JP7255895B2 - バクテリオファージおよびその変異体を使用したがんおよび感染を処置する組成物および方法 - Google Patents
バクテリオファージおよびその変異体を使用したがんおよび感染を処置する組成物および方法 Download PDFInfo
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Description
本出願は、2017年8月28日に出願された米国仮特許出願第62/551,045号の優先権を主張する。この出願は、その全体が参照により本明細書に組み込まれる。
政府支援
がんの処置および予防のための有効なワクチンの開発は、大きな科学的挑戦である。腫瘍細胞は抗原性であり得るが、大きな障壁は、それらの低い固有免疫原性および腫瘍細胞による免疫抑制のために、腫瘍関連抗原に対する免疫反応が低いことである。その結果として、免疫系を活性化し、腫瘍特異的免疫を生成するための革新的な戦略が必要である。
分析HPLC Rt=19.90分(A/B:(95:5)→(95:5)、200μL/分、5分、(95:5)→(40:60)、200μL/分、55分);分取HPLC Rt=12.75分(A/B:(95:5)→(55:45)、20mL/分、40分);HR-ESI-MS,m/z:729.9983([M+3H]3+,計算値729.9974),1094.4977([M+2H]2+,計算値1094.4923);収率:38%(11.0mg、5.03μmol).
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A.定義
「a」および「an」という冠詞は、本明細書では、冠詞の文法的対象の1つまたは1つを超える(すなわち、少なくとも1つ)を指すために使用される。例として、「要素(an element)」は、1つの要素または1つを超える要素を意味する。
B.カプシド
表A カプシドおよび関連GenBank番号のリスト
[エシェリキアウイルスQβ](GenBankAEQ25550.1)
コートタンパク質[腸内細菌ファージM11](GenBank AAC06250.1)
コートタンパク質[腸内細菌ファージSP](GenBank AEQ25562.1)
コートタンパク質[腸内細菌ファージFI sensu lato](Genbank NP_695027.1)
カプシドタンパク質[エシェリキアウイルスFI](Genbank ACT66758.1)
コートタンパク質[エシェリキアウイルスQβ](Genbank ACY07224.1)
A鎖、バクテリオファージQβカプシド(Genbank 1QBE_A)
カプシドタンパク質[エシェリキアウイルスQβ](ACT66734.1)
カプシドタンパク質[エシェリキアウイルスQβ](ACT66730.1)
カプシドタンパク質[エシェリキアウイルスQβ](ACT66742.1)
リードスルータンパク質[エシェリキアウイルスQβ](ACY07231.1)
A1タンパク質[エシェリキアウイルスQβ](AAA16663.1)
リードスルータンパク質[エシェリキアウイルスQβ](AEQ25545.1)
マイナーカプシドタンパク質A1(Q8LTE1.2)
リードスルータンパク質[エシェリキアウイルスQβ](ACY07227.1)
リードスルータンパク質[エシェリキアウイルスQβ](ACY07235.1)
カプシドタンパク質[エシェリキアウイルスQβ](ACT66738.1)
リードスルータンパク質[エシェリキアウイルスQβ](AEQ25549.1)
リードスルータンパク質[エシェリキアウイルスQβ](AEQ25541.1)
リードスルータンパク質[エシェリキアウイルスQβ](ACY07223.1)
リードスルータンパク質[エシェリキアウイルスQβ](ACT66735.1)
Rnaオペレーターヘアピンを有する複合体のA鎖、バクテリオファージQβコートタンパク質(4L8H_A)
リードスルータンパク質[エシェリキアウイルスQβ](ACT66731.1)
リードスルータンパク質[エシェリキアウイルスQβ](ACT66743.1)
リードスルータンパク質[エシェリキアウイルスQβ](ACT66739.1)
カプシドタンパク質[エシェリキアウイルスQβ](ACT66746.1)
メジャーコートタンパク質[エシェリキアウイルスQβ](NP_046751.1)
リードスルータンパク質[エシェリキアウイルスQβ](ACT66747.1)
