JP2019537609A - 癌の検出及び治療におけるナノデバイス - Google Patents
癌の検出及び治療におけるナノデバイス Download PDFInfo
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Abstract
Description
本願は、2016年11月15日に出願された米国仮出願第62/422,480号と、2016年11月16日に出願された米国仮出願第62/422,714号とに基づく優先権を主張し、それらの両方は、参照によって全体として本明細書に組み込まれる。
・術中に腫瘍組織を同定するためのQDの蛍光特性に起因した腫瘍標識化。
・EGFRへのセツキシマブの結合によるEGFR阻害。
・コンジュゲートのナノサイズによるEPR(Enhanced Permeability and Retention)効果に起因した相乗的な(synergized)腫瘍取込み。
・QDの機能に起因した腫瘍光線療法効果であって、細胞の自殺カスケード(アポトーシス)を引き起し得る熱として一重項酸素を生成するか又はエネルギーを凝縮させる。
CA125:癌抗原125(CA125)は、ムチン16(MUC16)としても知られている。
CA19−9:炭水化物抗原19−9(CA19−9)、別名、癌抗原19−9又はシアル化ルイス(a)抗原。
CD20:CD20は、MS4A1遺伝子によってコードされ、初期B細胞又は形質細胞ではなくB細胞の表面に発現する活性グリコシル化(activated-glycosylated)リンタンパク質である。
CD25:CD25は、インターロイキン2受容体α鎖(IL2RA)タンパク質である。
CD30:別名、TNFRSF8は、腫瘍壊死因子受容体ファミリータンパク質である。
CD33:別名、シアル酸結合免疫グロブリン様レクチン3(SIGLEC−3)。
CD52:分化抗原群53。別名、ケンブリッジ病理学(Cambridge Pathology)抗原−1(Campath−1抗原)。
CD73:分化抗原群73。別名、エクト−5’−ヌクレオチダーゼ(NT5E)。
CD109:分化抗原群109。グリコシルホスファチジルイノシトール(GPI)結合糖タンパク質であって、トランスフォーミング増殖因子β結合に関与する。
CEA:癌胎児性抗原
CTLA−4:細胞傷害性Tリンパ球関連タンパク質4。
EGFR:上皮成長因子受容体。別名、上皮成長因子受容体(EGFR又はHER1)は、erbB受容体チロシンキナーゼファミリーに属する。
HER2:ヒト上皮成長因子受容体2
PD−L1:プログラム化デスリガンド−1(PD−L1)。分化抗原群274(CD274)又はB7ホモログ(homolog)1(B7−H1)としても知られている。
QD:量子ドット
QY:量子収量
RANK:核因子κBの受容体活性化因子
SLN:センチネルリンパ節
VEGF−A:血管内皮成長因子A
分子シーディングプロセスを使用して、非毒性QDを生成した。概要を説明すると、500〜700nmの範囲で発光する非官能化インジウム系QDの調製を以下のようにして行った。ジブチルエステル(約100ml)及びミリスチン酸(MA)(10.06g)を三つ口フラスコに入れて、真空下で約70℃で1時間脱気した。この期間の後、窒素を導入し、そして温度を約90℃に上げた。約4.7gのZnS分子クラスタ[Et3NH]4[Zn10S4(SPh)16]を加え、混合物を約45分間撹拌した。次に、温度を約100℃に上げて、続いてIn(MA)3(1M、15ml)を滴下し、続いてトリメチルシリルホスフィン(TMS)3P(1M、15ml)を滴下した。反応混合物を撹拌しながら温度を約140℃に上げた。140℃で、ジ−n−ブチルセバケートエステルに溶解させたミリスチン酸インジウム(In(MA)3)(1M、35ml)(5分間撹拌したままにした)と、ジ−n−ブチルセバケートエステルに溶解させた(TMS)3P(1M、35ml)を更に滴下した。