JP2015525784A - 活動性結核菌感染を治療するための組成物及び方法 - Google Patents
活動性結核菌感染を治療するための組成物及び方法 Download PDFInfo
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Abstract
Description
本出願は、それら全てが全体として参照により本明細書に組み込まれる、2012年8月3日に出願された米国仮特許出願第61/679,612号及び2013年3月15日に出願された同第61/791,213号の優先権を主張する。
ASCIIテキストファイルにおける次の提出物の内容は、全体として参照により本明細書に組み込まれる: 配列表(ファイル名:712192000940SeqList.txt、記録された日:2013年7月31日、大きさ:36KB)のコンピュータ読み取り可能な形態(CRF)。
本開示は、哺乳動物における、活動性結核菌(Mycobacterium tuberculosis)一次感染、又は潜伏感染の再活性化から生じる活動性感染を治療するための方法及び組成物、並びに活動性結核菌感染に対する化学療法レジメンの有効性を改善するための方法及び組成物に関する。
本明細書において、「約」及び「から本質的になる」という用語は、他に指示がなければ、指示された範囲、値又は構造の±20%を意味する。用語「1つの(a)」及び「1つの(an)」は、本明細書で使用するとき、「1つ以上の」列挙の成分を指すものと理解するべきである。代替(例えば、「又は」)の使用は、選択肢のいずれか1つ、両方又はそれらの任意の組合せを意味するものと理解するべきである。本明細書で使用するとき、「含む(include)」、「有する」及び「含む(comprise)」なる用語は同義的に使用され、これらの用語及び変形体は非限定的なものと見なすことが意図される。
記載した通り、本開示は、一態様において、本明細書に記載されている、融合ポリペプチドを含む単離されたマイコバクテリウム属種ポリペプチド、及びそれを含有する組成物、並びに活動性TB感染を治療するための化学療法剤と組み合わせたそれらの使用を提供する。概して、本開示のポリペプチドは、単離されたポリペプチドであり、本明細書に開示されているアミノ酸配列に由来する断片(例えば、抗原性/免疫原性部分)であってもよく、又は本明細書に開示されているアミノ酸配列全体を含んでもよい。本開示のポリペプチド、その抗原性/免疫原性断片、及び他の改変体は、従来の組換え技術及び/又は合成技術を用いて調製し得る。
本開示はまた、別の態様において、単離されたポリヌクレオチド、特に、本開示の融合ポリペプチド(例えば、ID93)をコードするポリヌクレオチド、並びにこのようなポリヌクレオチドを含む組成物を提供する。本明細書で使用するとき、用語「DNA」及び「ポリヌクレオチド」及び「核酸」とは、特定の種の全ゲノムDNAを含まない単離されているDNA分子を指す。したがって、ポリペプチドをコードするDNAセグメントとは、まだ1つ以上のコード配列を含有し、DNAセグメントが得られる種の全ゲノムDNAから実質的に離れて単離されたか、又は精製されたDNAセグメントを指す。用語「DNAセグメント」及び「ポリヌクレオチド」には、DNAセグメント及びこのようなセグメントのより小さな断片が含まれ、さらに、例えば、プラスミド、コスミド、ファージミド、ファージ、ウイルスなどを含む組換えベクターが含まれる。
別の態様では、本開示は、細胞又は動物に対して、単独で、又は1つ以上の他の治療様式と組み合わせて投与するための、医薬として許容される又は生理学的に許容される溶液中の、本明細書に開示されているポリヌクレオチド、ポリペプチド若しくは他の組成物の1つ以上の製剤に関する。このような医薬組成物は、適した免疫刺激剤/アジュバント系と一緒に製剤化される場合、ワクチンとして使用するのに特に好ましい。組成物はまた、診断に関する用途にも適している。
1.哺乳動物における活動性結核感染を治療する方法であって、該方法は、活動性結核感染を有する哺乳動物に、化学療法剤と、免疫学的に有効な量の治療用ワクチンを投与するステップを含み、ここで、該ワクチンは、結核菌群のマイコバクテリウム属種由来のMtb抗原又はその免疫原性断片を含む医薬組成物を含む、上記方法。
TB再発及び活動性TB感染の再活性化のSWR/Jマウスモデルの開発
