JP2006502964A - 特定の器官または組織に対する全身性免疫応答の標的化のための方法および組成物 - Google Patents
特定の器官または組織に対する全身性免疫応答の標的化のための方法および組成物 Download PDFInfo
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Abstract
Description
癌は、今日、世界で最も破壊的な健康問題の1つであり続けており、米国ではおよそ5人に一人が罹っている。研究により数多くの異なる種類の治療法が発見されており、例えば、微小管形成を妨げる抗代謝剤、アルキル化剤、白金系剤、アントラサイクリン、抗生剤、トポイソメラーゼ阻害剤等、化学療法に一般に使用される細胞傷害性剤が挙げられる。また、従来の外科療法および放射線療法が改善されている一方で、免疫変調および遺伝子治療を含む最先端の治療法が開発されている。それにもかかわらず、数千もの潜在的抗癌剤が評価されているとはいえ、ヒト癌の治療は依然として、最適状態に及ばない多くの治療選択を与える合併症および副作用が伴う。
概して、本発明は、器官または組織に局所的に局在化するか、また直接投与されるとともに、器官または組織で局所的な免疫応答を生成する薬剤の投与と併用して、器官もしくは組織特異的疾患または症状に対する免疫応答を生成する治療有効量のワクチンを投与することによって、被験体の組織もしくは器官特異的疾患または症状に対する全身性免疫応答を生成する方法を提供する。好ましい実施形態では、器官もしくは組織特異的疾患または症状は腫瘍または癌腫であり、ワクチンは腫瘍ワクチンである。別の好ましい実施形態では、ワクチンは、GM−CSFを発現する弱毒化した腫瘍細胞株である。別の実施形態では、器官または組織に局所的に局在化する薬剤は、特定の器官または組織に対して天然の指向性を有するウイルス、細菌、酵母、または真菌である。好ましくは、局所的に局在化する薬剤は、Listeria monocytogenesの弱毒化株である。また、さらに好ましくは、生物は、新生血管内皮を局所的に局在化する。
(4.1. 概略)
一般に、本発明は、器官もしくは組織に対する指向性を持つ1種類以上の薬剤または所望の器官もしくは組織に特異的に局在化することが可能な1種類以上の薬剤を用いて、単独に生じた免疫応答を特定の器官または組織(例えば、癌に冒された器官または組織)へ標的化する方法および組成物を提供する。本発明は、特異的に標的化された免疫応答を生成する方法および組成物が、全身性免疫応答を生ずる第2の免疫薬(例えば、ワクチン)と併用される場合に、特に有益である。好ましい実施形態では、本発明は前進的に生じた全身性免疫応答(例えば、ワクチンにより生じるもの)に関連した潜在的な問題を回避する手段を提供する。特に、そのような免疫応答は一カ所に定まるものではなく、特定の器官または組織を標的化しない。特定の別の例では、免疫応答は、所望の特定標的器官または組織に対してアクセスすることができない。さらに別の例では、一カ所に定まらない免疫応答は、たとえ接近または集中することができるとしても、特定の器官または組織で所望の影響を生ずるには不十分な強さである。本発明は、免疫応答、例えばワクチン(腫瘍ワクチン等)によって生じた免疫応答に対する促進された組織および/または器官特異的指向性の薬剤および方法を提供する。
便宜上、明細書、実施例、および添付の請求の範囲で用いた特定の用語および句の意味は以下の通りである。特に定義しない限り、本明細書で用いた全ての技術用語および科学用語は、この発明が属する技術分野の当業者が共通して理解するものと同様の意味を有する。
本発明は、ワクチン、特に組織または器官(新生物性形質転換による影響を受け、ワクチンによって標的化される腫瘍細胞抗原を発現するもの)に対する一般的な全身性免疫応答を生じさせるために用いられる癌ワクチンを提供する。ワクチン技術に関する方法および組成物は、当該技術分野で知られており、例えば、米国特許第6,511,667号;同第6,503,503号;同第6,500,435号;同第6,488,934号;同第6,488,926号;同第6,479,056号;同第6,472,375号;同第6,455,492号;同第6,432,925号;および同第6,416,764号に記載されている。各々の内容を本明細書では援用する。一般化した抗腫瘍全身性免疫応答を生成するために腫瘍または癌ワクチンを本発明が提供するのに対して、腫瘍または癌ワクチン技術の方法および組成物は当該技術分野で知られており、例えば、米国特許第6,458,585号;同第6,432,925号;同第6,344,198号;同第6,338,853号;同第6,377,195号;同第6,316,256号;同第6,168,946号;同第6,106,829号;同第6,080,722号;同第5,993,829号;同第5,861,494号;同第5,786,204号;第5,750,102号;同第5,733,748号;同第5,705,151号;同第5,478,556号;同第5,290,551号;および同第5,030,621号に記載されている(これらの各々の内容は、その全体が本明細書中に援用される)。
