JP7086043B2 - Muc1-c癌タンパク質のhla-a24アゴニストエピトープ及び組成物及び使用方法 - Google Patents
Muc1-c癌タンパク質のhla-a24アゴニストエピトープ及び組成物及び使用方法 Download PDFInfo
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- JP7086043B2 JP7086043B2 JP2019204306A JP2019204306A JP7086043B2 JP 7086043 B2 JP7086043 B2 JP 7086043B2 JP 2019204306 A JP2019204306 A JP 2019204306A JP 2019204306 A JP2019204306 A JP 2019204306A JP 7086043 B2 JP7086043 B2 JP 7086043B2
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Description
本特許出願は、2013年10月23日出願の米国仮特許出願第61/894,482号(参照により組み込まれる)の利益を主張する。
本明細書と同時提出の、ヌクレオチド/アミノ酸の配列表は、その全体が参照により本明細書に組み込まれる。
MUC1(CD227)は、大型のN末端サブユニット(MUC1-N)が、小型のC末端サブユニット(MUC1-C)に共有結合したヘテロダイマーから構成される、I型膜糖タンパク質である。
et al.,J.Biol.Chem.,265:15294-9(1990)参照)。細胞質尾部は、βカテニン、上皮成長因子受容体(EGFR)、及びSrc等のシグナル伝達タンパク質との相互作用のための部位を含有する(Li et al.,J.Biol.Chem.,276:35239-42(2001)参照)。これらのタンパク質は、健全な細胞の側底部に位置しているため、タンパク質-MUC1相互作用が顕著であるとは考えられない。しかしながら、ヒト腫瘍細胞における極性の喪失は、細胞質尾部がシグナル伝達タンパク質に曝露されることを可能にし、相互作用が生じ得る(Vermeer et al.,Nature,422:322-6(2003)参照)。
に薬物耐性を患う患者における予後不良と高度に関連することも見出されている(Ren
et al.,上記;及びKhodarev et al.,Cancer Res.,69:2833-7(2009)参照)。
本発明は、配列番号1又は配列番号2のアミノ酸配列を含むペプチドを提供する。
2位~566位、又は(iii)異なるMUC1タンパク質からの対応する配列、に対して少なくとも80%同一であるアミノ酸配列を含み、及びMUC1抗原が、配列番号1又は配列番号2のアミノ酸配列を含む、融合タンパク質、を含む、酵母-MUC1免疫療法組成物も提供する。
本発明は、MUC1を発現又は過剰発現する癌を含むが、それらに限定されない癌の、予防又は治療的処置のためのワクチン及び他の組成物に用いられ得る、ヒト腫瘍関連抗原(TAA)のムチン1(MUC1)及びその類似体の、C末端サブユニットからのヒト細胞傷害性Tリンパ球(CTL)エピトープを含む、ペプチドを提供する。特に、本発明は、KYHPMSEYAL(配列番号1)又はKYTNPAVAL(配列番号2)のアミノ酸配列を含む、それらから本質的になる、又はそれらからなるペプチド、ポリペプチド、及びタンパク質を提供する。
を指し、該タンパク質は天然に生じるか、或いは合成由来であり、或いは、細胞組成物(全細胞、細胞溶解物、又は破壊された細胞)に対して、生物(全生物、溶解物又は破壊された細胞)に対して、又は炭水化物、若しくは他の分子若しくはその一部に対して設計される。抗原は、免疫系の要素(例、T細胞、抗体)が、in vitro、in vivo、又はex vivoで遭遇する、同一又は類似の抗原に対して、抗原特異的免疫応答(例、液性及び/又は細胞性免疫応答)を誘発し得る。
MHC経路を介して提示されるエピトープとは、サイズ及び構造属性が異なることを理解するであろう。例えば、クラスI MHC分子により提示されるT細胞エピトープは、一般的に8~11アミノ酸長である一方で、クラスII MHC分子によって提示されるエピトープは、長さはそれほど制限されず、最大25アミノ酸又はそれ以上であり得る。更に、T細胞エピトープは、該エピトープが結合した特異的なMHC分子に応じて、構造的特徴が予測されている。エピトープは、直鎖状配列エピトープ(linear sequence epitopes)又は立体構造エピトープ(保存された結合領域)であり得る。ほとんどの抗体は、立体構造エピトープを認識する。
