JP5807994B2 - アレルギー治療のための核酸 - Google Patents
アレルギー治療のための核酸 Download PDFInfo
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Description
本発明は、分子生物学及び医薬品の分野に関する。より詳細には、本発明は、DNAワクチンとして使用するための核酸、並びにこれを使用して、アレルギー応答に罹患している又はアレルギー応答の疑いのある患者を治療する方法に関する。
すなわち、本発明は、以下の(1)から(14)に関する。
(1) 単離又は精製核酸であって、順に、
シグナル配列をコードする配列、
細胞小器官内安定化ドメインをコードする配列、
アレルゲンドメインをコードする配列、
膜貫通ドメインをコードする配列、及び
エンドソーム/リソソーム標的ドメインをコードする配列、を含み、前記アレルゲンドメインは少なくとも1つのアレルゲンを含み、前記アレルゲンに関し天然に生じるシグナル配列を含まない、単離又は精製核酸。
(2) 前記細胞小器官内安定化ドメインが、リソソーム膜タンパク質(LAMP)をコードする配列を含む、前記(1)に記載の核酸。
(3) 前記細胞小器官内安定化ドメインが、LAMPポリペプチド、DC−LAMP、LAMP2、LAMP−3、LIMP II、又はENDOLYNをコードする配列を含む、前記(1)に記載の核酸。
(4) 前記アレルゲンドメインをコードする配列が、2つ以上のアレルゲンエピトープをコードする配列を含む、前記(1)に記載の核酸。
(5) 前記アレルゲンドメインをコードする配列が、2つ以上のアレルゲンをコードする配列を含む、前記(1)に記載の核酸。
(6) 前記アレルゲンが、2つ以上の異なる種に由来する、前記(5)に記載の核酸。
(7) 前記アレルゲンが、Cry J1、Cry J2、Cry J3、CJP−4、CJP−6、CJP−8、CPA63、Cha o 1、Jun a 1、Jun v 1、Cup a 1、Jun o 1、Cup s 1、Cha o 2、Jun a 2、Cup a 2、Jun a 3、Jun r 3、Cup s 3、Cup a 3、Ch4A、Ch4−1、PT−1、若しくはLTPアレルゲン、又は少なくとも1つのアレルゲン性エピトープを有するこれらの部分である、前記(1)に記載の核酸。
(8) 宿主において免疫応答を誘導するDNAワクチンである、前記(1)に記載の核酸。
(9) 前記アレルゲンドメインが、それぞれ同種に由来する2つ以上のアレルゲンをコードする配列を含む、前記(1)に記載の核酸。
(10) 前記アレルゲンドメインが、それぞれ異種に由来する2つ以上のアレルゲンをコードする配列を含む、前記(1)に記載の核酸。
(11) 対象においてアレルギー応答を低減、排除又は予防する方法であって、前記対象に、前記アレルゲン性エピトープに特異的なIgE応答の発生を低減又は排除するのに十分な量で、前記(1)に記載の前記DNAワクチンを投与することを含む、方法。
(12) 前記方法が、アレルギー応答を予防する、前記(11)に記載の方法。
(13) 前記方法が、少なくとも1つの臨床的なアレルギー症状を低減、排除又は予防する、前記(12)に記載の方法。
(14) 前記方法が、少なくとも1つの臨床的なアレルギー症状を予防する、前記(13)に記載の方法。
免疫化及び血清採取
6〜8週齢のBALB/c雌性マウスをHarlan Laboratories(Frederick,Maryland)から購入し、出願者らの動物施設(Rockville,Maryland)で維持した。DNA免疫は、50μgのプラスミドDNAを100μLの滅菌PBSに入れて、筋肉内又は皮内のいずれかに行った。血清は眼窩内出血により得て、以降に解析するために−20℃で保存した。感作させる際、マウスには、5ug/mLの組み換えCRYJ2(rCRYJ2)又は組み換えCRYJ1(rCYRJ1)のいずれかと、100μLのミョウバン(2mg/mL)とを合計200μLで注射した。毎週、マウスから採血し、血清は、CRYJ特異的な抗体に関し、ELISAにより解析した。
雌性モルモットを購入し、Spring Valley Laboratories(Woodline,MD)にて収容した。200μLの滅菌生理食塩水に入れた100μgのプラスミドDNAを筋肉内に投与し、DNA免疫化した。心臓出血から血清を得て、後の解析のため20℃で保存した。
Nunc Maxisorpイムノアッセイプレートを、rCRYJ2の5ug/mL濃度PBS溶液で、4℃で一晩コーティングした。1% BSA(PBS)により一晩ブロッキングした後、0.05% Tween−20(PBS−T)を含有させたPBSにより血清を希釈し、1時間インキュベートした。ペルオキシダーゼ複合ヤギ抗マウスIgG、IgG1又はIgG2a抗体(Jackson Laboratories)を使用し、ウェルに固定したCRYJ2に結合したIgG、IgG1、又はIgG2を検出した。TMB基質(KPL)を加え、酵素活性をTMB停止液により停止させた。このプレートを450nmで読み取りした。場合によっては、Sure Stop Solution(KPL)を使用し、プレートを650nmで読み取りした。