本発明は、さらに、T細胞媒介免疫応答を引き起こすために、腫瘍抗原をコードするDNAを被験体に導入するための手段を提供する。種々のそのようなDNAワクチン送達系が当該技術分野で知られており、その例を以下に示す。ワクチン接種の方法は急激に進歩している(例えば、総説として、Polandら、(2002)BMJ.324:1315−19を参照のこと)。DNAをベースとするワクチン接種は、所望の標的抗原(例えば、腫瘍抗原等の腫瘍特異的抗原)由来の改変配列を直接注射することで防御免疫応答を提供する。この抗原は、発現ベクター(例えば、ポックスウイルスまたはαウイルスをベースとしたベクタ)に挿入される。ひとたび宿主に送達されると、挿入されたDNAが限定的に複製され、興味のあるタンパク質を産生するので、宿主は該タンパク質に対する免疫応答を生じる。その最も単純化された形態では、裸のDNA(例えば、細菌プラスミドに挿入され、かつ免疫応答を生ずるために宿主に直接注入されたDNA配列。そのような裸のDNAワクチンを筋注で、またはワクチンDNAの経皮または皮内送達を介して、ヒトの筋組織に注射してもよい。B型肝炎表面抗原をコードするDNAをコートした微小金粒子を経皮送達させることで、CD8細胞傷害性リンパ球の産生を含む防御免疫応答を生ずる(Polandら(2001)Fourth annual Conference on Vaccine Research,Arlington,VA,4月23日〜25日:S37:57)(www.nfid.org/conferences/vaccine01−/abstracts/abss 37−40.pdfを参照のこと)。
特に好ましい実施形態において、本発明は、DNA癌ワクチンによって標的化される腫瘍抗原または他の腫瘍抗原をコードするDNAに対する微生物(例えば、細菌)をベースとした送達系を提供する。抗原送達に生存細菌送達系を用いることが最近、再考されている(MedinaおよびGuzman(2001)Vaccine 19:1573−1580;WeissおよびChakraborty(2001)Current Opinion in Biotechnology 12:467−72;ならびにDarjiら(2000)FEMS Immunol and Medical Microbiology 27:341−9)。
組織指向性免疫応答(例えば、肝腫瘍の治療のために肝臓内で)の生産のための好ましい薬剤であることに加え、Listeria monocytogenesを本発明のDNA腫瘍/癌ワクチンの送達として用いてもよい。グラム陽性細菌であるL.monocytogenesは、ヒトを含む広範囲の動物から食細胞および非食細胞に侵入し、宿主細胞の空胞から細胞質に内在化したあとに逃れる。細胞質では、宿主細胞の細胞骨格から成分をリクルートして運動性を持つものとなり、実質的に周囲の細胞へ広がる。
驚くべきことに、E.coli K12の研究室株を哺乳動物細胞の導入ベクターとしても使用することができる。栄養要求性dapB突然変異体をS.flexneriについて既に説明したようにして用いた。野生型E.coli K12は侵襲的ではないことから、S.flexneriの病原性プラスミドによってトランスフェクトされる。このプラスミドは、上皮起源の哺乳動物の細胞が感染することを可能にするだけではなく、ファゴソームからの続いて起こる逃避も容易にした。この大腸菌は、DNAを真核生物細胞へ導入する能力がある(Courvalinら、(1995)318:1207−12を参照のこと)。また、大腸菌が発生し、偽結核Yersiniaのインベーシン遺伝子を発現する。これらの細菌が宿主細胞に浸入することも可能ではあるが、空胞から出ることまでできなかった。それにも関わらず、発現プラスミドの導入が生じた(Grillot−Courvalin(1998)Nat Biotechnol 16:862−66を参照のこと)。細胞内リステリオライシンとともにインベーシンを発現するそのような細菌は、感染の多重度(MOI)が低いと導入率が適度に増加するだけであった。もしあるとすれば、インベーシンのみで処理した細菌またはインベーシンとリステリオライシンで処理した細菌との間で、導入率のわずかな違いが高MOIで検出された。このことは、ファゴソーム膜を横断して宿主細胞の核に発現プラスミドが導入されるポートを生成する能力を研究室E.coli K12が有することを示している。
