
HK1223028A1 (zh) | 2017-07-21 |
US9737596B2 (en) | 2017-08-22 |
CN102245197A (zh) | 2011-11-16 |
JP2012511578A (ja) | 2012-05-24 |
KR20110106338A (ko) | 2011-09-28 |
BR122021010546B1 (pt) | 2022-08-02 |
EP2355843B1 (en) | 2017-06-07 |
CA2744035A1 (en) | 2010-06-17 |
US9114099B2 (en) | 2015-08-25 |
JP6220111B2 (ja) | 2017-10-25 |
ES2639577T3 (es) | 2017-10-27 |
BRPI0922849B1 (pt) | 2023-01-24 |
EP2355843B8 (en) | 2017-08-02 |
CA2744035C (en) | 2018-07-24 |
BRPI0922849A2 (pt) | 2017-05-30 |
US20160022790A1 (en) | 2016-01-28 |
KR20170097234A (ko) | 2017-08-25 |
EP2355843A4 (en) | 2013-04-17 |
EP2355843A1 (en) | 2011-08-17 |
WO2010068647A1 (en) | 2010-06-17 |
CN105435218A (zh) | 2016-03-30 |
AU2009324707A1 (en) | 2010-06-17 |
AU2009324707B2 (en) | 2015-04-30 |
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