JP7145853B2 - 適応免疫調節のための方法および組成物 - Google Patents
適応免疫調節のための方法および組成物 Download PDFInfo
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- H04B1/00—Details of transmission systems, not covered by a single one of groups H04B3/00 - H04B13/00; Details of transmission systems not characterised by the medium used for transmission
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- H04B1/715—Interference-related aspects
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- H—ELECTRICITY
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- H04B1/00—Details of transmission systems, not covered by a single one of groups H04B3/00 - H04B13/00; Details of transmission systems not characterised by the medium used for transmission
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Description
本発明は、米国国立衛生研究所により授与されたR43 HL115903の下で政府の支援により行われたものである。米国政府は本発明において一定の権利を有する。
37 CFR 1.821-1.825によって要求される配列表は、本出願と共に電子ファイルで提出されている。配列表は参照により本明細書に組み入れられる。
本明細書に記載される特定の態様は、本発明がなされた時点で有効であった共同研究契約の範囲内で行われた活動の結果としてなされたものである。この共同研究契約に関わる当事者は、Board of Regents of the University of Texas SystemおよびThe Texas A&M University Systemである。
喘息は、好酸球性炎症、血清IgEレベルの上昇、粘液産生、および可逆的気流閉塞を特徴とする肺の複雑な炎症性疾患である。アレルギー性喘息を治療するための現在利用可能な治療薬は、即座の症状軽減をもたらし、いくつかは気道炎症さえも軽減する;しかし、それらは依然として不十分なままである。したがって、アレルギー性疾患を治療するためのさらなる戦略が必要とされている。
本発明の態様は、免疫反応を調節するための方法および組成物、ならびに炎症性疾患(例えば、COPD)が根底にある患者において下気道感染症を軽減するための組成物および方法に関する。
などのタイプCのオリゴデオキシヌクレオチド(ODN)、またはそのアナログである。特定の局面では、TLR9オリゴヌクレオチドは、ホスホロチオエートまたはホスホジエステル骨格を有する。いくつかの製剤または方法は、1、2、3、4種、またはそれ以上のTLR9オリゴヌクレオチドアゴニストの個別投与または組み合わせ投与を含み得る。TLRアゴニスト組成物は、抗炎症剤および/または他の薬学的に許容される賦形剤を含むことができる。ある局面では、抗炎症剤は、ベタメタゾン、トリアムシノロン、デキサメタゾン、プレドニゾン、モメタゾン、フルニソリド、およびブデソニドから選択され、特にブデソニドである。ある局面では、薬学的賦形剤はグリセロールである。
またはそのアナログである。特定の局面では、TLR9オリゴヌクレオチドはホスホロチオエートまたはホスホジエステル骨格を有する。いくつかの製剤または方法は、1、2、3、4種、またはそれ以上のTLR9オリゴヌクレオチドアゴニストの個別投与または組み合わせ投与を含み得る。
対象におけるI型過敏症を軽減するための方法であって、アレルゲン誘発性喘息を起こしやすい対象に、有効量の少なくとも2つのTLRアゴニストを含む組成物を投与することを含む、前記方法。
[本発明1002]
前記対象がアレルゲンに曝露されている、本発明1001の方法。
[本発明1003]