その後、温度をゆっくりと180℃に上げて、In(MA)3(1M、55ml)、続いて(TMS)3P(1M、40ml)を更に滴下した。このようにして前駆体を添加することで、発光極大が500nmから720nmまで徐々に増加するインジウム系粒子を作製した。所望の発光極大が得られた時点で反応を停止し、反応温度で半時間撹拌し続けた。この期間の後、混合物を約4日間(反応温度よりも約20乃〜40℃低い温度で)アニールした。この段階でUVランプも使用して、アニーリングを促進した。
メラミンヘキサメトキシメチルメラミン(HMMM)修飾蛍光ナノ粒子を、インビトロ及びインビボで生物学的標的を検出及び/又は調整するためのナノプローブとして生成及び使用するための方法の一実施形態が、本実施例で提供される。独特なメラミンベースのコーティングは、優れた生体適合性と、低毒性と、非常に低い非特異的結合とを示す。これらの独特の作用により、インビトロとインビボの両方で幅広い生物医学的用途が可能になる。
インビボ用途のためには、必要とされない限り、低い毒性プロフィールを有するQDが望ましい。ある実施形態では、カドミウム、鉛、及びヒ素などの重金属を含まない低毒性QDが提供されて、膵癌、結腸直腸癌、頭頸部癌、胃癌、脳腫瘍、前立腺癌及び食道癌を含む癌の画像誘導手術に使用される。
実施例2で引用した水溶性の官能基化QDを、カルボジイミドの化学的作用を用いてストレプトアビジン(SAV)に共有結合させて、表面COOH基をSAV分子のアミン末端と結合させた。例えば、以下のプロトコルを使用して、633nm放射水溶性QDをSAVにコンジュゲートした。
エッペンドルフチューブにいいて、1.2mgのカルボキシル官能化水溶性QDを100μlのMES活性化緩衝液(即ち、25μlの50mg/mlストックを100μlのMESに)と混合させた。MES緩衝液は、pH4.5の25mM脱イオン水溶液(2−(N−モルホリノ)エタンスルホン酸ヘミナトリウム塩(MES)、Sigma Aldrich)として調製される。これに、33μlの新たなEDC溶液(脱イオン水における30mg/mlストック、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(EDC)、Fisher Scientific)を加えて、混ぜた。これに、4μlの新たなsulfo−NHS(100mg/mlストック、ThermoFisher Scientific、脱イオン水中)を添加し、溶液を混ぜた。NanoSep300Kフィルタ(PALL NanoSep 300K Omega ultrafilters)を100μlのMESで予め湿らせた。MES/EDC/Sulfo−NHS/QD溶液をNanoSep300Kフィルタに添加し、500μlまでMESで満たした。5000rpm/15分でフィルタを遠心分離した。溜まったドットを50μlの活性化緩衝液に再分散させて、10μlのトラスツズマブ(ハーセプチン(登録商標)、HEPES緩衝液の25mM溶液における100mg/mlストック、pH8.5)と40μlのHEPES、pH 8.5とを含むエッペンドルフチューブに移した。溶液を十分に混ぜて、室温で一晩(約16乃至18時間)インキュベートした。16μlの6−アミノカプロン酸(6AC)(19.7mg/100mM)で溶液をクエンチした。第一級アミンを有する他の化合物を用いてクエンチを代替的に行うことができるであろうが、この実施形態では、COOHを有しており、製品のコロイド安定性を維持できることから6ACが選択されたことに留意のこと。予め湿らせたNanosep300Kフィルタ(100μlの1×PBS)に溶液を移し、1×PBSで500μlのラインまで満たした。