JP2018508533A - 方法 - Google Patents
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- JP2018508533A JP2018508533A JP2017546723A JP2017546723A JP2018508533A JP 2018508533 A JP2018508533 A JP 2018508533A JP 2017546723 A JP2017546723 A JP 2017546723A JP 2017546723 A JP2017546723 A JP 2017546723A JP 2018508533 A JP2018508533 A JP 2018508533A
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Abstract
Description
a)同じ細胞であってもよいし異なる細胞であってもよい、前記抗原分子または前記抗原分子の一部を発現させる第1の細胞およびチェックポイント阻害剤が結合し得る第2の細胞を提供することと、
b)少なくとも前記第1の細胞を、前記抗原分子、光感作性薬剤、および場合によってはTLRリガンドに接触させることと、
c)少なくとも前記第2の細胞を、チェックポイント阻害剤に接触させることと、
d)前記抗原分子が前記細胞のサイトゾルに放出され、その後、前記抗原分子または抗原分子の一部が前記第1の細胞の表面に提示されるように、少なくとも前記第1の細胞に、前記光感作性薬剤を活性化するのに有効な波長の光を照射することと、
を含み、
前記照射の前、前記照射中、および/または前記照射後に、前記第1の細胞および前記第2の細胞を互いに接触させる、方法を提供する。
Rは該化合物においてn回現れ、
全Rn基の0.1%〜99.9%(好ましくは0.5%〜99.5%)において、各RはA基であって、該A基は、
各R1は、同一であっても異なっていてもよいが、H、CH3、および−(CH2)b−CH3から選択され、aは1、2、3、4、または5であり、bは0、1、2、3、4、または5であって(対イオンは、例えば、Cl-であってもよい)、好ましくは、R1はCH3でありbは1である、基、
および
YはO、S、SO2、−NCH3、または−N(CH2)dCH3であり、cは1、2、3、4、または5であり、dは1、2、3、4、または5であって、好ましくは、YはNCH3でありcは1である、基
から選択される基であり、
各R基は同一であっても異なっていてもよく、
全Rn基の0.1%〜99.9%(好ましくは0.5%〜99.5%)において、各RはB基であって、該B基は
eは0、1、2、3、4、または5であり、fは1、2、3、4、または5であって、好ましくはeおよびfは1である、基
から選択される基であり、
R2は
WはO、S、NH、またはN(CH3)から選択される基であり、好ましくはNHである、基であり
R3は
VはCO、SO2、PO、PO2H、またはCH2から選択される基であって、好ましくはCOであり、
R4は、同一であっても異なっていてもよいが、H、−OH、−OCH3、−CH3、−COCH3、C(CH3)4、−NH2、−NHCH3、−N(CH3)2、および−NCOCH3から選択される基(o位、m位、またはp位が置換されている)であって、好ましくはHである、基であって、
各R基は同一であっても異なっていてもよい。
17: B:25%、A:75%
37: B:10%、A:90%
TLR受容体に対するリガンドは、全て本発明に包含される。「リガンド」なる語は、生体分子と複合体を形成し、生物学的目的をはたす物質を意味することが意図される。TLRリガンドとの関連において、リガンドは、シグナル誘因分子であり、標的TLR上のある部位に結合する。リガンドが、その同種受容体に結合する際に、受容体の化学構造を変えてもよい。受容体タンパク質の立体構造は、その機能状態を決定する。
