JP2021113196A - 標的型薬物デリバリーのための自己集合性分子 - Google Patents
標的型薬物デリバリーのための自己集合性分子 Download PDFInfo
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Abstract
Description
特定の実施形態では、本発明は、ペイロード、例えば毒性抗癌剤、癌免疫療法、またはイメージング剤を特定組織にデリバリーするための自己集合性タンパク質分子の使用に関する。特定の実施形態では、タンパク質はクラスリンまたはクラスリンの誘導体である。特定の実施形態では、タンパク質は内在性である。特定の実施形態では、タンパク質は非免疫原性である。特定の実施形態では、タンパク質はフェリチンまたはフェリチン誘導体である。
特定の実施形態では、本発明は、配列番号3に対して85%以上の配列相同性を有する重鎖を有するタンパク質に関する。特定の実施形態では、本発明は、重鎖が配列番号3に対して90%以上の配列相同性を有する本明細書中に記載されているタンパク質のいずれかに関する。特定の実施形態では、本発明は、重鎖が配列番号3に対して95%以上の配列相同性を有する本明細書中に記載されているタンパク質のいずれかに関する。特定の実施形態では、本発明は、重鎖が配列番号3に対して98%以上の配列相同性を有する本明細書中に記載されているタンパク質のいずれかに関する。特定の実施形態では、本発明は、重鎖が配列番号3に対して99%以上の配列相同性を有する本明細書中に記載されているタンパク質のいずれかに関する。特定の実施形態では、本発明は、重鎖が配列番号3を有する本明細書中に記載されているタンパク質のいずれかに関する。
特定の実施形態では、本発明は、タンパク質、第1ペイロード及び第1標的化剤を含むか、これらから本質的に構成されるか、またはこれらから構成される第1組成物に関し、タンパク質は外面及び内部空洞を含む三次元ケージ構造物の形態であり、第1標的化剤は三次元ケージ構造物の外面にコンジュゲートされている。特定の実施形態では、第1標的化剤は健常細胞と比較して癌細胞を選択的に標的化する。特定の実施形態では、第1標的化剤は癌細胞のような病的細胞を特異的に標的化する。
特定の実施形態では、本発明は、タンパク質がペイロードを細胞内にデリバリーすることができる本明細書中に記載されている組成物のいずれか(例えば、第1組成物または第2組成物)に関する。
特定の実施形態では、本発明は、ペイロードが任意の治療薬であり、好ましくはパクリタキセル、ゲムシタビンまたはアゾナフィド(例えば、参照により組み入れる米国特許No.8,008,316に記載されている化合物)のような抗癌剤である、本明細書中に記載されている第1組成物のいずれかに関する。
特定の実施形態では、本発明は、組成物が細胞特異性の治療薬及びイメージング剤のデリバリーシステムである、本明細書中に記載されている組成物のいずれかに関する。標的型治療薬デリバリーシステムは、薬物への全身暴露及びその関連副作用を軽減させながら、腫瘍のような部位での有効用量を高めることができる。
本発明の1つの態様は、癌の治療の必要がある被験者に対して、治療有効量の本明細書中に記載されている第1組成物のいずれか1つを投与することを含む、被験者における癌の治療方法に関し、ここで、第1ペイロードは抗癌剤である。
別の態様において、本発明は、1つ以上の医薬的に許容され得る担体(添加剤)及び/または希釈剤と一緒に処方した、治療有効量の1つ以上の上記した組成物を含む、医薬的に許容され得る組成物を提供する。以下に詳記するように、本発明の医薬組成物は、特に(1)経口投与、例えば液剤(drenches)(水性または非水性の溶液剤または懸濁液剤)、口腔内、舌下及び全身吸収を目的とするような錠剤、ボーラス剤、散剤、顆粒剤、舌に適用するためのペースト剤として;(2)非経口投与(例えば皮下、筋肉内、静脈内または硬膜外注射による)、例えば無菌の溶液剤もしくは懸濁液剤または徐放性製剤として;(3)局所投与、例えばクリーム剤、軟膏剤、または皮膚に適用される徐放性パッチ剤もしくはスプレー剤として;(4)膣内または直腸内投与、例えばペッサリー、クリーム剤またはフォーム剤としてに;(5)舌下投与;(6)眼内投与;(7)経皮投与に;または(8)鼻腔内投与に適応しているものを含めて、固体形態または液体形態で投与するために、製剤化され得る。
