JP2020505335A - ウイルス - Google Patents
ウイルス Download PDFInfo
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- JP2020505335A JP2020505335A JP2019537216A JP2019537216A JP2020505335A JP 2020505335 A JP2020505335 A JP 2020505335A JP 2019537216 A JP2019537216 A JP 2019537216A JP 2019537216 A JP2019537216 A JP 2019537216A JP 2020505335 A JP2020505335 A JP 2020505335A
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Abstract
Description
(a)導入遺伝子を有するウイルス粒子を培養し、精製すること、
(b)ウイルス粒子を医薬組成物に配合すること、
(c)任意に組成物を乾燥させること、及び
(d)組成物を患者への経口投与のために錠剤又はカプセルにパッケージすることを含む。
本発明は、患者に導入遺伝子を送達する方法を提供する。特に、本発明は、導入遺伝子を患者の標的細胞に送達する方法を提供する。方法は、導入遺伝子を有するウイルス粒子、特にアデノウイルス粒子の経口投与を含む。
以下でさらに検討するように、本発明は、概して、アデノウイルス粒子を使用して実施する。しかしながら、その他の適切なウイルスはアデノ随伴ウイルス、レンチウイルス及びHSV等の腫瘍溶解性ウイルス並びにワクシニアウイルスである。治療的適用を有するウイルスは当該技術分野において周知である。
本発明の方法は、概して、患者にアデノウイルス粒子を経口投与することを伴う。アデノウイルスは、基礎研究の主題として、並びに遺伝子治療及びワクチンに潜在的に使用するために、感染病原体として広く研究されている。多数のヒトアデノウイルス血清型が識別され、核酸の比較、繊維タンパク質の特徴及び生物特性に基づいて、6つの亜属(AからF)に分類される。例えば、グループAは、血清型12及び31を含み、グループBは血清型3及び7を含み、グループCは血清型2及び5を含み、グループDは、血清型8及び30を含み、グループEは、血清型4を含み、グループFは、血清型40及び41を含む。
ウイルス粒子は、熱安定性を提供する賦形剤と配合される。
概して、R1は、水素又はC1-6アルキルを表し、R4は水素を表す。概して、R2は、水素又はC1-6アルキルを表す。好ましくは、R1は、水素又はC1-6アルキルを表し、R4は水素を表し、R2は、水素又はC1-6アルキルを表す。より好ましくは、R1は、水素又はC1-6アルキルを表し、R4は水素を表し、R2はC1-6アルキルを表す。
概して、カルボン酸(carboxylate)及びRcのアミン置換基は、Rcアルキル部分の同炭素原子に結合する。概して、Rcは、C2-4又はC2-3アルキル部分である。
本発明の使用に適した糖として、グルコース、フルクトース、グリセルアルデヒド、ラクトース、アラビノース及びマルトース等の還元糖が挙げられ、好ましくはショ糖及びラフィノース等の非還元糖、より好ましくはショ糖が挙げられる。糖は、単糖、二糖、三糖又はその他のオリゴ糖であってもよい。「糖」という用語は、糖アルコールを含む。したがって、一実施形態において、非還元糖又は糖アルコールの使用が好ましい。
本発明では、ウイルス粒子、任意選択で1つ以上の糖並びに式(I)の化合物又はその生理学的に許容される塩若しくはエステル及び/或いは式(II)の化合物又はその生理学的に許容される塩若しくはエステルを含む水溶液は、概して乾燥させる。任意の適切な水溶液を使用してもよい。溶液は緩衝されてもよい。溶液は、HEPES、リン酸緩衝液、トリス緩衝液又は純水溶液であってもよい。