TLR受容体の配列は公知であり、本明細書で述べるリガンドのこれらの受容体への結合は、例えば上述したように評価されてもよい。例として、公知のTLRアミノ酸配列を下記表1に示す。
あるいは、TLR2と複合体を形成したTLR1の選択的アゴニストであるPam3Cys−Ser−(Lys)4三塩酸塩(エンゾ・ライフ・サイエンス社)を用いてもよい。
−ポリ(I:C)(HMW):高分子量、平均サイズは1.5〜8 kb;および
−ポリ(I:C)(LMW):低分子量、平均サイズは0.2〜1 kb。
高分子量の形態および低分子量の形態の両方が、本発明によって用いられるのに好ましい形態である。
R1は、場合によってはヒドロキシル基などで置換されていてもよいアミノアルキル基であり、R2は、場合によっては酸素族または窒素族が挿入されたアルキル基であって、好ましくは、
R1は、N−CH2−C(CH3)2−R3であり、
R2は、−CH2−X−CH2CH3または水素原子であり、
R3は、OHまたは水素原子、Xは、OまたはNHである。
上記化学式において、アルキル基は、C1−C10基であってもよい。
5’−Pu Pu CG Pu:Py CG Py Py−3’
および/または、1つ以上の共通配列5’−Pu Py CG Py Pu−3’を含む。場合によっては、CpGオリゴヌクレオチドは、3’末端または5’末端に長さが3〜8塩基のポリGテールを含んでいてもよい。
5’−tcgtcgttttcggcgc:gcgccg−3’(下線部が回文)
である、ODN2395である。
5’−tccatgacgttcctgacgtt−3’
である、ODN1826である。
a)同じ細胞であってもよいし異なる細胞であってもよい、前記抗原分子または前記抗原分子の一部を発現させる第1の細胞およびチェックポイント阻害剤が結合し得る第2の細胞を提供することと、
b)少なくとも前記第1の細胞を、前記抗原分子、光感作性薬剤、および場合によってはTLRリガンドに接触させることと、
c)少なくとも前記第2の細胞を、チェックポイント阻害剤に接触させることと、
d)前記抗原分子が前記細胞のサイトゾルに放出され、その後、前記抗原分子または抗原分子の一部が前記第1の細胞の表面に提示されるように、少なくとも前記第1の細胞に、前記光感作性薬剤を活性化するのに有効な波長の光を照射することと、
を含み、
前記照射の前、前記照射中、および/または前記照射後に、前記第1の細胞および前記第2の細胞を互いに接触させる、方法を提供する。一旦活性化されると、前記化合物を含む前記細胞内の細胞内区画は、これらの区画に含まれる分子を、サイトゾルへと放出する。
本明細書で定義される光感作性薬剤を含む第1の容器と、
本明細書で定義される上記抗原分子を含む第2の容器と、
本明細書で定義されるチェックポイント阻害剤を含む第3の容器と、場合によっては
本明細書で定義されるTLRリガンドを含む第4の容器と、
を含む、キットも提供する。
実施例1
本研究は、チェックポイント阻害剤である抗CTLA4および抗PD−1と組み合わせたPCIの、HPV誘導性癌に対するTC−1マウスモデルにおける効果を調べるために行われた。
マウス
C57BL/6マウスを、ハーラン社(Harlan)(ホルスト、オランダ)から購入した。全てのマウスは、特定病原体を除去した(SPF)条件下で飼育され、行った手順は、スイス家畜当局によって承認された。
0日目に、マウスの右脇腹の皮下へ、200,000個のTC−1腫瘍細胞(ジョンズ・ホプキンス大学、3400N.チャールズ・ストリート、バルティモア、MD21218−2695より使用許諾を得た)を接種した。