週齢を合わせた(4〜6週間の)雌性SWR/Jマウス及びC57BL/6マウスを、それぞれJackson及びCharles River Laboratoriesから購入した。UW-Madisonエアロゾルチャンバーを用いて、低用量(50〜100個の細菌)エアロゾル(LDA)のMtb H37Rv(ATCC #35718)でマウスを感染させた。活動性感染を有するマウスに存在する細菌数、肺内生菌数(5匹のマウス/群)を、当該技術分野において公知の方法によって、感染から15日、30日及び100日後に決定した。記号は平均+/-標準偏差を示す。活動性TB感染を有するSWR/JとC57BL/6株のマウスは、記載されるようにMtb H37Rvを感染させ(8匹のマウス/群)、生存をモニターした。モデルにおける化学療法の効果を評価するするために、感染から15日後、マウスの一部は、30日、60日又は90日間の連続日数投与される(Rx 30d、Rx 60d、Rx 90d)、イソニアジド(INH)(85mg/飲料水1L)とリファンピン(RIF)(50mg/飲料水1L)の投薬レジメンが開始された。マウスの追加群は、感染から30日目に、90日間の連続日数投与される、イソニアジド(INH)(85mg/飲料水1L)とリファンピン(RIF)(50mg/飲料水1L)の投薬レジメン(まとめて本明細書では化学療法による処置と称する)が開始された。雌性マウスは、0.15〜0.37mL/gを飲むことが推定されている(Bachmanov AA et al., 2002)。Mtb H37Rvについての最小阻害濃度は、RIFについては0.25μMであり、INHについては1.0μMである。
TB再発及び活動性TB感染の再活性化のSWR/JマウスモデルにおけるTBワクチンID93+化学療法の治療的有効性の評価
TLR4アンタゴニストGLA-SEとともに製剤化されたTBワクチン融合タンパク質ID83とID93又はそれらの成分抗原は、三用量で投与した場合、マウス及びモルモットモデルにおいて、TBに対する予防的防御を与えることが以前に実証されている(Baldwin et al., 2009, Bertholet et al., 2010)。ID93/GLA-SEワクチンは、CFUの減少又は生存率の改善によって測定した場合に、この製剤が、免疫治療的利益を与えるかどうかを決定するために、活動性感染のSWR/Jモデルにおいて試験された。SWR/Jマウス(群あたり6又は7匹のマウス)を、実施例1に記載されるようにMtbのLDAで感染させた。15日後(15日目)、マウスは、90日間(Rx 90d)、擬似処置又は抗生物質処置された。また、各群の抗生物質処置されたマウスの一部は免疫された。マウスは、抗生物質の治療的処置中(DTT; 15日目、36日目、57日目)又は抗生物質の治療的処置後(PTT; 107日目、128日目、149日目)のいずれかに、20μgのGLA-SEとともに製剤化された8μgのID93タンパク質を用いて、3回、3週間の間隔で免疫された。治療有効性は、経時的な生存率を追跡し、かつ、以前に記載(Bertholet et al., 2008)されたように肺ホモジネートをプレーティングすることによって決定された。活動性TB感染のSWR/Jマウスモデルにおいて治療的に投与されたID93/GLA-SEワクチン(--)は、感染後の生存頻度を増加させた(P<0.01)。
))との間に、肺CFUの差は観察されなかった(P>0.05)(図2B)。さらに、Rx+ID93/GLA-SE群とRx+GLA-SE群によって誘導された曝露後の有効性において有意差があり(4.419±0.17対4.938±0.16log10、P<0.05)、これは、これらの研究において観察された補助的な殺菌効果は抗原依存的であることを実証した。
化学療法の補助物としての治療的ID93/GLA-SEワクチンの投与は、活動性TB感染における生存を延長するのに必要とされる薬物療法の期間を減少させる
TB再発及び活動性TB感染の再活性化のSWR/Jマウスモデルにおいてさらに実験を行い、治療的ID93/GLASEワクチンの投与が、活動性TB感染における生存を延長するのに必要とされる薬物療法の期間を減少させ得るのかどうかを評価した。SWR/JマウスをMtb H37RvのLDAで感染させた。15日後、マウスは、上に記載されるとおり抗生物質を用いて60日又は90日間処置された(それぞれ、Rx 60d及びRx 90)。60日の抗生物質レジメンの完了後、マウスは、20μgのGLASEとともに製剤化された8μgのID93タンパク質を用いて、3回、3週間の間隔で免疫された(Rx 60d+ID93/GLA-SE; 77日目、98日目、119日目)。経時的にMtbによって引き起こされた動物の死亡(7匹のマウス/群)をモニターすることによって防御を評価した(P<0.05(ログランク検定)は有意であると考えられる)。(B-M)Mtb H37Rvによるチャレンジ後の肺組織の組織病理学的評価。炎症反応及び肉芽腫(g)形成は、H&E切片に示され(B-I)、AFB(矢印)の存在(J-M)が評価された。(B、F、J)擬似処置されたマウス、106日目; (C、J及びK)90日間の抗生物質療法、106日目; (D、H、L)90日間の抗生物質療法+ID93/GLA-SE、241日目; (E、I及びM)60日間の抗生物質療法+ID93/GLA-SE、295日目。示されたデータは、5匹のマウス/群の代表的なものである。