る抗原で、通常、天然抗原)である。腫瘍関連抗原(TAA)とも呼ばれる「癌抗原」は、腫瘍細胞が発現する抗原等の、癌に関連する、少なくとも1の抗原を含む抗原である。該抗原を標的とすることにより、腫瘍細胞及び/又は癌も標的となる。癌抗原は、1以上の腫瘍関連タンパク質を含む、1以上のタンパク質からの1以上の抗原を含み得る。特に、「MUC1抗原」は、MUC1タンパク質(MUC1-N、MUC1-C、又はMUC1-N及びMUC1-Cの両方が挙げられる)から誘導、設計、又は産生される抗原である。「MUC1アゴニスト抗原」は、本明細書に記載のエンハンサーアゴニストエピトープ等の、少なくとも1のアゴニストエピトープを含む、MUC1タンパク質(MUC1-N、MUC1-C又はMUC1-N及びMUC1-Cの両方が挙げられる)から誘導、設計、又は産生される抗原である。本発明の好適なエンハンサーアゴニストエピトープは、配列番号1又は配列番号2のアミノ酸配列を有する。
);Abe and Kufe,PNAS,90:282-286(1993);Hareuveni et al.,Eur.J.Biochem.,189(3):475-486(1990);Gendler et al.,J.Biol.Chem.,265(25):15286-15293(1990);Lan et al.,J.Biol.Chem.,265(25):15294-15299(1990);Tsarfaty et al.,Gene,93(2):313-318(1990);Lancaster,Biochem.Biophys.Res.Commun.,173(3):1019-1029(1990)参照)。MUC1-N領域及びMUC1-C領域の両方を含有する全長ヒトMUC1前駆体タンパク質の例は、SwissProt受入番号P15941.3(GI:296439295)に記載されており、本明細書では配列番号5で表される。選択的転写産物スプライシングにより、配列番号5をコードする遺伝子から、10の異なるMUC1アイソフォームが作製され得る。例えば、MUC1/Yとして知られるアイソフォームは、配列番号5の54位~1053位を欠いている。他の種々のアイソフォームが、このタンパク質のデータベースの説明に記載されている。
例えば、米国特許第6,546,643号;米国特許第7,118,738号;米国特許第7,342,094号;米国特許第7,696,306号;及び米国特許出願公開第2008/0063653号並びにPCT公開第2013/024972号に記載されており、本発明のMUC1抗原において、これらのエピトープのいずれか1以上が、該配列を、本明細書に記載の配列内の1以上のアミノ酸を付加、削除、又は、置換することによる等で、その位置(複数可)で、公開されたエピトープ配列に一致させるために、用いられ得る。
University Press,Oxford,United Kingdom,
2000;Sambrook et al.,Molecular Cloning:A
Laboratory Manual,3rd ed.,Cold Spring Harbor Press,Cold Spring Harbor,NY 2001;及びAusubel et al.,Current Protocols in Molecular Biology,GreenePublishing Associates and John Wiley&Sons,NY,1994参照)。
63、ワクシニアウイルスリスター(Lister)、ワクシニアウイルスニューヨークシティボードオブヘルス(New York City Board of Health)、ワクシニアウイルステンプルオブヘブン(Temple of Heaven)、ワクシニアウイルスコペンハーゲン(Copenhagen)、ACAM1000、ACAM2000、及び修飾ワクシニアウイルスアンカラ-バーバリアンノルディック(「MVA-BN」)が挙げられる、後に単離された種々の弱毒株又は分離株のいずれかの、両方を指す。
94012707で、欧州動物細胞培養機関(「ECACC」)、健康保護庁、微生物学局(Microbiology Services)、ポートダウン、ソールズベリー