さらなる処理スケジュールの概略を表3に示す。チェックポイント阻害剤である抗CTLA4および抗PD−1を、表3に示す時点において腹腔内注射によって投与した。チェックポイント阻害剤の用量は、抗CTLA4の場合は注射1回あたり100μg、抗PD−1の場合は200μgであった。両方のチェックポイント阻害剤を、バイオXセル社、10テクノロジー・ドライブ、スイート2B、ウエスト・レバノン、NH03784−1671、米国(mAb抗mCTLA−4、カタログ番号BE0131、およびmAb抗mPD−1、カタログ番号BE0146)から入手した。
1週間に2回または3回、直交する2本の直径を、デジタルノギスを用いて測定することによって、腫瘍のサイズを測定した。下記式を用いて、腫瘍の体積を計算した。
V=(W2×L)/2
ここで、Wは、測定した腫瘍の幅であり、Lは、その長径である。
材料および方法
C57BL/6マウス、TPCS2a、およびポリ(IC)は、実施例1と同様である。TRP−2ペプチド(配列はSVYDFFVWL)を、ユナイテッド・ペプチド社(ハーンドン、ヴァージニア州)から入手した。
マウスの腹部領域(3〜4cm2)の体毛を剃り、0日目、14日目、および35日目に、30G注射針を付けた0.3mlのBDミクロファイン(Micro-Fine)(登録商標)+インスリンシリンジ(BD社、ニュージャージー州、米国)を用いて、以下に詳述する通り、200μgのTRP−2ペプチド、100μgのTPCS2a、および10μgの高分子量ポリ(IC)で免疫化を行った。ワクチンは、遮光状態を保ち、調製後60分以内に用いた。ワクチンは、腹部の中心線の左右両側に、各50μlを1回ずつ計2回注射した。ワクチン注射後の特定の時点において、ゾレチル(Zoletil)混合物(体重1kgあたり10mg、ビルバック社(Virbac)、ノルウェー)を皮下注射することによって、マウスの麻酔を行い、関連する箇所に照射を行った。実験群の一部(下記参照)においては、各免疫化の直前に、抗CTLA4(3mg/kg、腹腔内投与)を投与した。
免疫化してから18時間後に、ルミソース(PCIバイオテック社)を用いて、ワクチン接種箇所に対する照射を6分間行った。
1回目の免疫化から60日後に、動物を殺処分して脾臓を取り出し、TRP−2ペプチドを用いて脾臓細胞を再刺激した後、インターフェロン−ガンマ(IFN−ガンマ)および腫瘍壊死因子アルファ(TNF−アルファ)に対する細胞内染色によって解析を行った。24穴プレート中、37℃で、TRP−2ペプチドによる脾細胞の刺激を一晩行った後、IFN−γに対する細胞内染色を行った。最後の4時間の間に、ブレフェルディンA(Brefelding A)を添加した。その後、細胞を洗浄し、4%ホルムアルデヒドを含むPBSを用いて、氷上で10分間、固定を行った。抗CD16/32を添加して、Fc受容体への非特異的な結合を防止した。その後、0.1%のNP40を含むPBSを用いて、透過処理を3分間行い、洗浄後、抗IFN−γ抗体、抗CD8抗体、および抗CD44抗体(eバイオサイエンス社(eBioscience)またはBDファーミンジェン社(BD Pharmingen))を用いて染色した。FACSカント(FACSCanto)(BDバイオサイエンス社(BD Biosciences)、サンノゼ、米国)を用いて細胞を取得し、FlowJo8.5.2ソフトウェア(ツリー・スター社(Tree Star, Inc.)、アシュランド、オレゴン州)を用いて解析を行った。腫瘍壊死因子アルファ(TNF−アルファ)に対する細胞内染色は、IFN−ガンマについて述べたのと同様に、抗TNF−アルファ抗体を用いて行った。
1.未処理:マウスの免疫化または照射を行わなかった。
2.TRP−2:全ての免疫化において、TRP−2ペプチドを用いてマウスの免疫化を行った。照射は行わなかった。
3.TRP−2+ポリ(IC):TRP−2ペプチドおよび10μgのポリ(IC)を用いてマウスの免疫化を行った。照射は行わなかった。