化学療法単独又は化学療法+ID93/GLA-SEワクチン接種を受けるSWR/Jマウスにおける免疫応答
ID93で刺激された脾細胞のサイトカインプロファイル
SWR/JマウスをLDA Mtb H37Rvで感染させ、実施例2に記載されるように、90日間の抗生物質単独、又は抗生物質とそれに続くID93/GLA-SEによる、3週間の間隔で3回の免疫のいずれかで処置した。ID93で刺激された脾細胞(感染後177日目又は241日目)の上清からのサイトカインプロファイルは、IFN-γ、IL-2、TNF、IL-5、IL-10、IL-13、及びIL-17に対する多重ビーズアレイによって、抗原又は培地のみの存在下で24時間インキュベーション後に分析された。ボックスプロットは、バックグラウンド減算後の中央値と四分位範囲を示す。Wilcoxon順位和検定からのP値。
細胞をブレフェルジンAの存在下でID93又は培地対照で8〜12時間刺激し、CD3、CD4、CD8、CD44、IFN-γ、IL-2及びTNFに対する蛍光色素を結合させた抗体で染色し、FACSによって分析した。(B及びC)パネルは、FACS分析のためのゲーティングスキームを示す。(D)下部パネルのボックスプロットは、バックグラウンド減算後の中央値と四分位範囲を示す。Wilcoxon順位和検定からのP値。ID93によるインビトロでの再刺激に応答して、炎症誘発性を示すサイトカインの一部、並びにTH1及びTH2機能群が有意に上方制御された(図4A)。感染した個体におけるMtb特異的免疫の可溶性メディエーターであるTNFは、ID93/GLA-SEで免疫された群において、241日目に有意に上方制御された(P<0.05)。さらに、ID93特異的IFN-γ、IL-2、及びIL-17応答が検出され、ワクチン接種されていない動物と比較して、ワクチン接種された動物において有意に高かった。TH2型IL-5サイトカインの濃度に有意差は検出されなかったが、有意なID93特異的IL-10及びIL-13応答が241日目に測定された。
カニクイザル(cynomolgus macaque)における抗生物質処置に対する補助物としてのID93/GLA-SE
NHPにおいて抗生物質に対する補助物として投与した場合の、ID93/GLA-SEの安全性を実証するために、カニクイザル(macaque)は1カ月のRIF/INH抗生物質の後、3回のワクチン投薬を投与された(図5A)。注射部位反応は最小であり、せいぜい僅かに知覚できる紅斑と浮腫(Draizeスケール範囲0〜1)を有し、体重及び体温に有意な変化はなかった(データ示さず)。7匹全部(100%)のRx+ID93/GLA-SE免疫されたNHPは、評価された最後の時点まで生存したが、一方、抗生物質単独群の6匹のNHP(85.7%)と擬似処置群の3匹のNHP(42.8%、P=0.44)がこの時点まで生存した(図5B)。Rx+ID93/GLA-SEで処置された4匹のサルは、(以前には陽性であった胸部X線における肺浸潤物によって評価したとき)実験の終了前に放射線学上の変化を示さないか、又はMtb感染を消散するかのいずれかであったが、一方、Rx単独又は擬似処置を受けているカニクイザルのいずれも、それらのMtb感染を消散せず、胸部X線は陽性のままであった(図5C)。Rx+ID93/GLA-SEで処置されたカニクイザルのうち40パーセントが、Rx単独群と比較した場合、Mtb細菌数における定量的差異を示すことによって、補助的免疫療法に対して劇的に反応した(P<0.05)(図5D)。興味深いことに、より低いCFUカウントを有するRx+ID93/GLA-SEカニクイザルはまた、実験の終了時に胸部X線が陰性であった。また、群割り当てと疾患組織の存在との間には組織病理学による相関があり、ID93/GLA-SEを受けている動物は最も健康な臓器を含有し、生理食塩水群は最も罹患した臓器を有した(p=0.003)(図5E)。全体として、これらの結果は、ID93/GLA-SEワクチンが、カニクイザルにおいて、曝露後の免疫療法剤として耐容性良好であることを実証した。
化学療法単独又は化学療法+ID83/GLA-SEワクチン接種を受けているBALB/cマウスにおける免疫応答