SP4 0JG、連合王国(「UK」)に寄託されたMVA-572;2000年12月7日に、寄託番号ECACC00120707で、ECACCに寄託されたMVA-575;2000年8月30日に、寄託番号V00080038で、ECACCに寄託されたMVA-バーバリアンノルディック(「MVA-BN」);及びMVA-BNの誘導体から成る群から選択される。更なる例示的なポックスウイルスベクターは、米国特許第7,211,432号に記載されている。
1以上の部分で違いを示すウイルスを指す。寄託されたウイルスと同じ「複製特性」を有するウイルスは、BHK細胞において、並びにヒト細胞株HEK293、143B、HeLa及びHaCatにおいて、CEF細胞における寄託株の増幅率と同様の増幅率で複製するウイルスである。
ミリー、STAT3、STn、TAG-72、形質転換成長因子アルファ(TGF-α)、形質転換成長因子ベータ(TGF-β)、チモシンβ-15、腫瘍壊死因子アルファ(TNF-α)、TP1、TRP-2、チロシナーゼ、血管内皮増殖因子(VEGF)、ZAG、p16INK4、及びグルタチオン-S-トランスフェラーゼ(GST)、並びにそれらの修飾型(例、CEA-6D)が挙げられるが、これらに限定されない。
composition)」、「酵母ベースのワクチン(yeast-based vaccine)」、又はこれらの語句の派生語でも参照される)も提供する。上述の通り、MUC1抗原を含有する酵母ベースの免疫療法組成物は、より具体的に、「酵母-MUC1免疫療法組成物」と、又はその派生語で呼ばれ得る。「免疫療法組成物」は、被験体において、少なくとも1の治療効果を達成するのに十分な免疫応答を誘発する組成物である。「酵母ベースの免疫療法組成物」(及びその誘導体)は、酵母ビヒクル成分及び抗原成分を含む組成物を指し、T細胞性の細胞性免疫応答を含むが、これに限定されない、細胞性免疫応答等の、免疫応答を誘発又は誘導し得る。免疫応答としては、一般的に、自然免疫応答及び獲得免疫応答の両方が挙げられ、酵母成分及び抗原成分の両方に対して生じる(抗原特異的免疫応答)。個体に投与する場合、好ましくは、酵母ベースの免疫療法組成物は、該個体に、少なくとも1の、保護、予防、又は治療上の利益を提供する。1つの態様においては、本発明に有用な酵母ベースの免疫療法組成物は、CD8+及び/又はCD4+T細胞性免疫応答、1つの態様においては、特に標的抗原に対する(例、癌抗原、好ましくはMUC1に対する)CD8+及びCD4+T細胞性免疫応答を誘導できる。CD4+免疫応答としては、TH1免疫応答、TH2免疫応答、TH17免疫応答、又は以上の任意の組合せが挙げられ得る。CD8+免疫応答としては、細胞傷害性Tリンパ球(CTL)応答が挙げられ得る。1つの態様においては、酵母ベースの免疫療法組成物は、被験体において制御性T細胞(Treg)の数及び/又は機能性を調節する。
タンパク質及び融合タンパク質は、本発明のエンハンサーアゴニストエピトープを組み込むように、更に修飾され得る。いくつかの実施形態においては、癌抗原及びMUC1抗原は同一のエレメントである。いくつかの実施形態においては、癌抗原は、MUC1抗原に加えて、他の癌抗原(本明細書中、腫瘍関連抗原又はTAAとも呼ばれる)を含む他の抗原を含む。本発明の1つの態様においては、癌抗原として有用な融合タンパク質は、2以上の抗原、例、MUC1抗原及びMUC1抗原ではない別の癌抗原(TAA)又は異なる2のMUC1抗原、を含み得る。1つの態様においては、融合タンパク質は、MUC1抗原の2以上の免疫原性ドメイン等の、1以上の抗原の2以上の免疫原性ドメイン、又はMUC1抗原の2以上のエピトープ等の、1以上の抗原の2以上のエピトープを含み得る。他の種々の癌抗原又はTAAが当該分野で知られており、本明細書中、他の箇所に記載されている。
ゼについては、TDH3とも呼ばれる)、ガラクトキナーゼ(GAL1)、ガラクトース-1-リン酸ウリジルトランスフェラーゼ(GAL7)、UDP-ガラクトースエピメラーゼ(GAL10)、シトクロムc1(CYC1)、Sec7タンパク質(SEC7)及び酸性ホスファターゼ(PHO5)をコードする遺伝子のプロモーターが挙げられるが、これらに限定されず、ADH2/GAPDH及びCYC1/GAL10プロモーター等のハイブリッドプロモーター、細胞中のグルコース濃度が低い(例、約0.1~約0.2%)場合に誘導されるADH2/GAPDHプロモーター、並びにCUP1プロモーター及びTEF2プロモーターが挙げられる。