前記アレルゲンがTLRアゴニストと組み合わせて投与される、本発明1002の方法。
[本発明1004]
前記TLRアゴニストが、TLR2/1アゴニスト、TLR2/6アゴニスト、TLR3アゴニスト、TLR4アゴニスト、TLR5アゴニスト、TLR9アゴニスト、およびTLR7アゴニストからなる群より選択される、本発明1001~1003のいずれかの方法。
[本発明1005]
前記組成物が、TLR9アゴニストおよびTLR2/6アゴニストを含む、本発明1001~1004のいずれかの方法。
[本発明1006]
前記TLRアゴニストの少なくとも1つがTLR2/6アゴニストである、本発明1001~1004のいずれかの方法。
[本発明1007]
TLR2/6アゴニストがジアシル化リポポリペプチドである、本発明1005または1006の方法。
[本発明1008]
TLR2/6アゴニストがPAM2CSK4である、本発明1005または1006の方法。
[本発明1009]
前記TLRアゴニストの少なくとも1つがTLR9アゴニストである、本発明1001~1004または1006~1009のいずれかの方法。
[本発明1010]
TLR9アゴニストがTLR9オリゴヌクレオチドアゴニストである、本発明1009の方法。
[本発明1011]
TLR9オリゴヌクレオチドアゴニストが、
などのタイプCのオリゴデオキシヌクレオチド(ODN)、またはそのアナログである、本発明1010の方法。
[本発明1012]
TLR9オリゴヌクレオチドが、ホスホロチオエートまたはホスホジエステル骨格を有する、本発明1010の方法。
[本発明1013]
TLR9アゴニストが、タイプCのオリゴデオキシヌクレオチド(ODN)である、本発明1009の方法。
[本発明1015]
前記少なくとも2つのTLRアゴニストが、PAM2CSK4およびタイプCオリゴデオキシヌクレオチド(CpG-ODN)である、本発明1001~1014のいずれかの方法。
[本発明1016]
CpG-ODNがODNM362である、本発明1015の方法。
[本発明1017]
PAM2CSK対CpG-ODNのモル比が4:1である、本発明1015の方法。
[本発明1018]
アレルゲンを投与することをさらに含む、本発明1001の方法。
[本発明1019]
前記アレルゲンが、前記少なくとも2つのTLRアゴニストと同時に投与される、本発明1018の方法。
[本発明1020]
TLR9オリゴヌクレオチドアゴニストおよびTLR2/6アゴニスト、抗炎症剤、または1種以上の薬学的賦形剤を含む、薬学的に許容される組成物であって、無菌でありかつ病原性微生物を本質的に含まない前記組成物。
[本発明1021]
TLR2/6アゴニストがPAM2CSK4である、本発明1020の組成物。
[本発明1022]
TLR9オリゴヌクレオチドアゴニストが、ODN2395またはODNM362またはODN10101または9merまたはH-Tel 22である、本発明1020の組成物。
[本発明1023]
TLR9オリゴヌクレオチドアゴニストが、ホスホロチオエートまたはホスホジエステル骨格を有する、本発明1020の組成物。
[本発明1024]
2つ、3つ、または4つのTLR9オリゴヌクレオチドアゴニストを含む、本発明1020の組成物。
[本発明1025]
抗炎症剤がブデソニドである、本発明1020の組成物。
[本発明1026]
薬学的賦形剤がグリセロールである、本発明1020の組成物。
本発明の他の目的、構成および効果は以下の詳細な説明から明らかになるであろう。しかしながら、詳細な説明および具体的な実施例は、本発明の特定の態様を示しているものの、本発明の精神および範囲内の様々な変更および修飾が、この詳細な説明から当業者に明らかになるために、例示としてのみ与えられていることを理解されたい。
アレルギー性喘息は、好酸球の浸潤、粘液産生の増加、気道過敏(AHR)、および気道リモデリングを伴う慢性呼吸器疾患である(Barnes, Nature Reviews Immunology (2008), 8, 183-92)。喘息の病態生理学の理解が最近進歩したにもかかわらず、一部の治療法は、望ましくない副作用を示すことがあるコルチコステロイドによる一般的な免疫抑制に依然として頼っており、一方、短時間作用型の薬物は即座に症状の緩和をもたらし得るが、まだいささか不十分である(Fanta, N Engl J Med (2009), 360:1002-14)。アレルギー性疾患の治療にはさらなる治療法が必要である。
