JP7483828B2 - Clostridium difficile感染症の処置 - Google Patents
Clostridium difficile感染症の処置 Download PDFInfo
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- JP7483828B2 JP7483828B2 JP2022172637A JP2022172637A JP7483828B2 JP 7483828 B2 JP7483828 B2 JP 7483828B2 JP 2022172637 A JP2022172637 A JP 2022172637A JP 2022172637 A JP2022172637 A JP 2022172637A JP 7483828 B2 JP7483828 B2 JP 7483828B2
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Description
□本願は2016年6月14日に出願の米国仮出願第62/349,914号の、米国特許法第119条(e)による優先権を主張し、参照によってその全体を本明細書中に組み込む。
本明細書において提供される幾つかの態様において、組成物は、少なくとも3、少なくとも4、少なくとも5、少なくとも6、少なくとも7、少なくとも8、少なくとも9、少なくとも10、少なくとも11、少なくとも12、少なくとも13、少なくとも14、少なくとも15、少なくとも16、少なくとも17、少なくとも18、少なくとも19または少なくとも20の精製された菌株を含む。
本明細書において提供される組成物の幾つかの態様において、菌株の1つ以上は、栄養増殖形態である。本明細書において提供される組成物の幾つかの態様において、菌株の各々は、栄養増殖形態である。
本明細書において提供される組成物の幾つかの態様において、菌株の1つ以上は、baiCD-である。本明細書において提供される組成物の幾つかの態様において、菌株の各々は、baiCD-である。本明細書において提供される組成物の幾つかの態様において、組成物は、胆汁酸の7-アルファ-脱ヒドロキシ反応を媒介しない。本明細書において提供される組成物の幾つかの態様において、組成物は、C.difficile毒素産生を阻害する。本明細書において提供される組成物の幾つかの態様において、組成物は、C.difficileの複製および/または生存を阻害する。
本明細書において提供される組成物の幾つかの態様において、組成物は、制御性T細胞(Treg)の増殖および/または蓄積を誘導する。
本明細書において提供される組成物の幾つかの態様において、組成物は、少なくとも3、少なくとも4、少なくとも5、少なくとも6、少なくとも7、少なくとも8、少なくとも9、少なくとも10、少なくとも11、少なくとも12、少なくとも13、少なくとも14、少なくとも15、少なくとも16、少なくとも17、少なくとも18、少なくとも19または少なくとも20の精製された菌株を含む。
本明細書において提供される組成物の幾つかの態様において、菌株の1つ以上は、栄養増殖形態である。本明細書において提供される組成物の幾つかの態様において、菌株の各々は、栄養増殖形態である。
本明細書において提供される組成物の幾つかの態様において、組成物は、1よりも多くのヒトドナーに由来する菌株を含む。
本明細書において提供される組成物の幾つかの態様において、組成物は、制御性T細胞(Treg)の増殖および/または蓄積を誘導する。
本明細書において提供される方法の幾つかの態様において、対象は、組成物の投与前に、抗生物質の1ドーズを投与されている。本明細書において提供される方法の幾つかの態様において、対象は、組成物の投与前に、抗生物質の1ドーズよりも多くを投与されている。本明細書において提供される方法の幾つかの態様において、対象は、組成物の投与前に、抗生物質を投与されていない。
本明細書において提供される方法の幾つかの態様において、投与は、制御性T細胞(Treg)の増殖および/または蓄積をもたらす。
組成物F
組成物F、株の群分け
*短鎖脂肪酸の凡例:
A、アセテート; B、ブチレート; L、ラクテート;
P、プロピオネート; S、スクシネート
図19に示すように、組成物Gは、次の16S rDNA配列を有する細菌を含有する:
配列番号27、配列番号43、配列番号44、配列番号51、配列番号55、配列番号68、配列番号72、配列番号70、配列番号24、配列番号34、配列番号37、配列番号46、配列番号76、配列番号77、配列番号35、配列番号62、配列番号26、配列番号63、配列番号67、配列番号40、配列番号38、配列番号47、配列番号56、配列番号25および配列番号32。
組成物G
幾つかの態様では、本開示は、配列番号86、配列番号95、配列番号98、配列番号110、配列番号122および配列番号123からなる群から選択される核酸配列と少なくとも97%の相同性を有する16S rDNA配列を含む2つ以上の精製された菌株を包含する組成物を提供する。