- Xが-S(O)2-を表す式(II)の化合物、若しくはMSM等の式(IIA)の化合物、又はその生理学的に許容される塩若しくはエステルの濃度は、好ましくは、0.2mM〜1M、例えば、0.35mM〜1M、3.5mM〜0.5M、0.035M〜0.5M又は0.035M〜0.25Mである。
- 式(I)の化合物、又はTMG等の式(IA)若しくは式(IB)の化合物或いはその生理学的に許容される塩又はエステルの濃度は、好ましくは、0.01M〜2M、例えば、0.07M〜2M、0.2M〜1.5M、0.23M〜1.5M又は0.07M〜0.7Mの濃度で使用される。
- Xが-S+(Rc)-を表す式(II)の化合物、若しくはS-メチル-L-メチオニン等の式(IIB)の化合物、又はその生理学的に許容される塩若しくはエステルの濃度は、好ましくは、0.005M〜2M、例えば、0.007M〜2M、0.02M〜2M、0.023M〜1.5M又は0.07M〜1Mである。
- N,N-ジメチルグリシン(DMG)等の式(I)の化合物又はその生理学的に許容される塩若しくはエステルの濃度は、糖が存在しない場合、5mM〜1.5M、又は70mM〜1.5M、若しくは〜1.2M、又は7mM〜1Mである。より好ましい濃度は、0.023M〜0.7M若しくは1M、又は0.07M〜0.7M若しくは1M、例えば約0.7Mである。
- N,N-ジメチルグリシン(DMG)等の式(I)の化合物又はその生理学的に許容される塩若しくはエステルの濃度は、1つ以上の糖が存在する場合、概して低く、1mM〜1M若しくは1.5M又は5mM〜1Mの範囲である。より好ましい濃度は、0.007M〜0.7M又は1M、例えば約0.007Mである。特に好ましい範囲は、0.5〜1.5Mである。
- 乾燥について水溶液中のN-アルキル化グリシン誘導体又はその塩若しくはエステルの濃度は、概して、0.1mM〜3M又は1mM〜2Mの範囲である。濃度は、1mM〜1.5M又は5mM〜1Mであってもよい。好ましい濃度は、0.1M〜1.5M又は0.5M〜1.25Mである。
- 乾燥について水溶液中の式(IIA)又は(IIC)のスルホン化合物の濃度は、概して、0.1mM〜3M、1mM〜2M又は0.2mM〜1Mの範囲である。濃度は、0.1M〜1.5M又は0.5M〜1.25Mであってもよい。
本明細書に記載の医薬組成物は、水性懸濁液若しくは溶液又はトローチの形態で投与され得るが、概して、錠剤又はカプセルとして投与される。組成物は、また、ゼラチンウエハーとして投与され得る。錠剤はコーティングされていても、コーティングされていなくともよい。好ましくは、組成物は、ゼラチンカプセル等のカプセルに組み込まれる。
患者は、概してヒトであるが、家畜動物、コンパニオンアニマル(イヌ又はネコ等)又は畜産動物(ヒツジ、ブタ、ウシ)等の動物でもあり得る。
本発明はまた、患者への経口投与のためのウイルス粒子を調製する方法を提供する。方法は、概して、ウイルス粒子を培養し、精製すること、粒子を組成物に配合すること、任意に組成物を乾燥させること、及び患者への経口投与のために組成物を錠剤又はカプセルにパッケージすることを含む。
2つのアデノウイルス(ヒトアデノウイルス5型(dE1/E3))構築物を標準的な分子生物学的技術によって調製した。第1のアデノウイルスは、INS(プロインスリン)発現を駆動するGIP(グルコース依存性インスリン分泌刺激ポリペプチド)プロモーター(GIP-INSとして示す)を有していた。使用した配列は、Biol Res 44:301-305、2011及びNCBI参照配列(プロインスリン)NM_019129.2/3に記載の1.2kbのラットGIP挿入物であった。第2のアデノウイルスは、「null」eGFP(720bp、Gene. 1996;173(1 Spec No):33-8)構築物(GIP-GFPとして示す)を有し、増強した緑色蛍光タンパク質を発現した。GFPの発現は、インスリンカセットについて、同プロモーター系を使用して制御した。