特定の実施形態では、本発明は、癌を治療またはイメージングするためのキットに関する。例えば、キットは1つ以上の上記した組成物、及び場合によりその使用のための説明書を含み得る。好ましくは、キットは第1組成物及び第2組成物を含む。さらに他の実施形態では、本発明は、1つ以上の医薬製剤または診断製剤、及び/または投与を実施するための1つ以上のデバイスを含む、キットを提供する。例えば、本発明のキットは、医薬製剤または診断製剤及び直接注射を実施するためのカテーテルを含み得る。
クラスリン重鎖の発現
クラスリンヒトアイソフォーム2重鎖を次のように大腸菌(E.coli)発現系のために最適化した:
クラスリン軽鎖の発現
クラスリン軽鎖(以下)を大腸菌において発現させた:
12.96mg,>85%,大腸菌由来の6Hisタグを有する可溶性タンパク質
標準としてBSAを用いるブラッドフォードタンパク質アッセイにより測定して、0.60mg/mL
1.8mL/チューブ,12チューブ
クマシーブルー染色SDS−PAGEゲルにより推定して、>85%
50mM Tris,15mM NaCl,10% グリセロール,pH8.0。
受領したら直ちに−20℃で保存
複数の凍結−融解を避けるために、最初の使用時に小分けし、−20℃で保存
この生成物は研究用のみに意図されている。ヒトまたは動物の診断及び治療用ではない。
256
28136.9
4.37
M1:SDS−PAGEタンパク質マーカー
レーン1:PE1130119−2タンパク質
M2:ウェスタンブロットタンパク質マーカー
レーン2:PE1130119−2タンパク質(抗6His抗体を用いる)
自己集合タンパク質の負荷
負荷後に自己集合する能力を評価するために、自己集合タンパク質に蛍光化合物を負荷した。
自己集合タンパク質の負荷(予測)
集合効率を調べるために、HC、LC及びFTCの各種比率、及び低pHを試験する。
1.薬物を軽鎖集合ケージに負荷または結合させた後、自己集合条件下で負荷した軽鎖を重鎖に負荷する(主ケージへの間接負荷)。
2.異なるオープン条件下及び自己集合条件下での薬物負荷を変化させるために薬物及びケージの直接混合を使用する。
3.異なるサイズの薬物、例えばパクリタキセルまたはゲムシタビンを使用する。
動物研究(予測)
動物モデルで負荷ビヒクルの有効性を薬物単独の有効性と比較する。
免疫原性応答を強化するための第1組成物及び第2組成物の共投与(予測)
第1組成物(第1自己集合クラスリンビヒクル、抗癌剤及び標的化剤を含む)と第2組成物(第2自己集合クラスリンビヒクル及び抗PD−1抗体を含む)の共投与は、第1組成物単独、第2組成物単独、及び第1組成物と第2組成物の付加効果と比較して高い治療効果を与えると予想される。第2組成物は更に免疫原ペイロードを含み得る。
以下にリストされているものを含めた本明細書中に挙げられているすべての刊行物及び特許文献は、個々の刊行物または特許文献それぞれが明確に且つ個別に参照により組み入れられることが示されているのと同様に、その全体が参照により本明細書に組み入れられる。
本発明の具体的な実施形態を検討してきたが、本明細書は例示であって、限定的でない。本発明の多くの変更が本明細書を精査したときに当業者に自明となるであろう。
Claims (57)
- タンパク質、第1ペイロード及び第1標的化剤を含む第1組成物であって、前記タンパク質は外面及び内部空洞を含む三次元ケージ構造物の形態であり、前記第1標的化剤は前記三次元ケージ構造物の外面にコンジュゲートされている、第1組成物。
- 前記第1ペイロードは、抗癌剤である、請求項1に記載の第1組成物。
- 前記抗癌剤は、パクリタキセル、ゲムシタビン、又はアゾナフィドである、請求項2に記載の第1組成物。
- 前記第1ペイロードは、イメージング剤である、請求項1に記載の第1組成物。