6週齢の雌性BALB/cマウス(Charles River, Wilmington, MA)を、吸入曝露システム(Glas-Col, Terre Haute,IN)と、肺に2.5〜3.0 log10 CFUを植え付けることを目的して7H9ブロスに10倍希釈した対数期ブロス培養物(600nmでの光学濃度は1.0)を用いて、結核菌H37Rvで感染させた。結核菌H37Rvはマウス継代から調製され、分注して凍結され、感染前に、10%オレイン酸-アルブミン-デキストロース-カタラーゼ(OADC)(Fisher, Pittsburgh, PA)と0.05% Tween 80を用いて、Middlebrook 7H9ブロスに継代培養された。5匹のマウスを感染から1日後に屠殺し、植え付けられた細菌数を確認した。残りのマウスは、表2に示される処置群に無作為化された。リファンピン(R)、イソニアジド(H)及びピラジナミド(Z)、総称してRHZでの処置は、感染から26日後に0日目で開始した。リファンピンとイソニアジド(Sigma, St. Louis, MO)は蒸留水中に1mg/mlで別々に溶解し、投薬溶液を生じさせた。ピラジナミド(Fisher Scientific, Suwanee, GA)は蒸留水中に15mg/mlになるように溶解し、投薬溶液を生じさせた。毎週溶液を調製し、分注し、使用前に4℃で維持した。4匹の対照群は、薬物ビヒクル(水)+GLA-SEアジュバント、薬物ビヒクル+ID83ワクチン、RHZ+ワクチンビヒクル(生理食塩水)、及びRHZ+GLA-SEアジュバントを受けた。試験群は、RHZ+ID83ワクチンを受けた。RHZ及び薬物ビヒクルは、強制経口投与によって、1週間に5日、12週間投与された。R又はビヒクルは、R吸収を制限する、以前に記載された薬物動態的薬物-薬物相互作用を避けるために、HZ又はビヒクルの少なくとも1時間前に投与された。
処置中の肺CFUカウント。D-26での平均(±SD)肺log10CFUカウントは2.78±0.21であった。処置開始時(DO)の平均CFUカウントは7.60+0.23であった。6週間の処置の後、肺CFUカウントは、ビヒクル+アジュバント群及びビヒクル+ワクチン群において約0.9 log10減少し、一方、RHZ+生理食塩水群、RHZ+アジュバント群及びRHZ+ワクチン群におけるCFUカウントは、それぞれ4.27、4.19及び4.44log10下がった(図6A)。12週間の処置の後、薬物ビヒクル処置群におけるCFUカウントは大いに安定であり、一方、抗生物質単独(RHZ+生理食塩水)、抗生物質+TLR4アジュバント(RHZ+アジュバント)、及び抗生物質+ID83ワクチン(RHZ+ワクチン)で処置された、それぞれ5匹のうち3匹のマウス、4匹のうち2匹のマウス、及び5匹のうち4匹のマウスは培養陰性であった(図6)。
随意的なHisタグを伴うID93融合ポリペプチド(配列番号1)
MGSSHHHHHHSSGLVPRGSHMTINYQFGDVDAHGAMIRAQAGSLEAEHQAIISDVLTASDFWGGAGSAACQGFITQLGRNFQVIYEQANAHGQKVQAAGNNMAQTDSAVGSSWAGTHLANGSMSEVMMSEIAGLPIPPIIHYGAIAYAPSGASGKAWHQRTPARAEQVALEKCGDKTCKVVSRFTRCGAVAYNGSKYQGGTGLTRRAAEDDAVNRLEGGRIVNWACNELMTSRFMTDPHAMRDMAGRFEVHAQTVEDEARRMWASAQNISGAGWSGMAEATSLDTMTQMNQAFRNIVNMLHGVRDGLVRDANNYEQQEQASQQILSSVDINFAVLPPEVNSARIFAGAGLGPMLAAASAWDGLAEELHAAAGSFASVTTGLAGDAWHGPASLAMTRAASPYVGWLNTAAGQAAQAAGQARLAASAFEATLAATVSPAMVAANRTRLASLVAANLLGQNAPAIAAAEAEYEQIWAQDVAAMFGYHSAASAVATQLAPIQEGLQQQLQNVLAQLASGNLGSGNVGVGNIGNDNIGNANIGFGNRGDANIGIGNIGDRNLGIGNTGNWNIGIGITGNGQIGFGKPANPDVLVVGNGGPGVTALVMGGTDSLLPLPNIPLLEYAARFITPVHPGYTATFLETPSQFFPFTGLNSLTYDVSVAQGVTNLHTAIMAQLAAGNEVVVFGTSQSATIATFEMRYLQSLPAHLRPGLDELSFTLTGNPNRPDGGILTRFGFSIPQLGFTLSGATPADAYPTVDYAFQYDGVNDFPKYPLNVFATANAIAGILFLHSGLIALPPDLASGVVQPVSSPDVLTTYILLPSQDLPLLVPLRAIPLLGNPLADLIQPDLRVLVELGYDRTAHQDVPSPFGLFPDVDWAEVAADLQQGAVQGVNDALSGLGLPPPWQPALPRLFST
