JP5274011B2 - 神経障害を治療するための組成物および方法 - Google Patents
神経障害を治療するための組成物および方法 Download PDFInfo
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Description
本発明は、Department of Health and Human Servicesによって授与された助成金の下で、政府の支援を受けて行われた。
本出願は、2004年6月25日出願の米国仮特許出願第60/582,999号(その全体が記載されているかのように、本明細書に参考として援用される)の優先権の利益を主張する。
神経障害(有害なタンパク質の凝集、異常なタンパク質の折り畳みに関連する神経変性障害および/または神経変性自己免疫障害(脳アミロイド形成(amylogenic)疾患など)が含まれる)の治療に有用な組成物を記載する。前記組成物の使用方法も記載する。
神経疾患は、一般に、1つまたは複数の中枢神経系領域由来のニューロンの喪失によって特徴づけられる。神経疾患の例には、アルツハイマー病、神経線維腫症、ハンチントン病、うつ病、筋萎縮性側索硬化症、多発性軟化症、脳卒中、パーキンソン病、および多発脳硬塞性痴呆が含まれる。これらは、起源および進行の両方が複雑であり、最も治療が困難な疾患型のいくつかであることが判明している。実際、いくつかの神経疾患について、有意な治療上の利点が得られる利用可能な薬物は存在しない。治療が困難であることは、これらの疾患がその犠牲者に与える破滅的影響を考えると、一層悲劇的である。
本発明は、治療を必要とする哺乳動物の神経疾患または神経障害を治療するための方法および組成物を提供する。神経疾患または神経障害は、タンパク質もしくはタンパク質性物質の全身もしくは局所的沈着(例えば、アミロイドーシス)、有害なタンパク質の凝集(タンパク質の誤折り畳み)、および/または神経変性自己免疫に関連し得る。アルツハイマー病および/または他の脳アミロイド形成疾患(プリオン関連疾患、ハンチントン病、パーキンソン病、および脳アミロイド血管症(CAA)が含まれる)が特に興味深い(Revesz,T.et al.(2003)J.Neuropathol.Exp.Neurol.62(9):885−98)。前記アミロイド関連疾患の治療は、総アミロイド負荷(可溶性および不溶性Aβ)または線維性Aβ−アミロイド負荷の決定によって測定される新規のアミロイド斑(沈着)の防止、現在のアミロイド斑レベルの維持、および/または既存のアミロイド斑量もしくは総脳アミロイドタンパク質量(斑中に沈着し得るAβが含まれる)の減少を含み得る。前記神経疾患または神経障害は、多発性硬化症などの細胞媒介性自己免疫疾患に関連し得る。前記自己免疫障害の治療は、自己反応性t細胞の形成の防止、既存の自己反応性T細胞濃度の維持、および/または自己反応性T細胞濃度の減少を含み得る。
用語「神経疾患」は、神経系のニューロン細胞が関わる疾患または障害をいう。詳細には、以下が含まれる:プリオン病(例えば、クロイツフェルト−ヤコブ病);発達中の脳の病変(例えば、アミノ酸代謝の先天性欠損(アルギニノコハク酸尿症、シスタチオニン尿症、高ヒスチジン血症、ホモシスチン尿症、高アンモニア血症、フェニルケトン尿症、チロシン血症、および脆弱X症候群など);成熟脳の病変(例えば、神経線維腫症、ハンチントン病、うつ病、筋萎縮性側索硬化症、多発性硬化症);成人期に襲われる症状(例えば、アルツハイマー病、クロイツフェルト−ヤコブ病、レビー小体病、パーキンソン病、ピック病);および脳の他の病変(例えば、脳の事故(mishap)、脳損傷、昏睡、種々因子による感染症、食事性欠乏症、脳卒中、多発性梗塞性痴呆、および心血管の事故)。
多発性硬化症(MS)の治療に有効なMBPの免疫学的アナログは、酢酸グラチラマー(GA)(すなわち、コポリマー−1(Cop−1))である(米国特許第3,849,550号、PCT出願WO/95/31990)。GAは、その市販されている形態では、6.0:1.9:4.7:1.0のモル比でL−アラニン、L−グルタミン酸、L−リジン、およびL−チロシンから構成されるランダムな合成ポリペプチドの混合物である。これは、MBPの免疫化学的模倣物として最初に合成された。例えば、GAに対する一定のモノクローナル抗体は、MBPと交差反応する(Teitelbaum et al.Proc.Natl.Acad.Sci.USA 88:9258(1991))。また、GAは、MBPに特異的なT抑制細胞を誘導することが見出されている(Lando et al.J.Immunol.123:2156(1979))。マウス実験では、GAがEAEの中枢神経系組織の破壊に関与するMBP特異的T細胞も特異的に阻害することが示されており(Teitelbaum et al.Proc.Natl.Acad.USA 85:9724(1995));およびAngelov,D.N.et al.PNAS 100(8):4790−4795(2003))は、GAを使用して筋萎縮性側索硬化症を治療することができ、十分に調節された自己免疫応答の誘導が、GAの投与によって増強することができる抗自己T細胞応答の存在下での生存に影響を与えるようであることを示している。
