JP6285368B2 - Cd4+t細胞応答を向上するための修飾されたエピトープ - Google Patents
Cd4+t細胞応答を向上するための修飾されたエピトープ Download PDFInfo
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Description
本発明は、T細胞エピトープを含む免疫原性ペプチドに関する。上記ペプチドは、CD4+T細胞応答が得られ得るように修飾される。当該CD4+T細胞応答は、上記修飾を含まない同じペプチドで得られたCD4+T細胞応答よりもはるかに強い。特にこの修飾は、ペプチドのMHC結合部位に隣接するがその外側の位置でのシステインの付加、システインの挿入または残基のシステインへの突然変異である。さらに、移植片拒絶の防止もしくは抑制または腫瘍細胞の根絶において、感染症、アレルギー性疾患、および自己免疫性疾患のような病気の治療、抑制または防止におけるこのような修飾されたペプチドの使用が開示される。
病原体に対するワクチン接種の目的は、可能な限り強い特定の免疫応答を誘発することである。このようなワクチン接種は、弱い内因性の免疫原性を有する抗原を利用する。このような弱い免疫原性の理由は、ヒト集団における組織適合性複合体の大きな多様性に関係付けられる。このような複合体は、CD8+T細胞への提示のためのクラスIまたはCD4+T細胞への提示のためのクラスIIのいずれも、抗原提示細胞と呼ばれる特殊化される細胞の表面にてT細胞に抗原を提示する。T細胞が活性化される強さは、抗原処理の後に得られたペプチドが装填された抗原提示細胞と特定のT細胞との間に形成されるシナプスの強さおよび持続期間に依存する。
本発明のある局面は分離された免疫原性ペプチドに関し、当該ペプチドは、
a)MHCタンパク質の間隙に結合するT細胞エピトープと、
b)エピトープのn末端および/またはc末端側に存在し、システイン残基を含む1個と6個との間のアミノ酸の配列とを含み、モチーフCxx[CST]または[CST]xxCを有する配列が、発生すれば、上記エピトープに隣接するかまたは最大7個のアミノ酸によって上記エピトープから離れている場合、上記システインは、当該モチーフを有する配列に発生せず、
上記分離された免疫原性ペプチドは人工ペプチドであり、部分a)およびb)において規定される配列は、上記抗原性タンパク質の野生型配列に発生する配列と異なる。
特定の実施形態では、上記ペプチドは、9個と100個との間のアミノ酸の長さ、9個と50個との間のアミノ酸の長さ、または9個と20個との間のアミノ酸の長さを有する。
上記T細胞エピトープが、MHCに結合するアミノ酸残基以外でそれに隣接するアミノ酸残基を含んでいる場合、上記隣接するアミノ酸残基が、上記T細胞エピトープのMHC結合領域に隣接する6個までのアミノ酸内に自然にシステインアミノ酸を含んでおらず、モノシステインまたはジシステインの酸化還元モチーフを含んでおらず、
上記システインアミノ酸は、T細胞エピトープのMHC結合領域の外側の位置に存在しており、上記システインアミノ酸は、上記位置にてT細胞エピトープに添加または挿入され、または上記システインアミノ酸は、T細胞エピトープの上記位置での非システインアミノ酸をシステインに突然変異させることにより得られる。
(a)上記抗原性タンパク質のT細胞エピトープからなるペプチド配列を提供するステップと、
(b)システイン残基を含む(a)配列のペプチド配列にリンクするステップとを含み、上記システイン残基は最大5個のアミノ酸によってエピトープ配列から離れており、モチーフ[CST]−xx−CまたはC−xx−[CST]を有する配列が、発生すれば、上記MHC結合領域に隣接するかまたは最大7個のアミノ酸によって上記MHC結合領域から離れている場合、上記システインは、当該モチーフを有する配列にシステインとして発生せず、さらに、
(c)ステップa)およびb)に規定されるような配列を含むペプチドを合成するステップを含む。
定義
本願明細書において使用される場合の「ペプチド」という用語は、ペプチド結合によって接続される2個と200個との間のアミノ酸のアミノ酸配列を含む分子を指すが、特定の実施形態では、(たとえば結合有機化合物のような)非アミノ酸構造を含み得る。本発明に従ったペプチドは、従来の20個のアミノ酸またはその修飾されたバージョンのいずれかを含み得るか、または化学ペプチド合成または化学もしくは酵素修飾によって組込まれた非自然発生のアミノ酸を含み得る。