一般に、標的となる器官または組織(例えば、癌治療の場合、癌によって影響を受ける器官または組織、および本発明の方法に関連した器官または組織)に対して指向性を持つ免疫活性化剤(例えば、感染性細菌、ウイルス、および真菌等の微生物)を提供する。感染性因子、例えば特定の器官または組織に対して自然指向性を持つウイルス、細菌、酵母、または真菌は、本発明のこの局面で使用するのに適している。さらに、特定の器官または組織に局在するように改変される任意の感染性因子を利用することができる(例えば、器官もしくは組織に存在するレセプターのリガンドと生物の外被、被膜、もしくは膜タンパク質との融合によって、または器官もしくは組織に特異的な抗体の表面発現もしくは該抗体に対する接合によって)。組織指向性に関して生物(例えば、細菌およびウイルス)を改変する方法は、当該技術分野で知られており、また、例えば米国特許第6,514,722号;同第6,475,482号;同第6,472,368号;同第6,462,070号;同第6,440,419号;同第6,428,788号;同第6,428,771号;同第6,416,960号;同第6,410,517号;同第6,399,575号;同第6,379,699号;同第6,339,070号;同第6,331,524号;同第6,329,501号;同第6,261,787号;同第6,261,544号;同第6,252,058号;同第6,251,392号;同第6,221,647号;同第6,214,622号;同第6,080,849号;同第6,071,890号;同第6,004,554号;同第5,965,132号;同第5,863,538号;同第5,855,866号;同第5,851,527号;同第5,820,859号;同第5,776,427号;および同第5,660,827号(これらの内容すべてが本明細書で援用される)が挙げられる。
1種類以上の組織または器官に対する自然指向性(natural tropism)を有する細菌が当該分野に知られており、次のような綱(class)を含むが、これに限定されるものではない:血液を冒す(すなわち、菌血症)ことが知られている細菌としては、コアグラーゼ陰性ブドウ球菌(coagulase−negative staphylococci)、Staphylococcus aureus、Streptococcus pneumoniae、他のStreptococcus種、Enterococcus、Escherichia coli、Klebsiella pneumoniae、Enterobacter、Proteus mirabilis、他のEnterobacterioceae、Pseudomonas aeruginosa、他のPseudomonas種、Haemophilus influenzae、Bacteroides fragilisが挙げられる。血液を冒すことが知られている他の細菌は、多くの好気性菌および嫌気性菌を含む。
本発明の特に好適な実施例において、Listeria monocytogenes(好ましくは、HIV−gagによって弱毒化したもの;LiebermanおよびFrankel(2002)Vaccine 20:2007−10;ならびにFriedmanら(2000)J Virol 74:9987−93を参照のこと)を腹腔内注射すると、その結果、この細菌は肝臓に局所的に局在化される(例えば、肝臓ガン治療用の肝臓腫瘍ワクチン増強における利用のために)。
Listeriaによる、宿主組織への侵入および集落形成は、概して、腸の関門を通過することで起こる。腸に達する前に、経口摂取されたListeriaは胃の厳しい環境に耐えなければならない。感染物質の経口摂取量は、シメチジン処置された実験動物への方が、未処置の動物より少なかった。そして、抗酸薬およびH2遮断薬の利用は、Listeria症に対する危険要因であると報告されてきた。このことは、胃の酸性が、汚染食物とともに摂取される、かなり多くのListeriaを破壊するかもしれないということを示している。
