JP6475166B2 - 新規mhc非依存性腫瘍関連抗原 - Google Patents
新規mhc非依存性腫瘍関連抗原 Download PDFInfo
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Description
更に提供されるのは、本発明の抗原を発現する核酸T細胞受容体鎖のような本発明の抗原に特異的な結合物質、及び本発明の抗原に対して反応性がある若しくは本発明のT細胞受容体を発現する単離されたT細胞を含む。
本発明は、さらに、本発明による抗原、核酸、結合物質あるいはT細胞を含む医薬組成物、特にワクチン組成物、及びMHC非依存的に本発明の抗原に特異的に反応性をもつT細胞の生成の方法に関係する。
(I)変異抗原が、腫瘍細胞内の点突発変異若しくは転移によって腫瘍形成中に展開する。それらの抗原は、厳密に腫瘍特異的である。
(II)癌/生殖細胞系抗原は、健康な体細胞組織中ではなくもっぱら成人の生殖細胞内でのみ通常発現される。しかしながら、癌細胞においては、後発的な調整の欠失により、生殖細胞特異的遺伝子が活性化されうる。
(III)異分化抗原は、腫瘍及びそれらの健康な先祖細胞で発現される。このような抗原に対するCTL反応は、しばしば自己免疫反応に帰着する。
(IV)過剰発現のTAAは、正常細胞ではほんの少しの発現しか見られないが、腫瘍では、それらの抗原は強く活性化される。
ヒト腫瘍は、異なるカテゴリーの抗原を通常発現し、またそれぞれHLAクラスI及びクラスII分子を経るこれらのタンパク質の各々から区別されるペプチドをさらに生み出し及び提示するかもしれない。
HLA非依存的認識は、接触性皮膚炎の2人の患者でニッケル反応性CD8陽性T細胞に(Moulonら J Invest Dermatol 2003)、相応する抗原を同定することなしにメラノーマ反応性T細胞クローンに(SomasundaramらJ Transl Med 2005)、及び腎臓細胞癌反応性T細胞クローンに(ワングら J Immunol 2008年)見出された;後者の抗原は最近公表された(花田ら 血液2011)。
例えば、腫瘍細胞は、抗原を生み出しそして提示する能力が減少し、自己由来のT細胞を刺激する能力を減少し、癌化細胞に関係する免疫原性タンパク質の完全なダウンレギュレーション及び/若しくは白血球接着分子あるいは他のアクセサリー分子の低い若しくはゼロ発現及びMHCクラスI及びクラスII対立遺伝子の選択的なダウンレギュレーションを示す。
後者は、すべてのクラスI/II抗原、あるいはそれらの単に一部に影響するかもしれない。機能または発現の部分的なHLA欠失は、単一のHLA対立遺伝子、HLAハプロタイプあるいは両対立形質のβ2m遺伝子欠失による完全なHLAクラスI欠失によって引き起こされうる(Aptsiauriら、Cancer Immunol Immunother 2008年;バナールM.ら、Cancer Immunol Immunother 61:1359-71、2012年)。かくして、HLA発現能を失った腫瘍は、HLA依存性T細胞に基づいたいかなる治療に対し耐性をもつ。実際、HLA機能の損傷は、腫瘍細胞の重要な「免疫回避」メカニズムの1つでありT細胞仲介免疫療法の応用範囲を狭めている。
したがって、本発明の抗原に対してT細胞は、HLAクラスI発現に完全に陰性か、あるいは少なくともHLA発現及び/又は機能の損傷を示す癌細胞を溶解するという驚くべき有利性を提供した。通常、このような細胞は、患者の生まれつきあるいは治療上引き起こされた免疫拒否反応を回避する。
(a)本発明のタンパク質、タンパク質断片あるいはポリペプチドをコードする鎖をもつ;
(b) (a)の鎖に相補的な鎖をもつ;
あるいは、
(c) (a) あるいは(b)に記述されるような分子とストリンジェントな条件の下でハイブリダイズする鎖をもつ。
ストリンジェントな条件は、当業者には周知、特にSambrookらの「Molecular Cloning」に知られている。それに加えて、核酸は、特に哺乳類/ヒト細胞での発現のために、タンパク質に相応する核酸配列を発現するのに必要なさらなる配列を持つ。使用された核酸は、細胞において、ペプチドに相応する核酸配列の発現をおこすのに適したベクター中に含まれうる。しかしながら、核酸は、提示細胞を形質転換するのにも使え、それは樹状細胞のような古典的抗原提示細胞に拘束されず、このような方法で、自身、それらの細胞表面上で、相当するタンパク質生産する。