胞子形成菌株の胞子形成を誘導する方法は、当分野において周知である(例えばParedes-Sabja et al., Trends Microbiol. (2011) 19(2):85-94を参照)。一般的に、胞子形成菌である菌株は、菌株にストレスを与えることにより胞子形態となり得る。胞子形成を誘導できるストレスの非限定的な例は、温度上昇、利用できる栄養分の変化、および/または化学物質(例えばエタノールまたはクロロホルム)に対する曝露である。なお、例えば胞子形成遺伝子を欠いているために非胞子形成菌である細菌には、ストレスにより胞子を形成させることができない点に留意する必要がある。全ての菌株が胞子形態である組成物を調製するためには、組成物の調製に用いる組成物または細菌培養物は、例えば組成物を加熱し、また非胞子形成細菌を化学的に分解することによって、胞子形態でない(例えば栄養増殖形態である)あらゆる細菌を殺菌するための処置に付すことができる。胞子形態の細菌は、例えば濾過により、非胞子形態細菌からその後分離することができる。
幾つかの態様では、対象は病原菌の保菌者であり、感染による影響(例えばC.difficile毒素により生じる下痢)を受けている。幾つかの態様では、対象は、無症候性の病原体の保菌者である。幾つかの態様では、対象は、C.difficileの保菌者である。幾つかの態様では、対象は、無症候性C.difficile保菌者である。幾つかの態様では、対象は、再発性または慢性の病原体感染症を経験している。幾つかの態様では、対象は、初発性の特定の病原体感染症に罹患している。幾つかの態様では、対象は、抗生物質により処置された結果、再発性の病原体感染症に罹患している。幾つかの態様では、対象は、抗生物質により処置された結果、初発性の病原体感染症に罹患している。幾つかの態様では、対象は、対象の感染症リスクが大きくなる処置を受けることになっている。幾つかの態様では、病原体による感染リスクを低下させるために、本明細書において提供される組成物が対象に投与される。
幾つかの態様では、本明細書中に開示される医薬組成物は、用量当たり組成物の各細菌を、10-7~10-1、10-6~10-1、10-5-10-1、10-4~10-1、10-3~10-1、10-2~10-1、10-7-10-2、10-6~10-2、10-5~10-2、10-4~10-2、10-3-10-2、10-7~10-3、10-6~10-3、10-5~10-3、10-4-10-3、10-7~10-4、10-6~10-4、10-5~10-4、10-7-10-5、10-6~10-5または10-7~10-6g含有する。幾つかの態様では、本明細書中に開示される医薬組成物は、用量当たり組み合わせた全細菌を、10-7~10-1、10-6~10-1、10-5~10-1、10-4~10-1、10-3~10-1、10-2~10-1、10-7~10-2、10-6~10-2、10-5~10-2、10-4~10-2、10-3~10-2、10-7~10-3、10-6~10-3、10-5~10-3、10-4~10-3、10-7~10-4、10-6~10-4、10-5~10-4、10-7~10-5、10-6~10-5または10-7~10-6g含有する。
マウスの飼育
Jackson Laboratories(Bar Harbor,ME)から購入し、換気式無菌ケージに収容されたC57BL/6Jメスマウスを用いて実験を行った。全ての動物をSPF設備において維持した。動物を、試験(すなわち抗生物質による試験コースの開始)の前に少なくとも3日間動物施設で馴化させた。C.difficile感染に関わる実験において、200μlのPBS中、10~104個のC.difficile VPI 10463の胞子をマウスに強制経口投与した。実験は、施設のガイドラインに従い行い、Institutional Animal Care and Use Committeeの承認を得て行った。無菌の餌料および飲料水を動物に供給した。
各菌株を健康ドナーから得た糞便材料から単離した。嫌気性チャンバー内の5%のウマ血液を含むEG(Eggerth Gagnon)寒天プレート上へ個々の菌株を15パーセントのグリセロール凍結ストックからストリークし、37℃で24~48時間インキュベートした。コロニーを事前に還元させた液体ペプトンイーストグルコース(PYG)培地に接種し、24~48時間、密度が濃くなるまで(嫌気性チャンバー中、スタティック)増殖させた。培養液の光学濃度(OD600)を評価し、嫌気性チャンバ内で生きたバイオ治療薬(LBP)カクテルを調製し、その際、PBS(無菌、前処理済)中、等しいCFU比カクテルとなるよう、OD600に基づき添加量を調整した。
糞便ペレットを回収し、嫌気性チャンバーへ移し(<2時間)、ピペットの先端を用いて、繰り返しピペッティングによって、手作業で事前に還元させた500μLのPBS中にホモジナイズした。糞便のホモジネートの段階希釈物を、事前に還元させたPBSにおいて調製し、その100μLを、タウロコール酸ナトリウムを含むシクロセリン-セフォキシチン-フルクトース寒天(TCCFA)プレート上にスプレッドし、37℃、嫌気条件下でインキュベートした。48時間のC.difficileのCFUを計数した。