4.TRP−2+PCI:TRP−2ペプチドおよび100μgのTPCS2aを用いてマウスの免疫化を行い、照射を行った。
5.TRP−2+ポリ(IC)+PCI:TRP−2ペプチド、10μgのポリ(IC)、および100μgのTPCS2aを用いてマウスの免疫化を行い、照射を行った。
6.TRP−2+ポリ(IC)+PCI+抗CTLA4:TRP−2ペプチド、10μgのポリ(IC)、および100μgのTPCS2aを用いてマウスの免疫化を行った。各免疫化の直前に、抗CTLA4(3mg/kg、腹腔内投与)を投与した。動物に対して照射を行った。
7.TRP−2+ポリ(IC)+抗CTLA4:TRP−2ペプチドおよび10μgのポリ(IC)を用いてマウスの免疫化を行った。各免疫化の直前に、抗CTLA4(3mg/kg、腹腔内投与)を投与した。動物に対して照射を行わなかった。
本研究は、チェックポイント阻害剤である抗CTLA4および抗PD−1(一緒に用いる)と組み合わせたPCI予防接種の、HPV誘導性癌に対するTC−1マウスモデルにおける効果を調べるために行われた。
マウスは、実施例1と同様である。0日目に、マウスの右脇腹の皮下へ、100,000個のTC−1腫瘍細胞(ジョンズ・ホプキンス大学、3400N.チャールズ・ストリート、バルティモア、MD21218−2695より使用許諾を得た)を接種した。チェックポイント阻害剤である抗CTLA4および抗PD−1、光感作性薬剤であるTPCS2a、およびHPV長鎖ペプチド抗原は、実施例1と同様である。
処理スケジュールの概略を表5に示す。
本研究は、チェックポイント阻害剤である抗CTLA4および抗PD−1(一緒に用いる)ならびにTLRリガンドであるポリ(IC)と組み合わせたPCI予防接種の、HPV誘導性癌に対するTC−1マウスモデルにおける効果を調べるために行われた。
実施例3と同様に、TC−1腫瘍細胞をマウスに接種した。チェックポイント阻害剤である抗CTLA4および抗PD−1、光感作性薬剤であるTPCS2a、HPV長鎖ペプチド抗原、およびポリ(IC)は、実施例1と同様である。
処理スケジュールの概略を表7に示す。
本研究は、チェックポイント阻害剤である抗PD−1と組み合わせたPCI予防接種の、HPV誘導性癌に対するTC−1マウスモデルにおける効果を調べるために行われた。
実施例3と同様に、TC−1腫瘍細胞をマウスに接種した。チェックポイント阻害剤である抗PD−1、光感作性薬剤であるTPCS2a、およびHPV長鎖ペプチド抗原は、実施例1と同様である。
処理スケジュールの概略を表9に示す。
Claims (37)
- 被験体において免疫応答を生じさせる方法であって、該方法は、抗原分子、光感作性薬剤、およびチェックポイント阻害剤を前記被験体に投与することと、前記光感作性薬剤を活性化するのに有効な波長の光を前記被験体に照射することと、を含み、免疫応答を生じる、方法。
- 前記チェックポイント阻害剤は、抗体であり、好ましくはモノクローナル抗体である、請求項1に記載の方法。
- 前記チェックポイント阻害剤は、抗CTLA4および抗PD−1から選択され、好ましくは(i)抗CTLA4および抗PD−1または(ii)抗CTLA4である、請求項1または2に記載の方法。
- 前記方法は、前記被験体をTLRリガンドに接触させることをさらに含む、請求項1〜3のいずれか1項に記載の方法。
- 前記TLRリガンドは、TLR3のリガンドであり、好ましくは二本鎖RNA分子であり、好ましくはポリ(I:C)である、請求項4に記載の方法。
- 前記抗原分子は、免疫応答を刺激することができる分子であり、好ましくはワクチン抗原またはワクチン成分であり、好ましくは2つ以上の抗原を含む、請求項1〜5のいずれか1項に記載の方法。
- 前記光感作性薬剤は、TPCS2a、AlPcS2a、TPPS4、およびTPBS2aから選択され、好ましくはTPCS2aである、請求項1〜6のいずれか1項に記載の方法。