i.本発明によるタンパク質、タンパク質断片あるいはポリペプチドを、好適には該ポリペプチドは全長CSF2RAかTRP-2を発現する第一の細胞、好適には腫瘍細胞、を準備すること、
ii.第一の細胞と末梢血単核細胞(PBMC)の集合体を接触させ、該PBMCを刺激すること、及び
iii.該細胞におけるMHC発現から非依存的に、(i)で使われたタンパク質、タンパク質断片あるいはポリペプチドを発現する細胞を認識する能力をもつT細胞を刺激済みPBMC集合体から選択する。
この態様において、MHCは好適にはMHCクラスI及び/またはクラスIIである。
(a) 該タンパク質、タンパク質断片又はポリペプチドを発現する該細胞は、MHCクラスI若しくはMHCクラスI及びIIを欠いている、及び/又は
(b) 該T細胞は、MHCクラスI若しくはIIに対する抗体の存在下で該タンパク質、タンパク質断片又はポリペプチドを発現している該細胞に対してのその活性がテストされた、及び/又は
(c) 該T細胞は、該タンパク質、タンパク質断片又はポリペプチドをコードするDNA又はRNAで形質転換された異種細胞に対するその反応性がテストされた、
ここで、(a)、(b)及び/又は(c)において、反応性を示すT細胞は、該細胞においてHLA/MHCの発現とは非依存的に、(i)で使われた該タンパク質、タンパク質断片又はポリペプチドを発現している細胞を認識する能力をもつT細胞である。
MLLLVTSLLLCELPHPAFLLIPEKSDLRTVAPASSLNVRFDSRTMNLSWDCQENTTFSKCFLTDKKNRVVEPRLSNNECSCTFREICLHEGVTFEVHVNTSQRGFQQKLLYPNSGREGTAAQNFSCFIYNADLMNCTWARGPTAPRDVQYFLYIRNSKRRREIRCPYYIQDSGTHVGCHLDNLSGLTSRNYFLVNGTSREIGIQFFDSLLDTKKIERFNPPSNVTVRCNTTHCLVRWKQPRTYQKLSYLDFQYQLDVHRKNTQPGTENLLINVSGDLENRYNFPSSEPRAKHSVKIRAADVRILNWSSWSEAIEFGSDDGNLGSVYIYVLLIVGTLVCGIVLGFLFKRFLRIQRLFPPVPQIKDKLNDNHEVEDEIIWEEFTPEEGKGYREEVLTVKEIT
MSPLWWGFLLSCLGCKILPGAQGQFPRVCMTVDSLVNKECCPRLGAESANVCGSQQGRGQCTEVRADTRPWSGPYILRNQDDRELWPRKFFHRTCKCTGNFAGYNCGDCKFGWTGPNCERKKPPVIRQNIHSLSPQEREQFLGALDLAKKRVHPDYVITTQHWLGLLGPNGTQPQFANCSVYDFFVWLHYYSVRDTLLGPGRPYRAIDFSHQGPAFVTWHRYHLLCLERDLQRLIGNESFALPYWNFATGRNECDVCTDQLFGAARPDDPTLISRNSRFSSWETVCDSLDDYNHLVTLCNGTYEGLLRRNQMGRNSMKLPTLKDIRDCLSLQKFDNPPFFQNSTFSFRNALEGFDKADGTLDSQVMSLHNLVHSFLNGTNALPHSAANDPIFVVLHSFTDAIFDEWMKRFNPPADAWPQELAPIGHNRMYNMVPFFPPVTNEELFLTSDQLGYSYAIDLPVSVEETPGWPTTLLVVMGTLVALVGLFVLLAFLQYRRLRKGYTPLMETHLSSKRYTEEA
METLLGPLILWLQLQWVSSKQEVTQIPAALSVPEGENLVLNCSFTDSAIYNLQWFRQDPGKGLTSLLLIQSSQREQTSGRLNASLDKSSGRSTLYIAASQSGDSATYLCAVGGNDYKLSFGAGTTVTVRANIQNSDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS
MGTRLFFYVALCLLWTGHMDAGITQSPRHKVTETGTPVTLRCHQTENHRYMYWYRQDPGHGLRLIHYSYGVKDTDKGEVSDGYSVSRSKTEDFLLTLESATSSQTSVYFCAISEKLAGAYEQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG
MASAPISMLAMLFTLSGLRAQSVAQPEDQVNVAEGNPLTVKCTYSVSGNPYLFWYVQYPNRGLQFLLKYITGDNLVKGSYGFEAEFNKSQTSFHLKKPSALVSDSALYFCAVRDMIEGGGNKLTFGTGTQLKVELNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWS
MGIRLLCRVAFCFLAVGLVDVKVTQSSRYLVKRTGEKVFLECVQDMDHENMFWYRQDPGLGLRLIYFSYDVKMKEKGDIPEGYSVSREKKERFSLILESASTNQTSMYLCASSRQGAVGQPQHFGDGTRLSILEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF
MSLSSLLKVVTASLWLGPGIAQKITQTQPGMFVQEKEAVTLDCTYDTSDPSYGLFWYKQPSSGEMIFLIYQGSYDQQNATEGRYSLNFQKARKSANLVISASQLGDSAMYFCAMRPHFGNEKLTFGTGTRLTIIPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWS
MGTRLFFYVALCLLWTGHMDAGITQSPRHKVTETGTPVTLRCHQTENHRYMYWYRQDPGHGLRLIHYSYGVKDTDKGEVSDGYSVSRSKTEDFLLTLESATSSQTSVYFCAISEKLAGAYEQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG*
黒色腫患者MA-MEL-86から、4つの異なったパーマネント腫瘍細胞株(MA-MEL-86A、-86B、-86C、-86F)が、個別のリンパ節転移から確立された。MA-MEL-86B及びMA-MEL-86Fの両方は、β2ミクログロブリン遺伝子における2対立遺伝子の変異によってそれらの細胞表面でHLAを発現しなかった。腫瘍細胞株MA-MEL-86Cは1つのHLAハプロタイプを失くしていた。対照的に、MA-MEL-86AラインはHLA I対立遺伝子をすべて発現したが、メラノソームの異分化抗原の非発現を、4つの腫瘍細胞株のうちの唯一のものとして示した(図1)
CSF2RAの同定
真核生物の発現ベクターpcDNA3.1に構築されたメラノーマ細胞株MEL-86AのcDNAライブラリーは、MLTC1A.1の応答者リンパ細胞で選別された。最初の工程で、100cDNAクローンから成るcDNAプールが、293T細胞へ患者のHLA I対立遺伝子で共トランスフェクトされた。トランスフェクタントはT細胞によって認識に関してテストされた。プールのうちの1つは反応性あることが見出された。続いて、ステップ毎にcDNAクローニングが行なわれた。このように、CSF2RAは、MLTC 1A.1の標的であると同定された(図3)。その後、HLA I陰性のメラノーマ細胞バリアントを検出することができ、CSF2RAに対して向けられたT細胞クローンが単離された。特に、CSF2RAに対するT細胞の交差反応性を見る場合、一つは抗原の特殊性を認識する。CSF2RA反応性T細胞は、利用可能なメラノーマ細胞ラインの60%を検出でき、また膵臓、結腸、肺、卵巣、骨髄性白血病と同様に胆嚢起源の腫瘍細胞株も検出することができた(表2)。
表2: CSF2RA反応性CTL 1A.1/506によって認識された同種異型の腫瘍株。
TRP-2の同定
パネル・テストで、既知の黒色腫に関連する抗原をコードする40cDNAクローンが、293T細胞へトランスフェクトされた。つづいて、トランスフェクタントは、MLTC 1C及び2Cの反応者リンパ細胞によって認識に関しテストされた。それら由来のMLTC及びCTLクローンの両方が、HLA I陰性の腫瘍細胞株MA-MEL-86B及び86Fを認識でき、またメラノソームの分化抗原TRP-2を標的化することを見出した。それらは、正常なメラノサイトと同様に研究所で利用可能なTRP-2-発現メラノーマ細胞株、及びTRP-2でトランスフェクション後、マウス、ハムスター及び猿起源の非メラノサイト細胞とも交差反応した(図8を参照)。HLA I分子の共トランスフェクションは必要でなかった。HLA非依存的TRP-2反応性T細胞は、トランスフェクションの後に、マウスメラノーマ細胞及びマウスTRP-2をも認識した。