Nanosep300Kフィルタと1×PBS緩衝液を用いた限外濾過を3サイクル行って、過剰なSAVを除去した。遠心分離の各サイクルは、5000rpmで20分間であって、各サイクル後に約400μlの1×PBSで再分散させた。最終濃縮物を100μlのPBSに再分散させた。 図6A及び図6Bは、HER2を発現する細胞に結合して同定する抗HER2mAb(トラスツズマブ、ハーセプチン(登録商標))にコンジュゲートされた赤色ナノ粒子を実証する。図6Aでは、抗HER2mAbにコンジュゲートされた赤色ナノ粒子を用いて、HER2陽性4T1細胞が処置された。図6Bは、対照HER2陰性4T1細胞を用いた同じ処置を示し、明るい蛍光はほとんど見られない。
複数のリガンドを選択する理由は、腫瘍細胞に関連する受容体の広範囲な標的化を可能にすることである。幾つかの実施形態では、複数のリガンドの特異性は、EGFR、PD−L1、PD−L2、HER2、CEA、CA19−9、CA125、テロメラーゼタンパク質及びサブユニット、CD20、CD25、CD30、CD33、CD52、CD73、CD109、VEGF−A、CTLA−4、及びRANKリガンドからなる群より選択された標的との結合に特異的な少なくとも1つのリガンドを含む。
・QDの蛍光特性による極度の腫瘍標識付けと、2つ以上の異なる結合タグによる官能化による高いタグ付け確率。
・EGFRへのセツキシマブの結合によるEGFRの阻害と、活性化T細胞のPD−L1媒介ダウンレギュレーションの阻害。
・コンジュゲートのナノサイズによってもたらされるEPR(Enhanced Permeability and Retention)効果による相乗的な腫瘍取込み。
・QDの機能に起因した腫瘍光線療法効果であって、細胞の自殺カスケード(アポトーシス)を引き起し得る熱として一重項酸素を生成するか又はエネルギーを凝縮させる。
Claims (36)
- 複数の標的特異性を有するナノ粒子コンジュゲート(ナノデバイス)であって、
複数の表面修飾水溶性量子ドット(QD)ナノ粒子を備えており、
各表面修飾水溶性量子ドットは、少なくとも2つの異なる標的特異的リガンドに化学的にコンジュゲートされている、ナノデバイス。 - 前記少なくとも2つの異なる標的特異的リガンドのうちの少なくとも1つが、EGFR、PD−L1、PD−L2、HER2、CEA、CA19−9、CA125、テロメラーゼタンパク質及びサブユニット、CD20、CD25、CD30、CD33、CD52、CD73、CD109、VEGF−A、CTLA−4、並びにRANKリガンドからなる群から選択される標的に特異的である、請求項1に記載のナノデバイス。
- 少なくとも1つの標的特異的リガンドが、EGFRに向けられたモノクローナル抗体である、請求項2に記載のナノデバイス。
- 少なくとも1つの標的特異的リガンドが、PD−L1に向けられたモノクローナル抗体である、請求項2に記載のナノデバイス。
- 前記表面改質水溶性QDナノ粒子が、少なくとも2つのリガンドに化学的にコンジュゲートされ、前記少なくとも2つのリガンドの1つはEGRFとの結合に特異的であり、前記少なくとも2つのリガンドの1つはPD−L1との結合に特異的である、請求項2に記載のナノデバイス。
- 前記表面改質水溶性QDナノ粒子が、セツキシマブ及びアテゾリズマブを含む少なくとも2つのリガンドに化学的にコンジュゲートされている、請求項5に記載のナノデバイス。
- 前記表面改質非毒性水溶性QDナノ粒子は、カドミウムフリーであって、ZnS、ZnSe、ZnTe、InP、InAs、InSb、AlP、AlS、AlAs、AlSb、GaN、GaP、GaAs、GaSb、PbS、PbSe、AgInS2、AgInS2/ZnS、Si、Ge、並びにそれらの合金及びドープされた誘導体からなる複数の材料の群から選択される半導体材料を含む、請求項1乃至6の何れかに記載のナノデバイス。
