JP7247097B2 - がん免疫療法のための新規pd-l1標的dnaワクチン - Google Patents
がん免疫療法のための新規pd-l1標的dnaワクチン Download PDFInfo
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Description
従来技術を考慮して、本発明の目的は、がん治療を標的とする新規の安全かつ効率的なPD-L1を提供することである。このような新規の治療アプローチは、がん患者の治療選択肢を改善するための大きな利点を提供するであろう。
第一の態様では、本発明は、PD-L1をコードする発現カセットを含むDNA分子の少なくとも1コピーを含むサルモネラの弱毒株に関する。
この研究の目的は、播種同系FBL-3赤白血病を保有するC57BL/6マウスにおける、2種類のサルモネラベースのPD-L1 DNAワクチンの抗腫瘍効果を調査することであった。VXM10mは、全長ネズミネイティブPD-L1(配列番号17の塩基配列を有する)をコードする発現プラスミドpVAX10で形質転換された、サルモネラ・チフィムリウム(Salmonella typhimurium)aroA株SL720である。VXM10maは、短縮型ネズミPD-L1(配列番号18の塩基配列を有する)、より具体的には17アミノ酸残基を切断したN末端をコードする発現プラスミドpVAX10で形質転換された、サルモネラ・チフィムリウム(Salmonella typhimurium)aroA株SL720である。
この研究の目的は、再負荷後の播種同系FBL-3赤白血病を保有するC57BL/6マウスにおける、2種類のサルモネラベースのPD-L1 DNAワクチンの抗腫瘍効果の長期効果を調査することであった。
この研究の目的は、播種同系FBL-3赤白血病を保有するC57BL/6マウスにおいて、治療的に投与されるVXM10m、およびVXM10maの抗腫瘍効果を調査することであった。
この研究の目的は、播種同系FBL-3赤白血病を保有するC57BL/6マウスにおいて、1、3、5、および7日目、ならびに14、21日目のブーストで108CFUおよび1010CFUで投与されたVXM10mおよびVXM10maに対する抗PD-L1応答を調査することであった。20日目に5.0×106個のFBL-3細胞の腹腔内投与(I.P. injection)によってすべての動物において腫瘍が誘発された。ワクチン接種および腫瘍誘発は基本的に実施例1に記載のとおりに行った。可溶性組換えマウスPD-L1をポジティブコントロール群においてCFA/IFAによる免疫に使用した。
この研究の目的は、1日おき(1、3、5、および7日目)に、VXM10m、VXM10ma、または空ベクターコントロールのいずれかの1010CFUで経口経路によって4回免疫した健康なC57BL/6マウス(群あたりn=5)のPD-L1エピトープに対して誘導されるT細胞応答を調査することであった(図19A)。
この研究の目的は、播種同系FBL-3赤白血病を保有するC57BL/6マウスにおける3番目のサルモネラベースのPD-L1 DNAワクチンの抗腫瘍効果の長期効果を調査することである。VXM10mbは、短縮型マウスPD-L1、より具体的にはN末端シグナル伝達ペプチドを含む細胞外ドメイン(アミノ酸配列の配列番号15;塩基配列の配列番号16)をコードする発現プラスミドpVAX10で形質転換したサルモネラ・チフィムリウム(Salmonella typhimurium)aroA株SL720である。実験は、基本的に実施例1および実施例2に記載されているように行われる。
この研究の目的は、播種同系FBL-3赤白血病を保有するC57BL/6マウスに治療的に投与されたVXM10mbの抗腫瘍効果を調査することである。実験は、基本的に実施例3に記載されているように行う。
Claims (17)
- PD-L1をコードする真核生物発現カセットを含むDNA分子の少なくとも1コピーを含む、サルモネラ・チフィTy21a(Salmonella typhi Ty21a)であるサルモネラの弱毒株を含む、がんの治療のための医薬組成物。
- 請求項1に記載の医薬組成物であって、ここで前期発現カセットは、一つのCMVプロモーターを含む、医薬組成物。
- PD-L1は、配列番号1において示されているアミノ酸配列を有するPD-L1、およびそれと少なくとも95%の配列同一性を有するタンパク質、
