JP5830015B2 - 合成グルコピラノシル脂質アジュバント - Google Patents
合成グルコピラノシル脂質アジュバント Download PDFInfo
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- JP5830015B2 JP5830015B2 JP2012514187A JP2012514187A JP5830015B2 JP 5830015 B2 JP5830015 B2 JP 5830015B2 JP 2012514187 A JP2012514187 A JP 2012514187A JP 2012514187 A JP2012514187 A JP 2012514187A JP 5830015 B2 JP5830015 B2 JP 5830015B2
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
Description
本願は、2009年6月5日出願の米国仮出願番号61/184,703に35U.S.C.§119(e)の利益を主張し、この仮出願の全体を、出典明示により本明細書の一部とする。
本発明の分野
本発明は、医薬およびワクチンの組成物の分野に関する。より具体的には、本明細書に記載の実施態様は、医薬およびワクチンの組成物、並びに、関連する予防および治療方法に関し、該組成物は、本明細書に記載のグルコピラノシル脂質アジュバント(GLA)を含む。
高等生物の免疫系は、外来物質(または「非自己」)物質を、馴染みのある、または、「自己」成分と区別し、外来物質は免疫反応を誘起するが、「自己」成分は無視または耐容されると特徴付けられてきた。免疫反応は、伝統的には、形質細胞として知られる分化したBリンパ球により抗原に特異的な抗体が産生される体液性反応、または、様々なタイプのTリンパ球が数々のメカニズムにより抗原を排除する、細胞媒介反応のいずれかに特徴付けられてきた。例えば、特異的抗原を認識できるCD4+ヘルパーT細胞は、サイトカインなどの可溶性メディエーターを放出することにより応答し、免疫反応に参加する免疫系のさらなる細胞をリクルートする。また、特異的抗原認識もできるCD8+細胞傷害性T細胞は、抗原を有する細胞または粒子に結合し、これを破壊または損傷することにより応答し得る。免疫学の分野では、通常は宿主において所望の免疫反応を誘導するために、様々な処方によってある種のワクチンを提供することが知られている。
本発明は、そのいくつかの態様において、ある種の合成グルコピラノシル脂質アジュバント(GLA)を免疫調節物質またはアジュバントとして有利に用いる、化合物、組成物および方法を対象とする。従って、本明細書に記載の本発明のある態様によると、下記式(I):
モノホスホリルリピドA(MPL)および他の関連アジュバントは、それの作用を、少なくとも部分的に、Toll様受容体(TLR)のアゴニストとして作用することにより媒介すると知られている。本発明のグルコピラノシル脂質アジュバント(GLA)化合物は、TLR受容体刺激に関連する3D構造研究に基づいて合理的に設計された。より具体的には、本発明によると、本発明のGLA化合物のアシル鎖の長さを、化合物の三次元構造で「平坦な」底を達成するように選択的に定義することにより、TLR受容体の結合部位内で適合の改善が達成され得、それにより、TLR刺激の増強および免疫賦活特性の増強をもたらす。加えて、本発明のGLA化合物の溶解性(例えば、水性溶液中)は、短縮されたアシル鎖長のために有利に改善され、それにより、効率的かつ効果的な化合物の製剤化を促進する。さらに、分子の底面に沿って分子を三次元的に「平坦に」するようにアシル鎖長を合わせるので、化合物を、ベシクル、例えばリポソーム製剤に、より効果的に組み込むことができる。
上記の通り、GLAは化学的に合成されるアジュバントであるので、実質的に均一な形態で製造できる。これは、GLA分子に関して、少なくとも80%、好ましくは少なくとも85%、より好ましくは少なくとも90%、より好ましくは少なくとも95%、またさらに好ましくは少なくとも96%、97%、98%または99%純粋であるGLA調製物を表す。
L1、L2、L3、L4、L5およびL6は、同一であるかまたは異なり、独立して、−O−、−NH−または−(CH2)−であり;
L7、L8、L9およびL10は、同一であるかまたは異なり、独立して、存在しないか、または、−C(=O)−であり;
Y1は酸の官能基であり;
Y2およびY3は、同一であるかまたは異なり、独立して、−OH、−SHまたは酸の官能基であり;
Y4は、−OHまたは−SHであり;
R1、R3、R5およびR6は、同一であるかまたは異なり、独立して、C8−13アルキルであり;そして、
R2およびR4は、同一であるかまたは異なり、独立して、C6−11アルキルである。