- 前記カドミウムフリー表面改質非毒性水溶性QDナノ粒子が、前記複数の材料の1つから形成されたコアと、前記複数の材料の別の1つから形成された複数のシェルとを含む、請求項7に記載のナノデバイス。
- 前記カドミウムフリー表面改質非毒性水溶性QDナノ粒子がコア/マルチシェルQDである、請求項8に記載のナノデバイス。
- 前記表面修飾水溶性量子ドット(QD)ナノ粒子が、リガンド相互作用剤及び表面修飾リガンドを含む、請求項1乃至6の何れかに記載のナノデバイス。
- 前記表面修飾QDナノ粒子が、ヘキサメトキシメチルメラミンを含む溶液中でQDへの前記リガンド相互作用剤及び前記表面修飾リガンドを化学的に付加することによって形成される、請求項10に記載のナノデバイス。
- 前記リガンド相互作用剤が、C8−20脂肪酸及びそのエステルである、請求項10に記載のナノデバイス。
- 前記表面改質リガンドがモノメトキシポリエチレンオキシドである、請求項10に記載のナノデバイス。
- ナノデバイスの少なくとも2つの集団を含むナノ粒子コンジュゲート(ナノデバイス)の混合物であって、
第1の標的特異的抗体で誘導体化された表面修飾水溶性量子ドット(QD)ナノ粒子を含む第1の標的特異的集団と、
第2の標的特異的抗体で誘導体化された表面修飾水溶性量子ドット(QD)ナノ粒子を含む第2の標的特異的集団と、
を含む混合物。 - 前記第1の標的特異的抗体がEGFRに特異的であり、前記第2の標的特異的抗体がPD−L1に特異的である、請求項14に記載の混合物。
- 腫瘍細胞によって過剰発現される細胞表面部に向けられる抗体に化学的に結合された非毒性水溶性量子ドット(QD)ナノ粒子を含むナノ粒子コンジュゲートを投与することによって、腫瘍細胞の細胞死、腫瘍縮小及び蛍光標識を同時に誘導する方法。
- 前記細胞表面部が上皮成長因子受容体(EGFR)である、請求項16に記載の方法。
- 前記腫瘍が膵臓腫瘍である、請求項16に記載の方法。
- 量子ドット(QD)ナノ粒子に結合した2つの又は3つ以上の異なる治療用抗体から構成されるナノ粒子コンジュゲート(ナノデバイス)であって、
前記2つの又は3つ以上の異なる治療用抗体は異なる標的特異性を有する、ナノデバイス。 - 前記QDナノ粒子が、EGFRに向けられた抗体とPD−L1に向けられた抗体と化学的にコンジュゲートしている、請求項19に記載のナノデバイス。
- 生物学的部分を検出する又は治療的に調節する方法において、
標的特異的誘導体化カドミウムフリー水溶性量子ドット(QD)を含む組成物を生物学的標的と物理的に相互作用させる工程であって、前記カドミウムフリー水溶性量子ドットは、COOH、NH2、SH、OH、スルホネート、ホスフェート、アジド、アリル、シリル及びPEG鎖からなる群から選択された1又は複数の官能基を含むように、メラミン架橋剤ヘキサメトキシメチルメラミン(HMMM)を用いて表面改質されており、更に、複数の異なる標的特異的リガンドを用いて前記1又は複数の官能基を介して誘導体化されている、工程と、
前記QDに励起波長の光を適用して、前記標的特異的誘導体化カドミウムフリー水溶性QDからの放射を促す工程と、
前記組成物と前記生物学的標的の間の相互作用のスペクトル放出を記録及び/又は画像化する工程と、
を含む、方法。 - 前記リガンドが、抗体、ストレプトアビジン、核酸、脂質、糖、薬物分子、タンパク質、ペプチド、及びアミノ酸からなる群のうちの1又は複数から選択される、請求項21に記載の方法。
- 前記検出が、血管形成、腫瘍境界、腫瘍転移、インビボでの診断、及びリンパ節進行のうちの1又は複数を画像化及び検出するために使用される、請求項21に記載の方法。
- 前記検出が、免疫化学、免疫蛍光、DNA配列分析、蛍光共鳴エネルギー移動、フローサイトメトリ、蛍光活性化細胞選別、及びハイスループットスクリーニングのうちの1又は複数において使用される、請求項21に記載の方法。