上述したように、T細胞抗原に4−アミノ酸酸化還元活性ペプチドタグ(「CXXC」または「CXX[S/T]」または「[S/T]XXC」モチーフ)を(上記タグが抗原のMHC結合部位の外側または隣接する状態で)添加することにより、活性化の際に、CD4+T細胞が細胞溶解性のCD4+T細胞に変換される。この変換は通常自然に生じず、自然な免疫応答中に誘導された細胞溶解性細胞は、細胞溶解性のCD8+T細胞に拘束される。上記の系を調査して本発明に結びつくさらに別の研究において、酸化還元活性タグにおけるシステイン残基の少なくとも1つを非システイン残基に(しかしながら非システイン残基としてセリンまたはトレオニンを除外して)変換することによって、T細胞抗原に加えられたペプチドタグの酸化還元反応の活性が消失されると、その後、CD4+T細胞が活性化され得るということが分かった。しかしながら驚くべきことに、この活性化は、システイン残基がペプチドタグ中に全くなかった場合よりもはるかに強かった。MHC結合領域または上記T細胞抗原の部位に隣接する単一のシステイン残基のT細胞抗原における存在が、上記のより強いCD4+T細胞活性化を誘発するのに十分であったことがさらに分かった。
上記T細胞エピトープが、MHCに結合するアミノ酸残基に隣接する(またはT細胞エピトープのMHC結合部位を構成するアミノ酸残基に隣接する)アミノ酸残基を含んでいる場合、上記隣接するアミノ酸残基は本来、当該T細胞エピトープのMHC結合領域に隣接(および接触)する6個までのアミノ酸内の位置にてシステインアミノ酸を含んでおらず、モノシステインもしくはジシステインの酸化還元または酸化還元活性モチーフを含んでおらず、
上記システインアミノ酸はT細胞エピトープのMHC結合領域の外側の位置にあり、当該システインアミノ酸は、上記位置にてT細胞エピトープに添加または挿入されるか、またはT細胞エピトープの上記位置にある非システインアミノ酸をシステインに突然変異させることで得られる。
・アレルギー性疾患に対するワクチン接種
T細胞エピトープの選択に使用され得るアレルゲンは典型的に、以下のものからなる群から選択されるアレルゲンである。すなわち、当該アレルゲンは、
−ピーナッツ(Ara h1)、たとえばタラのような魚(パラアルブミン)、卵白(オバルブミン)、たとえばエビのような甲殻類(トロポミオシン)、たとえば牛乳のようなミルク(ベータラクトグロブリン)、小麦(グルテン)、穀物、酒さ科(リンゴ、プラム、イチゴ)の果物、ユリ科、十字花科、ナス科およびセリ科の野菜、クルミ、胡麻、ピーナッツ、大豆および他のマメ科アレルゲン、香辛料、メロン、アボカド、マンゴー、イチジク、バナナなどに存在する食物アレルゲンと、
−ヒョウヒダニ(Dermatophagoides spp)またはヤケヒョウヒダニ(D. pteronyssinus)、コナヒョウヒダニ(D. farinae)およびササラダニ(D. microceras)、シワダニ(Euroglyphus maynei)またはタマニクダニ(Blomia sp.)から得られたイエダニアレルゲンと、
−ゴキブリ(Bla g2)または膜し類に存在する昆虫からのアレルゲンと、
−花粉、特に木、草および雑草の花粉からのアレルゲンと、
−動物、特に猫(Fel d1)、犬、馬およびげっ歯類(mus m1)からのアレルゲンと、
−菌類、特にアスペルギルス(aspf1)、アルタネリア(Alt A6)またはクラドスポリウム(cla h3)からのアレルゲンと、
−ラテックス、アミラーゼなどのような製品に存在する職業性アレルゲンと、からなる群から選択される。
・細胞内および細胞外の病原に対するワクチン接種
−細胞内の病原体は、細胞内の生活環を有するウイルス、バクテリア、マイコバクテリアまたは寄生生物に由来する任意の抗原からなる群から選択される。ウイルスは、ssDNAウイルス、dsDNAウイルスおよびRNAウイルスを含み、例として、ヘルペスウイルス科、フラビウイルス科およびピコルナウイルス科、インフルエンザ、麻疹および免疫不全ウイルスがある。バクテリアおよびマイコバクテリアは、結核菌、ヒトまたは動物に対して病原性の他のマイコバクテリア、エルジニア、ブルセラ、クラミジア、マイコプラズマ、リケッチア、サルモネラおよびシゲラを含む。寄生生物は、プラズモディウム、リーシュマニア、トリパノゾーマ、トキソプラズマゴンディ、リステリア、ヒストプラズマなどを含む。