指向性ウイルスの例として、肝臓に感染するA型、B型、C型、D型およびE型肝炎ウイルス、黄熱病ウイルス、ならびにエプスタインバーウイルスと、新生児または免疫易感染者の肝臓に感染するサイトメガロウイルス、単純ヘルペスウイルス、ならびに水痘および風疹ウイルスと、心臓に感染するCoxsackie Bウイルスと、腎臓に感染するサイトメガロウイルスと、筋肉に感染するCoxsackie B(胸間筋痛)ウイルスと、腺に感染するサイトメガロウイルスならびにおたふくかぜウイルスと、眼球に感染する単純ヘルペスウイルス、アデノウイルス、はしか、風疹、エンテロウイルスならびにCoxsackie A24ウイルスとが挙げられる。
本発明はさらに天然で、または化学的改変を介して、所望の腫瘍または器官を標的化する真菌および寄生虫生体等の他の薬剤を提供し、その上「非生存」炎症性薬剤(低分子等)をも提供する。
本発明は、腫瘍抗原をコードするものおよび免疫活性刺激因子をコードするもの(例えば、顆粒球マクロファージコロニー刺激因子のようなサイトカイン(GM−CFS、GenBank番号NM_000758および米国特許第5,641,663号を参照のこと、その内容は、本明細書中に組み込むものとする)と、他の核酸、その相同物、およびその一部分と、それらがコードするポリペプチドとを提供する。好適な核酸は、被験体遺伝子のヌクレオチド配列と、少なくとも約60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、さらに好ましくは85%相同、さらに好ましくは90%、さらに好ましくは95%、その上さらに好ましいのは、少なくとも99%相同である配列を有し、例えば、腫瘍抗原をコードする遺伝子核酸は、本発明の被験体核酸の1つで表される核酸配列と、少なくとも90%、さらに好ましくは95%、最も好ましくは、少なくとも約98〜99%同一であり、またその相補体も当然本発明の範囲内である。好ましい実施形態では、核酸は哺乳動物のものであり、特に好ましい実施形態では、被験体腫瘍抗原をコードするDNAのコード配列に対応するコード領域に対応する核酸配列の全てまたは一部分を含む。
哺乳動物生物から腫瘍抗原遺伝子をクローニングして決定したヌクレオチド配列はさらに、他の哺乳動物生物からの腫瘍抗原相同物と同様に、例えば、他の組織から得た他の細胞種類で、他の腫瘍抗原相同物を同定および/またはクローニングする際の使用のために設計されるプローブおよびプライマーの生成を可能にする。例えば、本発明は、十分に精製したオリゴヌクレオチドを含むプローブ/プライマーも提供し、このオリゴヌクレオチドは、厳密な条件下で、本発明の核酸(例えば、腫瘍抗原をコードする核酸)の1つから選択したセンスまたはアンチセンス配列の少なくとも約12、好ましくは25、さらに好ましくは40、50、または75の連続したヌクレオチドにハイブリダイズするヌクレオチド配列領域を含む。
本発明は、下記に記載するように、本発明で使用する抗原、腫瘍抗原、および腫瘍抗原発現遺伝子を提供する。
特定の実施形態では、例えば、遺伝子操作した全腫瘍細胞ワクチンと併用して、本発明は、本発明のワクチンおよび指向性薬剤とともに使用する免疫活性化抗原を提供する。様々なサイトカインおよび他の分子は、樹状細胞または他の腫瘍抗原提示細胞の増殖、分化、移動、および活性を促進でき、さらに、腫瘍抗原提示に対するT細胞の応答を誘引し高める樹状細胞の能力を増強できる。例えば、Banchereau Jら、「Dendritic cells and the control of immunity」Nature(1998)392:245−42;Young JWら、「The hematopoietic development of dendritic cells:a distinct pathway for myeloid differentiation」Stem Cells(1996)14:376−387;Cella Mら、「Origin,maturation and tumor antigen presenting function of dendritic cells」Curr Opin Immunol.(1997)9:10−16;Curti Aら、「Dendritic cell differentiation from hematopoietic CD34+ progenitor cells.」J Biol.Regul.Homeost.Agents(2001)15:49−52を参照のこと。