「アルキル」は、1個ないし20個の炭素原子を含み、ある種の好ましい実施態様では11個ないし20個の炭素原子を含む、直鎖または分枝鎖、非環式または環式、不飽和または飽和の脂肪族炭化水素を意味する。代表的な飽和直鎖アルキルは、メチル、エチル、n−プロピル、n−ブチル、n−ペンチル、n−ヘキシルなどを含み、ウンデシル、ドデシル、トリデシル、テトラデシル、ペンタデシル、ヘキサデシル、ヘプタデシル、オクタデシルなどを含み;一方、飽和分枝鎖アルキルは、イソプロピル、sec−ブチル、イソブチル、tert−ブチル、イソペンチルなどを含む。代表的な飽和環式アルキルは、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなどを含み;一方、不飽和環式アルキルは、シクロペンテニルおよびシクロヘキセニルなどを含む。環式アルキルは、本明細書で「ホモ環(homocycle)」または「ホモ環式環(homocyclic ring)」とも呼ばれる。不飽和アルキルは、隣接する炭素原子間に少なくとも1個の二重または三重結合を含む(各々、「アルケニル」または「アルキニル」と呼ばれる)。代表的な直鎖および分枝鎖のアルケニルは、エチレニル、プロピレニル、1−ブテニル、2−ブテニル、イソブチレニル、1−ペンテニル、2−ペンテニル、3−メチル−1−ブテニル、2−メチル−2−ブテニル、2,3−ジメチル−2−ブテニルなどを含み;一方、代表的な直鎖および分枝鎖のアルキニルは、アセチレニル、プロピニル、1−ブチニル、2−ブチニル、1−ペンチニル、2−ペンチニル、3−メチル−1−ブチニルなどを含む。
「C8−13アルキル」および「C6−11アルキル」は、各々8−13個または6−11個の炭素原子を含む上記で定義したアルキルを意味する。
他のより特定の実施態様では、本発明は、xが10−12の整数から選択される式(III)のGLA化合物を提供する。
を有するGLA化合物を提供する。
を有するGLA化合物を提供する。
上記の通り、本発明はGLA化合物を提供する。本発明のGLA化合物は、実施例でより詳細に記載する方法を含む、既知の有機合成技法により製造し得る。一般に、構造(I)のGLA化合物は、下記の合成スキームにより製造し得、すべての置換基は、断りのない限り上記定義の通りである。
反応スキーム1
GLAを用いる本明細書に記載のワクチン組成物および方法のある種の実施態様で使用するための抗原は、対象における免疫反応性の誘起または増強が望まれる任意の標的エピトープ、分子(生体分子を含む)、分子複合体(生体分子を含有する分子複合体を含む)、細胞内集合体、細胞または組織であり得る。頻繁に、抗原の用語は、関心のあるポリペプチド抗原を表す。しかしながら、抗原は、本明細書で使用するとき、関心のあるポリペプチド抗原をコードする組換えコンストラクト(例えば、発現コンストラクト)も表し得る。ある種の好ましい実施態様では、抗原は、感染、癌、自己免疫疾患、アレルギー、喘息または抗原特異的免疫反応の刺激が望ましいか、または有利である他の状態と関連する感染性病原体および/またはエピトープ、生体分子、細胞または組織であり得るか、または、これらに由来し得るか、または、これらと免疫学的に交差反応性であり得る。
本明細書に記載の通り、本発明のある種の実施態様は、医薬組成物を含むワクチン組成物および免疫アジュバント組成物を企図し、それは、本発明のGLA化合物に加えて、1種またはそれ以上のToll様受容体アゴニスト(TLRアゴニスト)を含む。Toll様受容体(TLR)は、多数の感染性病原体の中または上に存在し得るものなどの様々な保存された微生物の分子構造について宿主細胞に早期の認識能力を与える自然免疫系の細胞表面膜貫通型受容体を含む。(例えば、Armant et al., 2002 Genome Biol. 3(8):reviews3011.1-3011.6; Fearon et al., 1996 Science 272:50; Medzhitov et al., 1997 Curr. Opin. Immunol. 9:4; Luster 2002 Curr. Opin. Immunol. 14:129; Lien et al. 2003 Nat. Immunol. 4:1162; Medzhitov, 2001 Nat. Rev. Immunol. 1:135; Takeda et al., 2003 Ann Rev Immunol. 21:335; Takeda et al. 2005 Int. Immunol. 17:1; Kaisho et al., 2004 Microbes Infect. 6:1388; Datta et al., 2003 J. Immunol. 170:4102)。
CPG 7909: Cooper et al., "CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults." AIDS, 2005 Sep 23;19(14):1473-9.