同様に、いくつかの上流活性化配列(UAS:upstream activation sequence)(エンハンサーとも呼ばれる)が知られている。サッカロミセス・セレビシエにおける発現用の上流活性化配列としては、以下のタンパク質:PCK1、TPI、TDH3、CYC1、ADH1、ADH2、SUC2、GAL1、GAL7及びGAL10をコードする遺伝子のUAS、並びにGAL4遺伝子産物によって活性化される他のUASが挙げられるが、これらに限定されず、1つの態様においては、ADH2 UASが用いられる。ADH2 UASは、ADR1遺伝子産物によって活性化されることから、異種遺伝子がADH2 UASに作動可能に連結される場合、ADR1遺伝子を過剰発現するのが好ましい場合がある。サッカロミセス・セレビシエにおける発現用の転写終結配列としては、α因子、GAPDH、及びCYC1遺伝子の終結配列が挙げられる。
法は、例えば、Franzusoff et al.,Meth.Enzymol.,194,662-674(1991)に記載されている。酵母膜部分を含有する酵母膜粒子の画分、及び、酵母膜粒子の調製前に、抗原又は他のタンパク質を酵母により組換え発現させる場合には、目的の抗原又は他のタンパク質を含有する酵母膜粒子の画分、も用い得る。目的の抗原又は他のタンパク質は、膜の内側、膜のいずれかの表面上、又はそれらの組合せに担持され得る(即ち、タンパク質は、膜の内側及び外側の両方にあり得、及び/又は酵母膜粒子の膜を貫通し得る)。1つの実施形態においては、酵母膜粒子は、組換え酵母膜粒子であり、これは、膜の表面上に、又は少なくとも部分的に膜内に埋め込んで、少なくとも1の所望の抗原若しくは目的とする他のタンパク質を含む、無傷の、破砕された、若しくは破砕され再封入された、酵母膜であり得る。酵母細胞壁標品の例は、該酵母細胞壁標品が、被験体に投与されると、疾患標的に対して所望の免疫応答を刺激するように、その表面上に、又は少なくとも部分的に細胞壁内に埋め込んで、抗原を担持する、単離された酵母細胞壁の標品である。
marxianus var.lactis)、ピキア・パストリス(Pichia pastoris)、ロドトルラ・ルブラ(Rhodotorula rubra)、シゾサッカロミセス・ポンベ(Schizosaccharomyces pombe)、及びヤロウィア・リポリティカ(Yarrowia lipolytica)が挙げられ
るが、これらに限定されない。これら種の多くが、様々な亜種、タイプ、サブタイプなどを含み、これらが、前述した種内に含まれることが意図されることは、理解すべきである。1つの態様においては、本発明において用いられる酵母種としては、S.セレビシエ、C.アルビカンス、H.ポリモルファ、P.パストリス及びS.ポンべが挙げられる。S.セレビシエは、操作するのが比較的容易であり、食品添加物としての使用に「一般に安全と認められる(Generally Recognized As Safe)」又は「GRAS」(GRAS、食品医薬品局による提案規定(FDA propsed Rule)62FR18938、1997年4月17日)であることから、有用である。本発明の1つの実施形態は、例えば、S.セレビシエ cir°株等の、プラスミドを特に高いコピー数に複製することができる酵母株である。該S.セレビシエ株は、そのような、1以上の標的抗原(複数可)及び/又は抗原融合タンパク質(複数可)及び/又は他のタンパク質を高レベルで発現させることを可能にする発現ベクターを担持できる株の1つである。本発明で有用な、別の酵母株は、サッカロミセス・セレビシエ W303αである。更に、N結合グリコシル化を伸長させる酵素の変異等の、発現した標的抗原又は他のタンパク質の翻訳後修飾低減を示すものを含む、任意の変異酵母株が本発明において用いられ得る。本発明の1つの態様においては、酵母ベースの免疫療法組成物は、野生型株(正常なグリコシル化を有する)により作製される同一の抗原と比較して、低グリコシル化されたタンパク質としてMUC1抗原を産生する変異酵母株を用いて、作製される。かかるMUC1抗原は、腫瘍細胞が発現するMU1抗原により類似する可能性があり、次いで、抗原提示細胞によって、固有のT細胞エピトープにプロセシングされ得るので、特定の抗腫瘍反応を増強する。
には、少なくとも1から少なくとも約6又はそれ以上の範囲であり、約2~約6の抗原及び/又は他のタンパク質を含む。