免疫系はしばしば次のように分類される:(a)病原体を継続的に撃退するために「最前線」の即時防御を提供する構成要素を含む自然免疫、および(b)特定の病原体を標的とするように特別に設計された抗体の産生とT細胞の作製または刺激を含む適応(獲得)免疫。適応免疫を用いて、生体は特定の病原体に対する特異免疫を経時的に獲得することができる。この応答は生じるまでに何日もかかるので、初期の侵入を防ぐには効果的でないが、それは通常その後の感染を防ぐだけでなく、長く続く感染を一掃するにも役立っている。
現在、アレルギー性疾患および喘息は通常、以下の薬物のうちの1つ以上を用いて治療されている:(1)抗ヒスタミン薬および抗ロイコトリエン薬、これらは炎症性メディエーターのヒスタミンおよびロイコトリエンに拮抗する;(2)局所または全身性(経口または注射用)コルチコステロイド薬、これらは広範囲の炎症性メカニズムを抑制する;および(3)短時間または長時間作用型の気管支拡張薬、これらは喘息で狭窄した気道の平滑筋を弛緩させる。全身性コルチコステロイド薬の長期使用は、多くの重篤な副作用を引き起こすことが知られており、代替療法が利用可能な場合には回避することが望ましい。
特定の態様では、免疫調節組成物はアレルゲン成分を含むか、またはアレルゲン成分と共に投与される。アレルゲン成分は、微生物(例:細菌、ウイルス、真菌)、花粉(例:農場植物、木、雑草、イネ科植物)、動物のフケ、膜翅目の毒液、昆虫(例:イエダニ)、植物性食物、および動物性食物を含むがこれらに限定されない、1つ以上のアレルゲンまたはその誘導体を含むことができる。
慢性炎症性成分を示す非常に多くの疾患が存在する。それらには、限定するものではないが、以下が含まれる:炎症性関節疾患(例えば、慢性関節リウマチ、変形性関節症、多発性関節炎、痛風)、慢性炎症性結合組織疾患(例えば、エリテマトーデス、強皮症、シェーグレン症候群、多発性筋炎および皮膚筋炎、血管炎、混合性結合組織病(MCTD)、腱炎、滑膜炎、細菌性心内膜炎、骨髄炎、乾癬)、慢性炎症性肺疾患(例えば、慢性呼吸器疾患、肺炎、線維化性肺胞炎、慢性気管支炎、慢性閉塞性肺疾患(COPD)、気管支拡張症、気腫、珪肺症および他の塵肺症、結核)、慢性炎症性腸疾患および胃腸管炎症性疾患(例えば、潰瘍性大腸炎、クローン病)、慢性神経炎症性疾患(例えば、慢性炎症性脱髄性多発根ニューロパチー、慢性炎症性脱髄性多発ニューロパチー、多発性硬化症、ギラン-バレー症候群、重症筋無力症)、他の炎症性疾患(例えば、乳腺炎、蹄葉炎、喉頭炎、慢性胆嚢炎、橋本甲状腺炎、炎症性胸部疾患)、傷に埋め込まれた異物によって引き起こされる慢性炎症、ならびにエキセントリックな運動後の筋肉損傷による急性炎症性組織損傷(例えば、遅発性筋肉痛、DOMS)。ある局面では、炎症性の状態または疾患は、限定するものではないが、慢性炎症性肺疾患(例えば、慢性呼吸器疾患、肺炎、線維化性肺胞炎、慢性気管支炎、慢性閉塞性肺疾患(COPD)、気管支拡張症、気腫、珪肺症および他の塵肺症、結核)からなる群より選択される。特定の局面では、炎症性疾患はCOPDである。
Toll様受容体(TLR)は高度に保存された膜貫通タンパク質であり、パターン認識のための複数のロイシンリッチリピートを有する細胞外ドメイン、膜貫通αヘリックス、および細胞内シグナル伝達のためのToll/インターロイキン-1受容体(TIR)ドメインからなる。少なくとも13種の哺乳動物TLRが、それぞれ原形質膜またはエンドソーム膜のいずれかに特異的に局在して同定されており、それぞれがPAMPのユニークな補体を検出する(Akira et al., 2006; Shi et al., 2006)。PAMP認識時に、細胞質TIRアダプタータンパク質の組み合わせのTLR特異的動員を介してシグナル伝達が起こる。他の4つのアダプターの1つ以上と共同して、TIRアダプタータンパク質MyD88は、ほとんどのTLRからのシグナル伝達に必要である。TLR3およびTLR4から観察されるMyD88非依存性のシグナル伝達事象は、TRAMの関与を伴ってまたは伴わずに、TIRアダプターTRIF(TICAM-1としても知られる)を必要とする(Yamamoto et al., 2003)。TLR特異的TIRアダプターシグナル伝達カスケードは、NF-κBなどの受容体特異的転写因子、活性化タンパク質-1およびインターフェロン調節因子(IRF)を活性化して、炎症性および抗菌性遺伝子の発現をもたらす(Akira et al., 2006; O'Neill, L.A., and Bowie, 2007; Takeda, K., and Akira, 2004)。