MTINYQFGDVDAHGAMIRAQAGSLEAEHQAIISDVLTASDFWGGAGSAACQGFITQLGRNFQVIYEQANAHGQKVQAAGNNMAQTDSAVGSSWAGTHLANGSMSEVMMSEIAGLPIPPIIHYGAIAYAPSGASGKAWHQRTPARAEQVALEKCGDKTCKVVSRFTRCGAVAYNGSKYQGGTGLTRRAAEDDAVNRLEGGRIVNWACNELMTSRFMTDPHAMRDMAGRFEVHAQTVEDEARRMWASAQNISGAGWSGMAEATSLDTMTQMNQAFRNIVNMLHGVRDGLVRDANNYEQQEQASQQILSSVDINFAVLPPEVNSARIFAGAGLGPMLAAASAWDGLAEELHAAAGSFASVTTGLAGDAWHGPASLAMTRAASPYVGWLNTAAGQAAQAAGQARLAASAFEATLAATVSPAMVAANRTRLASLVAANLLGQNAPAIAAAEAEYEQIWAQDVAAMFGYHSAASAVATQLAPIQEGLQQQLQNVLAQLASGNLGSGNVGVGNIGNDNIGNANIGFGNRGDANIGIGNIGDRNLGIGNTGNWNIGIGITGNGQIGFGKPANPDVLVVGNGGPGVTALVMGGTDSLLPLPNIPLLEYAARFITPVHPGYTATFLETPSQFFPFTGLNSLTYDVSVAQGVTNLHTAIMAQLAAGNEVVVFGTSQSATIATFEMRYLQSLPAHLRPGLDELSFTLTGNPNRPDGGILTRFGFSIPQLGFTLSGATPADAYPTVDYAFQYDGVNDFPKYPLNVFATANAIAGILFLHSGLIALPPDLASGVVQPVSSPDVLTTYILLPSQDLPLLVPLRAIPLLGNPLADLIQPDLRVLVELGYDRTAHQDVPSPFGLFPDVDWAEVAADLQQGAVQGVNDALSGLGLPPPWQPALPRLFST
MGSSHHHHHHSSGLVPRGSHMGTHLANGSMSEVMMSEIAGLPIPPIIHYGAIAYAPSGASGKAWHQRTPARAEQVALEKCGDKTCKVVSRFTRCGAVAYNGSKYQGGTGLTRRAAEDDAVNRLEGGRIVNWACNELMTSRFMTDPHAMRDMAGRFEVHAQTVEDEARRMWASAQNISGAGWSGMAEATSLDTMTQMNQAFRNIVNMLHGVRDGLVRDANNYEQQEQASQQILSSVDINFAVLPPEVNSARIFAGAGLGPMLAAASAWDGLAEELHAAAGSFASVTTGLAGDAWHGPASLAMTRAASPYVGWLNTAAGQAAQAAGQARLAASAFEATLAATVSPAMVAANRTRLASLVAANLLGQNAPAIAAAEAEYEQIWAQDVAAMFGYHSAASAVATQLAPIQEGLQQQLQNVLAQLASGNLGSGNVGVGNIGNDNIGNANIGFGNRGDANIGIGNIGDRNLGIGNTGNWNIGIGITGNGQIGFGKPANPDVLVVGNGGPGVTALVMGGTDSLLPLPNIPLLEYAARFITPVHPGYTATFLETPSQFFPFTGLNSLTYDVSVAQGVTNLHTAIMAQLAAGNEVVVFGTSQSATIATFEMRYLQSLPAHLRPGLDELSFTLTGNPNRPDGGILTRFGFSIPQLGFTLSGATPADAYPTVDYAFQYDGVNDFPKYPLNVFATANAIAGILFLHSGLIALPPDLASGVVQPVSSPDVLTTYILLPSQDLPLLVPLRAIPLLGNPLADLIQPDLRVLVELGYDRTAHQDVPSPFGLFPDVDWAEVAADLQQGAVQGVNDALSGLGLPPPWQPALPRLFST
HLANGSMSEVMMSEIAGLPIPPIIHYGAIAYAPSGASGKAWHQRTPARAEQVALEKCGDKTCKVVSRFTRCGAVAYNGSKYQGGTGLTRRAAEDDAVNRLEGGRIVNWACNELMTSRFMTDPHAMRDMAGRFEVHAQTVEDEARRMWASAQNISGAGWSGMAEATSLDTMTQMNQAFRNIVNMLHGVRDGLVRDANNYEQQEQASQQILSSVDINFAVLPPEVNSARIFAGAGLGPMLAAASAWDGLAEELHAAAGSFASVTTGLAGDAWHGPASLAMTRAASPYVGWLNTAAGQAAQAAGQARLAASAFEATLAATVSPAMVAANRTRLASLVAANLLGQNAPAIAAAEAEYEQIWAQDVAAMFGYHSAASAVATQLAPIQEGLQQQLQNVLAQLASGNLGSGNVGVGNIGNDNIGNANIGFGNRGDANIGIGNIGDRNLGIGNTGNWNIGIGITGNGQIGFGKPANPDVLVVGNGGPGVTALVMGGTDSLLPLPNIPLLEYAARFITPVHPGYTATFLETPSQFFPFTGLNSLTYDVSVAQGVTNLHTAIMAQLAAGNEVVVFGTSQSATIATFEMRYLQSLPAHLRPGLDELSFTLTGNPNRPDGGILTRFGFSIPQLGFTLSGATPADAYPTVDYAFQYDGVNDFPKYPLNVFATANAIAGILFLHSGLIALPPDLASGVVQPVSSPDVLTTYILLPSQDLPLLVPLRAIPLLGNPLADLIQPDLRVLVELGYDRTAHQDVPSPFGLFPDVDWAEVAADLQQGAVQGVNDALSGLGLPPPWQPALPRLFST