2培地である。U2培地は、以下の成分:15g/Lのグルコース、6.7g/Lの硫酸アンモニウム含有酵母窒素原基礎培地、並びに各々0.04mg/mLのヒスチジン、トリプトファン、及びアデニン、及び0.06mg/mLのロイシン、を含む。本発明の酵母ベースの免疫療法組成物の培養に好適な培地の別の非限定的な例は、UL2培地である。UL2培地は、以下の成分:15g/Lのグルコース、6.7g/Lの硫酸アンモニウム含有酵母窒素原基礎培地、並びに各々0.04mg/mLのヒスチジン、トリプトファン、及びアデニンを含む。
母断片が、免疫応答を増強するための抗原(例、DNAワクチン、タンパク質サブユニットワクチン、死滅若しくは不活性化病原体、ウイルスベクターワクチン)を含む他の組成物と共に、提供若しくは投与され得る。酵母を、アジュバントとして用いる小片に粉砕するために、例えば、酵素処理、化学的処理又は物理的な力(例、機械的せん断若しくは超音波破砕)が用いられ得る。
クター、若しくは細胞又は組成物を含み得る。本発明のベクター及び組成物は、他の任意の薬剤若しくは組成物又は癌の予防又は治療に有用なプロトコール或いは癌、及び特にMUC1発現又は過剰発現と関連する癌、の任意の症状を治療又は改善する任意の化合物を更に含み得るか、又はそれらと共に(同時に、逐次的に又は断続的に)投与され得る。例えば、組成物は1以上の他の医薬活性剤又は薬物を含み得る。医薬組成物における使用に好適であり得る、かかる他の医薬活性薬剤又は薬物の例としては、抗癌剤(例、化学療法剤又は放射線療法剤)、代謝拮抗薬、ホルモン、ホルモンアンタゴニスト、抗生物質、抗ウイルス薬、抗真菌薬、シクロフォスファミド、及びそれらの組み合わせが挙げられる。好適な抗癌剤としては、アルキル化剤、葉酸アンタゴニスト、プリンアンタゴニスト、ピリミジンアンタゴニスト、紡錘体毒、トポイソメラーゼ阻害剤、アポトーシス誘導剤、血管新生抑制剤、ポドフィロトキシン、ニトロソウレア、シスプラチン、カルボプラチン、インターフェロン、アスパラギナーゼ、タモキシフェン、ロイプロリド、フルタミド、メゲストロール、マイトマイシン、ブレオマイシン、ドキソルビシン、イリノテカン、タキソール、ゲルダナマイシン(例、17-AAG)、及び当該分野で知られる種々の抗癌ペプチド並びに抗体が挙げられるが、これらに限定されない。
ブロピリミン(Upjohn)、ガンマインターフェロン(Genentech)、GM-CSF(顆粒球単球コロニー刺激因子;Genetics Institute)、IL-2(Cetus又はHoffman-LaRoche)、ヒト免疫グロブリン(Cutter Biological)、IMREG(Imreg of New Orleans,La.から)、SK&F 106528、腫瘍壊死因子(TNF)-α、及びTNF-βが挙げられるが、これらに限定されない。
因子(TNF)-α、B7.1、B7.2、ICAM-1、ICAM-2、LFA-1、LFA-2、LFA-3、CD70、CD72、RANTES、G-CSF、GM-CSF、OX-40L、41BBL、抗CTLA-4、IDO阻害剤、抗PDL1、抗PD1、及びそれらの組み合わせ等の、任意の好適な免疫刺激/調節分子が用いられ得る。好ましくは、組成物は、B7.1、ICAM-1、及びLFA-3の組み合わせ(TRICOMとも呼ばれる)を含む。1以上の免疫刺激/調節分子が、1以上の免疫刺激/調節分子をコードする核酸を含むベクター(例、ポックスウイルスベクター等の組換えウイルスベクター)の形態で投与され得る。例えば、1以上の免疫刺激/調節分子(例、IL-12)が、DNAプラスミドの形態で、キトサンあり又はなしで投与され得る。或いは、1以上の免疫刺激/調節分子が、キトサンと混合されたタンパク質(例、組換えIL-12)等、タンパク質(例、組換えタンパク質)として投与され得る。1以上の免疫刺激/調節分子は、また、本発明の酵母ベースの免疫療法組成物と組合わせて、又は同時に投与され得る。
本発明のペプチド、ポリペプチド、核酸、ベクター、細胞、又はそれらの組成物は、MUC1を発現する腫瘍の発症を予防し、阻害し、若しくは遅延させるため、並びに/又は腫瘍の移動及び/若しくは他の組織への腫瘍の浸潤(転移)を予防し、阻害し、若しくは遅延させるため、並びに/又は、個体における癌の進行を一般的に予防し若しくは阻害するために用いられ得る。本発明のペプチド、ポリペプチド、核酸、ベクター、細胞、又はそれらの組成物は、個体における全身腫瘍組織量を減少させること;個体における腫瘍の成長を阻害すること;個体の生存を増加させること;及び/又は個体における癌の進行を予防する、阻害する、反転させる、若しくは遅延させることによる等で、癌の少なくとも1の症状を改善するためにも用いられ得る。本発明のペプチド、ポリペプチド、核酸、ベクター、細胞、又はそれらの組成物は、MUC1を発現する癌の任意の段階で、被験体を治療するために用いられ得る。