本明細書で交換可能に使用される「TLR9オリゴヌクレオチドアゴニスト」、「CpG-ODN」、「CpG核酸」、「CpGポリヌクレオチド」、および「CpGオリゴヌクレオチド」は、TLR9受容体を刺激または活性化するポリヌクレオチドを指す。特に、「CpG-ODN」、「CpG核酸」、「CpGポリヌクレオチド」、および「CpGオリゴヌクレオチド」は、少なくとも1つの5'-CG-3'部分を含み、多くの態様では、非メチル化5'-CG-3'部分を含む。一般に、TLR9オリゴヌクレオチドアゴニストは、修飾ヌクレオチドもしくは修飾ヌクレオシドの配列を含むかまたはそれからなり得る少なくとも6個のヌクレオチド塩基を有する、一本鎖または二本鎖のDNAもしくはRNAポリヌクレオチドである。ある態様では、CpG核酸の5'-CG-3'部分はパリンドロームヌクレオチド配列の一部である。ある態様では、CpG核酸の5'-CG-3'部分は非パリンドロームヌクレオチド配列の一部である。TLR9オリゴヌクレオチドは、オリゴヌクレオチドアナログであり得る。
TLR2アゴニストには、単離された天然のTLR2アゴニストおよび合成のTLR2アゴニストが含まれる。TLR2アゴニストの天然源から単離されたTLR2アゴニストは、一般に精製されており、例えば、精製されたTLR2アゴニストは、純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。合成TLR2アゴニストは標準的な方法によって調製され、一般的に純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。
TLR3アゴニストには、単離された天然のTLR3アゴニストおよび合成のTLR3アゴニストが含まれる。TLR3アゴニストの天然源から単離されたTLR3アゴニストは、一般に精製されており、例えば、精製されたTLR3アゴニストは、純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。合成TLR3アゴニストは標準的な方法によって調製され、一般的に純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。
適切なTLR4アゴニストには、単離された天然のTLR4アゴニストおよび合成のTLR4アゴニストが含まれる。TLR4アゴニストの天然源から単離されたTLR4アゴニストは、一般に精製されており、例えば、精製されたTLR4アゴニストは、純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。合成TLR4アゴニストは標準的な方法によって調製され、一般的に純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。
適切なTLR5アゴニストには、単離された天然のTLR5アゴニストおよび合成のTLR5アゴニストが含まれる。TLR5アゴニストの天然源から単離されたTLR5アゴニストは、一般に精製されており、例えば、精製されたTLR4アゴニストは、純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。合成TLR5アゴニストは標準的な方法によって調製され、一般的に純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。
適切なTLR7アゴニストには、単離された天然のTLR7アゴニストおよび合成のTLR7アゴニストが含まれる。TLR7アゴニストの天然源から単離されたTLR7アゴニストは、一般に精製されており、例えば、精製されたTLR7アゴニストは、純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。合成TLR7アゴニストは標準的な方法によって調製され、一般的に純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。
適切なTLR8アゴニストには、単離された天然のTLR8アゴニストおよび合成のTLR8アゴニストが含まれる。TLR8アゴニストの天然源から単離されたTLR8アゴニストは、一般に精製されており、例えば、精製されたTLR8アゴニストは、純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。合成TLR8アゴニストは標準的な方法によって調製され、一般的に純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。