- N,N-ジメチルグリシン(DMG)(0.2M)、
- メチルスルホニルメタン(MSM)(0.2M)及び
- ショ糖(0.4M)。
BChE(ブチリルコリンエステラーゼ)発現を駆動するCMV(サイトメガロウイルス)プロモーターから構成されるアデノウイルス(ヒトアデノウイルス5型(dE1/E3))構築物を標準的な分子生物学的技術によって調製し、Ad5-CMV-BChEとして示した。NCBI参照配列:-ブチリルコリンエステラーゼNM_022942.1、ラット種を使用した。
ジカ抗原(E及びNS1)発現を駆動するCMVプロモーターから構成されるアデノウイルス(血清型5)構築物(dE1/E3)を調製し、Ad5_FP(E/NS1)_GWとして示した。高力価のウイルスストックをHEK293細胞のウイルス培養によって調製し、次に、賦形剤(0.4Mのショ糖、0.2MのDMG、0.2のMSM)と配合し、凍結乾燥した。得られたケーキ、粉末をブタゼラチンカプセルに充填し、次に、腸溶コーティングして、より低いGI送達を高めた。
クロミミマーモセットにおいて、経口ジカワクチンの試験を行った(免疫前対照の2匹、プラセボの2匹、ワクチン接種の2匹)。前述のようにワクチン製剤を調製し、腸溶コーティングされたカプセルに充填した(1用量につき2.1x108TCID50のワクチン及び2.5x108TCID50のプラセボ)。カプセルを製造後約1か月間、周囲温度で保管した。カプセルを0日目及び13日目に2回投与した。
Claims (72)
- 導入遺伝子を有するウイルス粒子を含む産物の経口投与を含む、患者の標的細胞に導入遺伝子を送達する方法。
- ウイルス粒子がアデノウイルス粒子である、請求項1に記載の方法。
- 産物が腸溶コーティングをさらに含む、請求項1又は2に記載の方法。
- 導入遺伝子が治療用タンパク質をコードする、請求項1から3の何れか一項に記載の方法。
- 治療用タンパク質がインスリン又はブチリルコリンエステラーゼである、請求項4に記載の方法。
- 導入遺伝子が1つ以上の抗原をコードする、請求項1から4の何れか一項に記載の方法。
- 導入遺伝子が1つ以上のジカウイルス抗原をコードする、請求項6に記載の方法。
- ジカウイルス抗原がエンベロープタンパク質(E)及び/又はNS1に由来する、請求項7に記載の方法。
- 導入遺伝子が1つ以上の単純ヘルペスウイルス(HSV)、任意選択でHSV2、抗原をコードする、請求項6に記載の方法。
- HSV抗原が糖タンパク質C(gC)、糖タンパク質D(gD)及び/又は糖タンパク質E(gE)に由来する、請求項9に記載の方法。
- 導入遺伝子の発現が組織特異的プロモーターによって制御される、請求項1から10の何れか一項に記載の方法。
- プロモーターがグルコース依存性インスリン分泌刺激ポリペプチドプロモーターである、請求項11に記載の方法。
- 治療用タンパク質がインスリンであり、インスリンの発現がグルコース依存性インスリン分泌刺激ポリペプチドプロモーターによって制御される、請求項12に記載の方法。
- アデノウイルス粒子が
(a)ウイルス粒子、
(b)任意選択で1つ以上の糖並びに
(c)式(I)の化合物又はその生理学的に許容される塩若しくはエステル
R1は、水素若しくはC1-6アルキルを表し、
R4は、水素を表し、又は
R1及びR4は、それらが結合する原子と一緒になってピロリジン環を形成し、
R2は、水素、C1-6アルキル又は-(CH2)2-5NHC(O)(CH2)5-15CH3を表し、
R3は、C1-6アルキルを表す)
及び/或いは式(II)の化合物又はその生理学的に許容される塩若しくはエステル
