JP2018528191A - 抗体を生成する新規な方法 - Google Patents
抗体を生成する新規な方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
Description
本出願は、2015年8月19日に出願された米国仮出願番号第62/207,022号に基づく優先権を主張しており、この仮出願はその全体が参考として本明細書中に援用される。
本出願はEFS−Webを介してASCIIフォーマットで提出された配列表を含有し、本明細書よって参考としてその全体が組み込まれる。前記ASCIIコピーは、2016年8月16日に作成され、Combined_SA_01_PCT_ST25_V2.txtと名付けられ、サイズは10,883,263バイトである。
抗体を作るための方法はおよそ100年以上の間存在し、当業者によりルーチン的に使用されている。例えば、Morrisonら、Science 229:1202(1985);Oiら、BioTechniques 4:214(1986);Cabillyら、米国特許第4,816,567号;Taniguchiら、EP171496;Morrisonら、EP 173494;Neubergerら、WO8601533;Robinsonら、WO8702671;Boulianneら、Nature 312:643(1984);Neubergerら、Nature 314:268(1985)を参照。抗体を産生するための改良された方法はこれらの初期の方法を拡張したもので、現在市販されている治療抗体の多くを産生するのに使用されてきた。例えば、ファージディスプレイおよびトランスジェニックマウス、すなわち、ヒト免疫グロブリン遺伝子を含有するマウスなどの技術は、完全ヒト抗体を産生するのに使用されてきた。しかし、ある特定の抗原は、最新の技法を使用している場合でも抗体を惹起するために研究者の能力を要求し続けている。
交差架橋を除去するまたは加えると抗原プロセシングを改善するのかまたは阻害するのかに関して一致した意見はない。したがって、タンパク質安定性を増加するまたは減少すると、抗体の広く多様なアレイを含む免疫応答が改善されるのかどうかに関しては当技術分野では明確ではない。
したがって、以前得られたものとは異なり、より広いレパートリーの抗体を提供できる抗体を産生する新しい改良された方法を開発する必要性が存在し続けている。
本要旨は、以下の詳細な説明においてさらに記載されている概念の選択を簡略化した形態で紹介するために提供されている。本要旨は、特許請求されている主題の重要な特色または本質的な特色を特定することを意図しておらず、特許請求されている主題の範囲を決定する補助として使用されることも意図していない。
概説
本明細書には、タンパク質の3−D立体構造を維持しつつ開始タンパク質の立体構造動力学を変化させることを通してタンパク質の「ペプチド原性潜在力(petidogenic potency)」を使用することにより抗体の産生を増強することを含む、免疫応答を生成する新規の方法を記載している。次いで、これらのペプチド原性タンパク質は、ワクチンとして使用して免疫応答を開始する、および/または抗体を産生するのに使用することができる。
定義
タンパク質の立体構造動力学を変化させる方法
ペプチド原性タンパク質は開始タンパク質と類似する立体構造を有する
抗体を産生するためのペプチド原性タンパク質の使用
ワクチン接種
ペプチド原性タンパク質をコードするポリヌクレオチドの動物への導入
製剤
ペプチド原性抗原の産生
ペプチド原性タンパク質を作成するために、開始タンパク質をそのコア残基で修飾(例えば、1つまたは複数の変異)してその立体構造動力学を変更することができる。複数の異なるペプチド原性タンパク質を設計および発現させて、動物(例えば、ウサギ)を免疫して、ポリクローナル抗体応答を生成することができる。あるいは、ペプチド原性タンパク質をコードするポリヌクレオチドを、直接的に動物に投与してin vivoでペプチド原性タンパク質を作成することができる。応答は、以下の2つの相補的かつ相互に補強される方法によってモニターされる(Georgiouら、2014年;図2):