適切なTLR9アゴニストには、単離された天然のTLR9アゴニストおよび合成のTLR9アゴニストが含まれる。TLR9アゴニストの天然源から単離されたTLR9アゴニストは、一般に精製されており、例えば、精製されたTLR9アゴニストは、純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。合成TLR9アゴニストは標準的な方法によって調製され、一般的に純度が少なくとも約80%、少なくとも約90%、少なくとも約95%、少なくとも約98%、少なくとも約99%、または99%超である。
などのタイプCのオリゴデオキシヌクレオチド(ODN)、またはそのアナログである。特定の局面では、TLR9オリゴヌクレオチドはホスホロチオエートまたはホスホジエステル骨格を有する。
いくつかの態様では、TLR9リガンドは多量体である。多量体TLR9リガンドは、非共有結合で連結された、または共有結合で連結された、かつ互いに直接連結された、または1つ以上のスペーサーを介して連結された、2、3、4、5、6、7、8、9、10またはそれ以上の、上記のような個々の(単量体の)核酸TLR9リガンドを含む。適切なスペーサーには、それらが生体適合性である限り、核酸および非核酸分子が含まれる。ある態様では、多量体TLR9リガンドは単量体TLR9リガンドの直線状アレイを含む。他の態様では、多量体TLR9リガンドは単量体TLR9リガンドの分岐状またはデンドリマー状のアレイである。
本組成物での使用に適したTLR9リガンドは様々な方法で修飾することができる。例えば、TLR9リガンドは、骨格ホスフェート基の修飾(例えば、メチルホスホネート、ホスホロチオエート、ホスホロアミデートおよびホスホロジチオエートヌクレオチド間結合)を含むことができ、そうした修飾は、例えば、インビボでのそれらの安定性を高めて、それらを治療用途に特に適したものにし得る。特に有用なホスフェート基の修飾は、核酸TLR9リガンドのホスホロチオエートまたはホスホロジチオエート形態への変換である。ホスホロチオエートおよびホスホロジチオエートは、それらの未修飾オリゴヌクレオチド対応物よりもインビボでの分解に対してより抵抗性であり、TLR9リガンドの半減期を増加させて、治療される対象にとってそれらをより利用しやすくする。
本発明者らは、本明細書に記載の組成物による刺激を研究するためのモデルとしてマウスを使用した。本明細書に記載の組成物への対象の単回および反復曝露の効果は確認されており、早期死亡、体重減少、または行動変化などの明らかな肉眼的所見は一切観察されていない。
ミリグラム(mg)もしくはマイクログラム(mcg)またはμg/mlもしくはマイクログラム/mlまたはmMもしくはμM(またはその中で導き出される任意の範囲)の各TLRアゴニスト、またはTLRアゴニスト類の組み合わせの合計量、または抗原もしくはアレルゲンを含む組成物であり得る。
(またはその中で導き出される任意の範囲)の各TLRアゴニストまたはTLRアゴニスト類の組み合わせの合計量を含む溶液を収容することができる。
本明細書に記載の組成物はいずれもキットに含めることができる。非限定的な例では、TLRまたはO/P組成物の調製および/または送達のための試薬類がキットに含められる。特定の局面では、キットは持ち運ぶことができ、喘息吸入器が携帯されるのと同様に人により携帯され得る。
以下の実施例ならびに図面は、本発明の好ましい実施態様を実証するために含まれる。実施例または図面に開示された技術は、本発明の実施において十分に機能することが本発明者らによって見出された技術を表しており、したがって、その実施に最もよく使われる方法を構成すると見なされることが当業者には理解されよう。しかしながら、開示された特定の実施態様に多くの変更を加えることができ、それでもなお本発明の精神および範囲から逸脱することなく同様のまたは類似の結果が得られることを、本開示を踏まえて、当業者は理解すべきである。
喘息性免疫反応を調節するための肺自然免疫の活性化
この研究では、本発明者らは、実験的喘息マウスモデルを用いて、喘息性免疫反応の調節における誘導型自然抵抗性の役割の可能性について調べた。血清免疫グロブリンおよび気管支肺胞洗浄(BAL)液の示差的細胞数の分析は、OVAと共にO/Pをエアロゾル投与すると、OVA特異的IgEレベルならびにBAL中の好酸球が顕著に減少することを明らかにした。反対に、本発明者らは、Th1免疫のマーカーである血清IgG2aレベルの増加を観察した。まとめると、我々の知見は、特定の抗原と組み合わせたO/Pによる肺自然免疫の活性化が、アレルギー性免疫反応を非アレルギー性のものに切り替えることができることを示唆する。