MITNLRRRTAMAAAGLGAALGLGILLVPTVDAHLANGSMSEVMMSEIAGLPIPPIIHYGAIAYAPSGASGKAWHQRTPARAEQVALEKCGDKTCKVVSRFTRCGAVAYNGSKYQGGTGLTRRAAEDDAVNRLEGGRIVNWACN
MTSRFMTDPHAMRDMAGRFEVHAQTVEDEARRMWASAQNISGAGWSGMAEATSLDTMTQMNQAFRNIVNMLHGVRDGLVRDANNYEQQEQASQQILSS
MNFAVLPPEVNSARIFAGAGLGPMLAAASAWDGLAEELHAAAGSFASVTTGLAGDAWHGPASLAMTRAASPYVGWLNTAAGQAAQAAGQARLAASAFEATLAATVSPAMVAANRTRLASLVAANLLGQNAPAIAAAEAEYEQIWAQDVAAMFGYHSAASAVATQLAPIQEGLQQQLQNVLAQLASGNLGSGNVGVGNIGNDNIGNANIGFGNRGDANIGIGNIGDRNLGIGNTGNWNIGIGITGNGQIGFGKPANPDVLVVGNGGPGVTALVMGGTDSLLPLPNIPLLEYAARFITPVHPGYTATFLETPSQFFPFTGLNSLTYDVSVAQGVTNLHTAIMAQLAAGNEVVVFGTSQSATIATFEMRYLQSLPAHLRPGLDELSFTLTGNPNRPDGGILTRFGFSIPQLGFTLSGATPADAYPTVDYAFQYDGVNDFPKYPLNVFATANAIAGILFLHSGLIALPPDLASGVVQPVSSPDVLTTYILLPSQDLPLLVPLRAIPLLGNPLADLIQPDLRVLVELGYDRTAHQDVPSPFGLFPDVDWAEVAADLQQGAVQGVNDALSGLGLPPPWQPALPRLF
MTINYQFGDVDAHGAMIRAQAGSLEAEHQAIISDVLTASDFWGGAGSAACQGFITQLGRNFQVIYEQANAHGQKVQAAGNNMAQTDSAVGSSWA
Claims (42)
- 哺乳動物における活動性結核感染を治療する方法であって、該方法は、活動性結核感染を有する哺乳動物に、1つ以上の化学療法剤と併用した、免疫学的に有効な量の治療用ワクチンを投与するステップを含み、ここで、該ワクチンは、単離された融合ポリペプチドを含む医薬組成物を含み、該融合ポリペプチドは、(a)結核菌群のマイコバクテリウム属種由来の抗原Rv1813、Rv3620及びRv2608の組み合わせを含み、該抗原は共有結合している、又は(b)該抗原の組み合わせに対して少なくとも90%の同一性を有する配列を含む、上記方法。
- 治療用ワクチンが、(a)マイコバクテリウム属種抗原Rv2608、Rv3619、Rv3620及びRv1813の組み合わせ、又は(b)該抗原の組み合わせに対して少なくとも90%の同一性を有する配列、を含む融合ポリペプチドを含む、請求項1に記載の方法。
- マイコバクテリウム属種抗原Rv2608、Rv3619、Rv3620及びRv1813が、結核菌抗原Rv2608、Rv3619、Rv3620及びRv1813である、請求項2に記載の方法。
- 融合ポリペプチドが、配列番号1に記載のアミノ酸配列又はそれに対して少なくとも90%の同一性を有する配列を含む、請求項3に記載の方法。
- 融合ポリペプチドが、配列番号2に記載のアミノ酸配列又はそれに対して少なくとも90%の同一性を有する配列を含む、請求項3に記載の方法。
- 治療用ワクチンが、(a)マイコバクテリウム属種抗原Rv2608、Rv3620及びRv1813の組み合わせ、又は(b)該抗原の組み合わせに対して少なくとも90%の同一性を有する配列、を含む融合ポリペプチドを含む、請求項1に記載の方法。
- マイコバクテリウム属種抗原Rv2608、Rv3620及びRv1813が、結核菌抗原Rv2608、Rv3620及びRv1813である、請求項6に記載の方法。
- 融合ポリペプチドが、配列番号3若しくは配列番号4に記載のアミノ酸配列、又は配列番号3若しくは配列番号4に対して少なくとも90%の同一性を有する配列を含む、請求項6に記載の方法。
