JP6325534B2 - 膵臓癌患者用dnaワクチン - Google Patents
膵臓癌患者用dnaワクチン Download PDFInfo
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- JP6325534B2 JP6325534B2 JP2015518890A JP2015518890A JP6325534B2 JP 6325534 B2 JP6325534 B2 JP 6325534B2 JP 2015518890 A JP2015518890 A JP 2015518890A JP 2015518890 A JP2015518890 A JP 2015518890A JP 6325534 B2 JP6325534 B2 JP 6325534B2
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Description
高コピー数のpUC複製開始点を、pBR322の低コピー数のpMB1複製開始点で置換することによって改変された。低コピー数の変更は、代謝負担を低減し、構築物をより安定化させるようになる。プラスミドpVAX10.VR2−1構築物の詳細は、図2に示されている。作製された発現ベクター骨格は、指定されたpVAX10であった。この発現ベクター骨格内への配列番号2に記載のヒトVEGFR−2の核酸配列を挿入することで、発現プラスミドpVAX10.VR2−1を得た。
表1:患者の選択基準
表2:VMX01に特異的なT細胞応答
研究シードロット(RSL)調製の第1工程は、弱毒化チフス菌Ty21a株の分離と、それに続くプラスミドDNA(pVAX10.VR2−1)を用いた弱毒化細菌の形質転換から成った。
−7.58kbのpVAX10−VR2.1プラスミド配列の全体を、(ソフトウェア解析によって)〜1.5kbの5つの部分に細分した。各部分を、両方の鎖のオリゴヌクレオチド間に重複領域を有する、それぞれ40〜50bpのオリゴヌクレオチドに細分した。
−次に、試験管内合成オリゴヌクレオチドを、T4ポリヌクレオチドキナーゼと共にインキュベーションすることによってリン酸化した。
−適当な条件下での重複オリゴヌクレオチドのアニーリング処理後に、Taq DNAリガーゼ酵素で整列したオリゴヌクレオチドを接続した。
−連結工程の完了時に、PCRを、連結プラスミド断片(〜1.5kb)の収率を高めるために、外へ向かう位置にアニーリングしたプライマーを使用して実施した。
−調製用アガロースゲル電気泳動法を実施して、PCR産物を単離した。
−単離したPCR産物を、TOPOベクター(Invitrogen K#4575-40)にクローン化し、繁殖のためのTOP10E.コリ(E. coli)細胞内に形質転換した。
−TOPOプラスミドの分離後に、制限処理と配列検定をおこなった。
−単離した整列断片を、オーバラップPCRを介して組み立てた。このプロセスのあとには、pVAX10.VR2−1プラスミドを線状に構築することが続いた。
−XhoI制限消化(図2は、ただ一つの制限部位がpVAX10.VR2−1プラスミド内に存在しているのを見る)とT4リガーゼを介した共有結合後に、繁殖のためにE.コリを環状プラスミドで形質転換した。
−最終的なプラスミド配列検定後に、pVAX10.VR2−1プラスミドをS.チフスTy21a株に形質転換した。
この第I相試験では、安全性、耐容性、並びにVXM01に対する免疫学的及び臨床的応答を調べた。無作為化、プラセボ対照、二重盲検用量漸増試験には、局所進行性又はステージIV膵臓癌の45人の患者を含んでいた。患者には、標準的治療としてのゲムシタビンに加えて4つの用量のVXM01又はプラセボを与えた。106CFU〜1010CFUのVXM01の用量を本試験で評価した。独立したデータ安全性モニタリング委員会(DSMB)が用量漸増決定にかかわった。主要評価項目としての安全性に加えて、VXM01特異的免疫反応、並びに臨床反応パラメーターを評価した。
動物におけるこのアプローチの有効性及び安全性を、発明者らによって複数回、正当であると確認した。発明者らによる追実験では、膵臓癌の2つの異なったモデルにおけるこのワクチンの活性が示された。