マウスの群に対し、3つの抗生物質レジメンを用いて、C.difficileに対する感受性について評価した:(1)抗生物質カクテル、(2)クリンダマイシン投与、または(3)セフォペラゾン投与(図2および3)。抗生物質カクテルは、-10日目から-3日目まで飲料水中のカナマイシン(0.4mg/ml)、ゲンタマイシン(0.035mg/ml)、コリスチン(0.056mg/ml)、メトロニダゾール(0.215mg/ml)、バンコマイシン(0.045mg/ml)、次に腹腔内クリンダマイシン単回注射(200μg/マウス)からなった。クリンダマイシンの投与は、-1日目に、クリンダマイシン(200μg/マウス)の単回腹腔内注射で行った。日の表記は、C.difficileへの感染日の0日目に対して相対的である。
組成物A、
組成物B、
組成物C、
組成物D、
組成物E(例えばNarushima et al., Gut Microbes (2014) 5(3) 333-339)および
組成物I:Clostridium scindens、Pseudoflavonifractor capillosusおよびBlautia hanseniiの混合物(図5)。
10~12週齢のマウスの群を、C.difficileマウスモデルに用いた(図9)。マウスに対し、例1にて説明したようにセフォペラゾン処置を行った。1つのマウスの群には、次に、セフォペラゾン処理終了2日後に、例1および2にて説明したように組成物B(マウス当たり108CFU)を強制経口投与した。他のマウスの群には、セフォペラゾン処置の後、生きたバイオ治療薬を投与しなかった(対照)。24時間後に、マウスをC.difficileに感染させ(104個のC.difficile胞子)、次に生存率/死亡率(図10)、体重(図11)およびC. difficile量(糞便g当たりのCFU、図12)について評価した。これらの結果は、C.difficile感染前の組成物Bによる処置が、C.difficile感染に対する有効な防御または処置であることを証明する例2の結果を確認するものである。
図13は、生きているバイオ治療薬(LBP)組成物Fの株を示す。属-種分類は、単離された株の配列に基づく最も近い種を示す。図14は、組成物F中の株のClostridiumクラスターによる分類を示す。
図19は、組成物Gの株を示す。属-種の表記は、単離した株の配列に基づく最も近い種を示す。組成物Gは、組成物Fの株のサブセットを包含する。マウスの群に対し、上の例にて説明したようにセフォペラゾンを投与し、次にLBPを投与した。
組成物B;
組成物B-1(組成物BにBacteroidesを添加);
組成物B-2(組成物BからFlavonifractor plautiiを除き、Bacteroidesを添加);
組成物F;
組成物G;
エタノール処理したヒト糞便サンプル;
エタノール処理した組成物B;
凍結させた組成物B;または
組成物J:エタノール処理したClostridium innocuum、Clostridium bolteaeおよびClostridium symbiosum;
(図20も参照)。
マウスの群に対し、上記のとおりセフォペラゾン処置を行い、次にヒトの糞便移植、組成物B、組成物B+4種の胞子または組成物Hを投与した(図25)。「組成物B+4種の胞子」とは、組成物Bに加え、胞子形態の以下の4つの株を指す:Clostridium bolteae、Anaerotruncus colihominis、Clostridium symbiosumおよびClostridium innocuum。組成物Hは、胞子形態の以下の6つの株を含有する:Clostridium bolteae、Anaerotruncus colihominis、Clostridium symbiosum、Clostridium innocuum、Clostridium disporicumおよびErysipelatoclostridium ramosum(図26)。
ベロ細胞(アフリカミドリザル腎臓上皮由来の上皮細胞)は、C.difficileのB毒素を含む種々の細菌毒素に感受性である。C.difficileのB毒素に対する細胞の曝露により、Rho、RacおよびCdc42の機能が阻害され、それによりF-アクチンの減少、細胞形態の変化(例えば細胞の球状化)、最終的にはアポトーシスに至る。
組成物Bの、インビトロ混合培養競合アッセイによるClostridium difficile増殖を抑制する能力を算定した。グリセロール凍結ストックから、組成物B、C.difficile(Cdiff)、Clostridium bifermentansおよびBacteroides thetaiotaomicronの個々の株を、ウマ血液を含むEggerth-Gagnon寒天プレート(EG+HB)上へストリークした。各株の単一コロニーを、その後ブレーンハートインフュージョン(BHI)液体培地に接種し、24~48時間純粋培養して増殖させた。
組成物Bの各株を、インビトロでの個々の短鎖脂肪酸(SCFA)産生について評価した。組成物Bの株を嫌気性チャンバー内で純粋培養により増殖させた。液体培地での培養後の使用済み上清を遠心分離して回収し、フィルター滅菌し、それから<-70℃で保存した。凍結させた清澄な上清試料を短鎖脂肪酸(SCFA)について分析した。