エアロゾル化OVA-O/Pは総IgE血清レベルおよびOVA-IgE血清レベルを低下させる:
エアロゾル化O/Pを用いた予備的研究は、様々なウイルスによって引き起こされる呼吸器感染症を予防することができる気道上皮の強力な防御反応を実証している(Evans et al., Annu Rev Physiol (2010), 72:413-35; Clement et al., Am J Respir Crit Care Med (2008), 177:1322-30; Evans et al., Am J Respir Cell Mol Biol (2010), 42:40-50; Tuvim et al., PLoS ONE (2009) 4:e4176)。アレルギー性喘息に対するO/Pの有益なまたは有害な影響の可能性を評価するために、本発明者らは従来のマウス(BALB/c)オボアルブミン感作・チャレンジモデルを使用した(図1A)。本発明者らは、血清IgEを測定することによってアレルギー表現型のアトピー(atopy)を評価した。エアロゾル化OVA+/-O/Pで免疫化およびチャレンジしたマウスにおける総IgEレベルの試験は、エアロゾルチャレンジマウス(図1B、グループ4~8)と免疫化しただけのマウス(図1B、グループ2~3)との間で顕著な増加を明らかにした。しかしながら、本発明者らは、OVA単独対OVA-O/P(6X)で免疫化およびチャレンジしたマウスの間で有意な変化を観察しなかった(グループ4対グループ6)が、OVA-O/Pで9回(9X)エアロゾルチャレンジしたマウスでは、総IgEの顕著な減少が観察された(図1B、グループ3対グループ6)。
次に、本発明者らは、総IgG、IgG1およびIgG2a血清レベルを測定することによってIgG免疫グロブリンのサブクラスを評価して、OVA-O/Pエアロゾルチャレンジモデルが免疫反応を調節するかどうかを調べた(図2)。OVAによる免疫化およびエアロゾルチャレンジを受けた全てのマウスは、総IgGの血清レベルの上昇を示した(図2、上のパネル、グループ3~4、6~8)が、エアロゾルによってO/P(PUL-042)単独を投与されたマウスは示さなかった(図2、上のパネル、グループ5)。総IgGレベルの上昇は免疫付与プロトコルの成功を反映している。さらに、OVA単独で処置したマウス(上のパネル、グループ6)とOVA-O/Pで処置したマウス(上のパネル)との比較は、これら2つのグループ間での総IgGの有意差を明らかにしなかった(図2、上のパネル、グループ4対グループ6)。
アレルギー性炎症を研究するために、従来のアレルギー感作モデルがよく使用される。しかしながら、この感作/チャレンジプロトコルがエアロゾル化O/Pを用いた免疫調節研究に最適であるかどうかは不明であった。最適な時間的および定量的アレルギー感作モデルを確立するために、強力なアレルギー反応を生じさせるのに必要とされるOVAエアロゾルチャレンジの最低回数を決定するための研究が計画された(図3A)。図3A(上のパネル)に示すように、マウスにOVA/ミョウバンを1回(グループ2、4~6)または1週間間隔で2回(グループ3、7~9)IP注射し、続いて7日目に開始して様々なOVAエアロゾルチャレンジを行った。
最適なアレルギー感作/エアロゾルチャレンジモデルを確立した後、本発明者らは、OVA-O/Pのエアロゾル投与に関する以下のパラメータを定義しようとした:(1)エアロゾル投与の最低回数;および(2)エアロゾル処置のタイミング。この目的のために、マウスをOVAで2回免疫化し、OVA単独(グループ2)またはOVA-O/Pのいずれかを用いて、図5Aに示すように様々な間隔でエアロゾルチャレンジする包括的な実験を計画した。
マウス:
雌BALB/cマウス(6~10週齢)をCharles River社(Wilmington, MA)から購入し、飼料と水を自由に摂取させながら12時間/12時間の明/暗サイクルでケージあたり5匹のマウスを飼育した。全ての実験手順は、Texas A&M HSCのInstitute of Biosciences and Technologyの施設内動物実験倫理委員会(IAUCUC)によって承認された。