プロテオソーム(例えば、IVX−908またはプロトリン)を配合したGAを、例えば、注射によるか鼻腔内に投与することができる。注射によって送達した場合、このような送達は、1回の注射(組み合わせた同時投与)であり得る。あるいは、GA組成物およびプロテオソームベースの組成物を、個別に送達させることができるか、第1の部位にGA組成物(プロテオソームを含まない)のみを投与し、第2の部位にプロテオソームベースの組成物(すなわち、GAを含まない)のみを投与する、同時または一過性に異なる時間で起こり得る複数の部位への注射によって送達させることができる。GAを注射によって投与し、それと同時または別に、プロテオソームベースの組成物を、例えば、鼻腔内投与することができることも意図される。したがって、本発明の1つの実施形態では、GA組成物を注射によって送達させ、個別に、プロテオソームベースの組成物を鼻腔内に送達させる。
それぞれ米国特許第5,961,970号または同第5,716,637号に記載のように、GAを含むサブミクロンのエマルジョンまたはナノエマルジョンを投与するか、GAをこれらに配合することができる。組成物は、水性連続相として約0.5〜約50%の油、約0.1〜約10%の乳化剤、約0.05〜約5%の非イオン性界面活性剤、および約0.00001〜約1.0%のGAを含む水中油滴型サブミクロンのエマルジョンを含む。サブミクロンのエマルジョンの平均液滴サイズは、約0.03μmと約0.5μm、好ましくは0.05μmと0.2μmとの間の範囲である。
本発明はまた、例えば、プロテオソームベースの組成物と共に処方したGAまたはGAを含まないプロテオソームベースの組成物で哺乳動物を免疫する工程と、前記ペプチド、そのフラグメント、または誘導体の減少または阻害が、抗体が生成されることなく起こることと、本明細書中でB細胞欠損(μMT)マウスを使用して証明したところ、抗体応答を誘発することができないこととを含む、アミロイド−βペプチド(可溶性および/または不溶性)、そのフラグメントまたは誘導体のレベルを阻害または減少させる方法を含む。理論に拘束されることを望まないが、好ましくは、アミロイド(例えば、Aβアミロイド)の阻害または減少は、脳または周辺部で見出すことができる脳局在化小膠細胞、好中球、および/またはマクロファージなどの免疫細胞の活性化を介し、これらの細胞の活性化は、任意の抗体または抗原に特異的な機構と無関係である。哺乳動物において実験的アレルギー性脳脊髄炎(EAE)(髄膜脳炎が含まれる)を発症することなく減少または阻害されることが最も好ましい。
米国特許第6,476,201号および同第5,961,970号の主題は、多価サブユニットワクチン各成分に対する至適な免疫応答を刺激するために、どのようにして適切な成分を適切に関連させ、それぞれが免疫系の細胞によって有効に認識およびプロセシングされることができるような免疫系を利用することができるのかについて記載している。このような認識およびプロセシングには、例えば、鼻上皮内に存在する膜細胞(M細胞)による取り込みおよびその後の内在する宿主免疫系細胞への送達が含まれ得る。このような非共有結合によって複合体化したワクチンの主な例には、広範な種々の抗原(ペプチド、リポペプチド、膜貫通タンパク質、トキソイド化タンパク質、ポリサッカリド、またはリポポリサッカリド(LPS))と非共有結合的に複合体化ナイセリア外膜タンパク質からなり得るプロテオソームベースのワクチンが含まれる(さらなる概説については、以下の引例を参照のこと:米国特許第5,726,292号、Immunogenicity and Efficacy of Oral or Intranasal Shigella flexneri 2a and Shigella sonnei Proteosome−Lipopolysaccharide Vaccines in Animal Models;Infect.Immun.61:2390;Mallett,C.P.,T.L.Hale,R.Kaminski,T.Larsen,N.Orr,D.Cohen,and G.H.Lowell.(1995));Intranasal or intragastric immunization with proteosome−Shigella lipopolysaccharide vaccines protect against lethal pneumonia in a murine model of shigellosis(Infect.Immun.63:2382−2386;Lowell G H,Kaminski R W,Grate S et al.(1996));Intranasal and intramuscular proteosome−staphylococcal enterotoxin B(SEB)toxoid vaccines:immunogenicity and efficacy against lethal SEB intoxication in mice(Infec.Immun.64:1706−1713;Lowell,G.H.(1990));Proteosomes,Hydrophobic Anchors,Iscoms and Liposomes for Improved Presentation of Peptide and Protein Vaccines,(in New Generation Vaccines:G.C.Woodrow and M.M.Levine,eds.(Marcel Dekker,NY)Chapter 12(pp.141−160));およびProteosome−lipopeptide vaccines:enhancement of immunogenicity for malaria CS peptides;(Lowell,G.H.,W.R.Ballou,L.F.Smith,R.A.Wirtz,W.D.Zollinger and W.T.Hockmeyer(1988)Science 240:800))。