はアジュバントと組み合わせて投与され得、リポソーム中に取り込まれ得(例、米国特許第5,643,599号、米国特許第5,464,630号、米国特許第5,059,421号、及び米国特許第4,885,172号に記載)、ナノ粒子中に取り込まれ得(例、VERSAMUNE(商標)ナノテクノロジー)、サイトカインとともに投与され得、生物学的応答修飾物質(例、インターフェロン、インターロイキン-2(IL-2)とともに投与され得、コロニー刺激因子(CSF、GM-CSF、及びG-CSF)とともに投与され得、及び/又は投与された、免疫応答を増強することが知られる、当該分野の他の試薬であり得る。
は細胞の有効性は、当該分野で知られているin vivo又はin vitroパラメーターによって決定され得る。これらのパラメーターとしては、抗原特異的な細胞毒性アッセイ、MUC1又はMUC1エピトープを発現する腫瘍の退縮、MUC1又はMUC1エピトープを発現する癌細胞の阻害、サイトカインの産生などが挙げられるが、これらに限定されない。
ることを含む。
increments)投与され得る。1つの実施形態においては、投与スケジュールは、数週間から、数ヶ月、数年の期間に亘って、酵母ベースの免疫療法組成物の用量が、少なくとも1、2、3、4、5、6、7、8、9、10回、又はそれ以上投与されるものである。1つの実施形態においては、用量は、毎週、又は隔週、又は3週毎に1回、又は毎月、1、2、3、4、5、6、7、8、9、10又はそれ以上の用量について投与され、続いて、毎週、隔週、3週毎に1回、又は毎月、癌に対する、所望の予防的又は治療的
処置を達成するために、必要に応じた用量が投与される。望まれる場合、次いで、更なるブースターが、維持又は寛解療法と同様又はより長い間隔(数ヶ月又は数年)で与えられ得る。
は放射線療法等の、他の治療的処置と組み合わせて投与され得る。
レイン酸、ステアリン酸、及びイソステアリン酸が挙げられる。オレイン酸エチル及びミリスチン酸イソプロピルは、脂肪酸エステルの好適な例である。
本実施例では、HLA-A24 MUC1-Cアゴニストエピトープの解析について説明する。
.Immunol.,152:163-75(1994))。American Peptide Company(Sunnyvale,CA)が、MUC1のMUC1-C領域から、結合親和性を増加させるため、9-merペプチド及び10-merペプチドの類似体を、単一アミノ酸置換により合成した(表1)。ペプチドの純度は>90%だった。
2.1細胞は、C.Britten博士(Johannes Gutenberg University,Mainz,Germany)から入手し、0.5mg/mLのG418(Mediatech,Manassas,VA)を追加した完全培地中で維持した。
本実施例では、配列番号1を含み、GI-6108として知られる、酵母ベースのMUC1アゴニスト免疫療法組成物の製造を実証する。
本実施例では、GI-6108及びGI-6108-DECとして知られる本発明の酵母-MUC1免疫療法組成物が、MUC1特異的T細胞を活性化し得ることを実証する。
151位)のスレオニンがロイシンで置換され、それによってアゴニストペプチドを作製していることを除く)。
いて、「T細胞なし」のコントロールも含めた。24時間培養の上清を回収し、分泌インターフェロンγ(IFN-γ)についてスクリーニングした。結果を表5に示す(T細胞によって産生されるIFN-γの量として、pg/mlで表す)。
本実施例では、MUC1陽性の癌を患う被験体における第1相臨床試験について説明する。
TD)又は観察された至適用量(best dose)での患者の拡大コホート(N=10)が、更なる研究のために選択される。結果は、一次エンドポイントとして安全性を、二次エンドポイントとして、抗原特異的T細胞応答(例、治療中に出現又は増幅する、MUC1特異的CD8+T細胞)及び臨床活性をモニターする。
本実施例では、MUC1-CのHLA-A24アゴニストエピトープが、MUC1特異的細胞を活性化し得ることを実証する。
Claims (18)
- 配列番号2のアミノ酸配列からなるペプチドをコードする単離された核酸。
- 請求項1の核酸を含む、単離されたベクター。