合成TLRリガンド(O/Pと呼ばれる)をInvivoGen社(San Diego, CA)から購入し、内毒素フリーの水中に再調製して、8mlの滅菌PBS中に次の濃度で懸濁した:Pam2 10μg/ml;ODN2395 20μg/ml。オボアルブミン(OVA)(OVA 20g、グレードV、生理食塩水pH7.4中のミョウバン2.25mg;Sigma社, St. Louis, MO)を週1回の腹腔内(IP)注射により1週間または2週間投与してマウスを感作した。感作したマウスを、Aerotech IIネブライザー(CIS_US, Inc.)を用いて、最大換気と肺全体への均一なエアロゾル曝露を促進するために5%CO2を補充した室内空気の存在下に、O/Pと組み合わせてまたはO/Pなしで、0.9%生理食塩水中の2.5%(wt/vol)オボアルブミンのエアロゾルに30分間曝露した。
96ウェルのEasywash高結合平底プレート(Corning社)を用いた標準的なサンドイッチELISA技術によって血清免疫グロブリンの濃度を測定した。TBSのみで希釈したコーティング試薬を除いて、全ての試薬をアッセイ希釈液(TBS+0.1%BSA[Calbiochem])で希釈した。全ウェルを洗浄緩衝液(TBS+0.1%Tween-20)で、洗浄1回につき5分間、3回洗浄し、TMB基質試薬(BD Biosciences社)を暗所で30分間添加することによって全てのサンプルを発色させた。2N H2SO4を加えて反応を停止させ、吸光度を450nmで読み取った。データに使用された全ての測定値は標準曲線の直線部に入った。
気管カニューレ(ルアースタブアダプタ(luer stub adapter)、BD Biosciences社)を介してPBSの2つの1mlアリコートを注入して引き出すことによりBALを得た。総白血球数は血球計(Houser Scientific社, Horsham, PA)を用いて測定した;示差的細胞計数のためのスライドは、300μlのBAL液を500×gで5分間サイトスピンにかけ、その後ライト-ギムザ染色を行うことによって作製した。
2つのグループのデータを、スチューデントt検定を用いて比較した。有意性についてのP値を0.05未満に設定した。全ての結果は平均±SEMとして表される;全てのグループは、特に明記しない限り、実験条件あたり10匹のマウス(n=10)を含んでいた。
Claims (7)
- 対象におけるI型過敏症を軽減するための方法に用いるための、PAM2CSK4およびODNM362を含む医薬であって、前記方法が、アレルゲン誘発性喘息を起こしやすい対象に、有効量の該PAM2CSK4およびODNM362を投与することを含む、前記医薬。
- 前記対象がアレルゲンに曝露されている、請求項1に記載の医薬。
- 前記アレルゲンがPAM2CSK4およびODNM362と組み合わせて投与される、請求項2に記載の医薬。
- PAM2CSK4対ODNM362のモル比が4:1である、請求項1~3のいずれか一項に記載の医薬。
- アレルゲンを投与することをさらに含む、請求項1に記載の医薬。
- 前記アレルゲンが、PAM2CSK4およびODNM362と同時に投与される、請求項5に記載の医薬。
- 前記対象がアレルギー性喘息を有する、請求項1~6のいずれか一項に記載の医薬。
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US11826422B2 (en) | 2023-11-28 |
IL266562A (en) | 2019-07-31 |
WO2018087699A2 (en) | 2018-05-17 |
KR102515202B1 (ko) | 2023-03-29 |
US20190269773A1 (en) | 2019-09-05 |
CA3043480A1 (en) | 2018-05-17 |
JP2020500189A (ja) | 2020-01-09 |
KR20190104519A (ko) | 2019-09-10 |
EP3538218A2 (en) | 2019-09-18 |
CN110234401A (zh) | 2019-09-13 |
MX2019005502A (es) | 2020-10-01 |
AU2017356673A1 (en) | 2019-05-30 |
WO2018087699A3 (en) | 2018-06-28 |
EP3538218A4 (en) | 2020-06-17 |
CN110234401B (zh) | 2024-03-01 |
BR112019009469A2 (pt) | 2019-07-30 |
AU2017356673B2 (en) | 2023-11-09 |
US20240033348A1 (en) | 2024-02-01 |
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