以下に、交換可能に使用することができる、用語「生理学的に許容可能なキャリア」および「薬学的に許容可能なキャリア」は、生物が著しい炎症を引き起こすことがなく、且つ投与した化合物の生物活性および性質を排除しないキャリアまたは希釈剤をいう。
斑へのさらなる沈着および/または既に形成していることが明らかな斑を阻害または減少させ、そして/または既存のAβ凝集体の除去を刺激し、そして/または斑内に含まれないかもしれないAβの減少を刺激するのに十分な量で投与する。これを達成するための適量を、「治療有効用量または治療有効量」と定義する。
**コントロールは、未処置(n=5)およびBSA/CFA処置(n=3)動物を組み合わせており、これは、これらの群の間で差異が認められなかったためである。総脳Aβについて、未処置=126.7±19.5;BSA/CFA 123.7±33.2。チオフラビン陽性Aβ斑領域の%:未処置:2.8±0.5;BSA/CFA=2.2±0.9。
a コントロールに対してp<0.05。
b コントロールに対してp<0.001;Aβに対してp<0.05
c コントロールに対してp<0.01
d コントロールに対してp<0.01;Aβに対してp=0.05。
a コントロールに対してp<0.02、GAに対してp<0.02
b コントロールおよびGAに対してp<0.001、IVX−908に対してp<0.04
c コントロールに対してp<0.001、GAに対してp<0.002、IVX−908に対してp<0.002。
* データは、各処置についての3つの切片およびコントロールについての6つの切片(3つの未処置+表1のように処置した3つのBSA/CFA)の定量を示す。
a r=−0.7 CD11b対Aβ原線維領域の%
b r=−0.65 CD3対Aβ原線維領域の%;r=0.74 CD3対CD11b
c r=−0.7 M−CSFR対Aβ原線維領域の%;r=0.92 M−CSFR対CD11b
d r=−0.8 IFN−γ対Aβ原線維領域の%;r=0.9 IFN−γ対CD11b;r=0.85 IFN−γ対CD3
e r=0.91 TGF−β対Aβ原線維領域の%;r=−0.77 TGF−β対CD11b;r=−0.6TGF−β対CD3
f r=0.67 IL−10対Aβ原線維領域の%;r=−0.4 IL−10対CD11b
g p=0.0007 CD11b対GA;p<0.05 IFN−γ対GA;p=0.0011 TGF−β対GA
i コントロールに対してp<0.05
ii コントロールに対してp<0.02
iii コントロールに対してp<0.001
iv コントロールに対してp<0.001。
マウス。(B6XD2)F1(平均年齢は14月齢)または(B6XSJL)F1 APP+(WTまたはμMT)(平均年齢は16月齢)APPトランスジェニックマウスを、全ての適用可能なガイダンスにしたがって、Brigham and Woman’s Hospitalの無発熱物質施設に収容し、使用した。
Claims (15)
- 哺乳動物の神経疾患または神経障害を治療するための医薬の製造のためのプロテオソームベースの組成物の使用であって、
該プロテオソームベースの組成物が、(a)(i)Neisseria meningitidis由来のプロテオソームと(ii)内因性リポポリサッカリドを含む、プロテオソームベースのアジュバント;および(b)(i)Neisseria meningitidis由来のプロテオソームと(ii)赤痢菌種(Shigella)、大腸菌種(Escherichia)、クレブシエラ種(Klebsiella)、シュードモナス種(Pseudomonas)、ヘモフィルス種(Haemophilus)、ブルセラ種(Brucella)、またはプレシオモナス種(Plesiomonas)から得られた外因性リポポリサッカリドを含む、プロテオソームベースのアジュバントから選択され、
該神経疾患または神経障害がβ-アミロイド疾患である、前記使用。 - 前記医薬が、前記プロテオソームベースの組成物と同一の処方物または個別の処方物のいずれかで、酢酸グラチラマーをさらに含む、請求項1に記載の使用。
- 前記β-アミロイド疾患が、早発性アルツハイマー病、遅発性アルツハイマー病、および前駆症状性アルツハイマー病からなる群から選択される、請求項1に記載の使用。
- 前記β-アミロイド疾患の治療により、可溶性アミロイドβペプチドまたは不溶性アミロイドβペプチドが減少し、該不溶性アミロイドβペプチドが線維性アミロイドβペプチドを含む、請求項1に記載の使用。