無菌下で脾臓を摘出し、引裂き、単個細胞懸濁液を調製した。一次応答を試験するため、脾細胞を24ウェルプレート(4×105個/ウェル)で、10μg/mL、5μg/mL、又は2.5μg/mLのrCRYJ2存在下又は非存在下で72時間培養した。
IFN−γ及びIL−4の存在に関し、ELISAにより上清を解析した。IFN−γ及びIL−4に関しては、適した抗体対を使用し、製造元の指示に従って実施した。マウス組み換えIFN−γ及びIL−4を用い標準曲線を作成した。全ての抗体及びサイトカインはInvitrogen(Carlsbad,CA)から購入した。IFN−γ及びIL−4アッセイの検出限界はそれぞれ20及び10pg/mLであった。
本発明の核酸コンストラクトを使用して、形質転換細胞において1つ又は複数のアレルゲンを発現させることができることを示すため、ヒト293細胞をCryJ2−LAMPプラスミド、CryJ1+J2−LAMPプラスミド(図4)、CryJ1−LAMPプラスミド、CryJ1プラスミド(CryJ1シグナル配列は非存在;図7)、及びベースとなるプラスミドベクターのみ(陰性対照;配列番号1)により形質移入した。実験結果を図9に示す。
プラスミド上のコード領域として、あるいは本発明に従うコンストラクトに対するアレルゲンドメインとして投与したとき、本発明のコンストラクトから産生されたキメラタンパク質が、MHC II経路によりプロセシングを受けているか決定するために、一連の実験を実施して、CryJ2タンパク質に対する免疫応答を比較した。結果を、図10のパネルA及びBに示す。
図11は、IgG2a産物及びIgG1産物の両方を異なる濃度で投与した4種のDNA免疫後のCryJ2特異的応答を示す。マウス群(n=5)には、第0、7、14、及び21日目に、10μg、50μg、又は100μgのCRYJ2−LAMPプラスミドDNA又はベクターDNAのいずれかを筋肉内投与した。最後のDNA免疫から3週間後、マウスを屠殺し、サイトカイン誘導アッセイのため脾臓を摘出した。
この一連の実験では、刺激した脾臓細胞の上清中のサイトカイン分泌は、マーカーとしてIL−4及びIFN−γを使用して求めた。具体的には、第42日目にマウス(n=3)脾臓細胞を採取し、10μg/mL、5μg/mL、2.5μg/mLの存在下で、又はrCRYJ2の比存在下で培養した。無感作のマウス由来の脾臓細胞を陰性対照として使用した。rCRYJ2刺激した脾細胞のIF−4及びIFN−γ濃度は、pg/mLでEFISAにより測定した。
DNA−LAMP−CryJ2ワクチンの治療効果を試験するため、マウス群(n=5)に、5μgのrCRYJ2組み換えタンパク質を3回注射して感作し、4週間後から、CRYJ2−LAMPプラスミドDNAを、間隔を一週間ずつ(7日間)開けて4回注射し処置した。DNA免疫により、IgG2aの追加免疫効果が誘導され、IgG1抗体が一過性に増加したことから、DNAワクチンのTh1誘導性の調節効果が示される。追加して、第167日目及び第174日目の2回DNAを免疫することにより、CRYJ2特異的なIgG2a応答が追加免疫され、かつIgG1応答においては、ほとんど変化はなかった。マウスの視認試験により、肉体的な困難性又は皮膚反応は存在しないことが明らかとなった。同様に、食欲において変化は見られず、あるいは明らかな嗜眠も見られなかった。IgG1及びIgG2aの力価に対する影響を、それぞれ図13のパネルA及びBに示す。
サイトカイン誘導に関しCryJ2−LAMP DNAワクチンの治療効果も試験した。第183日めにマウス(n=3)の脾細胞を採取し、濃度を変えてrCRYJ2により刺激した。無感作のマウス由来の脾臓細胞を陰性対照として使用した。rCRYJ2刺激した脾細胞のIL−4及びIFN−γ濃度は、pg/mLでELISAにより測定した。CRYJ2−LAMPワクチン投与群において、ベクター群と比較して、IFN−γの著しい発現増加が検出された。しかしながら、IL−4発現はベクター群と差は見られなかった。Cry 12−LAMP DNA免疫の結果、IFN−γが増加することは、抗原特異的Th1細胞の補充及びTh1サイトカイン環境の生成に関与する可能性がある。この実験により得られたデータを、図14、パネルA及びBに示す。
Cry J2タンパク質、pDNA−Cry J2(LAMP不含有)及びCry 12−LAMP−vaxによりマウスを免疫した。第0、1、2、3、4、及び7日目に血清サンプルを採取し、感受性のサンドイッチイムノアッセイにおいて、遊離のCry J2タンパク質の存在を評価した。タンパク質及びLAMP不含有免疫において遊離のCry J2が検出された。しかしながら、Cry J2−LAMP−vax免疫マウスを用いる任意の実験におけるいずれの時点においても、遊離アレルゲンは検出されなかった(検出限界2ng/mL)。これらの上清が示すデータを図12に提供する。