−細胞外の病原は、主として細胞外の生活環を有するウイルス、バクテリアおよび寄生生物からなる群から選択され、本発明において使用される抗原はそこから由来し得る。
・腫瘍に対するワクチン接種
本発明の生成物によってターゲットとされ得る例示的な腫瘍と、本発明において使用され得る例示的な関連する抗原とは、以下のものからなる群から選択される。すなわち、当該群は、
−いくつかのメラノーマにおいて同定されるMAGEのような腫瘍遺伝子と、
−腎臓または副甲状腺のような軟組織癌腫上に発現されるとともに多発性骨髄腫において発現されるサイクリンD1のような腫瘍原遺伝子と、
−いくつかの癌腫およびいくつかのホジキンタイプのリンパ腫におけるエプスタインバーウイルスからのもののようなウイルス由来のタンパク質と、
−サバイビンまたはbcl2のような抗アポトーシス因子である生存因子と、
−濾胞性リンパ腫もしくは多発性骨髄腫におけるB細胞受容体またはT細胞悪性腫瘍におけるT細胞受容体決定子に由来するイディオタイプ決定子のようなクローン形質の決定子と、からなる。
・上述したようなアレルギー性疾患
・自己免疫疾患
自己免疫性疾患は、次のものからなる群から選択される。当該群は、
(a)アジソン病、溶血性または悪性貧血、グッドパスチャー症候群、グレーヴス病、特発性血小板減少性紫斑病、インスリン依存性糖尿病、若年性糖尿病、ブドウ膜炎、クローン病、潰瘍性大腸炎、天疱瘡、アトピー性皮膚炎、自己免疫性肝炎、原発性胆汁性肝硬変症、自己免疫性肺炎、自己免疫性心臓炎、重症筋無力症、糸球体腎炎および自発不妊といった臓器特異的疾患と、
(b)紅斑性狼瘡、乾癬、脈管炎、多発性筋炎、強皮症、多発性硬化症、強直性脊椎炎、慢性関節リウマチおよびシェーグレン症候群のような全身性疾患と、からなる。したがって、自己免疫障害は自身の細胞または組織に関し、特定の哺乳類生物体の自身の構成部分である抗原(たとえばタンパク質)を意味する「自己抗原」への反応を含む。このメカニズムでは、自己抗原に対する免疫反応を導入するB細胞および/またはT細胞によって上記自己抗原が認識される。
本発明において用いられる同種抗原は、以下のものに由来する群から選択される。すなわち当該群は、
−クラスIまたはクラスIIの主要組織適合性複合体と、
−副組織適合性複合体と、
−組織特異性抗原と、
に由来する。
・同種因子への免疫反応
本発明で使用される同種因子は次のものからなる群から選択される。すなわち当該群は、
−第III因子、第IX因子およびスタフィロキナーゼを含む、凝固欠陥または繊維素溶解欠陥のための置換療法と、
−成長ホルモンまたはインシュリンのようなホルモンと、
−サイトカイン、ならびにインターフェロンα、インターフェロンγ、GM−CSFおよびG−CSFのような成長因子と、
−アレルギー性疾患における抗IgE抗体、移植片拒絶における抗CD3および抗CD4抗体、さまざまな自己免疫性疾患、非ホジキンリンパ腫における抗CD20抗体、ならびに腎不全におけるエリトロポイエチンを含む免疫応答の調整のための抗体と、からなる。
・末梢血球を提供するステップと、
・これらの血球(cells)を本発明に従った免疫原性ペプチドに接触させるステップとを含み、T細胞抗原が感染因子に由来しており、さらに
・IL−2が存在する状態でこれらの血球(cells)を展開するステップを含む。
・本発明に従った免疫原性ペプチドを提供するステップと、
・対象に免疫原性ペプチドを投与するステップとを含み、T細胞エピトープは感染因子に由来しており、さらに
・増殖性が増加したCD4+エフェクター細胞の集団を得るステップを含む。
・末梢血球を提供するステップと、
・これらの血球(cells)を本発明に従った免疫原性ペプチドに接触させるステップとを含み、T細胞エピトープは自己抗原または同種抗原に由来しており、さらに
・IL−2が存在する状態でこれらの血球(cells)を展開するステップを含む。
・本発明に従った免疫原性ペプチドを提供するステップを含み、T細胞エピトープは、自己抗原または同種抗原に由来しており、さらに
・対象に免疫原性ペプチドを投与するステップと、
・抑制性が増加したCD4+調節性細胞の集団を得るステップとを含む。