- 前記抗原分子は、ペプチドであり、好ましくは黒色腫ペプチドまたはヒトパピローマウイルス(HPV)ペプチドである、請求項1〜7のいずれか1項に記載の方法。
- 前記方法は、予防接種の方法である、請求項1〜8のいずれか1項に記載の方法。
- 疾患、障害、または感染を治療または予防するための、好ましくは癌を治療または予防するための、好ましくは黒色腫またはパピローマウイルスに関連する癌を治療または予防するための、請求項1〜9のいずれか1項に記載の方法。
- 前記被験体は、哺乳類であり、好ましくはネコ、イヌ、ウマ、ロバ、ヒツジ、ブタ、ヤギ、ウシ、マウス、ラット、ウサギ、またはモルモットであり、最も好ましくは前記被験体はヒトである、請求項1〜10のいずれか1項に記載の方法。
- 前記抗原分子、光感作性薬剤、チェックポイント阻害剤、および場合によっては前記TLRリガンドは、前記被験体に、同時に投与されるか、別々に投与されるか、または順次投与される、請求項1〜11のいずれか1項に記載の方法。
- 請求項1、6または8のいずれか1項に記載の抗原分子、請求項1または7に記載の光感作性薬剤、請求項1〜3のいずれか1項に記載のチェックポイント阻害剤、および場合によっては請求項4または5に記載のTLRリガンド、ならびに1つ以上の薬学的に許容される希釈剤、担体、または賦形剤を含む、医薬組成物。
- 細胞の表面に抗原分子または抗原分子の一部を発現させる方法であって、該方法は、
a)同じ細胞であってもよいし異なる細胞であってもよい、前記抗原分子または前記抗原分子の一部を発現させる第1の細胞およびチェックポイント阻害剤が結合し得る第2の細胞を提供することと、
b)少なくとも前記第1の細胞を、前記抗原分子、光感作性薬剤、および場合によってはTLRリガンドに接触させることと、
c)少なくとも前記第2の細胞を、チェックポイント阻害剤に接触させることと、
d)前記抗原分子が前記細胞のサイトゾルに放出され、その後、前記抗原分子または抗原分子の一部が前記第1の細胞の表面に提示されるように、少なくとも前記第1の細胞に、前記光感作性薬剤を活性化するのに有効な波長の光を照射することと、
を含み、
前記照射の前、前記照射中、および/または前記照射後に、前記第1の細胞および前記第2の細胞を互いに接触させる、方法。 - 前記抗原分子は、請求項6または8に記載の抗原分子であり、前記光感作性薬剤は、請求項7に記載の光感作性薬剤であり、前記チェックポイント阻害剤は、請求項2または3に記載のチェックポイント阻害剤であり、かつ/または前記TLRリガンドは、請求項4または5に記載のTLRリガンドである、請求項14に記載の方法。
- 前記抗原分子は、請求項6に記載の抗原分子であり、前記抗原提示によって、免疫応答が刺激される、請求項15に記載の方法。
- 前記方法は、インビトロまたはエキソビボで行われる、請求項14〜16のいずれか1項に記載の方法。
- 前記第1の細胞は、抗原提示細胞であり、好ましくは樹状細胞またはマクロファージである、請求項14〜17のいずれか1項に記載の方法。
- 前記第2の細胞は、T細胞である、請求項14〜18のいずれか1項に記載の方法。
- 前記方法を行っている間に、前記第1の細胞および第2の細胞を互いに接触させ、前記方法を行っている間に、前記抗原分子、光感作性薬剤、チェックポイント阻害剤、および場合によっては前記TLRリガンドを、前記第1の細胞および第2の細胞の両方と接触させる、請求項14〜19のいずれか1項に記載の方法。
- 前記第1の細胞および第2の細胞を、前記抗原分子、光感作性薬剤、およびチェックポイント阻害剤、ならびに場合によっては前記TLRリガンドと、同時に接触させるか、別々に接触させるか、または順次接触させる、請求項14〜20のいずれか1項に記載の方法。