Xは、-S(O)2-又は-S+(Rc)-を表し、
Ra及びRbは、独立してC1-6アルキルを表し、
Rcは、カルボン酸アニオン及びアミン(-NH2)部分で置換されたC1-6アルキルを表す)
を含む医薬組成物に配合される、請求項1から13の何れか一項に記載の方法。 - 水溶液が式(I)の化合物若しくはその生理学的に許容される塩又は式(II)の化合物若しくはその生理学的に許容される塩を含む、請求項14に記載の方法。
- 式(I)の化合物がN,N-ジ(C1-6アルキル)-、N,N,N-トリ(C1-6アルキル)-、若しくはN-C1-6アルキル-グリシン又はその生理学的に許容される塩若しくはエステルである、請求項14又は15に記載の方法。
- 式(I)の化合物が、(a)N,N-ジメチルグリシン、N,N,N-トリメチルグリシン、若しくはN-メチルグリシン又はその生理学的に許容される塩若しくはエステル或いは(b)N-メチルグリシン、N,N-ジメチルグリシン、若しくはN,N,N-トリメチルグリシン又はその塩酸塩である、請求項16に記載の方法。
- 式(I)の化合物がN,N-ジメチルグリシン又はその生理学的に許容される塩若しくはエステルである、請求項17に記載の方法。
- 請求項14又は15に記載の方法であって、
式(I)の化合物が式(IA)の化合物又はその生理学的に許容される塩若しくはエステルであり、
式(I)の化合物が式(IB)の化合物又はその生理学的に許容される塩若しくはエステルであり、
式(II)の化合物が式(IIA)の化合物又はその生理学的に許容される塩若しくはエステルであり、
式(II)の化合物が式(IIB)の化合物又はその生理学的に許容される塩若しくはエステルである、
- 式(I)又は(II)の化合物がジメチルスルホン、トリメチルグリシン、コカミドプロピルベタイン、プロリンベタイン若しくはS-メチル-L-メチオニン又はその生理学的に許容される塩若しくはエステルである、請求項14、15又は19の何れか一項に記載の方法。
- (a)水溶液が1つ以上の糖を含み、式(I)若しくは(II)の化合物又はその生理学的に許容される塩若しくはエステルの濃度が0.1mM〜2.5Mであり、糖濃度、又は2つ以上の糖が存在する場合、合計糖濃度が少なくとも0.01Mであり、或いは(b)式(I)若しくは(II)の化合物又はその生理学的に許容される塩若しくはエステルの濃度が0.1mM〜3Mである、請求項15から20の何れか一項に記載の方法。
- 式(I)若しくは(II)の化合物又はその生理学的に許容される塩若しくはエステルの濃度が(a)0.001M〜2.5M、0.01M〜2.5M若しくは0.1M〜2M、又は(b)7mM〜1.5M若しくは0.07M〜0.7M、又は(c)7mM〜1.5M若しくは0.07M〜1M、又は(d)0.05M〜2M、0.02M〜2M若しくは0.07M〜1Mである、請求項15から20の何れか一項に記載の方法。
- 水溶液が式(I)の化合物又はその生理学的に許容される塩及び式(II)の化合物又はその生理学的に許容される塩を含む、請求項14に記載の方法。
- 水溶液が、請求項13から15の何れか一項で定義される通りの式(I)の化合物又はその生理学的に許容される塩及び式(IIC)のスルホン化合物
- 前記水溶液中の式(I)の化合物又はその生理学的に許容される塩の濃度が0.1〜1.5Mである、請求項24に記載の方法。
- 式(IIC)のスルホン化合物がメチルスルホニルメタンである、請求項24又は25に記載の方法。
- 前記水溶液中の式(IIC)のスルホン化合物の濃度が0.1〜1.5Mである、請求項24から26の何れか一項に記載の方法。
- (a)糖濃度若しくは合計糖濃度が0.1M〜3M若しくは0.2M〜2Mであり、(b)溶液が少なくとも0.1Mの濃度で若しくは2つ以上の糖が存在する場合、合計糖濃度で1つ以上の糖を含み、又は(c)水溶液の糖濃度が0.05〜1Mである、請求項14から27の何れか一項に記載の方法。