マイナーコートタンパク質[エシェリキアウイルスQβ](NP_046750.1)
コートタンパク質[腸内細菌ファージSP](ACY07244.1)
コートタンパク質[腸内細菌ファージSP](ACY07240.1)
A1タンパク質[腸内細菌ファージM11](AAC06251.1)
コートタンパク質[腸内細菌ファージSP](AEQ25558.1)
カプシドタンパク質[エシェリキアウイルスFI](ACT66762.1)
メジャーコートタンパク質[エシェリキアウイルスFI](YP_009208147.1)
カプシドタンパク質[エシェリキアウイルスFI](ACT66750.1)
コートタンパク質[腸内細菌ファージSP](ACY07248.1)
リードスルータンパク質[腸内細菌ファージSP](ACY07251.1)
リードスルータンパク質[腸内細菌ファージSP](AEQ25561.1)
リードスルータンパク質[腸内細菌ファージSP](ACY07243.1)
マイナーカプシドタンパク質A1(P09677.1)
リードスルータンパク質[腸内細菌ファージFI sensu lato](NP_695026.1)
カプシドタンパク質[エシェリキアウイルスFI](ACT66754.1)
リードスルータンパク質[腸内細菌ファージSP](AEQ25553.1)
リードスルータンパク質[腸内細菌ファージSP](ACY07239.1)
リードスルータンパク質[腸内細菌ファージSP](AEQ25557.1)
リードスルータンパク質[エシェリキアウイルスFI](ACT66759.1)
メジャーコートタンパク質[腸内細菌ファージNL95](AAC14703.1)
リードスルータンパク質[エシェリキアウイルスFI](ACT66763.1)
リードスルータンパク質[腸内細菌ファージSP](ACY07247.1)
A1タンパク質[エシェリキアウイルスFI](YP_009208146.1)
リードスルータンパク質[エシェリキアウイルスFI](ACT66751.1)
リードスルータンパク質[エシェリキアウイルスFI](ACT66755.1)
A1タンパク質[腸内細菌ファージNL95](AAC14704.1)
7aは、Fiedler,Jら、Biomacromolecules 2012,13(8),2339-2348に対応する;42aは、Prasuhn,Dら、JACS 2008,130(4),1328-1334に対応する;42bは、Udit,Aら、ChemBioChem 2009,10(3),503-510に対応する。43は、Hovlid,M.Lら、The Scripps Research Institute,La Jolla,2014に対応する。
表C:バクテリオファージQβカプシドのリスト
N10K(配列番号1の10位のアスパラギンがリジンに変異)
K13R(配列番号1の13位のリジンがアルギニンに変異)
A38K(配列番号1の38位のアラニンがリジンに変異)
A40C(配列番号1の40位のアラニンがシステインに変異)
A40S(配列番号1の40位のアラニンがセリンに変異)
T75K(配列番号1の75位のトレオニンがリジンに変異)
D102C(配列番号1の102位のアスパラギン酸がシステインに変異)
D102S(配列番号1の102位のアスパラギン酸がセリンに変異)
A117K(配列番号1の117位のアラニンがリジンに変異)
C.ワクチン組成物およびその医薬組成物/製剤
D.治療方法
以下の実施例は、本開示の主題の代表的な実施形態の実施について指針を当業者に提供するために含まれている。本開示および当該分野の技術の一般的なレベルを考慮して、当業者は、以下の実施例が単なる例示目的であり、本開示の主題の範囲から逸脱せずに多数の変更、改変および変化が用いられ得ることを認識し得る。以下の実施例は、限定ではなく例示として提供される。
実施例1:材料および方法
i.QβVLPの部位特異的変異誘発
表1.PCR試薬
表3:変異体βVLPの構築に使用したプライマー
iii.QβまたはmQβコンジュゲートの合成および特性評価(Yin,Zら、ACS Chemical Biology 2015,10(10),2364-2372)
iv.サイズ排除クロマトグラフィー(SEC)
v.非変性アガロースゲル
vi.温度可変UV-Vis分光法によるウイルスカプシドの熱安定性測定
vii.動的光散乱(DLS)および透過型電子顕微鏡法(TEM)
viii.免疫研究(Yin,Zら、ACS Chemical Biology 2015,10(10),2364-2372)