CpG 10101: Bayes et al., "Gateways to clinical trials." Methods Find. Exp. Clin. Pharmacol. 2005 Apr;27(3):193-219.
Vollmer J., "Progress in drug development of immunostimulatory CpG oligodeoxynucleotide ligands for TLR9." Expert Opinion on Biological Therapy. 2005 May; 5(5): 673-682
本発明で提供されるある種の実施態様は、GLA化合物に加えて、アジュバント活性を有するがGLA以外のものである組成物の成分を表す少なくとも1種のコアジュバントを含有する、医薬組成物を含むワクチン組成物および免疫アジュバント組成物を含む。そのようなアジュバント活性を有するコアジュバントは、ヒト(例えば、ヒトの患者)、非ヒト霊長類、哺乳動物または認識された免疫系を有する他の高等真核生物などの対象に投与されると、免疫反応の強度および/または寿命を変更(即ち、統計的に有意な増加または減少、そして、ある種の好ましい実施態様では、増強または増加)できる組成物を含む(例えば、Powell and Newman, "Vaccine design - The Subunit and Adjuvant Approach", 1995, Plenum Press, New York 参照)。本明細書に開示のある種の実施態様では、GLAおよび所望の抗原、および、場合により1種またはそれ以上のコアジュバントは、GLAと同時に投与され得るか、または、その投与において時間および/または空間的に離れていてもよい(例えば、異なる解剖学的部位で)所望の抗原に対する免疫反応を変更し得る、例えば誘起または増強し得るが、ある種の本発明の実施態様は、そのように限定されることを意図せず、従って、特定の抗原を含まないが、TLRアゴニスト、コアジュバント、イミダゾキノリン免疫反応変更因子、および、ダブルステムループ免疫変更因子(dSLIM)の1種またはそれ以上を含んでもよい組成物におけるGLAの投与も企図する。
本明細書に開示のある種の実施態様に従って使用するための他のコアジュバントには、ブロックコポリマーまたは生物分解性ポリマーが含まれ、これは、関連分野の当業者に周知の重合体の化合物のクラスを表す。GLAワクチン組成物またはGLA免疫アジュバントに含まれ得るブロックコポリマーまたは生物分解性ポリマーの例には、Pluronic(登録商標) L121 (BASF Corp., Mount Olive, NJ; see, e.g., Yeh et al., 1996 Pharm. Res. 13:1693; 米国特許第5,565,209号)、CRL1005(例えば、Triozzi et al., 1997 Clin Canc. Res. 3:2355)、乳酸−グリコール酸共重合体(PLGA)、ポリ(乳酸)(PLA)、ポリ−(D,L−ラクチド−コ−グリコリド)(PLG)、およびpolyI:Cが含まれる。(例えば、Powell and Newman, "Vaccine design - The Subunit and Adjuvant Approach", 1995, Plenum Press, New York 参照)
本明細書に開示のある種の実施態様によると、GLAワクチン組成物は、抗原をコードする核酸配列に作動可能に連結したプロモーターを含む少なくとも1種の組換え発現コンストラクトを含み得る。ある種のさらなる実施態様では、組換え発現コンストラクトは、アデノウイルス、アデノ随伴ウイルス、ヘルペスウイルス、レンチウイルス、ポックスウイルスまたはレトロウイルスベクターなどのウイルスベクター中に存在する。本明細書で提供されるポリペプチド抗原の発現用のそのような発現コンストラクトおよびベクターを製造および使用するための組成物および方法は当分野で知られており、例えば、Ausubel et al. (Eds.), Current Protocols in Molecular Biology, 2006 John Wiley & Sons, NY による。組換え発現コンストラクトの非限定的な例は、一般的に、例えば、米国特許第6,844,192号;第7,037,712号;第7,052,904号;第7,001,770号;第6,106,824号;第5,693,531号;第6,613,892号;第6,875,610号;第7,067,310号;第6,218,186号;第6,783,981号;第7,052,904号;第6,783,981号;第6,734,172号;第6,713,068号;第5,795,577号および第6,770,445号などに見出され、それらの教示は、本明細書で開示するある種の実施態様において使用するために、本明細書で提供されるポリペプチド抗原の発現に適合させることができる。