樹状細胞または他の腫瘍抗原提示細胞の分化、成熟、展開、および活性を調節する分子の例としては、CD40リガンド、顆粒球マクロファージコロニー刺激因子(GM−CSF)、FMS様レセプターチロシンキナーゼ3リガンド(Flt3リガンド、FL)、インターロイキン(IL)1−α、IL1−β、IL−3、IL−4、IL−6、IL−12、IL−13,IL−15,腫瘍壊死因子α(TNF−α)、顆粒球コロニー刺激因子(G−CSF)、幹細胞因子(SCF,キット(kit)リガンド(KL)、Steel因子(SF、SLF)、およびMast細胞増殖因子(MGF)としても知られる)、腫瘍壊死因子(TNF)関連活性誘導サイトカイン(TRANCE)、腫瘍壊死因子関連アポトーシス誘導リガンド(TRAIL)、および形質転換成長因子β1等のリガンドが挙げられる。上記分子のいずれかに帰する1つ以上の活性を有する融合タンパク質は、樹状細胞または他の腫瘍抗原提示細胞の分化、成熟、展開、または活性を調節してもよい。これらのリガンド、融合タンパク質、または他の分子のいずれも、ベクター発現系で第2の遺伝子発現カセットとしてコードされることが可能である。
本発明はさらに、腫瘍抗原または免疫活性タンパク質をコードし、宿主細胞中で、腫瘍抗原または免疫活性タンパク質を発現するために用いることのできるプラスミドおよびベクターを提供する。宿主細胞は、いずれの原核細胞または真核細胞でもよい。したがって、完全長タンパク質の全てまたは選択した部分をコードする、哺乳動物の腫瘍抗原タンパク質のクローニングから得たヌクレオチド配列を用いて、微生物または真核細胞プロセスを介して腫瘍抗原ポリペプチドの組み換え体を生産できる。発現ベクター等の遺伝子構築物へのポリヌクレオチド配列のライゲーションと、宿主、すなわち真核(酵母、鳥類、昆虫類、または哺乳動物)細胞または原核(細菌)細胞のどちらかへの形質転換またはトランスフェクションとは、この技術で周知の標準手順で行う。
本発明は、上述のワクチンおよび指向的免疫賦活剤を含む薬学的組成物を提供する。一局面においては、本発明は、上述の化合物を1 つ以上治療有効量含み、1種以上の薬学的に受容可能なキャリア(添加物)、および/または希釈剤と共に処方される薬学的に受容可能な組成を提供する。また別の局面にある特定の実施形態においては、本発明の化合物は、そのまま、または薬学的に受容可能なキャリアと混合して投与してもよく、さらに他の化学療法治療薬と併せて投与してもよい。従って、組み合せ(併用)療法(conective(combination)therapy)は、順次的(sequential)、同時的(simultaneous)、および別個的なもの(separate)を含み、言い換えると、次のものが投与されるとき、最初に投与されたものの治療効果が完全に消滅していないような、有効化合物の同時投与(co−administration)である。
主題の化合物の薬学的に受容可能な塩は、有毒でない、該化合物の通常塩、もしくは第4アンモニウム塩を含み、例えば、無害な無機酸または有機酸に由来する。例えば、そのような通常の非有毒塩は、塩酸、臭化水素酸、硫酸、スルファミン酸、リン酸、ショウ酸などの無機酸から合成した塩を含み、さらに、酢酸、プロピオン酸、琥珀酸、グリコール酸、ステアリン酸、乳酸、リンゴ酸、酒石の酸性のクエン酸、アスコルビン酸、パルミチン酸、マレイン酸、ヒドロキシマレイン酸、フェニル酢酸、グルタミン酸、安息香酸、サリチル酸、スルファニル酸、2−アセトキシ安息香酸フマル酸、トルエンスルホン酸、メタンスルホン酸、エタンジスルホン酸、シュウ酸、イソチオシアン酸等の有機酸から調製した塩を含む。
本発明はさらに、患者に主題の薬学的組成物を有効量投与することを含む、癌性腫瘍を治療する新規治療方法を提供する。本発明の方法は、いかなる癌性腫瘍の治療に使用してもよい。ある実施形態において、その方法は、患者に主題の薬学的組成物を有効量、非経口投与することを含む。1つの実施形態において、その方法は、患者に主題の組成を動脈内投与することを含む。他の実施形態において、その方法は、主題の組成物を患者の癌性腫瘍の動脈血供給源へ、有効量、直接投与することを含む。1つの実施形態において、その方法は、カテーテルを用いて、主題の組成物を癌性腫瘍の動脈血供給源へ、有効量、直接投与することを含む。カテーテルを用いて主題の組成を投与する実施形態において、カテーテルの挿入を螢光透視法によって誘導もしくは観察してもよく、あるいは、カテーテル挿入を誘導および/または観察できる当技術分野で公知の他の方法によって、それを行ってもよい。別の実施形態において、その方法は、化学的塞栓治療を含む。例えば、化学的塞栓法は、1種以上の化学療法治療薬および油性基剤(例えば、エチドール中のポリビニルアルコール)と混合した樹脂様材料を含む組成物で、癌性腫瘍に血液供給している血管を遮断する工程を含んでもよい。さらに他の実施形態において、その方法は、患者に主題の組成物を全身投与することを含む。