- 活動性結核感染が、結核菌の活動性一次感染である、請求項1〜8のいずれか一項に記載の方法。
- 活動性結核感染が、再活性化結核感染である、請求項1〜8のいずれか一項に記載の方法。
- 活動性結核感染が、脱力、疲労、発熱、悪寒、体重減少、食欲不振、無食欲、寝汗、又はそれらの任意の組み合わせの臨床症状と関連する、請求項1〜8のいずれか一項に記載の方法。
- 活動性結核感染が、肺活動性TB感染である、請求項1〜8のいずれか一項に記載の方法。
- 肺活動性結核感染が、持続性の咳、粘り気の強い粘液、胸痛、喀血、又はそれらの任意の組み合わせの臨床症状と関連する、請求項12に記載の方法。
- 活動性結核感染が、哺乳動物の臓器において、指数関数的な速度、対数関数的な速度、又は半対数関数的な速度で増殖し、繁殖し、増大し又は活動的に増えるMtb細菌によって特徴付けられる、請求項1〜8のいずれか一項に記載の方法。
- 活動性結核感染が、抗酸性染色(AFS)アッセイ、細菌培養アッセイ、IGRテスト、皮膚テスト、及び抗原刺激後の全血若しくは単離されたPBMCの細胞内サイトカイン染色からなる群から選択されるアッセイを用いて同定される、請求項1〜8のいずれか一項に記載の方法。
- 哺乳動物が多剤耐性(MDR)結核菌に感染している、請求項1〜8のいずれか一項に記載の方法。
- 哺乳動物が、カルメット・ゲラン桿菌(Bacillus Calmette-Guerin)(BCG)を用いて事前に免疫されていた、請求項1〜16のいずれか一項に記載の方法。
- 哺乳動物がヒトである、請求項1〜17のいずれか一項に記載の方法。
- 1つ以上の化学療法剤が、イソニアジド、リファンピン又はそれらの組み合わせである、請求項1〜18のいずれか一項に記載の方法。
- 哺乳動物が、最初に、一定期間にわたって1つ以上の化学療法剤を投与され、続いて、治療用ワクチンを投与される、請求項1〜19のいずれか一項に記載の方法。
- 哺乳動物が、最初に、治療用ワクチンを投与され、続いて、一定期間にわたって1つ以上の化学療法剤を投与される、請求項1〜19のいずれか一項に記載の方法。
- 1つ以上の化学療法剤と治療用ワクチンの投与が同時である、請求項1〜19のいずれか一項に記載の方法。
- 1回以上のその後の時に、哺乳動物に治療用ワクチンを投与することをさらに含み、ここで、1回以上のその後の時に哺乳動物に残存する結核感染が、活動性結核感染であってもよく又はそうでなくてもよい、請求項1〜22のいずれか一項に記載の方法。
- ワクチンがアジュバントをさらに含む、請求項1〜23のいずれか一項に記載の方法。
- R1、R3、R5及びR6がC11〜14アルキルであり、R2及びR4がC12〜15アルキルである、請求項25に記載の方法。
- R1、R3、R5及びR6がC11アルキルであり、R2及びR4がC13アルキルである、請求項25に記載の方法。
- R1、R3、R5及びR6がC11アルキルであり、R2及びR4がC9アルキルである、請求項25に記載の方法。
- 活動性結核感染に対する化学療法の時間経過を減少させる方法であって、該方法は、活動性結核感染を有する哺乳動物に、化学療法と併用した、免疫学的に有効な量の治療用ワクチンを投与することを含み、それによって、活動性結核感染に対する化学療法の時間経過の減少をもたらし、ここで、該ワクチンは、単離された融合ポリペプチドを含む医薬組成物を含み、該融合ポリペプチドは、(a)結核菌群のマイコバクテリウム属種由来の抗原Rv1813、Rv3620及びRv2608の組み合わせを含み、該抗原は共有結合しており、又は(b)該抗原の組み合わせに対して少なくとも90%の同一性を有する配列を含み、またここで、該ワクチンは、結核に対する免疫応答を誘導する、上記方法。
- 治療用ワクチンが、(a)マイコバクテリウム属種抗原Rv2608、Rv3619、Rv3620及びRv1813の組み合わせ、又は(b)該抗原の組み合わせに対して少なくとも90%の同一性を有する配列、を含む融合ポリペプチドを含む、請求項29に記載の方法。
- マイコバクテリウム属種抗原Rv2608、Rv3619、Rv3620及びRv1813が、結核菌抗原Rv2608、Rv3619、Rv3620及びRv1813である、請求項30に記載の方法。
- 融合ポリペプチドが、配列番号1に記載の配列又はそれに対して少なくとも90%の同一性を有する配列を含む、請求項31に記載の方法。
- 融合ポリペプチドが、配列番号2に記載の配列又はそれに対して少なくとも90%の同一性を有する配列を含む、請求項31に記載の方法。
- 治療用ワクチンが、(a)マイコバクテリウム属種抗原Rv2608、Rv3620及びRv1813の組み合わせ、又は(b)該抗原の組み合わせに対して少なくとも90%の同一性を有する配列、を含む融合ポリペプチドを含む、請求項29に記載の方法。