従って、本発明は、免疫反応を開始できる宿主における免疫反応を変更(即ち、統計的に有意な増加または減少、例えば、当業者に周知の適当な対照に対して)するための組成物を提供する。当業者に知られている通り、免疫反応は、宿主の免疫状態のいかなる能動的な変更でもあり得、それは、宿主の免疫状態の維持および/または調節に関与する1種またはそれ以上の組織、器官、細胞または分子の構造または機能におけるいかなる変更も含み得る。典型的には、免疫反応は、可溶性免疫グロブリンまたは抗体;サイトカイン、リンホカイン、ケモカイン、ホルモン、増殖因子などの可溶性メディエーター、並びに、他の可溶性小型ペプチド、炭水化物、ヌクレオチドおよび/または脂質メディエーター;免疫系の細胞の機能または構造的特性の変化により測定される細胞の活性化状態の変化、例えば細胞増殖、運動性の変化、特別な遺伝子発現または細胞溶解的挙動などの特別な活動の誘導;表面抗原発現プロフィールの変化またはアポトーシス(プログラムされた細胞死)の開始を含む、免疫系の細胞による細胞の分化;または、免疫反応の存在を検出し得る他の基準のインビボまたはインビトロの測定を含むがこれらに限定されない、様々な周知のパラメーターのいずれによっても検出し得る。
医薬組成物は、一般的に、少なくとも1種の本発明のGLA化合物を含み、例えば、抗原、TLRアゴニスト、コアジュバント(場合により、サイトカイン、イミダゾキノリン免疫反応変更因子、および/または、dSLIMを含む)、および/または、組換え発現コンストラクトから選択される1種またはそれ以上の本発明で提供される成分を、医薬的に許容し得る担体、補助剤または希釈剤と組み合わせて、さらに含み得る。
他の実施態様では、本発明の組成物は、エアロゾル化できるように製剤化される。
実施例1
2−アジド−2−デオキシ−D−グルコピラノシド(2)
2−アジド−2−デオキシ−4,6−O−ベンジリデン−D−グルコピラノシド(3)
TERT−ブチルジメチルシリル−2−アジド−4,6−O−ベンジリデン−2−デオキシ−β−D−グルコピラノシド(4)
TERT−ブチルジメチルシリル−3−O−アリルオキシカルボニル−2−アジド−4,6−O−ベンジリデン−2−デオキシ−D−グルコピラノシド(5)
TERT−ブチルジメチルシリル−3−O−アリルオキシカルボニル−2−アジド−6−O−ベンジル−2−デオキシ−D−グルコピラノシド(6)
TERT−ブチルジメチルシリル−3−O−アリルオキシカルボニル−2−アジド−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−D−グルコピラノシド(7)
TERT−ブチルジメチルシリル−3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−(9−フルオレニルメトキシカルボニルアミノ)−D−グルコピラノシド(8)
3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−(9−フルオレニルメトキシカルボニルアミノ)−D−グルコピラノシド(9)
TERT−ブチルジメチルシリル−6−O−{3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−ドデカノイル]−2−デオキシ−β−D−グルコピラノシド(11)
TERT−ブチルジメチルシリル−6−O−{3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−ドデカノイル]−2−[(R)−3−4−メトキシベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(12)
脂質A(13a)
脂質A(13b)
TERT−ブチルジメチルシリル−6−O−[3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−(9−フルオレニルメトキシカルボニルアミノ)−β−D−グルコピラノシル]−2−アジド−4−O−ベンジル−2−デオキシ−β−D−グルコピラノシド(15)
TERT−ブチルジメチルシリル−6−O−{3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−2−デオキシ−β−D−グルコピラノシド(16)
TERT−ブチルジメチルシリル−6−O−{3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(17)
TERT−ブチルジメチルシリル−6−O−{6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(18)
TERT−ブチルジメチルシリル−6−O−{6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−3−O−[(R)−3−(P−メトキシ)ベンジルオキシテトラデカノイル]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(19)
TERT−ブチルジメチルシリル−6−O−{6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−3−O−[(R)−3−テトラデカノイルオキシ−テトラデカノイル]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(10)