(a)免疫した動物の血液、脾臓、および骨髄からB細胞を精製すること、重鎖および軽鎖の可変領域コードするmRNAからcDNAを単離すること、ならびにディープDNAシークエンシングを介してこのレパートリーを分析すること;ならびに
(b)固体の支持体に付着させた抗原を使用して免疫血清からポリクローナルFabまたは(Fab’)2断片を免疫親和性精製すること、溶出させたFab/(Fab’)2をプロテアーゼで消化すること、および得られたペプチドをLC/MS/MSを使用してシークエンシングすること。
(実施例2)
ウシ膵臓トリプシン阻害剤のペプチド原性タンパク質。
(実施例3)
本発明の好ましい標的。
立体構造動力学における変更を測定するアッセイ
(実施例5)
ペプチド原性を測定するアッセイ
一実施形態では、タンパク質分解に向けたペプチド原性タンパク質の挙動の検査は、それらを、タンパク質抗原プロセシングに決定的に重要であることが公知である酵素の1つであるカテプシンLの作用に供することによって測定される(Hsieh,C. S.、deRoos,P.、Honey,K.、Beers,C.、およびRudensky,A. Y.(2002年)J. Immunol. 168巻、2618〜2625頁)。タンパク質分解に対するペプチド原性タンパク質の感受性は、リソソームのカテプシンLを使用してアセスメントされる。ペプチド原性タンパク質(0.5ug/ul)は、様々な量(例えば、1.5m単位)の酵素を50mM酢酸ナトリウム緩衝液pH4.5中に含むもので、様々な時間の長さで37℃でインキュベートされる。消化は0.1% TFAを使用して停止され、タンパク質分解はC18逆相カラム(Vydac、Hesperia、CA)における逆相HPLCによってモニターされる。タンパク質分解性産物の溶出は、0.1% TFAを含有するアセトニトリル/水の直線勾配で実施される。
別の実施形態では、タンパク質分解に向けたペプチド原性タンパク質の挙動の検査は、それらを、アルファ−キモトリプシンおよびカルボキシペプチダーゼYの作用に供することによって測定される。アルファ−キモトリプシンは、芳香族アミノ酸のカルボキシル末端で切断するエンドペプチダーゼである;カルボキシペプチダーゼYは、カルボキシル末端から連続的にアミノ酸を除去するエキソペプチダーゼである。これらの酵素でのタンパク分解性消化は、不安定な立体構造に対して特異的であり、それ故、ペプチド原性タンパク質の立体構造安定性が、タンパク分解性消化に対するそれらの耐性/感受性を決定する。0.5mlの20mM HEPES緩衝食塩水pH7.5中の1mg/mlでのペプチド原性タンパク質が、100ugのウシ膵臓からのアルファ−キモトリプシンおよび酵母からのカルボキシペプチダーゼYで37℃でインキュベートされる。各インキュベーションは様々な時点で終了され、消化された試料は−20℃で分析するまで貯蔵される。試料は、15%アクリルアミドゲルに通す還元条件下でのドデシル硫酸ナトリウムポリアクリルアミドゲル電気泳動(SDS−PAGE)によって分析され、次に可視化のためクーマシーブリリアントブルーで染色される。
別の実施形態では、タンパク質分解に向けたペプチド原性タンパク質の挙動の検査は、それらを、骨髄由来樹状細胞のリソソーム抽出物の作用に供することによって測定される。ペプチド原性タンパク質は、骨髄由来樹状細胞からの粗製リソソーム抽出物からの等量のタンパク質の存在下で様々な濃度でインキュベートされる。混合物は、0.1Mクエン酸ナトリウム緩衝液、0.5% TritonX−100、および2mMジチオスレイトール中pH4.5でインキュベートされる。各インキュベーションは様々な時点で終了され、消化された試料は−20℃で分析するまで貯蔵される。試料は、SDS−PAGEによって分析される。実験は、水酸化アルミニウムなどのアジュバントにおけるペプチド原性タンパク質の前吸着がある場合および無い場合で反復される。骨髄由来樹状細胞は、顆粒球マクロファージコロニー刺激因子中で培養される骨髄から抗CD11cマイクロビーズを使用ことで精製される。例えば、Delamarreらの図4を参照されたい。