- 前記イメージング剤は、蛍光体、発色団、化学発光剤、放射性核種、又は造影剤である、請求項4に記載の第1組成物。
- 前記第1標的化剤は、健常細胞と比較して癌細胞を選択的に標的化する、請求項1〜5のいずれかに記載の第1組成物。
- 前記第1標的化剤は、癌細胞を特異的に標的化する、請求項1〜5のいずれかに記載の第1組成物。
- 前記第1標的化剤は、抗体である、請求項1〜7のいずれかに記載の第1組成物。
- 前記タンパク質は、クラスリン又はクラスリン誘導体である、請求項1〜8のいずれかに記載の第1組成物。
- 前記タンパク質は、重鎖又は軽鎖を含む、請求項1〜9のいずれかに記載の第1組成物。
- 前記タンパク質は、重鎖及び軽鎖を含む、請求項1〜9のいずれかに記載の第1組成物。
- 前記重鎖は、約100kDa〜約300kDaの分子量を有している、請求項11に記載の第1組成物。
- 前記重鎖は、約190kDaの分子量を有している、請求項11に記載の第1組成物又は第2組成物。
- 前記重鎖は、配列番号3に対して85%以上の配列相同性を有している、請求項11〜13のいずれかに記載の第1組成物。
- 前記重鎖は、配列番号3を有している、請求項11〜13のいずれかに記載の第1組成物。
- 前記軽鎖は、約15kDa〜約45kDaの分子量を有している、請求項11〜15のいずれかに記載の第1組成物。
- 前記軽鎖は、約28kDaの分子量を有している、請求項11〜15のいずれかに記載の第1組成物。
- 前記軽鎖は、配列番号6に対して85%以上の配列相同性を有している、請求項11〜19のいずれかに記載の第1組成物。
- 前記軽鎖は、配列番号6を有している、請求項11〜19のいずれかに記載の第1組成物。
- 前記三次元ケージ構造物は、約10nm〜約100nmの直径を有している、請求項1〜19のいずれかに記載の第1組成物。
- 前記三次元ケージ構造物は、実質的に球状である、請求項1〜20のいずれかに記載の第1組成物。
- 前記三次元ケージ構造物は、非共有結合的に集合している、請求項1〜21のいずれかに記載の第1組成物。
- 前記三次元ケージ構造物は、約37℃、pH約7で実質的に安定である、請求項1〜22のいずれかに記載の第1組成物。
- 前記三次元ケージ構造物は、約37℃、pH約5.5で実質的に不安定である、請求項1〜23のいずれかに記載の第1組成物。
- 前記第1組成物は、インビボで細胞をトランスフェクトすることができる、請求項1〜24のいずれかに記載の第1組成物。
- タンパク質、第2ペイロード及び第2標的化剤を含む第2組成物であって、前記タンパク質は、外面及び内部空洞を含む三次元ケージ構造物の形態であり、前記第2標的化剤は、前記三次元ケージ構造物の外面にコンジュゲートされている、第2組成物。
- 前記第2標的化剤は、健常細胞と比較して癌細胞を選択的に標的化しない、請求項26に記載の第2組成物。
- 前記第2標的化剤は、抗体である、請求項26又は請求項27に記載の第2組成物。
- 前記第2標的化剤は、抗PD−1抗体である、請求項26又は請求項27に記載の第2組成物。
- 前記タンパク質は、クラスリン又はクラスリン誘導体である、請求項26〜29のいずれかに記載の第2組成物。
- 前記タンパク質は、重鎖又は軽鎖を含む、請求項26〜29のいずれかに記載の第2組成物。
- 前記タンパク質は、重鎖及び軽鎖を含む、請求項26〜29のいずれかに記載の第2組成物。
- 前記重鎖は、約100kDa〜約300kDaの分子量を有している、請求項32に記載の第2組成物。
- 前記重鎖は、約190kDaの分子量を有している、請求項32に記載の第2組成物。
- 前記重鎖は、配列番号3に対して85%以上の配列相同性を有している、請求項32〜34のいずれかに記載の第2組成物。
- 前記重鎖は、配列番号3を有している、請求項32〜34のいずれかに記載の第2組成物。
- 前記軽鎖は、約15kDa〜約45kDaの分子量を有している、請求項32〜36のいずれかに記載の第2組成物。
- 前記軽鎖は、約28kDaの分子量を有している、請求項32〜36のいずれかに記載の第2組成物。