a- 及びb- T細胞受容体鎖-(TCR)cDNAsが、CSF2RA特異CTL 1A.3/46から単離され、レトロウイルス・ベクターへ2シストロン性の構成物としてクローン化された(図13A)。続いて、ヒト定常領域が、ヒトT細胞における異所的発現後に、内生的TCR鎖での形質導入されてのペアリングを最小にするために、マウスTCR定常領域によって置き換えられた(キメラ化又はマウス化)。
Claims (17)
- 腫瘍疾患の予防又は治療における使用のための医薬組成物であって、
ここで該腫瘍が、機能的な主要組織適合抗原(MHC)クラスI複合体を欠いており、かつ、MHCクラスI提示複合体の変更によって免疫回避を示し、
該医薬組成物が、GM-CSF受容体α鎖(CSF2RA)(配列番号1)又はチロシナーゼ関連タンパク質2(TRP-2)(配列番号2)のアミノ酸配列由来の少なくとも8つの連続するアミノ酸を含むタンパク質、タンパク質断片又はポリペプチドであって、前記タンパク質、タンパク質断片又はポリペプチドはT細胞反応を引き起こすことができ及び/又は同系統のT細胞受容体を結合することができる、前記タンパク質、タンパク質断片又はポリペプチドを含む、医薬組成物。 - MHC-非依存性T細胞反応、又は、MHCクラスI非依存性T細胞反応、又は、MHCクラスI及びII非依存性T細胞反応をもたらすことができる、請求項1に記載の医薬組成物。
- MHCクラスI非依存性T細胞又はMHCクラスI及びII非依存性T細胞によって発現された同系統のT細胞受容体を結合することができる、請求項1又は2に記載の医薬組成物。
- 増殖性の疾患、腫瘍疾患又は悪性腫瘍の予防、診断又は治療における使用のための、請求項3に記載の医薬組成物。
- 前記腫瘍が、CSF2RA(配列番号1)及び/又はTRP-2(配列番号2)、又はCSF2RA若しくはTRP-2に少なくとも95%の配列同一性を持っているタンパク質を発現する、請求項4に記載の医薬組成物。
- 前記腫瘍が、皮膚の腫瘍、又は黒色腫若しくは膠芽腫である、請求項4又は5に記載の医薬組成物。
- 前記腫瘍が、CSF2RAを発現する、請求項4又は5に記載の医薬組成物。
- 腫瘍疾患の予防又は治療における使用のための医薬組成物であって、
ここで該腫瘍が、機能的なMHCクラスI複合体を欠いており、かつ、MHCクラスI提示複合体の変更によって免疫回避を示し、
該医薬組成物が、請求項1〜7のいずれか一に記載のタンパク質、タンパク質断片又はポリペプチドをコードする単離核酸分子を含む、医薬組成物。 - 腫瘍疾患の予防又は治療における使用のための医薬組成物であって、
ここで該腫瘍が、機能的なMHCクラスI複合体を欠いており、かつ、MHCクラスI提示複合体の変更によって免疫回避を示し、
該医薬組成物が、請求項8に記載の核酸分子を含むベクターを含む、医薬組成物。 - 腫瘍疾患の予防又は治療における使用のための医薬組成物であって、
ここで該腫瘍が、機能的なMHCクラスI複合体を欠いており、かつ、MHCクラスI提示複合体の変更によって免疫回避を示し、
該医薬組成物が、請求項8に記載の核酸分子又は請求項9に記載のベクターを含む細胞を含む、医薬組成物。 - 配列番号9〜14の全て、又は配列番号21〜26の全て、又は配列番号15〜20の全てを含む、T細胞受容体α鎖又はその結合性断片、及びT細胞受容体β鎖又はその結合性断片である結合剤であって、
ここで該T細胞受容体がMHCクラスI複合体から非依存的にCSF2RA又はTRP-2を認識し、及び
ここで配列番号9〜11はそれぞれCTL 1A.1/506のα鎖配列のCDR1〜3であり、配列番号12〜14はそれぞれCTL 1A.1/506のβ鎖配列のCDR1〜3であり、配列番号15〜17はそれぞれCTL 2C/417のα鎖配列のCDR1〜3であり、配列番号18〜20はそれぞれCTL 2C/417のβ鎖配列のCDR1〜3であり、配列番号21〜23はそれぞれCTL 1A3/46のα鎖配列のCDR1〜3であり、及び配列番号24〜26はそれぞれCTL 1A3/46のβ鎖配列のCDR1〜3である、結合剤。 - 配列番号3及び配列番号4の全ての配列、又は配列番号7及び配列番号8の全ての配列、又は配列番号5及び配列番号6の全ての配列を含む、請求項11に記載の結合剤であって、