ix.酵素結合免疫吸着測定法(ELISA)
x.細胞培養
xi.フローサイトメトリー実験
xii.抗腫瘍免疫保護(腫瘍チャレンジ)
xiii.液体クロマトグラフィー質量分析(LCMS)
xiv.透過型電子顕微鏡法(TEM)の画像
xv.Tn1およびTn2の合成
合成手順
N-(フルオレン-9-イルメトキシカルボニル)-O-(3,4,6-トリ-O-アセチル-2-アジド-2-デオキシ-α-D-ガラクトピラノシル-L-セリンベンジルエステル(SI-11)(Ludek,Oら、Carbohydrate Research 2010,345(14),2074-2078)
N-(フルオレン-9-イルメトキシカルボニル)-O-(3,4,6-トリ-O-アセチル-2-アセトアミド-2-デオキシ-α-D-ガラクトピラノシル-L-セリン2-エタノリルアミド(SI-14):
実施例3:Qbの主要なB細胞エピトープは線形配列内に存在しない
実施例4:抗Qb抗体レベルを減少させるためのQb変異体の設計
実施例6:新たなmQβは抗キャリア免疫反応を減少させ得るが、TACA抗原に対する抗体のレベルをさらに有意に増強し得る。
実施例7:mQb-Tnは、Tn発現腫瘍細胞と強く結合することができる抗Tn抗体を誘導した
実施例8:mQb-Tnコンジュゲートは、腫瘍チャレンジからのマウスの完全な保護を提供した
考察
実施例9:MUC1ベースの抗がんワクチンの合理的設計
実施例10:実施例11~15の材料および方法
一般的な実験手順および合成方法
MUC1(糖)ペプチドの合成
MUC5B糖ペプチド合成の一般的な方法
Qβ-MUC1コンジュゲートの合成および特性評価
ELISAによる抗体力価およびサブタイプの評価
マイクロアレイスポッティングおよびインキュベーション
フローサイトメトリーによる腫瘍細胞への抗体結合の検出
補体依存性細胞傷害
インビトロCTLアッセイ
インビボCTLアッセイ
実施例11:Qβ-MUC1コンジュゲートの合成
Fmoc化学を使用して固相ペプチド合成(SPPS)により、MUC1(糖)ペプチドの合成を実施した(スキーム1)。
ペプチド鎖へのFmoc保護アミノ酸のカップリングを、(2-(1H-ベンゾトリアゾール-1-イル)-
Qβ-VLPへのMUC1のライゲーションを、バイオコンジュゲーションのために最適化された銅触媒による
実施例12:Qβ-MUC1コンジュゲートはロバストな力価の抗MUC1 IgG抗体を生成し得、高密度のMUC1は高レベルのIgGに重要である
手持ちのQβ-MUC1コンジュゲートを用いて、それらの免疫反応誘導能力を調査した。C57BL6マウス群を、注射当たりの総MUC1濃度を等しくして前記コンジュゲートで隔週に3回免疫(すなわち、0日目、14日目および28日目に注射)した。最終ブーストの1週間後(35日目)に血清サンプルを採取し、免疫に使用した特定のMUC1糖ペプチド構造に対する酵素結合免疫吸着測定法(ELISA)により、抗体力価およびサブタイプを決定した。
実施例13:Qβ-MUC1コンジュゲート10~13により誘導された抗体のマイクロアレイ分析
実施例14:Qβ-MUC1コンジュゲートにより誘導されたIgG抗体はMUC1発現腫瘍細胞に結合することができ、補体媒介性細胞傷害により腫瘍細胞を選択的に死滅させる
実施例15:Qβ-MUC1による免疫は、インビトロおよびインビボでMUC1特異的CTLを誘導し得る
実施例16:実施例17~26の材料および方法{FH:これはTg原稿に対応する}
実施例17:免疫寛容MUC1トランスジェニックマウスにおける免疫MUC1構造に対する高いIgG力価の産生にもかかわらず、第1世代Qβ-MUC1構築物5~8は、強い腫瘍細胞結合のためのIgG抗体を誘発することができなかった
実施例18:WTおよびTgマウス由来の誘導抗体のエピトーププロファイリングは、エピトープ設計に関する重要な洞察を提供した
実施例19:MUC1ペプチドの遊離C末端に対して抗体が誘発された
実施例20:C末端から連結したMUC1を有する第2世代のQβ-MUC1コンジュゲート35~37の合成および評価
実施例21:第3世代Qβ-MUC1コンジュゲート42~43およびKLH-MUC1コンジュゲート44の合成
実施例22:MUC1.TgマウスにおいてQβ-MUC1 43により誘導された抗体は、第2世代Qβ-MUC1 37およびKLH-MUC1 44と比較して、MUC1発現腫瘍細胞への最も強い結合を示した。