・末梢血球を提供するステップと、
・これらの血球(cells)を本発明に従った免疫原性ペプチドに接触させるステップとを含み、T細胞エピトープは腫瘍に由来した抗原に由来しており、さらに、
・IL−2が存在する状態でこれらの血球(cells)を展開するステップを含む。
・本発明に従った免疫原性ペプチドを提供するステップを含み、T細胞エピトープは腫瘍に由来した抗原に由来しており、さらに
・対象に免疫原性ペプチドを投与するステップと、
・増殖性が増加したエフェクターCD4+T細胞の集団を得るステップとを含む。
結核菌は毎年、何千もの死の原因である。唯一の利用可能なワクチン接種であるカルメット・ゲラン・マイコバクテリウム・ボビスに基づくワクチン(Calmette-Guerin Mycobacterium bovis-based vaccine;BCG)は、効率的ではない。さらに、いくつかのマイコバクテリウム株は、従来の化学療法に対する耐性を示している。抗原特異性CD4+細胞は結核において発生することが公知であり(Winslow et al. (2003) J. Immunol.170: 2046-2052)、これは予防可能である(Khader et al. (2007) Nature Immunol. 8:369-377)。
インフルエンザウイルスは、他のウイルスと同様に、絶対的な細胞内病原である。その高い程度の感染性と急速に突然変異する能力と関連付けられる理由により、年ごとに獲得免疫が作用しなくなり毎年、何百万もの人々に影響することは周知である。当該ウイルスは、非常に有意な罹患率および死亡率とをもたらす。現在のワクチン接種ストラテジは、ヘマグルチニンおよびノイラミニダーゼのような、高いタイターの特異抗体を誘導する表面タンパク質を利用するが、感染細胞を除去する細胞溶解性のT細胞の誘発についてはかなり非能率的である。
(本例では同種因子と呼ばれる)治療タンパク質の投与は、医学における慣例である。一例は、血友病A患者における凝固経路の第VIII因子の投与である。多くの場合、このような投与は、治療タンパク質の活性を認識および中和する抗体の誘発が発生するという問題がある。血友病Aでは、第VIII因子の注入によって治療される患者の約30%には、第VIII因子の凝血促進活性を抑制する抗体が発生する。したがって、望ましくない抗同種因子抗体が具体的に除去され得る方法を有することは有利である。
病原性CD4+T細胞は、アレルギーおよび自己免疫性疾患を含む多くの病理の重要な要素として考えられる。このような細胞はB細胞が抗体を生成するのを支援するようサイトカインを生成し、完全な活性化およびエフェクター機能の獲得のためにCD8+T細胞39に支援を提供する。したがって、具体的に病原性のCD4+T細胞を除去することが実現可能であろう方法が非常に望ましい。
実施例2において報告された実験は、隣接残基において単一のシステインを含むALKのクラスII拘束エピトープを包含するペプチドでのマウスの直接的な免疫処置により、腫瘍成長の有意な遅延および腫瘍サイズの減少が得られたということを示す。SEQ ID NO:5のペプチドは、クラスII拘束CD4+T細胞に対して活性化特性の増加を誘発した。このような前免疫のインヴィヴォ効果は、腫瘍細胞に対する細胞溶解性によるCD8+T細胞の誘発に帰着された。CD8+T細胞は、完全なエフェクター特性を得るようCD4+T細胞によって提供される補助を必要とするということは当技術において周知である。
Claims (6)
- 活性化された非細胞溶解性CD4+T細胞の集団を調製するためのインヴィトロの方法であって、9個と50個との間のアミノ酸の単離された免疫原性ペプチドを末梢血球の集団に投与するステップを含み、前記ペプチドは、
a)抗原性タンパク質の8個または9個のアミノ酸のMHCクラスII T細胞エピトープと、
b)a)の前記8個または9個のアミノ酸エピトープ配列のn末端および/またはc末端側に存在し、還元システイン残基を含む1個と6個との間のアミノ酸の配列とを含み、前記1個と6個との間のアミノ酸の配列は、C−xx−[CST]または[CST]−xx−C酸化還元モチーフ配列を含まない、方法。 - 部分b)に規定される前記配列は、ただ1つのシステインを含む、請求項1に記載の方法。
- 前記免疫原性ペプチドは、9個と20個との間のアミノ酸の長さを有する、請求項1または2に記載の方法。