- 前記軽鎖は、配列番号6に対して85%以上の配列相同性を有している、請求項32〜38のいずれかに記載の第2組成物。
- 前記軽鎖は、配列番号6を有している、請求項32〜38のいずれかに記載の第2組成物。
- 前記三次元ケージ構造物は、約10nm〜約100nmの直径を有している、請求項26〜40のいずれかに記載の第2組成物。
- 前記三次元ケージ構造物は、実質的に球状である、請求項26〜41のいずれかに記載の第2組成物。
- 前記三次元ケージ構造物は、非共有結合的に集合している、請求項26〜42のいずれかに記載の第2組成物。
- 前記三次元ケージ構造物は、約37℃、pH約7で実質的に安定である、請求項26〜43のいずれかに記載の第2組成物。
- 前記三次元ケージ構造物は、約37℃、pH約5.5で実質的に不安定である、請求項26〜44のいずれかに記載の第2組成物。
- 前記第2組成物は、インビボで細胞をトランスフェクトすることができる、請求項26〜45のいずれかに記載の第2組成物。
- 癌の治療の必要がある被験者における癌の治療方法であって、前記被験者に対して治療有効量の請求項1〜3又は6〜25のいずれかに記載の第1組成物を投与することを含み、第1ペイロードが抗癌剤である、方法。
- 癌の治療の必要がある被験者における癌の治療方法であって、
前記被験者に対して治療有効量の請求項1〜3又は6〜25のいずれかに記載の第1組成物を投与することと、ここで、第1ペイロードが抗癌剤であり、
前記被験者に対して治療有効量の請求項26〜46のいずれかに記載の第2組成物を投与することと
を含む、方法。 - 前記癌は、肺癌である、請求項47又は請求項48に記載の方法。
- 前記癌は、非小細胞性肺癌(NSCLC)である、請求項47又は請求項48に記載の方法。
- 前記癌は、膵臓癌である、請求項47又は請求項48に記載の方法。
- 画像作成の必要がある被験者の画像の作成方法であって、前記被験者に対して検出可能量の請求項1又は4〜25のいずれかに記載の第1組成物を投与することと、ここで、第1ペイロードがイメージング剤であり、
画像を作成することと
を含む、方法。 - 前記被験者は、哺乳動物である、請求項47〜52のいずれかに記載の方法。
- 前記被験者は、ヒトである、請求項47〜52のいずれかに記載の方法。
- 請求項1〜25のいずれかに記載の第1組成物及び医薬的に許容され得る担体又は希釈剤を含む医薬製剤。
- 請求項26〜46のいずれかに記載の第2組成物をさらに含む、請求項55に記載の医薬製剤。
- 請求項26〜46のいずれかに記載の第2組成物、及び医薬的に許容され得る担体又は希釈剤を含む医薬製剤。
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US11666664B2 (en) | 2023-06-06 |
AU2016242920A1 (en) | 2017-10-12 |
HK1248540A1 (zh) | 2018-10-19 |
EP3936121A1 (en) | 2022-01-12 |
MA41866A (fr) | 2018-02-06 |
WO2016161129A1 (en) | 2016-10-06 |
JP2018513142A (ja) | 2018-05-24 |
AU2016242920B2 (en) | 2021-10-21 |
EP3277268A4 (en) | 2018-12-05 |
EP3277268A1 (en) | 2018-02-07 |
CA2980329A1 (en) | 2016-10-06 |
MX2022009027A (es) | 2022-08-11 |
US20180140719A1 (en) | 2018-05-24 |
CN107613963A (zh) | 2018-01-19 |
CA2980329C (en) | 2024-01-23 |
US20200078472A1 (en) | 2020-03-12 |
MX2017012187A (es) | 2018-01-09 |
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