- マイコバクテリウム属種抗原Rv2608、Rv3620及びRv1813が、結核菌抗原Rv2608、Rv3620及びRv1813である、請求項34に記載の方法。
- 融合ポリペプチドが、配列番号3若しくは4に記載の配列、又は配列番号3若しくは配列番号4に対して少なくとも90%の同一性を有する配列を含む、請求項35に記載の方法。
- 化学療法の時間経過が、約3カ月以下、約5カ月以下又は約7カ月以下に短縮される、請求項29〜36のいずれか一項に記載の方法。
- ワクチンがアジュバントをさらに含む、請求項29〜37のいずれか一項に記載の方法。
- R1、R3、R5及びR6がC11〜14アルキルであり、R2及びR4がC12〜15アルキルである、請求項39に記載の方法。
- R1、R3、R5及びR6がC11アルキルであり、R2及びR4がC13アルキルである、請求項39に記載の方法。
- R1、R3、R5及びR6がC11アルキルであり、R2及びR4がC9アルキルである、請求項40に記載の方法。
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PCT/US2013/053482 WO2014042780A1 (en) | 2012-08-03 | 2013-08-02 | Compositions and methods for treating an active mycobacterium tuberculosis infection |
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MX2018014270A (es) * | 2016-05-21 | 2019-02-14 | Infectious Disease Res Inst | Composiciones y metodos para tratar la tuberculosis secundaria e infecciones po micobacteria no tuberculosa. |
GB201909953D0 (en) * | 2019-07-11 | 2019-08-28 | Sec Dep For Environment Food And Rural Affairs Acting Through The Animal And Plant Health Agency | Diagnostic reagents |
US11679163B2 (en) | 2019-09-20 | 2023-06-20 | Hdt Bio Corp. | Compositions and methods for delivery of RNA |
GB2605538A (en) | 2020-03-23 | 2022-10-05 | Hdt Bio Corp | Compositions and methods for delivery of RNA |
MX2023007648A (es) | 2020-12-23 | 2023-08-29 | Access To Advanced Health Inst | Adyuvantes de vacuna de solanesol y métodos para prepararlos. |
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HRP20240164T1 (hr) | 2024-04-12 |
EP2879701A1 (en) | 2015-06-10 |
ZA201501242B (en) | 2017-08-30 |
RU2659149C2 (ru) | 2018-06-28 |
PT2879701T (pt) | 2024-02-12 |
EP2879701A4 (en) | 2016-01-20 |
ZA201702091B (en) | 2018-12-19 |
US20150182612A1 (en) | 2015-07-02 |
ES2969734T3 (es) | 2024-05-22 |
RU2015107435A (ru) | 2016-09-27 |
CN104812404A (zh) | 2015-07-29 |
EP2879701B1 (en) | 2023-11-15 |
BR112015002483A2 (pt) | 2017-11-07 |
US11369672B2 (en) | 2022-06-28 |
WO2014042780A1 (en) | 2014-03-20 |
MX2015001557A (es) | 2015-10-08 |
US20200038498A1 (en) | 2020-02-06 |
EP4299138A2 (en) | 2024-01-03 |
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