- 前記複数の異なる標的特異的リガンドが、EGFR、PD−L1、PD−L2、HER2、CEA、CA19−9、CA125、テロメラーゼタンパク質及びサブユニット、CD20、CD25、CD30、CD33、CD52、CD73、CD109、VEGF−A、CTLA−4、並びにRANKリガンドからなる群から選択される標的に対する特異性を有するリガンドである、請求項21乃至24の何れかに記載の方法。
- 各集団が異なる標的特異性を有する複数のリガンド集団で誘導体化されたカドミウムフリー水溶性量子ドットを含むマルチリガンドナノデバイス。
- 少なくとも1つの標的特異的抗体リガンドと、ストレプトアビジン、核酸、脂質、糖類、薬物分子、タンパク質、ペプチド、及びアミノ酸から選択される更なるリガンドとを含んでおり、前記抗体リガンドは、前記更なるリガンドを送達するための標的リガンドとして作用する、請求項26に記載のマルチリガンドナノデバイス。
- 少なくとも2つの標的特異的抗体リガンドを含んでおり、そのうちの少なくとも1つは、EGFR、PD−L1、PD−L2、HER2、CEA、CA19−9、CA125、テロメラーゼタンパク質及びサブユニット、CD20、CD25、CD30、CD33、CD52、CD73、CD109、VEGF−A、CTLA−4、並びにRANKリガンドからなる群から選択される標的に対する特異性を有するリガンドである、請求項26に記載のマルチリガンドナノデバイス。
- 癌を検出及び処置するための医薬として使用するために製造されたマルチリガンドナノデバイスであって、
複数のリガンド集団で誘導体化されたカドミウムフリーの水溶性量子ドット(QD)を含んでおり、各リガンド集団は、癌細胞に過剰発現する異なる標的に対する特異性を有する、マルチリガンドナノデバイス。 - 低侵襲内視鏡検査又は腹腔鏡検査による術前診断又は術中診断に利用される、請求項29に記載のマルチリガンドナノデバイス。
- 循環系又は腹部内への注入と、正常細胞に対して腫瘍細胞内での集中とに適している、請求項29又は30に記載のマルチリガンドナノデバイス。
- モノメトキシポリエチレンオキシドで表面改質することによって、循環系又は腹部内への注入と、正常細胞に対して腫瘍細胞内での集中とに適している、請求項31に記載のマルチリガンドナノデバイス。
- 内視鏡的に又は腹腔鏡的に適用されるQD励起光源に曝すことによって、集中したマルチリガンドナノデバイスを蛍光発光させることができ、蛍光は撮像カメラによって検出可能である、請求項29又は請求項30に記載のマルチリガンドナノデバイス。
- 前記癌細胞に過剰発現する異なる標的は、EGFR、PD−L1、PD−L2、HER2、CEA、CA19−9、CA125、テロメラーゼタンパク質及びサブユニット、CD20、CD25、CD30、CD33、CD52、CD73、CD109、VEGF−A、CTLA−4、並びにRANKリガンドから選択される、請求項29又は請求項30に記載のマルチリガンドナノデバイス。
- 前記癌細胞に過剰発現する異なる標的がEGFR及びPD−L1である、請求項34に記載のマルチリガンドナノデバイス。
- 前記カドミウムフリー水溶性量子ドットが少なくとも50%の量子収率を有する、請求項29又は請求項30に記載のマルチリガンドナノデバイス。
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EP3541430A1 (en) | 2019-09-25 |
WO2018091884A1 (en) | 2018-05-24 |
KR20190082260A (ko) | 2019-07-09 |
KR102274985B1 (ko) | 2021-07-12 |
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