- 請求項1の核酸を含む、単離された細胞。
- 細胞がヒトのである、請求項3の細胞。
- 抗原提示細胞又は腫瘍細胞である、請求項3又は4の細胞。
- (a)請求項1の核酸、及び
(b)医薬的に許容可能な担体
を含む、組成物。 - 免疫刺激/調節分子をさらに含む、請求項6の組成物。
- 酵母-MUC1免疫療法組成物であって:
(a)酵母ビヒクル;及び
(b)少なくとも1のムチン1(MUC1)抗原を含む融合蛋白質をコードする核酸を含み、
前記MUC1抗原は、配列番号16のアミノ酸配列からなる、免疫療法組成物。 - 酵母ビヒクルが全酵母である、請求項8の酵母-MUC1免疫療法組成物。
- 融合タンパク質が酵母により発現されている、請求項8又は9の酵母-MUC1免疫療法組成物。
- 酵母ビヒクルが熱で不活性化されている、請求項8~10のいずれか1項の酵母-MUC1免疫療法組成物。
- 酵母ビヒクルがサッカロマイセス・セレビシエ由来である、請求項8~11のいずれか1項の酵母-MUC1免疫療法組成物。
- 5.5~8のpHレベルで維持された培地中で、MUC1抗原を発現する全酵母を培養することにより製造された、請求項8~12のいずれか1項の酵母-MUC1免疫療法組成物。
- MUC1を発現する癌の発症を予防するか、又は遅延させるための、請求項8~13のいずれか1項の酵母-MUC1免疫療法組成物。
- 癌が上皮細胞起源である、請求項14の酵母-MUC1免疫療法組成物。
- 癌が:乳癌、小腸癌、胃癌、膵臓癌、腎臓癌、膀胱癌、子宮癌、卵巣癌、精巣癌、肺癌、結腸癌、前立腺癌、黒色腫、食道癌、多発性骨髄性白血病(MML)、慢性リンパ球性白血病(CLL)、急性骨髄性白血病(AML)、バーキットリンパ腫、ホジキンリンパ腫、分泌組織の癌、及びそれらの転移性癌から成る群から選択される、請求項14の酵母-MUC1免疫療法組成物。
- 個体において癌が検出されていない、請求項14~16のいずれか1項の酵母-MUC1免疫療法組成物。
- 個体は癌を発症するリスクが高い、請求項14~17のいずれか1項の酵母-MUC1免疫療法組成物。
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JP6788500B2 (ja) * | 2013-10-23 | 2020-11-25 | アメリカ合衆国 | Muc1−c癌タンパク質のhla−a24アゴニストエピトープ及び組成物及び使用方法 |
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AU2019203443C1 (en) | 2021-04-29 |
CA2928140A1 (en) | 2015-04-30 |
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WO2015061416A3 (en) | 2015-08-27 |
CA3205348A1 (en) | 2015-04-30 |
EP3060232A2 (en) | 2016-08-31 |
EP3412304A2 (en) | 2018-12-12 |
AU2014340201B2 (en) | 2019-02-21 |
US20210253656A1 (en) | 2021-08-19 |
ES2693213T3 (es) | 2018-12-10 |
JP2016540500A (ja) | 2016-12-28 |
AU2019203443A1 (en) | 2019-06-06 |
US11732017B2 (en) | 2023-08-22 |
US10508141B2 (en) | 2019-12-17 |
US20160251406A1 (en) | 2016-09-01 |
US11155588B2 (en) | 2021-10-26 |
CA2928140C (en) | 2023-09-26 |
AU2014340201A1 (en) | 2016-05-12 |
JP6788500B2 (ja) | 2020-11-25 |
EP3412304A3 (en) | 2019-03-20 |
JP2020058350A (ja) | 2020-04-16 |
US20230331797A1 (en) | 2023-10-19 |
US20200109181A1 (en) | 2020-04-09 |
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