マウスにおける前臨床毒性試験には、ヒトワクチンVXM01を用いて行われたマウスにおける単回用量毒性試験が含まれるが、それに制限されなかった。VXM01がヒト宿主に特異的なので、マウスにおけるヒトワクチンの試験は、プロセス関連の不純物の推定される影響、及び心血管、呼吸、又は中枢神経系障害に関連する可能性がある標徴及び症状に注目した。抗VEGFR−2のT細胞応答に関する毒性プロフィールを調査するために、反復投与毒性試験を、マウスにおいて用量依存的T細胞反応を引き起こすVXM01のマウスアナログ構築物を使用して実施した。発明者らの先の観察によると、処置関連死及び毒物学的に重要な臨床徴候は、これらの試験を通じて観察されることはなく、そして、これらの試験は、製薬認可基準(GLP)に従って実施した。
実施した試験は、
手術不能又はステージIV膵臓癌の患者における実験用ワクチンVXM01の単−センター、プラセボ対照、二重盲検用量漸増試験であった。前記ワクチンを、標準的治療のゲムシタビン処置に対する追加物として与えた。
患者の選択及び治験デザイン:
VXM01に対する応答を、ワクチン接種前、その最中、及びその後の様々な時点でINFγ ELISpotによって検出した、VXM01やプラセボ処置した患者の末梢血におけるVEGFR2に特異的なT細胞の頻度を観察することによって評価した。
増大なし: グレード0
明らかな増大だが<3×: グレード1
≧3×だが<5×の増大: グレード2
≧5×の増大: グレード3
腫瘍灌流を、動的造影磁気共鳴画像化(DCE-MRI)中の造影剤通過時間(Ktrans)によって評価して、処置応答を特徴づけした。動的造影T1加重画像化を実施した。DCE-MRIを、処置の0日後、38日後及び3か月後に1.5テスラシステム(Magnetom Aera, Siemens, Erlangen, Germany)で評価した。動的造影MR画像化を、VIBE(容量補間息止め)シークエンスを用いて実施した。その目的のために、8mlのガドビストからなる用量を注射した。
VEGFR−2に特異的なT細胞媒介性を更に特徴づけるために、VXM01の抗血管形成活性、血管新生バイオマーカーであるVEGF Aの付随的変化、ヒトIV型コラーゲン及び血圧を観察した。
VEGF Aを、市販のアッセイキット(ELISA Kit Quantikine Human VEGF A Immunoassay, R&D Systems, Cat.-No.: DVE00)を使用したELISAによって、ヒト血清サンプル中で評価した。そのアッセイを添付文書に記載のとおり使用し、そして、事前におこなったバリデーションに従ってこの試験プランの一部を改変した(580.132.2786)。
ヒトIV型コラーゲンを、市販のアッセイキット(Human Collagen IV ELISA, Serum, KAMIYA BIOMEDICAL COMPANY, Cat.-No.: KT-035)を使用したELISAによってヒト血清サンプル中で評価した。そのアッセイを添付文書に記載のとおり使用し、そして、事前におこなったバリデーションに従ってこの試験プランの一部を改変した(580.132.3645)。
抗血管形成有効性の薬力学的マーカーとしての血圧(収縮期と弛緩期)及びパルスレートを、仰臥位での5分間の安静後に評価した。平均収縮期血圧の変化は、処置群において+3.6mmHg及び+3.9mmHgであったのに対して、プラセボでは−8.8mHg及び9.1mmHgであった(d38にてp=0.08)。最初のワクチン接種用量後(38日目まで)の平均血圧に対する効果を、図9にグラフを使って示す。
細菌ビヒクルに対する免疫応答を評価するために、抗チフス菌IgG及びIgM免疫グロブリンを、2種類の市販アッセイキット(チフス菌IgG ELISA, Cat. No. ST0936G及びチフス菌IgM ELISA, Cat. No. ST084M; Calbiotech. Inc., 10461 Austin Dr, Spring Valley, CA 91978, USA)を使用したELISAによって検出した。これらのアッセイは定性分析であった。そのアッセイを添付文書に記載のとおり使用し、そして、事前におこなったバリデーションに従ってこの試験プランの一部を改変した(580.132.2785)。
キャリブレーターOD×キャリブレーター係数(CF)。
<0.9 ELISAではチフス菌IgG又はIgMに対する検出可能な抗体がない
0.9〜1.1 境界線上の陽性
>1.1 ELISAによってチフス菌IgG又はIgMに対する抗体が検出可能