組成物Bの菌株の各々を対数増殖期にまで増殖させ、組み合わせてマウスあたり約108cfuの合計ドーズとした。無菌マウスに、組成物Bまたは陰性対照を強制経口投与により接種し、4週間のコロニー形成の後、犠牲死させた。粘膜固有層白血球を、標準的な手順によって個々のマウスの結腸組織から単離し、フローサイトメトリにより算定した。制御性T細胞の含量を、CD4+T細胞中のFoxp3陽性細胞のパーセンテージとして評価した。
Claims (23)
- 精製された細菌混合物を含む組成物であって、精製された細菌混合物が、
(i)Flavonifractor plautiiに属する菌株;
(ii)Anaerotruncus colihominisに属する菌株;
(iii)Sellimonas intestinalisに属する菌株;
(vi)Clostridium symbiosumに属する菌株;
(v)Clostridium bolteaeに属する菌株;
(vi)Dorea longicatenaに属する菌株;
(vii)Blautia productaに属する菌株;および
(viii)Clostridium innocuumに属する菌株
を含む、組成物。 - 精製された細菌混合物を含む組成物であって、精製された細菌混合物が8~10の菌株からなり、
(i)Flavonifractor plautiiに属する1以上の菌株;
(ii)Anaerotruncus colihominisに属する1以上の菌株;
(iii)Sellimonas intestinalisに属する1以上の菌株;
(vi)Clostridium symbiosumに属する1以上の菌株;
(v)Clostridium bolteaeに属する1以上の菌株;
(vi)Dorea longicatenaに属する1以上の菌株;
(vii)Blautia productaに属する1以上の菌株;および
(viii)Clostridium innocuumに属する1以上の菌株
を含む、組成物。 - 精製された細菌混合物を含む組成物であって、精製された細菌混合物が、
(i)Flavonifractor plautiiに属する菌株;
(ii)Anaerotruncus colihominisに属する菌株;
(iii)Sellimonas intestinalisに属する菌株;
(vi)Clostridium symbiosumに属する菌株;
(v)Clostridium bolteaeに属する菌株;
(vi)Dorea longicatenaに属する菌株;
(vii)Blautia productaに属する菌株;および
(viii)Clostridium innocuumに属する菌株
からなる、組成物。 - 菌株の1つ以上が、胞子形成菌である、請求項1から3のいずれか一項に記載の組成物。
- 菌株の1つ以上が、胞子形態である、請求項1から4のいずれか一項に記載の組成物。
- 菌株の各々が、胞子形態である、請求項1から5のいずれか一項に記載の組成物。
- 菌株の1つ以上が、栄養増殖形態である、請求項1から5のいずれか一項に記載の組成物。
- 菌株の各々が、栄養増殖形態である、請求項1から4のいずれか一項に記載の組成物。
- 菌株が、ヒト由来の菌株である、請求項1から8のいずれか一項に記載の組成物。
- 菌株が、1よりも多くのヒトドナーに由来する、請求項1から9のいずれか一項に記載の組成物。
- 菌株が、凍結乾燥されている、請求項1から10のいずれか一項に記載の組成物。
- 請求項1から11のいずれか一項に記載の組成物および薬理学的に許容される賦形剤を含む医薬組成物。
- 経口送達用に製剤化されている、請求項12に記載の医薬組成物。
- 小腸への送達用に製剤化されている、請求項12または13に記載の医薬組成物。
- 結腸への送達用に製剤化されている、請求項12から14のいずれか一項に記載の医薬組成物。
- 1つ以上の腸溶性ポリマーをさらに含む、請求項12から15のいずれか一項に記載の医薬組成物。
- カプセルの形態である、請求項12から16のいずれか一項に記載の医薬組成物。
- 対象においてClostridium difficile感染症を処置する方法における使用のための、請求項1から11のいずれか一項に記載の組成物または請求項12から17のいずれか一項に記載の医薬組成物。
- Clostridium difficile感染症が、初発性のClostridium difficile感染症である、請求項18に記載の組成物または医薬組成物。
- Clostridium difficile感染症が、再発性のClostridium difficile感染症である、請求項18に記載の組成物または医薬組成物。
- 対象が、組成物または医薬組成物の投与前に1ドーズの抗生物質を投与される、請求項18から20のいずれか一項に記載の使用のための組成物または医薬組成物。
- 抗生物質が、バンコマイシン、カナマイシン、ゲンタマイシン、コリスチン、メトロニダゾール、クリンダマイシン、フィダキソマイシンまたはセフォペラゾンである、請求項21に記載の使用のための組成物または医薬組成物。
- 抗生物質が、バンコマイシンである、請求項21または22に記載の使用のための組成物または医薬組成物。
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