実施例23:糖ペプチドマイクロアレイの結果により、抗体認識におけるMUC1-Tn選択性が裏付けられた。
実施例23:Qβ-MUC1 43により誘導された抗体は、補体媒介性細胞傷害(CDC)および抗体依存性細胞媒介性細胞傷害(ADCC)機構の両方を介して、優れた殺腫瘍活性を示した。
実施例24:Qβ-MUC1 43のワクチン接種は、転移モデルにおいて有意な腫瘍保護を示した。
実施例25:Qβ-MUC1 43のワクチン接種は、固形腫瘍モデルにおいて有意な腫瘍保護を提供した。
実施例26:MUC1.TgマウスにおけるQβ-MUC1 43誘導性血清によるヒト乳がん対正常組織への結合における高い選択性
実施例27:Qβ抗がんワクチン候補
参照による組み込み
均等物
本発明は、例えば、以下の項目を提供する。
(項目1)
カプシドにコンジュゲートされた抗原を含むワクチン組成物であって、前記カプシドが少なくとも1個の非天然変異を含む、ワクチン組成物。
(項目2)
前記カプシドが、少なくとも1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、または20個の変異を含む、項目1に記載のワクチン組成物。
(項目3)
前記少なくとも1個の非天然変異がジスルフィド結合変異である、項目1に記載のワクチン組成物。
(項目4)
前記抗原が、炭水化物抗原、ペプチド、タンパク質、核酸および有機分子抗原からなる群より選択される、項目1に記載のワクチン組成物。
(項目5)
前記抗原が炭水化物抗原である、項目4に記載のワクチン組成物。
(項目6)
前記炭水化物抗原が、(a)ムチン1(MUC1)、(b)ムチン4(MUC4)、(c)ガングリオシドGD2(GD2)、(d)フコシルガングリオシドGM1(GM1)、(e)アセチル化GD2、(f)ガングリオシドGD3(GD3)、(g)アセチル化GD3、(h)フコシルガングリオシドGM2(GM2)、(i)グロボ-H、(j)ルイスA、(k)ルイスY、(l)ポリシアル酸、(m)シアリル-ルイスA、(n)Tf、(o)Tn、(p)sTn、Tn1およびTn2からなる群より選択される、項目5に記載のワクチン組成物。
(項目7)
前記炭水化物抗原がMUC1である、項目6に記載のワクチン組成物。
(項目8)
前記炭水化物抗原がGD2または9-NHAc-GD2である、項目6に記載のワクチン組成物。
(項目9)
前記カプシドがバクテリオファージカプシドである、項目1に記載のワクチン組成物。
(項目10)
前記バクテリオファージが、(a):バクテリオファージQβ;(b)バクテリオファージR17;(c)バクテリオファージfr;(d)バクテリオファージGA;(e)バクテリオファージSP;(f)バクテリオファージMS2;(g)バクテリオファージM11;(h)バクテリオファージMX1;(i)バクテリオファージNL95;(j)バクテリオファージf2;(k)バクテリオファージPP7;(l)バクテリオファージAP205;および(m)バクテリオファージP22からなる群より選択される、項目9に記載のワクチン組成物。
(項目11)
前記バクテリオファージがバクテリオファージQβである、項目10に記載のワクチン組成物。
(項目12)
前記変異が、N10K、A38K、A40C、A40S、T75K、D102C、D102SまたはA117Kまたはそれらの組み合わせから選択される少なくとも1個の変異を含む、項目2に記載のワクチン組成物。
(項目13)
前記カプシドが、A40C/D102C、A40S/D102SまたはA43C/Q98Cから選択される少なくとも2個の変異を含む、項目2に記載のワクチン組成物。
(項目14)
前記カプシドが、A40C/D102C/K13RまたはA38K/A40C/D102Cから選択される少なくとも3個の変異を含む、項目2に記載のワクチン組成物。
(項目15)
被験体におけるがんを予防または処置するための方法であって、前記被験体に項目1に記載のワクチン組成物を投与することを含む、方法。
(項目16)
被験体における病原性感染を予防または処置する方法であって、前記被験体に項目1に記載のワクチン組成物を投与することを含む、方法。
(項目17)
炎症性疾患を予防または処置する方法であって、前記被験体に項目1に記載のワクチン組成物を投与することを含む、方法。
(項目18)
神経変性疾患を予防または処置する方法であって、前記被験体に項目1に記載のワクチン組成物を投与することを含む、方法。
(項目19)
前記病原性感染が細菌感染、真菌感染またはウイルス感染である、項目16に記載の方法。