大便、体液、涙液、唾液、尿及び血液中の細菌流出を、既存のある中央サービス研究室(Huntingdon Life Sciences, Huntingdon, UK)にて、GLPに従いかつて正当であると確認されたと伝えられた正当であると確認した方法に従って、VXM01−01−DE試験において観察した。体液中のVXM01の流出及び生体分布を、平板及び濃縮培養で決定した。VXM01担体細菌の同定を、血清学的凝集及びPCR法で決定した。
部門I:あらゆる水平プラスミド移行を検出するための平板培養法
部門II:VXM01の生きたCFUを検出するための液体濃縮培養
水平プラスミド移行の検出のための分析部門I:
−0日目:5つの試験サンプルをそれぞれ3枚のTSA(+カナマイシン)平板上に播種し、37℃にて一晩インキュベートする。
−1日目:選択プレート上のVXM01(Ty21a)と非VXM01形態型とを視覚的に識別。非VXM01形態型を選抜し(それぞれ9つのコロニー)、凝集用の寒天平板(+カナマイシン)及び翌日のPCR分析用のそれぞれのプールした形態型の並行液中培養(+カナマイシン)に画線接種する。
−2日目:液状の形態型プールそれぞれのPCR。
VXM01の検出のための分析部門II:
−0日目:5つの試験サンプルそれぞれのための液体濃縮培養(+カナマイシン)の調製。
−1日目:それぞれの液体濃縮培養に対する直接的なPCR。プラスミドに関してPCRが陽性であった場合の翌日の血清学的解析のための寒天平板培養(+カナマイシン)上への画線接種。
−2日目:VXM01(Ty21a)の存在の血清学的確認。
Claims (12)
- VEGF受容体タンパク質をコードする真核性発現カセットを含む組換DNA分子を少なくとも1コピー含む、チフス菌(Salmonella typhi)の弱毒化変異株Ty21aを含むヒトの癌免疫療法に用いられるワクチンであって、ここで前記VEGF受容体タンパク質が、配列番号1に記載のアミノ酸配列を有するヒトVEGFR−2からなる群より選択され、前記ワクチンは経口投与されると共に、前記ワクチンの単回用量量が106〜109コロニー形成単位(colony forming units:CFU)である、ワクチン。
- 前記プラスミドが、図2に示す7580bpのpVAX10.VR2−1であると共に、配列番号3に記載の配列を有し、前記ワクチンがVXM01で表される、請求項1に記載のワクチン。
- 前記癌が膵臓癌である、請求項1又は2に記載のワクチン。
- 前記膵臓癌がステージIV又は局所進行性の膵臓癌である、請求項3に記載のワクチン。
- 前記癌が転移を含む、請求項1〜4の何れか一項に記載のワクチン。
- 免疫療法処置が化学療法及び/又は放射線療法を伴う、請求項1〜5の何れか一項に記載のワクチン。
- 化学療法剤がゲムシタビンである、請求項6に記載のワクチン。
- 前記ワクチンによる免疫療法処置が化学療法による治療周期の間に実施される、請求項6又は7に記載のワクチン。
- 前記ワクチンの単回用量量が1×106、1×107、又は1×108コロニー形成単位(colony forming units:CFU)である、請求項1〜8の何れか一項に記載のワクチン。
- 前記ワクチンの単回用量量が1×108CFU未満であり、又は前記ワクチンの単回用量量が1×106〜1×107CFUである、請求項1〜8の何れか一項に記載のワクチン。
- 前記単回用量量が、106〜108、又は106〜107のコロニー形成単位(colony forming units:CFU)を含む、請求項1〜8の何れか一項に記載のワクチン。
- 配列番号1のVEGFR−2タンパク質をコードするDNAを含むプラスミドにより形質転換された弱毒化チフス菌(Salmonella typhi)株Ty21aを含むワクチンVXM01であって、前記プラスミドが、7580bpのプラスミドDNAであると共に、CMVプロモーターの調節下にあるVEGFR−2のcDNAと、カナマイシン耐性遺伝子と、pMB1 oriとを含み、pVAX10.VR2−1で表されると共に、ヒトの癌免疫療法のワクチンとして使用され、ここで前記ワクチンは経口投与されると共に、前記ワクチンの単回用量量が106〜109コロニー形成単位(colony forming units:CFU)であるワクチンVXM01。
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