本発明は、様々な癌を治療するためのキットを提供する。例えば、キットは、上述の薬学的組成物を1種以上含んでもよい。それらの組成物は、薬学的に受容可能な賦形剤を含む薬学的組成物であってもよい。キットを包含する他の実施形態において、本発明は、本発明の薬学的組成物を含むキットを提供し、必要に応じてそれらの使用説明書を提供する。さらに他の実施形態において、本発明は、1種以上の薬学的組成物と、そのような組成物の投与を実現する1つ以上の装置とを含むキットを提供する。例えば、主題のキットは、組成物の癌性腫瘍への直接動脈注入を実現するため、薬学的組成物およびカテーテルを含んでもよい。1つの実施形態において、その装置は、動脈内カテーテルである。そのようなキットには、例えば、治療、診断、および他のアプリケーションを含む、様々な用途がある。
以下の実施例は、GM−CSF分泌腫瘍細胞ワクチン、および発癌した腫瘍部位に自然局在するか、もしくは局在化可能な、弱毒指向性細菌を併用した、新生腫瘍および転移性腫瘍を含む癌の治療に、本発明の方法および組成物を適用するガイダンスを熟練した技術者に提供するものである。特に、以下の実施例は、GM−CSF分泌腫瘍細胞ワクチンの併用による転移性肝臓癌の治療が、肝臓へ局在する弱毒細菌株の配送よって強化されるが、弱毒化細菌が局在しない他の組織に対するGM−CSF分泌腫瘍細胞ワクチンの効化が強化されないことを明らかにする。従って、以下の実施例は、疾患、特に癌を治療する併用療法に対する広範な支持を提供するもので、全身腫瘍ワクチンおよび疾患器官もしくは組織に指向的な薬剤(例えば、指向性弱毒細菌もしくはウイルス、または、疾患領域への直接的適用によって局在化可能な他のそのような薬剤)を含む。
生後6〜8週間のメスのBALB/cマウスは、National Cancer Instituteから購入され、CT26と共に、以下の実験で使用された。CT26は、BALB/cマウス由来の結腸直腸がん腫瘍細胞系である。それらのマウスを、ペントバルビタール(50mg/kg、腹腔内投与)で麻酔にかけた。脾臓を露出させるため、各マウスを腹壁切開した。血管茎を完全に残したまま、チタンクリップを用いて、脾臓を2つの半脾臓(hemi−spleen)に分割した。(図1を参照)。27ゲージの注射針を用い、半脾臓の1つに、300μlのハンクス平衡塩類溶液(Hanks Balanced Salt Solution(HBSS))中のCT26細胞0個、1×104個、1×105個、1×106個を注入した。細胞は、その後、脾静脈および門脈に流れ込み、肝臓で腫瘍沈着物を形成した。その後、CT26に汚染された半脾臓を手術により除去し、腫瘍細胞なしの機能的な半脾臓を残した。(図2を参照)。
実験のこのセットにおいては、転移性肝臓癌モデルにおいて記載されたように、マウスを脾臓経由で1×105個のCT26細胞によって処置した。マウスに、CT26腫瘍チャレンジの7日前より週2回、腫瘍チャレンジ当日、腫瘍チャレンジ3日後、および腫瘍チャレンジ7日後に、ハンクス平衡塩類溶液(HBSS)で免疫化するか、または、紫外線照射された(5000rad)GM−CSFを分泌する遺伝子改変CT26細胞(GM/CT26)1×106個で免疫化した。4週目に、マウスを安楽死させ、それらの肝臓を、巨視的および顕微鏡的転移性疾患両方の存在に関して分析した。2つの実験のデータを、図5に要約する。
Listeria monocytogenes(LM)のHIV−gag弱毒化株との併用療法における、GM−CSF分泌腫瘍細胞ワクチンの効果をテストするため実験を行った。図6のExperiment Aにおいて、マウスは、以前に記載されているように、転移性肝臓癌で処置された。24匹のマウスを、6匹のマウスからなる4つの群に分割し、以下の処置を与えた。
GM+3:紫外線照射(5000rad)された1×106個のGM/CT26を、腫瘍処置の3日後から、週2回、3週間
Listeria:1×106個コロニー形成ユニット(CFU)のLMを、腫瘍処置の6日後から、腹腔内接種
GM+3/Listeria:上述の通りの、GM/CT26ワクチンと、LM接種との併用療法。