- 前記アミロイドβペプチドが不溶性である、請求項4に記載の使用。
- 前記β-アミロイド疾患がアルツハイマー病である、請求項1に記載の使用。
- 前記β-アミロイド疾患の治療により、脳内のアミロイド負荷増加が防止される、現在の該アミロイド負荷が維持される、または該アミロイド負荷が減少する、請求項6に記載の使用。
- 前記アミロイドがβ−アミロイドペプチドである、請求項7に記載の使用。
- 前記アミロイド負荷が、総β−アミロイドペプチド負荷を含み、該総β−アミロイドペプチド負荷が、線維性アミロイド負荷を含む、請求項7に記載の使用。
- 前記プロテオソームがNeisseria meningitidisに由来し、前記外因性リポポリサッカリドがShigella flexneriに由来する、請求項1または2に記載の使用。
- 前記医薬が、薬学的に許容可能な希釈剤、賦形剤、安定剤、またはキャリアをさらに含む、請求項1または2に記載の使用。
- 神経疾患または神経障害の治療に使用するための、酢酸グラチラマーおよびプロテオソームベースの組成物を含む組成物であって、
該プロテオソームベースの組成物が、(a)(i)Neisseria meningitidis由来のプロテオソームと(ii)内因性リポポリサッカリドを含む、プロテオソームベースのアジュバント;および(b)(i)Neisseria meningitidis由来のプロテオソームと(ii)赤痢菌種、大腸菌種、クレブシエラ種、シュードモナス種、ヘモフィルス種、ブルセラ種、またはプレシオモナス種から得られた外因性リポポリサッカリドを含む、プロテオソームベースのアジュバントから選択され、
該神経疾患または神経障害がβ-アミロイド疾患である、前記組成物。 - 前記プロテオソームがNeisseria meningitidisに由来し、前記外因性リポポリサッカリドがShigella flexneriに由来する、請求項12に記載の組成物。
- 薬学的に許容可能な希釈剤、賦形剤、安定剤、またはキャリアをさらに含む、請求項12または13に記載の組成物。
- 神経疾患または神経障害の治療を必要とする哺乳動物の神経疾患または神経障害を治療するための医薬の製造のための、
プロテオソームベースの組成物;または
酢酸グラチラマー組成物と組み合わされるかまたは処方されたプロテオソームベースの組成物
の使用であって、
該プロテオソームベースの組成物が、(a)(i)Neisseria meningitidis由来のプロテオソームと(ii)内因性リポポリサッカリドを含む、プロテオソームベースのアジュバント;および(b)(i)Neisseria meningitidis由来のプロテオソームと(ii)赤痢菌種、大腸菌種、クレブシエラ種、シュードモナス種、ヘモフィルス種、ブルセラ種、またはプレシオモナス種から得られた外因性リポポリサッカリドを含む、プロテオソームベースのアジュバントから選択され、
治療有効量の該医薬の投与により、該哺乳動物において抗体独立性応答が誘発され、
該神経疾患または神経障害がβ-アミロイド疾患である、前記使用。
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WO2009027105A2 (en) | 2007-08-31 | 2009-03-05 | Neurimmune Therapeutics Ag | Method of providing patient specific immune response in amyloidoses and protein aggregation disorders |
DE102007044487A1 (de) * | 2007-09-18 | 2009-04-02 | Universität Leipzig | Verwendung des umgekehrten Zelldifferenzierungsprogramms (OCDP) zur Behandlung degenerierter, im pathologischen Zustand befindlicher Organe |
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WO2009105641A2 (en) | 2008-02-20 | 2009-08-27 | New York University | Preventing and treating amyloid-beta deposition by stimulation of innate immunity |
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JP5792276B2 (ja) | 2010-03-31 | 2015-10-07 | トムソン ライセンシングThomson Licensing | ビデオデータのトリック再生 |
JP5883018B2 (ja) | 2010-10-27 | 2016-03-09 | ザ ジェネラル ホスピタル コーポレイション | 少なくとも1つの血管内部の血圧を測定するための装置、システム、および方法 |
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