- 前記エピトープ配列と前記システイン残基との間にアミノ酸なしで、前記システイン残基は、N末端またはC末端方向に8個または9個のアミノ酸の前記エピトープ配列に隣接して位置する、請求項1〜3のいずれか1項に記載の方法。
- 前記T細胞エピトープは感染因子のT細胞エピトープである、請求項1〜4のいずれか1項に記載の方法。
- 前記T細胞エピトープは、自己抗原、アレルゲン、同種因子、同種移植片の抗原または腫瘍関連抗原からなる群から選択される抗原のT細胞エピトープである、請求項1〜5のいずれか1項に記載の方法。
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Cited By (2)
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US10850981B2 (en) | 2017-04-25 | 2020-12-01 | Ica Trinova, Llc | Methods of producing a gas at a variable rate |
US11912568B2 (en) | 2018-03-14 | 2024-02-27 | Ica Trinova, Llc | Methods of producing a gas at a controlled rate |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10850981B2 (en) | 2017-04-25 | 2020-12-01 | Ica Trinova, Llc | Methods of producing a gas at a variable rate |
US11518676B2 (en) | 2017-04-25 | 2022-12-06 | Ica Trinova Llc | Methods of producing a gas at a variable rate |
US11912568B2 (en) | 2018-03-14 | 2024-02-27 | Ica Trinova, Llc | Methods of producing a gas at a controlled rate |
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RU2724994C2 (ru) | 2020-06-29 |
AU2013214700B2 (en) | 2017-09-28 |
KR20140128977A (ko) | 2014-11-06 |
EP3756675A1 (en) | 2020-12-30 |
GB201201511D0 (en) | 2012-03-14 |
JP2018076329A (ja) | 2018-05-17 |
EP2809332A1 (en) | 2014-12-10 |
HK1204283A1 (en) | 2015-11-13 |
US20210188913A1 (en) | 2021-06-24 |
KR102228843B1 (ko) | 2021-03-18 |
CN104220080A (zh) | 2014-12-17 |
ZA201405197B (en) | 2015-10-28 |
AU2013214700A1 (en) | 2014-07-24 |
JP6931598B2 (ja) | 2021-09-08 |
KR20200010557A (ko) | 2020-01-30 |
CA2863126A1 (en) | 2013-08-08 |
CN104220080B (zh) | 2018-10-12 |
RU2014135406A (ru) | 2016-03-27 |
BR112014017862A2 (pt) | 2017-06-27 |
JP2015506365A (ja) | 2015-03-02 |
WO2013113076A1 (en) | 2013-08-08 |
US20140370044A1 (en) | 2014-12-18 |
US10899795B2 (en) | 2021-01-26 |
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