Listeria monocytogenes(LM)のHIV−gag弱毒化株との併用療法における、GM−CSF分泌腫瘍細胞ワクチンの効果を、転移性肺癌モデルおよび転移性結腸直腸癌モデルでテストするため実験を行った。この実験(図7)では、5×105のCT26細胞を尾静脈注射することによって、マウスを転移性肺癌処置した。以下の群各々は、それぞれ9匹もしくは10匹のマウスを有した。
GM+3:紫外線照射(5000rad)された1×106個のGM/CT26を、腫瘍処置の3日後から、週2回、3週間
Listeria:1×106個コロニー形成ユニット(CFU)のLMを、腫瘍処置の6日後から、腹腔内接種
GM+3/Listeria:上述の通りの、GM/CT26ワクチンと、LM接種との併用療法。
Listeria注入による、肝腫瘍ワクチンの強化を示す実験を繰り返した。図9は、ワクチン処置、Listeria処置、または腫瘍ワクチンおよびListeriaの併用処置された肝臓癌保持マウスの生存率の比較を示す。マウスを、第0日目に1×105個のCT26細胞で肝臓癌処置した。マウスを、3日目から計3週間、週2回、ワクチン接種するか、第6日目に1×106個のListeriaを単回投与するか、あるいはワクチン接種とListeria感染の併用を行い、それらの生存率を追った。
Listeriaによる、腫瘍ワクチンの免疫反応強化の動作メカニズムを分析するため、まず、様々な処置群において、肝臓に浸潤しているAH1腫瘍抗原特異的CD8 T細胞のレベルを比較した。図8は、肝臓に浸潤しているAH1腫瘍抗原特異的CD8 T細胞レベルの、様々な処置群における比較を示す。マウスを、3つの処置群に分割した。全てのマウスを、第14日目に屠殺した。群1は、第0日目腫瘍処置した。群2は、腫瘍処置をせず、第3日目、第7日目、および第11日目にワクチン処置した。群3は、第0日目腫瘍処置し、第3日目、第7日目、および第11日目にワクチン処置した。14日後にマウスを屠殺し、その後リンパ細胞を分離するため、マウス肝臓をコラゲナーゼ、およびヒアルロニダーゼを用いて消化し、フィコール密度勾配上で遠心した。AH1腫瘍抗原ペプチドまたはコントロール群ペプチドB galのいずれかを結合したLdIg二量体で染色することによって、CD8リンパ細胞の腫瘍抗原特異性を分析した。
この研究は、Public Health Service NIH−NCI SPORE助成金番号5P50 CA 62924−08、およびJohns Hopkins UniversityからのClinical Scientist awardによって補助された。
(等価物および参考による援用)
当業者は、本明細書に記載した特定のポリペプチド、核酸、細胞、投薬形態、方法、分析、および試薬に対する多数の等価物を認識するであろうし、また日常的な範囲の実験によってそれらを確認することができる。そのような等価物は、本発明の範囲内にあると考えられ、以下の請求に内包される。
Claims (26)
- 被験体の器官もしくは組織特異的疾患または症状に対する全身性免疫応答を生成する方法であって、
該器官もしくは組織特異的疾患または症状に対する全身性免疫応答を生成するワクチンの治療有効量を投与する工程と、
該器官もしくは組織に局所的に局在化するか、または直接投与されて、該器官もしくは組織で局所的な免疫応答を生成する薬剤を投与する工程とを包含し、
それによって、該器官もしくは組織特異的疾患または症状に対する全身性免疫応答を生成する方法。 - 前記器官もしくは組織特異的疾患または症状が腫瘍または癌腫であり、前記ワクチンが腫瘍ワクチンである、請求項1に記載の方法。
- 前記腫瘍または癌腫が肝臓癌である、請求項2に記載の方法。
- 前記ワクチンがGM−CSFを発現する弱毒化した腫瘍細胞株である、請求項3に記載の方法。
- 前記器官または組織に局所的に局在化する前記薬剤が前記特定の器官または組織に対して天然指向性を有するウイルス、細菌、酵母または真菌からなる群より選択される、請求項1〜4のいずれかに記載の方法。
- 局所的に局在化する前記薬剤がListeria monocytogenesの弱毒化株である、請求項1〜4のいずれかに記載の方法。
- 前記生物が新生血管内皮に局所的に局在化する、請求項5に記載の方法。
- 前記薬剤が遺伝子操作されて前記器官または組織に局所的に局在化するとともに、ウイルス、細菌、酵母、および真菌からなる群から選択される生物である、請求項1〜4のいずれかに記載の方法。
- 前記遺伝子操作された生物が前記器官または組織により発現されるレセプターのリガンドを発現する、請求項8に記載の方法。