TERT−ブチルジメチルシリル−6−O−{3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−デカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−2−デオキシ−β−D−グルコピラノシド(20)
TERT−ブチルジメチルシリル−6−O−{3−O−アリルオキシカルボニル−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−デカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(21)
TERT−ブチルジメチルシリル−6−O−{6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−ドデカノイルオキシ−テトラデカノイルアミノ]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(22)
TERT−ブチルジメチルシリル−6−O−{6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−デカノイルオキシ−テトラデカノイルアミノ]−3−O−[(R)−3−(P−メトキシ)ベンジルオキシテトラデカノイル]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(23)
TERT−ブチルジメチルシリル−6−O−{6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−デカノイルオキシ−テトラデカノイルアミノ]−3−O−[(R)−3−デカノイルオキシ−テトラデカノイル]−β−D−グルコピラノシル}−2−アジド−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−デオキシ−β−D−グルコピラノシド(24)
TERT−ブチルジメチルシリル−6−O−{6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−デカノイルオキシ−テトラデカノイルアミノ]−3−O−[(R)−3−デカノイルオキシ−テトラデカノイル]−β−D−グルコピラノシル}−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシテトラデカノイル]−2−[(R)−3−ベンジルオキシ−テトラデカノイルアミノ]−2−デオキシ−β−D−グルコピラノシド(25)
6−O−6−O−ベンジル−2−デオキシ−4−O−(1,5−ジヒドロ−3−オキソ−3λ 5 −3H−2,4,3−ベンゾジオキサホスフェピン−3−イル)−2−[(R)−3−デカノイルオキシ−テトラデカノイルアミノ]−3−O−[(R)−3−デカノイルオキシ−テトラデカノイル]−β−D−グルコピラノシル−4−O−ベンジル−3−O−[(R)−3−ベンジルオキシ−テトラデカノイル]−2−[(R)−3−ベンジルオキシ−テトラデカノイルアミノ]−2−デオキシ−α−D−グルコピラノース(26)
(3R)−((2R,3S,4R,5S)−3−((R)−3−(デカノイルオキシ)テトラデカンアミド)−2−(((3S,4R,5S)−3,6−ジヒドロキシ−5−((R)−3−ヒドロキシテトラデカンアミド)−4−((R)−3−ヒドロキシテトラデカノイルオキシ)テトラヒドロ−2H−ピラン−2−イル)メトキシ)−6−(ヒドロキシメチル)−5−(ホスホノオキシ)テトラヒドロ−2H−ピラン−4−イル)3−(デカノイルオキシ)テトラデカノエート(IX)
メチル3−オキソテトラデカノエート(29)
(R)−メチル3−ヒドロキシテトラデカノエート(30)
(R)−メチル3−(ベンジルオキシ)テトラデカノエート(31)
(R)−3−(ベンジルオキシ)テトラデカン酸(33)
(R)−メチル3−(4−メトキシベンジルオキシ)テトラデカノエート(32)
(R)−3−(4−メトキシベンジルオキシ)テトラデカン酸(34)
(R)−3−(4−メトキシベンジルオキシ)テトラデカノイルクロリド(35)
(R)−2−オキソ−2−フェニルエチル3−ヒドロキシテトラデカノエート(37)
(R)−2−オキソ−2−フェニルエチル−3−デカノイルオキシテトラデカノエート(39)
(R)−3−(デカノイルオキシ)テトラデカン酸(40)
(R)−メチル3−ヒドロキシテトラデカノエート(39)
(R)−3−ヒドロキシテトラデカン酸(36)
(R)−2−オキソ−2−フェニルエチル−3−テトラデカノイルオキシテトラデカノエート(46)
(R)−3−(テトラデカノイルオキシ)テトラデカン酸(47)
TERT−ブチルジメチルシリル−2−アジド−4−O−ベンジル−2−デオキシ−β−D−グルコピラノシド(47)
インビボでのTH1型免疫反応の誘導
この実施例は、下記の構造(IX)を有する例示的な本発明のGLA化合物について、インビボでのTh1型免疫賦活活性を立証する:
インビボでのTH1およびTH2型免疫反応の誘導
この実施例は、ID83と呼ばれる結核菌抗原を含有するワクチンにおいて、化合物IXのインビボでのTh1およびTh2型免疫賦活活性を立証する。標準的な免疫学的方法論および試薬を用いた (Current Protocols in Immunology, Coligan et al. (Eds.) 2006 John Wiley & Sons, NY)。