- 組成物が非還元糖又は糖アルコールを含む、請求項14から28の何れか一項に記載の方法。
- 2つ以上の糖を使用し、糖のうちの1つがショ糖である、請求項14から29の何れか一項に記載の方法。
- その他の糖に対するショ糖の濃度の比が1:1〜20:1である、請求項30に記載の方法。
- その他の糖がラフィノースである、請求項30又は31に記載の方法。
- 組成物がマンニトールを含む、請求項14から31の何れか一項に記載の方法。
- マンニトールである1つの糖が存在し、又はショ糖及びラフィノースである2つの糖が存在する、請求項14から29の何れか一項に記載の方法。
- 水溶液がショ糖又はマンニトールを含む、請求項29に記載の方法。
- 組成物が0.2MのN,N-ジメチルグリシン、0.2Mのジメチルスルホン及び0.4Mのショ糖を含む、請求項14に記載の方法。
- 組成物が乾燥粉末である、請求項14から36の何れか一項に記載の方法。
- 組成物が錠剤又はカプセルの形態で患者に投与される、請求項14から37の何れか一項に記載の方法。
- 錠剤又はカプセルが腸溶コーティングされる、請求項37に記載の方法。
- 導入遺伝子を有するウイルス粒子を含む医薬組成物を含む、患者に経口投与するための錠剤又はカプセル。
- ウイルスがアデノウイルスである、請求項40に記載の錠剤又はカプセル。
- 組成物が請求項14又は16から25の何れか一項で定義される通りの式(I)の化合物又はその生理学的に許容される塩若しくはエステル、及び/或いは請求項14、19から24、26又は27の何れか一項で定義される通りの式(II)の化合物又はその生理学的に許容される塩若しくはエステル、並びに任意選択で1つ以上の糖、好ましくはショ糖を含む、請求項40又は41に記載の錠剤又はカプセル。
- 糖が請求項28から35の何れか一項で定義される通りである、請求項42に記載の錠剤又はカプセル。
- 組成物が0.2MのN,N-ジメチルグリシン、0.2Mのジメチルスルホン及び0.4Mのショ糖を含む、請求項40又は41に記載の錠剤又はカプセル。
- 導入遺伝子が治療用タンパク質をコードする、請求項40から44の何れか一項に記載の錠剤又はカプセル。
- 治療用タンパク質がインスリン又はブチリルコリンエステラーゼである、請求項45に記載の錠剤又はカプセル。
- 導入遺伝子が1つ以上の抗原をコードする、請求項40から45の何れか一項に記載の錠剤又はカプセル。
- 導入遺伝子が1つ以上のジカウイルス抗原をコードする、請求項47に記載の錠剤又はカプセル。
- 導入遺伝子が、エンベロープタンパク質(E)及び/又はNS1に由来する1つ以上のジカウイルス抗原をコードする、請求項48に記載の錠剤又はカプセル。
- 導入遺伝子が1つ以上のHSV、任意選択でHSV2、抗原をコードする、請求項47に記載の錠剤又はカプセル。
- 導入遺伝子が、糖タンパク質C(gC)、糖タンパク質D(gD)及び/又は糖タンパク質E(gE)に由来する1つ以上のHSV抗原をコードする、請求項50に記載の錠剤又はカプセル。
- 導入遺伝子の発現が組織特異的プロモーターによって制御される、請求項40から51の何れか一項に記載の錠剤又はカプセル。
- プロモーターがグルコース依存性インスリン分泌刺激ポリペプチドプロモーターである、請求項52に記載の錠剤又はカプセル。
- 治療用タンパク質がインスリンであり、インスリンの発現がグルコース依存性インスリン分泌刺激ポリペプチドプロモーターによって制御される、請求項53に記載の錠剤又はカプセル。
- 組成物を錠剤又はカプセルにパッケージする前に乾燥させる、請求項40から54の何れか一項に記載の錠剤又はカプセル。
- 腸溶コーティングでコーティングされる、請求項40から55の何れか一項に記載の錠剤又はカプセル。