- 前記器官または組織レセプターの前記リガンドが前記生物の外被または被膜タンパク質へ融合している、請求項9に記載の方法。
- 前記器官または組織が新生血管内皮である、請求項8に記載の方法。
- 前記遺伝子操作された生物が新生血管内皮により発現されるレセプターのリガンドを発現する、請求項9に記載の方法。
- 前記薬剤が天然指向性を持たない生物であり、直接注射、経皮カテーテル、外科的処置、および閉ループ潅流からなる群から選択される物理的手段により前記器官または組織へ直接投与される、請求項1に記載の方法。
- 前記器官または組織が肺であり、前記投与方法が吸入である、請求項1に記載の方法。
- 前記器官または組織が肺であり、前記投与方法が経口摂取である、請求項1に記載の方法。
- 前記器官または組織に局所的に局在化するか、また直接投与される前記薬剤がケモカイン、サイトカイン、および接着分子からなる群から選択される免疫または炎症の活性化因子を産生する遺伝子操作された生物である、請求項1に記載の方法。
- 前記器官または組織に局所的に局在化するか、また直接投与される前記薬剤が炎症性薬剤である、請求項1に記載の方法。
- 被験体の組織または器官に局在化する腫瘍または癌腫を治療する方法であって、
該腫瘍または癌腫に対する免疫応答を生成する腫瘍ワクチンの治療有効量を投与することと、
該器官または組織に局所的に局在化するか、また直接投与されるとともに、該器官および組織で、局所的な免疫応答を生成する薬剤を投与することとを含み、
それによって、該被験体の前記組織または器官に局在化する該腫瘍または癌腫を治療する方法。 - 前記腫瘍または癌腫が肝腫瘍であり、前記腫瘍ワクチンが全腫瘍細胞ワクチンを分泌するGM−CFSであり、前記病変器官または組織に局所的に局在化する前記薬剤がListeria monocytogenesの弱毒化株である、請求項18に記載の方法。
- 前記腫瘍ワクチンがDNA腫瘍ワクチンである、請求項18に記載の方法。
- 器官もしくは組織特異的疾患または症状に対する免疫応答を生成する治療有効量のワクチンと、
該器官または組織に局所的に局在化するか、また直接投与されるとともに、該器官または組織で、局所的な免疫応答を生成する薬剤と
を含む、被験体の該器官もしくは組織特異的疾患または症状に対して全身性免疫応答を生成するための処方物。 - 腫瘍または癌腫に対する免疫応答を生成する治療有効量の腫瘍ワクチンと、
該器官または組織に局所的に局在化するか、また直接投与されるとともに、該器官または組織で、局所的な免疫応答を生成する薬剤と
を含む、被験体の該組織または器官に局在化する該腫瘍または癌腫を治療するための処方物。 - 前記器官または組織に局所的に局在化するか、また直接投与されるとともに、該器官または組織で、局所的な免疫応答を生成する該薬剤が弱毒化した細菌である、請求項21または22に記載の処方物。
- 前記弱毒化した細菌がHIV−gagで弱毒化したListeria monocytogenesである、請求項23に記載の処方物。
- 被験体の器官もしくは組織特異的疾患または症状に対する全身性免疫応答を生成するためのキットであって、
該器官もしくは組織特異的疾患または症状に対する免疫応答を生成するワクチンと、
該器官もしくは組織に局所的に局在化するか、また直接投与されるとともに、該器官もしくは組織で局所的な免疫応答を生成する薬剤とを含むキット。 - 被験体の組織または器官に局在化する腫瘍または癌腫を治療するためのキットであって、
該腫瘍または癌腫に対する免疫応答を生成する腫瘍ワクチンと、
該器官もしくは組織に局所的に局在化するか、または直接投与されるとともに、該器官もしくは組織で局所的な免疫応答を生成する薬剤とを含むキット。
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PCT/US2003/003650 WO2003065787A2 (en) | 2002-02-06 | 2003-02-06 | Methods and compositions for the targeting of a systemic immune response to specific organs or tissues |
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JP (1) | JP2006502964A (ja) |
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