(d)骨髄由来樹状細胞によるインターナリゼーション後のタンパク質分解
(実施例6)
抗体産生およびシークエンシング
(実施例7)
ペプチド原性タンパク質の混合物を使用する免疫
(実施例8)
ペプチド原性タンパク質の混合物を使用する免疫の別の例
(実施例9)
ペプチド原性タンパク質の混合物をコードする配列を使用する免疫
(実施例10)
ペプチド原性タンパク質をコードするmRNAを使用する免疫
(実施例11)
ファージディスプレイを使用するペプチド原性タンパク質に対する親和性成熟抗体
(実施例12)
抗体の特徴付けおよび交差反応性を測定するため使用されるアッセイ
(実施例13)
ワクチン接種
[引用文献]
Claims (31)
- 免疫応答を生成する方法であって、
a.開始タンパク質由来のペプチド原性タンパク質の混合物を設計するステップであって、前記ペプチド原性タンパク質が前記開始タンパク質と比べて変化した立体構造動力学を有し、前記ペプチド原性タンパク質が立体構造において前記開始ペプチドに類似している、ステップと
b.動物にペプチド原性タンパク質の前記混合物を導入するステップと、
c.免疫応答を生成するステップと
を含む、方法。 - 前記立体構造動力学を、
a.前記開始タンパク質の3−D構造を調べ、前記開始タンパク質の非表面アミノ酸残基を同定し、前記開始タンパク質中の少なくとも1つの非表面アミノ酸残基を置き換えて前記ペプチド原性タンパク質を作成すること;または
b.前記開始タンパク質の3−D構造のモデルを調べ、前記開始タンパク質の非表面アミノ酸残基を同定し、前記開始タンパク質中の少なくとも1つの非表面アミノ酸残基を置き換えて前記ペプチド原性タンパク質を作成すること;または
c.異なる種由来の前記開始タンパク質にオルソロガスなタンパク質にわたって保存されたアミノ酸相同性のパターンを比較して前記開始タンパク質の非表面アミノ酸残基を同定し、前記開始タンパク質中の少なくとも1つの非表面アミノ酸残基を置き換えて前記ペプチド原性タンパク質を作成すること;または
d.前記開始タンパク質の少なくとも1つの非表面アミノ酸残基を置き換えて、前記ペプチド原性タンパク質を作成すること;または
e.少なくとも1つの非表面アミノ酸残基をより小さなアミノ酸残基で置き換えること;または
f.少なくとも1つの非表面アミノ酸残基をアラニンもしくはグリシンで置き換えること;または
g.前記開始タンパク質中の少なくとも1つのジスルフィド結合を取り除くこと
により変化させる、請求項1に記載の方法。 - 前記開始タンパク質内で、少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、または20のアミノ酸を置き換える、請求項1または2のいずれかに記載の方法。
- 前記開始タンパク質の立体構造動力学を、
a.少なくとも1つのスレオニンをバリン、アラニン、グリシンもしくはセリンで;または
b.少なくとも1つのシステインをアラニン、バリン、グリシン、セリンもしくはスレオニンで;または
c.少なくとも1つのバリンをアラニン、グリシン、ロイシンもしくはイソロイシンで;または
d.少なくとも1つのロイシンをアラニン、バリン、グリシン、もしくはイソロイシンで;または
e.少なくとも1つのイソロイシンをアラニン、バリン、ロイシン、もしくはグリシンで;または
f.少なくとも1つのプロリンをメチオニン、アラニン、バリン、ロイシン、イソロイシン、もしくはグリシンで;または
g.少なくとも1つのメチオニンをアラニン、バリン、ロイシン、イソロイシンもしくはグリシンで;または
h.少なくとも1つのフェニルアラニンをチロシン、メチオニン、ヒスチジン、アラニン、バリン、ロイシン、イソロイシンもしくはグリシンで;または