その他の哺乳動物における、本発明の核酸コンストラクトの機能に関する化学的な理解を深めるために、CryJ2−LAMP DNAワクチンを免疫した後、組み換えCryJ2タンパク質に暴露した雌性モルモットで試験を実施した。試験結果を図16、パネルA及びBに示す。
ニュージーランド白色種ウサギに、4.128mgのCRYJ2−LAMP DNAを筋肉内注射した。年齢及び性別を一致させた対照ウサギには生理食塩水のみを投与した。ウサギは第1、14、28、42、及び56日目に免疫した。第1、14、28、42、56、58、及び85日目にウサギから血清サンプルを得た。CryJ2−LAMPプラスミド又は生理食塩水の複数回筋肉内注射後1:100希釈したウサギ血清の平均吸光度を図17に示す。図に見られるとおり、データは、生理食塩水を投与したウサギの平均吸光度は0.100未満であることを示す。CRYJ2−LAMP DNAによる処置群のウサギの吸光度は、一般的に、第42日目まで増加し、一部の場合では、第85日目まで増加した。
直近25年をかけて、落花生アレルギー患者における感作をもとに、8種の重大な落花生アレルゲンを同定した。3種の主要な落花生アレルゲンは、ほとんど共通して落花生アレルギー患者のIgEにより認識され、65〜100%はAra h1(63.5kDaの種子貯蔵タンパク質ビシリンファミリータンパク質)を認識し、71〜100%はAra h2(17kDaの種子貯蔵コングルチニンファミリータンパク質)を認識し、45〜95%はAra h3(14kDaの種子貯蔵グリシニンファミリータンパク質)を認識する。これらの3種のタンパク質は、落花生依存性アレルギー応答及び即時型過敏反応を誘引する一般的な原因となるだけでなく、強力なアレルギー応答を促進することも明白である。落花生アレルギーの免疫療法のための基盤としてこれらのアレルゲンを標的とすることには、多様な落花生アレルギー集団の中でも強力なアレルギー応答からの広範な保護をもたらす可能性がある。現在、アレルギーの免疫療法剤として、低アレルギー性の形態の、3種の主要なアレルゲン及び加熱殺菌細菌アジュバントを使用する、第I相臨床試験が実施中である。この試験は進行中であるものの、製造プロセスが非常に複雑であることに起因して、このような治療法の最終的な商業化には課題がある。
本出願の一部として提供される公式の配列リストに提供される配列に加えて、以降の配列が本開示の一部を構成する:
1.Cry1−Cry2−LAMPキメラコンストラクトのコード領域のヌクレオチド配列は次のとおりである。
Claims (9)
- 配列番号3で表されるアミノ酸配列と同一性が90%以上のアミノ酸配列からなり、Th2記憶細胞に比べて、Cry J2に特異的なTh1記憶細胞の補充を誘導するCRY J2−LAMPキメラタンパク質をコードする核酸。
- 配列番号3で表されるアミノ酸配列、又は前記アミノ酸配列において1若しくは10個以下のアミノ酸が置換、欠失、挿入及び/又は付加されたアミノ酸配列からなり、Th2記憶細胞に比べて、Cry J2に特異的なTh1記憶細胞の補充を誘導するCRY J2−LAMPキメラタンパク質をコードする核酸。
- 配列番号3で表されるアミノ酸配列からなるCRY J2−LAMPキメラタンパク質をコードする核酸。
- 請求項1〜3の何れか一項に記載の核酸、及び製薬学的に許容され得る担体を含有してなる、医薬組成物。
- さらに、配列番号5で表されるアミノ酸配列と同一性が90%以上のアミノ酸配列からなり、Cry J1内に含有されるエピトープに特異的な免疫グロブリンGの血清濃度の増加をもたらすCRY J1−LAMPキメラタンパク質をコードする核酸を含有してなる、請求項4に記載の医薬組成物。
- さらに、配列番号5で表されるアミノ酸配列、又は前記アミノ酸配列において1若しくは10個以下のアミノ酸が置換、欠失、挿入及び/又は付加されたアミノ酸配列からなり、Cry J1内に含有されるエピトープに特異的な免疫グロブリンGの血清濃度の増加をもたらすCRY J1−LAMPキメラタンパク質をコードする核酸を含有してなる、請求項4に記載の医薬組成物。
- さらに、配列番号5で表されるアミノ酸配列からなるCRY J1−LAMPキメラタンパク質をコードする核酸を含有してなる、請求項4に記載の医薬組成物。
- 請求項4〜7の何れか一項に記載の医薬組成物を含有してなる、核酸ワクチン。
- 請求項4〜7の何れか一項に記載の医薬組成物を含有してなる、花粉症を治療及び/又は予防するための核酸ワクチン。
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