ここで配列番号3がCTL 1A.1/506のTCRα鎖配列であり、配列番号4がCTL 1A.1/506のTCRβ鎖配列であり、配列番号5がCTL 2C/417のTCRα鎖配列であり、配列番号6がCTL 2C/417のTCRβ鎖配列であり、配列番号7がCTL 1A3/46のTCRα鎖配列であり、及び配列番号8がCTL 1A3/46のTCRβ鎖配列である、結合剤。 - マウス定常領域及びヒト可変領域を含むキメラT細胞受容体である請求項11又は12に記載の結合剤。
- 請求項11〜13のいずれか一に記載の結合剤を含む、単離T細胞。
- MHC非依存的T細胞を生成する生体外の方法であって、
(i)請求項1〜7のいずれか一に記載のタンパク質、タンパク質断片又はポリペプチド、あるいは、全長CSF2RA又はTRP-2を発現する第一の細胞を提供すること、
(ii)末梢血単核細胞(PBMC)の集合体を、前記第一の細胞と接触させ、それによって前記PBMCを刺激すること、及び
(iii)前記第一の細胞におけるMHCの発現から非依存的に、該第一の細胞を認識する能力をもつT細胞を、刺激されたPBMC集合体から選択すること
を含む、生体外の方法。 - 請求項15に記載の方法であって、(iii)において、前記第一の細胞におけるMHCの発現から非依存的に、該第一の細胞を認識するT細胞の能力が、該第一の細胞に対する前記T細胞の反応性をテストすることで決定され、ここで、
(a)前記第一の細胞は、MHCクラスI又はMHCクラスI及びIIを欠いており、
(b)前記T細胞は、MHCクラスI又はIIに対する抗体の存在下で、該第一の細胞に対してその反応性がテストされ、及び/又は
(c)前記T細胞は、前記タンパク質、タンパク質断片又はポリペプチド、あるいは、全長CSF2RA又はTRP-2をコードするDNA若しくはRNAで形質転換された異種の細胞に対してその反応性についてテストされ;
ここで、上記(a),(b)及び/又は(c)において、反応性を示すT細胞が、該第一の細胞におけるMHCの発現から非依存的に、該第一の細胞を認識する能力をもつT細胞である、方法。 - 請求項11〜13のいずれか一に記載の結合剤、又は請求項14に記載の単離T細胞、又はこれらのワクチン形態を含む医薬組成物。
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PL2932264T3 (pl) | 2019-09-30 |
EP2932264A1 (en) | 2015-10-21 |
TR201905447T4 (tr) | 2019-05-21 |
CA3108192A1 (en) | 2014-06-19 |
US9861688B2 (en) | 2018-01-09 |
EP2932264B1 (en) | 2019-01-30 |
PT2932264T (pt) | 2019-05-21 |
AU2013357239A1 (en) | 2015-06-18 |
AU2019236675A1 (en) | 2019-10-17 |
JP2016501268A (ja) | 2016-01-18 |
DK2932264T3 (da) | 2019-05-06 |
CA2894966C (en) | 2021-03-30 |
HUE042967T2 (hu) | 2019-07-29 |
AU2019236675B2 (en) | 2022-02-24 |
WO2014091034A1 (en) | 2014-06-19 |
CA2894966A1 (en) | 2014-06-19 |
ES2721159T3 (es) | 2019-07-29 |
US10987413B2 (en) | 2021-04-27 |
US20180099033A1 (en) | 2018-04-12 |
US20150313978A1 (en) | 2015-11-05 |
SI2932264T1 (sl) | 2019-05-31 |
AU2013357239B2 (en) | 2019-10-17 |
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