ならびに配列番号2において示されているアミノ酸配列を有するPD-L1、およびそれと少なくとも95%の配列同一性を有するタンパク質、
ならびに配列番号13において示されているアミノ酸配列を有するPD-L1、およびそれと少なくとも95%の配列同一性を有するタンパク質、
からなる群から選択される、
請求項1または2に記載の医薬組成物。 - PD-L1が、配列番号3、配列番号4、または配列番号14において示されている核酸配列によってコードされている、請求項3に記載の医薬組成物。
- 前記DNA分子は、カナマイシン抗生物質耐性遺伝子、pMB1 ori、および一つのCMVプロモーターをさらに含む、請求項1~4のいずれか一項に記載の医薬組成物。
- 前記治療はがん免疫療法である、請求項1~5のいずれか1項に記載の医薬組成物。
- 前記がんの治療は、化学療法、放射線療法または生物学的がん療法をさらに含む、請求項1~6のいずれか1項に記載の医薬組成物。
- 前記生物学的がん療法は、腫瘍抗原、および/または腫瘍間質抗原をコードする、さらなる真核生物発現カセットを含むさらなるDNA分子の少なくとも1コピーを含むサルモネラの少なくとも一つのさらなる弱毒株の投与を含み、
ここで、前記サルモネラの少なくとも一つのさらなる弱毒株は、サルモネラ・チフィTy21a(Salmonella typhi Ty21a)である、請求項7に記載の医薬組成物。 - 前記少なくとも一つのさらなるDNAワクチンによってコードされる前記腫瘍抗原は、ウィルムス腫瘍タンパク質(WT1)、メソテリン(MSLN)、CEA、CMV pp65、からなる群から選択される、
および/または、前記少なくとも一つのさらなるDNAワクチンによってコードされる前記腫瘍間質抗原は、VEGFR-2、またはヒト線維芽細胞活性化タンパク質(FAP)である、
請求項8に記載の医薬組成物。 - 前記少なくとも一つのさらなるDNAワクチンによってコードされる前記腫瘍抗原は、
配列番号6において示されているアミノ酸配列を有するウィルムス腫瘍タンパク質(WT1)、
配列番号7において示されているアミノ酸配列を有するメソテリン(MSLN)、
配列番号8において示されているアミノ酸配列を有するCEA、
配列番号9において示されているアミノ酸配列を有するCMV pp65、
配列番号10において示されているアミノ酸配列を有するCMV pp65、および
配列番号11において示されているアミノ酸配列を有するCMV pp65、
からなる群から選択される、ならびにここで
前記少なくとも一つのさらなるDNAワクチンによってコードされる前記腫瘍間質抗原は、
配列番号12において示されているアミノ酸配列を有するVEGFR-2、およびヒト線維芽細胞活性化タンパク質(FAP)からなる群から選択される、
請求項9に記載の医薬組成物。 - 前記医薬組成物は、経口投与に好適である、請求項1~10のいずれか一項に記載の医薬組成物。
- 前記がんは、リンパ腫、白血病、骨髄腫、肺がん、非小細胞肺がん(NSCLC)、黒色腫、腎細胞がん、卵巣がん、神経膠芽腫、メルケル細胞がん、膀胱がん、頭頸部がん、結腸直腸がん、食道がん(esophagial cancer)、子宮頸がん、胃がん、肝細胞がん、前立腺がん、乳がん、膵臓がん、および甲状腺がんから選択される、請求項1~11のいずれか一項に記載の医薬組成物。
- 前記サルモネラの弱毒株の単回投与量は、105~1011コロニー形成単位(CFU)を含む、請求項1~12のいずれか一項に記載の医薬組成物。
- PD-L1の発現パターン、および/または患者のPD-L1に対する前免疫応答を評価する工程を含む、個別化がん免疫療法で使用するためのものである、請求項1~13のいずれか一項に記載の医薬組成物。
- PD-L1は配列番号1、配列番号2、または配列番号13において示されているアミノ酸配列を有する、請求項1~14のいずれか一項に記載の医薬組成物。
- 前記DNA分子は、配列番号5において示されているDNA配列を有する、請求項1~15のいずれか一項に記載の医薬組成物。
- 前記サルモネラの弱毒株の単回投与量は、106~109コロニー形成単位(CFU)を含む、請求項13に記載の医薬組成物。
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