i.少なくとも1つのチロシンをフェニルアラニン、メチオニン、ヒスチジン、アラニン、バリン、ロイシン、イソロイシンもしくはグリシンで;または
j.少なくとも1つのトリプトファンをチロシン、フェニルアラニン、メチオニン、ヒスチジン、アラニン、バリン、ロイシン、イソロイシンもしくはグリシンで;または
k.少なくとも1つのアスパラギン酸を、グルタミン酸、グルタミン、アスパラギン、グリシン、セリン、スレオニン、アラニン、バリン、ロイシン、もしくはイソロイシンで;または
l.少なくとも1つのアスパラギンをグリシン、セリン、スレオニン、アラニン、バリン、ロイシン、イソロイシン、グルタミン、グルタミン酸もしくはアスパラギン酸で;または
m.少なくとも1つのグルタミン酸をアスパラギン酸、アスパラギン、グルタミン、グリシン、セリン、スレオニン、アラニン、バリン、ロイシン、もしくはイソロイシンで;または
n.少なくとも1つのグルタミンを、グルタミン酸、アスパラギン酸、アスパラギン、グルタミン、グリシン、セリン、スレオニン、アラニン、バリン、ロイシン、もしくはイソロイシンで;または
o.少なくとも1つのリシンをアルギニン、ヒスチジン、グリシン、セリン、スレオニン、アラニン、バリン、メチオニン、ロイシン、もしくはイソロイシンで;または
p.少なくとも1つのアルギニンをリシン、ヒスチジン、グリシン、セリン、スレオニン、アラニン、バリン、メチオニン、ロイシン、もしくはイソロイシンで;または
q.少なくとも1つのヒスチジンをフェニルアラニン、チロシン、リシン、アルギニン、グリシン、セリン、スレオニン、アラニン、バリン、グルタミン、アスパラギン、ロイシン、メチオニンもしくはイソロイシンで;または
r.少なくとも1つのアラニンをグリシンまたはプロリンで;または
s.少なくとも1つのグリシンをアラニンもしくはプロリンで;または
t.少なくとも1つのセリンをアラニンもしくはグリシンで;または
u.少なくとも1つの残基を非天然アミノ酸で;または
v.上記の組み合わせのいずれか
で置き換えることによって変化させる、請求項1から3のいずれか一項に記載の方法。 - 前記ペプチド原性タンパク質の立体構造動力学の変化が:
a.前記開始タンパク質と比べた場合の融解温度の変化;または
b.安定化のギブズ自由エネルギーもしくはタンパク質分解感受性アッセイの変化;または
c.安定化のギブズ自由エネルギーの変化が、尿素もしくはグアニジニウム塩酸塩アンフォールディングなどの変性剤調節平衡アンフォールディングにより測定される、ギブズ自由エネルギーの変化
により測定される、請求項1から4のいずれか一項に記載の方法。 - 類似の立体構造が:
a.前記ペプチド原性タンパク質と前記開始タンパク質の両方に結合する交差反応抗体;または
b.交差反応性が、免疫沈降アッセイ、表面プラズモン共鳴、等温滴定熱量測定、斜入射反射差(OI−RD)、ウェスタンブロット、放射免疫アッセイ、ELISA(酵素結合免疫吸着アッセイ)、「サンドイッチ」免疫アッセイ、ゲル拡散沈降反応、免疫拡散アッセイ、凝集アッセイ、補体固定アッセイ、免疫放射定量アッセイ、蛍光免疫アッセイ、および/もしくはプロテインA免疫アッセイにより測定される、(a)の前記交差反応抗体;または
c.交差反応性が結合アッセイにより測定される、(a)の前記交差反応抗体;または
d.10−9M未満もしくはこれに等しい解離定数(KD)を有する、(a)の前記交差反応抗体;または
e.10−8M未満もしくはこれに等しい、10−7M未満もしくはこれに等しい、もしくは10−6M未満もしくはこれに等しい解離定数(KD)を有する、(a)の前記交差反応抗体;
により測定される、請求項1から5のいずれか一項に記載の方法。 - 前記開始タンパク質が:
a.ヒト免疫不全ウイルス(HIV)のエンベロープ糖タンパク質、HIV gp120、HIV gp41、HIV gp160、エボラ抗原、ウイルス抗原、細菌抗原、寄生虫抗原、アレルゲン、毒液、毒素、腫瘍関連抗原、膜貫通ドメインタンパク質、Gタンパク質共役受容体、イオンチャネル、C型肝炎ウイルス抗原、B型肝炎ウイルス抗原、MERS−CoV抗原、Zikaウイルス抗原、インフルエンザウイルス抗原、マラリア抗原;および/または
b.表2に収載されるマラリア抗原のうちのいずれか1つ;および/または
c.表5に収載される標的のうちのいずれか1つ;および/または
d.MAGE−A1、MAGE−A2、MAGE−A3、MAGE−A4、MAGE−A5、MAGE−A6、MAGE−A7、MAGE−A8、MAGE−A9、MAGE−A10、MAGE−A11、MAGE−A12、GAGE−I、GAGE−2、GAGE−3、GAGE−4、GAGE−5、GAGE−6、GAGE−7、GAGE−8、BAGE−I、RAGE−1、LB33/MUM−1、PRAME、NAG、MAGE−Xp2(MAGE−B2)、MAGE−Xp3(MAGE−B3)、MAGE−Xp4(MAGE−B4)、MAGE−C1/CT7、MAGE−C2、NY−ESO−I、LAGE−I、SSX−I、SSX−2(HOM−MEL−40)、SSX−3、SSX−4、SSX−5、SCP−IおよびXAGE、メラニン細胞分化抗原、p53、ras、CEA、MUC1、PMSA、PSA、チロシナーゼ、メランA、MART−1、gp100、gp75、アルファ−アクチニン−4、Bcr−Abl融合タンパク質、Casp−8、ベータ−カテニン、cdc27、cdk4、cdkn2a、coa−1、dek−can融合タンパク質、EF2、ETV6−AML1融合タンパク質、LDLR−フコシルトランスフェラーゼAS融合タンパク質、HLA−A2、HLA−A11、hsp70−2、KIAAO205、Mart2、Mum−2、および3、neo−PAP、ミオシンクラスI、OS−9、pml−RARアルファ融合タンパク質、PTPRK、K−ras、N−ras、トリオースリン酸イソメラーゼ、GnTV、Herv−K−mel、NA−88、SP17、およびTRP2−Int2、(MART−I)、E2A−PRL、H4−RET、IGH−IGK、MYL−RAR、エプスタインバーウイルス抗原、EBNA、ヒトパピローマウイルス(HPV)抗原E6およびE7、TSP−180、MAGE−4、MAGE−5、MAGE−6、p185erbB2、p180erbB−3、c−met、nm−23H1、PSA、TAG−72−4、CA 19−9、CA 72−4、CAM 17.1、NuMa、K−ras、アルファ−フェトタンパク質、13HCG、BCA225、BTAA、CA 125、CA 15−3(CA 27.29\BCAA)、CA 195、CA 242、CA−50、CAM43、CD68\KP1、CO−029、FGF−5、G250、Ga733(EpCAM)、HTgp−175、M344、MA−50、MG7−Ag、MOV18、NB\170K、NY−CO−1、RCAS1、SDCCAG16、TA−90(Mac−2結合タンパク質\シクロフィリンC関連タンパク質)、TAAL6、TAG72、TLP、TPS、チロシナーゼ関連タンパク質、TRP−1、TRP−2、またはサイトメガロウイルスリンタンパク質65(pp65)から選択される腫瘍関連抗原
から選択される、請求項1から8のいずれか一項に記載の方法。 - 前記ペプチド原性タンパク質が前記動物に直接投与される、請求項1から7のいずれか一項に記載の方法。
- 前記ペプチド原性タンパク質が:
a.同じ開始タンパク質;または
b.複数の開始タンパク質;または
c.複数の関連する開始タンパク質
由来である、請求項1から8のいずれか一項に記載の方法。 - a.前記ペプチド原性タンパク質をコードするポリヌクレオチドの混合物を得るステップと;
b.ポリヌクレオチドの前記混合物を動物内に導入するステップであって、前記ペプチド原性タンパク質が前記ポリヌクレオチドから発現される、ステップと
をさらに含む、請求項1から9のいずれか一項に記載の方法。 - 前記ポリヌクレオチドが:
a.in vitroで合成される;または
b.DNA;または
c.in vitroで転写された(IVT)mRNA;または
d.ポリ(A)テイルを含むIVT mRNA;または
e.5’キャップを含むIVT mRNA
である、請求項10に記載の方法。 - 前記ポリヌクレオチドが:
a.いかなるターゲティング構成成分とも会合していない;または
b.細胞もしくは臓器を標的に前記ポリヌクレオチドを向けることができるターゲティング構成成分と会合している;または
c.細胞もしくは臓器を標的に前記ポリヌクレオチドを向けることができるターゲティング構成成分と会合しており、前記ターゲティング構成成分がベクターである、
請求項10または11のいずれかに記載の方法。 - 請求項1から9のいずれか一項に記載のペプチド原性タンパク質または請求項10から12のいずれか一項に記載のポリヌクレオチドを含む動物。
- 前記動物が哺乳動物、ヒト、マウス、ウサギ、ラマ、またはウシである、請求項1から12のいずれか一項に記載の方法または請求項13に記載の動物。
- 前記動物が前記ポリヌクレオチドを注射されている、請求項10から12もしくは14のいずれか一項に記載の方法または請求項13に記載の動物。
- 前記ポリヌクレオチドが
a.前記動物の筋肉内に直接注射される;
b.前記動物内に複数回注射される、
請求項15に記載の方法。 - 前記免疫応答が抗体を産生する、請求項1から12または14から17のいずれか一項に記載の方法。
- 前記抗体を単離するステップをさらに含む、請求項17に記載の方法。
- 前記抗体が完全ヒト抗体、キメラ抗体、ヒト化抗体、モノクローナル抗体、および/またはポリクローナル抗体である、請求項18に記載の方法。
- 請求項17から19のいずれか一項に記載の方法により産生される抗体。
- 前記ポリクローナル抗体が、単一の単離された抗体種を得るためにさらに分画される、請求項19に記載の方法。
- 請求項21に記載の方法により産生される単一抗体種。
- 前記抗体が親和性成熟している、請求項17から19もしくは21のいずれか一項に記載の方法または請求項20で産生される抗体または請求項22で産生される単一抗体種。
- 前記親和性成熟が:
a.ファージディスプレイ、酵母ディスプレイ、もしくはリボソームディスプレイ;または
b.パニング技法
により起こる、請求項23に記載の方法または抗体。 - 請求項23または24のいずれかに記載の方法により産生される抗体。
- 請求項20、22、または25のいずれか一項に記載の抗体をコードするポリヌクレオチド。
- 異種プロモーターをさらに含む、請求項26に記載のポリヌクレオチド。
- ベクター配列をさらに含む請求項26または27のいずれかに記載のポリヌクレオチド。
- 請求項11から12または25から28のいずれか一項に記載のポリヌクレオチドを含む宿主細胞。
- ペプチド原性タンパク質の混合物をコードするポリヌクレオチドの混合物。
- 前記ポリヌクレオチドが:
a.同じ開始タンパク質由来のペプチド原性タンパク質の混合物をコードする;または
b.複数の開始タンパク質由来のペプチド原性タンパク質の混合物をコードする;または
c.複数の関連する開始タンパク質由来のペプチド原性タンパク質の混合物をコードする;または
d.in vitroで合成される;または
e.DNAである;または
f.in vitroで転写された(IVT)mRNAである;または
g.ポリ(A)テイルを含むIVT mRNAである;または
h.5’キャップを含むIVT mRNAである、
請求項30に記載のポリヌクレオチドの混合物。
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US20180244759A1 (en) | 2018-08-30 |
EP3337822A1 (en) | 2018-06-27 |
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