(項目20)
前記ワクチン組成物を全身投与する、項目15~19のいずれか一項に記載の方法。
(項目21)
前記全身投与が、経口投与、静脈内投与、皮内投与、腹腔内投与、皮下投与および筋肉内投与からなる群より選択される、項目20に記載の方法。
(項目22)
前記組成物を腫瘍内投与または腫瘍周囲投与する、項目15に記載の方法。
(項目23)
前記がんが固形腫瘍である、項目15に記載の方法。
(項目24)
前記がんが、口腔がん、乳がん、脳がん、小児がん、卵巣がん、前立腺がん、膵臓がん、肺がん、肝臓がん、咽喉がん、胃がんおよび腎臓がんからなる群より選択される、項目15に記載の方法。
(項目25)
前記がんが肺がんである、項目24に記載の方法。
(項目26)
前記がんが乳がんである、項目24に記載の方法。
(項目27)
前記小児がんが神経芽細胞腫である、項目24に記載の方法。
(項目28)
前記被験体が哺乳動物である、項目15~198のいずれか一項に記載の方法。
(項目29)
前記哺乳動物がヒトである、項目28に記載の方法。
Claims (20)
- カプシドにコンジュゲートされた抗原を含むワクチン組成物であって、前記カプシドが少なくとも1個の非天然変異を含み、前記カプシドが、配列番号3に記載されるアミノ酸配列において、N10K、A38K、A40C、A40S、T75K、D102C、D102SまたはA117K、またはそれらの任意の組み合わせから選択される少なくとも1個の非天然変異を有するアミノ酸配列を含む、ワクチン組成物。
- 前記カプシドが、少なくとも2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、または20個の変異を含む、請求項1に記載のワクチン組成物。
- 前記少なくとも1個の非天然変異がジスルフィド結合変異である、請求項1に記載のワクチン組成物。
- 前記抗原が炭水化物抗原である、請求項1に記載のワクチン組成物。
- 前記炭水化物抗原が、(a)ムチン1(MUC1)、(b)ムチン4(MUC4)、(c)ガングリオシドGD2(GD2)、(d)フコシルガングリオシドGM1(GM1)、(e)アセチル化GD2、(f)ガングリオシドGD3(GD3)、(g)アセチル化GD3、(h)フコシルガングリオシドGM2(GM2)、(i)グロボ-H、(j)ルイスA、(k)ルイスY、(l)ポリシアル酸、(m)シアリル-ルイスA、(n)Tf、(o)Tn、(p)sTn、Tn1およびTn2からなる群より選択される、請求項4に記載のワクチン組成物。
- 前記炭水化物抗原がMUC1である、請求項5に記載のワクチン組成物。
- 前記炭水化物抗原がGD2または9-NHAc-GD2である、請求項5に記載のワクチン組成物。
- 前記カプシドが、A40C/D102C、A40S/D102SまたはA43C/Q98Cから選択される少なくとも2個の変異を含む、請求項1に記載のワクチン組成物。
- 前記カプシドが、A40C/D102C/K13RまたはA38K/A40C/D102Cから選択される少なくとも3個の変異を含む、請求項1に記載のワクチン組成物。
- 被験体におけるがんの処置または予防において使用するための、請求項1に記載のワクチン組成物。
- 前記ワクチン組成物を全身投与する、請求項10に記載の使用のためのワクチン組成物。
- 前記全身投与が、経口投与、静脈内投与、皮内投与、腹腔内投与、皮下投与および筋肉内投与からなる群より選択される、請求項11に記載の使用のためのワクチン組成物。
- 前記組成物を腫瘍内投与または腫瘍周囲投与する、請求項10に記載の使用のためのワクチン組成物。
- 前記がんが固形腫瘍である、請求項10に記載の使用のためのワクチン組成物。
- 前記がんが、口腔がん、乳がん、脳がん、小児がん、卵巣がん、前立腺がん、膵臓がん、肺がん、肝臓がん、咽喉がん、胃がんおよび腎臓がんからなる群より選択される、請求項10に記載の使用のためのワクチン組成物。
- 前記がんが肺がんである、請求項15に記載の使用のためのワクチン組成物。
- 前記がんが乳がんである、請求項15に記載の使用のためのワクチン組成物。
- 前記小児がんが神経芽細胞腫である、請求項15に記載の使用のためのワクチン組成物。
- 前記被験体が哺乳動物である、請求項10に記載の使用のためのワクチン組成物。
- 前記哺乳動物がヒトである、請求項19に記載の使用のためのワクチン組成物。
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