ヒト細胞におけるTLR4依存的免疫疫賦の誘導
この実施例は、ヒト細胞における化合物IXの免疫賦活活性を立証する。1)TLR4、MD−2およびCD14または2)TLR2およびTLR6をコードする発現ベクターを有するHEK293細胞(InvivoGen)を使用して化合物IXをインビトロで試験し、化合物の活性およびTLR4への依存性を明確にし、TLR2の活性化を除外した。TLRシグナル伝達経路の活性化の際に増殖培地にアルカリホスファターゼが分泌されるように、これらのHEK293細胞株を、さらにNF−kBレポーターベクターpNifty−2で安定に形質移入した。形質移入された細胞株を、5x104細胞/ウェルで96ウェルプレートに播き、化合物IXおよび他のアジュバントの連続希釈物を含有する培地で培養して16−24時間刺激した。分泌されたアルカリホスファターゼの活性を、QUANTIBlue(登録商標)アッセイ(InvivoGen)を使用してこの培養培地中で測定した。PBSの負の対照を上回るNF−kBの増強としてデータを測定した。このアッセイを使用して、化合物IXは、0.1μg/mlという低濃度で、2倍を超えるNF−kBの増強を示した(図3)。これらの実験の結果は、TLR2の誘導と関連するとは考えられない化合物IXの明確なTLR4アゴニスト活性を立証した。化合物IXは、MD2およびTLR4の報告された原子構造の構造的検討に基づいて設計された。そのため、それが結合し、商業的に承認されたTLR4アゴニスト(MPL(登録商標))のものと同様のプロフィールを誘起するという事実は、驚異的かつ予想外の結果である。より具体的には、化合物IXのプロフィールは、サイトカインレベルが負の副作用が生じる点まで上昇すると予想される前に、濃度が上昇するにつれて急速に、有利に一定になる。従って、化合物IXおよび他の本発明の例示的化合物は、幅広い濃度範囲にわたって安全に投与できると予想され、このことは、患者間の臨床的成果の再現性および成人および小児で変動する用量での安全性の観点で非常に望ましい。これに関して、化合物IXの低いサイトカイン活性は驚異的かつ望ましい結果であり、それは臨床用の製剤におけるその安全な使用をさらに助長する。
ヒト血液細胞における免疫賦活性サイトカインの誘導
この実施例では、ヒト白血球細胞を化合物IXで刺激し、免疫賦活性サイトカインの誘導を検出するためにELISAアッセイを実施した。化合物IXおよび他のアジュバントの連続希釈(1:5)を、リン酸緩衝塩水で、96ウェルプレート中、全部で7個の希釈物になるよう実施した。2人の異なるドナーから新しく採取したヒト血液100μlを混合し、アジュバント希釈物100μlと共にインキュベートした。20時間のインキュベーションに続き、プレートを遠心分離し、上清(約70μl)を回収し、赤血球細胞を除き、標準的な生化学的手順を使用してMIP−1−αおよびTNF−αのELISAを実施するまで、−20℃で保存した。これらの実験の結果は、化合物IXが初代ヒト血液細胞で免疫賦活活性を有することをさらに裏付けた(図4)。加えて、これらの初代ドナーの結果は、ヒト細胞株で見られる結果に類似し、これらの重要な知見を、この化合物の可能な用量範囲および安全性プロフィールに関して拡大する。
Claims (8)
- 下記の式(V):
L 1 およびL 3 は−O−であり;
L 2 およびL 4 は−NH−であり;
R 1 、R 3 、R 5 およびR 6 は、同一であるかまたは異なり、独立して、C 10−12 アルキルであり;そして、
R 2 およびR 4 は、同一であるかまたは異なり、独立して、C 8−10 アルキルである]
を有するGLA化合物、または、その医薬的に許容し得る塩。 - GLA化合物が以下の構造(IX):
を有する、請求項1に記載のGLA化合物、または、その医薬的に許容し得る塩。 - 抗原または抗原をコードする組換え発現ベクターと共に請求項1または請求項2に記載の化合物を含むワクチン組成物。
- 組換え発現コンストラクトがウイルスベクターである、請求項3に記載のワクチン組成物。
- ウイルスベクターが、アデノウイルスベクター、アデノ随伴ウイルスベクター、ヘルペスウイルスベクター、レンチウイルスベクター、ポックスウイルスベクターおよびレトロウイルスベクターからなる群から選択される、請求項4に記載のワクチン組成物。
- 対象において抗原特異的免疫反応を誘起または増強するためのワクチンの製造における、請求項1または請求項2に記載の化合物の使用。
- 請求項1または請求項2に記載の化合物および医薬的に許容し得る担体または補助剤を含む医薬組成物。
- 対象において非特異的免疫反応を刺激するための医薬の製造における、請求項7に記載の医薬組成物の使用。
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JP2016028042A (ja) * | 2009-06-05 | 2016-02-25 | インフェクシャス ディズィーズ リサーチ インスティチュート | 合成グルコピラノシル脂質アジュバント |
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