- 患者への経口投与のための導入遺伝子を有するウイルス粒子を調製する方法であって、
(a)導入遺伝子を有するウイルス粒子を培養し、精製すること、
(b)ウイルス粒子を医薬組成物に配合すること、
(c)任意選択で組成物を乾燥させること、及び
(d)組成物を患者への経口投与のために錠剤又はカプセルにパッケージすることを含む方法。 - ウイルス粒子がアデノウイルス粒子である、請求項57に記載の方法。
- ウイルス粒子が請求項14から36の何れか一項に記載の組成物に配合される、請求項57又は58に記載の方法。
- 導入遺伝子が治療用タンパク質をコードする、請求項57、58又は59に記載の方法。
- 治療用タンパク質がインスリン又はブチリルコリンエステラーゼである、請求項60に記載の方法。
- 導入遺伝子が1つ以上の抗原をコードする、請求項57から60の何れか一項に記載の方法。
- 導入遺伝子が1つ以上のジカウイルス抗原をコードする、請求項62に記載の方法。
- 導入遺伝子が、エンベロープタンパク質(E)及び/又はNS1に由来する1つ以上のジカウイルス抗原をコードする、請求項63に記載の方法。
- 導入遺伝子が1つ以上のHSV、任意選択でHSV2、抗原をコードする、請求項62に記載の方法。
- 導入遺伝子が、糖タンパク質C(gC)、糖タンパク質D(gD)及び/又は糖タンパク質E(gE)に由来する1つ以上のHSV抗原をコードする、請求項65に記載の方法。
- 導入遺伝子の発現が組織特異的プロモーターによって制御される、請求項57から66の何れか一項に記載の方法。
- プロモーターがグルコース依存性インスリン分泌刺激ポリペプチドプロモーターである、請求項67に記載の方法。
- 治療用タンパク質がインスリンであり、インスリンの発現がグルコース依存性インスリン分泌刺激ポリペプチドプロモーターによって制御される、請求項68に記載の方法。
- 錠剤又はカプセルが腸溶コーティングでコーティングされる、請求項57から69の何れか一項に記載の方法。
- 導入遺伝子を有するウイルス粒子の経口投与を含む、患者の標的細胞に導入遺伝子を送達する方法に使用するためのウイルス粒子を含む産物。
- ウイルス粒子がアデノウイルス粒子である、請求項71に記載の使用するための産物。
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JP2021168616A (ja) * | 2020-04-16 | 2021-10-28 | デンカ株式会社 | アデノウイルスの免疫測定方法及び免疫測定器具 |
JP7436274B2 (ja) | 2020-04-16 | 2024-02-21 | デンカ株式会社 | アデノウイルスの免疫測定方法及び免疫測定器具 |
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CA3048313A1 (en) | 2018-07-12 |
WO2018127702A1 (en) | 2018-07-12 |
US20190350846A1 (en) | 2019-11-21 |
AU2018206304A1 (en) | 2019-07-04 |
EP3565591A1 (en) | 2019-11-13 |
MX2019008105A (es) | 2020-07-22 |
IL267785A (en) | 2019-09-26 |
JP2023098938A (ja) | 2023-07-11 |
CN110621350A (zh) | 2019-12-27 |
KR20190104051A (ko) | 2019-09-05 |
BR112019014004A2 (pt) | 2020-02-11 |
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