- 細胞表面に抗原分子または抗原分子の一部を発現する細胞またはその集団であって、細胞は、請求項14〜21のいずれか1項に記載の方法によって得ることができ、好ましくは樹状細胞である、細胞。
- 請求項22に記載の細胞または細胞の集団、および1つ以上の薬学的に許容される希釈剤、担体、または賦形剤を含む、医薬組成物。
- 予防または治療に用いられる、請求項22に記載の細胞または細胞集団、または請求項13または23に記載の組成物。
- 被験体の免疫応答を刺激するのに用いられる、好ましくは前記被験体の疾患、障害、または感染を治療または予防するための、好ましくは予防接種および/または癌の治療または予防のための、請求項22に記載の細胞または細胞集団、または請求項13または23に記載の組成物。
- 被験体の免疫応答を刺激する薬物の調製のための、好ましくは前記被験体の疾患、障害、または感染を治療または予防するための、好ましくは予防接種および/または癌の治療または予防のための、請求項22に記載の細胞集団、または請求項13〜23に記載の組成物の使用。
- 前記刺激、治療、または予防は、前記被験体に前記薬物を投与することを含む、請求項26に記載の使用。
- 予防または治療に用いる、請求項1、6または8のいずれか1項に記載の抗原分子、請求項1または7に記載の光感作性薬剤、請求項1〜3のいずれか1項に記載のチェックポイント阻害剤、および場合によっては請求項4または5に記載のTLRリガンド。
- 被験体の免疫応答を刺激するのに用いられる、好ましくは前記被験体の疾患、障害、または感染を治療または予防するための、好ましくは予防接種および/または癌の治療または予防のための、請求項28に記載の使用のための抗原分子、光感作性薬剤、チェックポイント阻害剤、および場合によってはTLRリガンドであって、好ましくは、前記使用は、請求項1〜12または請求項14〜21のいずれか1項に記載の方法を含む、抗原分子、光感作性薬剤、チェックポイント阻害剤、およびTLRリガンド。
- 請求項28または29に記載の使用のための、請求項1〜6、7または8のいずれか1項に記載の前記抗原分子、光感作性薬剤、チェックポイント阻害剤、および場合によってはTLRリガンドであって、前記使用は、抗原分子または抗原分子の一部を細胞表面に発現する細胞の集団を調製するために請求項14〜21のいずれか1項に記載の方法を含み、好ましくは前記細胞は樹状細胞である、前記抗原分子、光感作性薬剤、チェックポイント阻害剤、およびTLRリガンド。
- 前記細胞の集団は、前記被験体に投与されるものである、請求項30に記載の使用のための前記抗原分子、光感作性薬剤、チェックポイント阻害剤、および場合によってはTLRリガンド。
- 被験体の免疫応答を刺激するための、好ましくは前記被験体の疾患、障害、または感染を治療または予防するための、好ましくは予防接種および/または癌の治療または予防のための薬物の製造における、請求項1〜6または8のいずれか1項に記載の抗原分子、および/または請求項1または7に記載の光感作性薬剤、および/または請求項1〜3のいずれか1項に記載のチェックポイント阻害剤、および場合によっては請求項4または5に記載のTLRリガンドの使用であって、好ましくは前記免疫応答は、請求項1〜12に記載の方法で刺激される、使用。
- 前記薬物は、請求項14〜21のいずれか1項に記載の方法によって得ることができる、前記被験体に投与するための、抗原分子または抗原分子の一部を細胞の表面に発現する細胞集団を含む、請求項32に記載の使用。
- 請求項14〜21のいずれか1項に記載の方法において、前記抗原分子、および/または光感作性薬剤、および/またはチェックポイント阻害剤、および場合によっては前記TLRリガンドを用いて、前記薬物の製造のための前記細胞の集団を得る、請求項33に記載の使用。
- 被験体の免疫応答を刺激するのに同時に、別々に、または順次用いられる、好ましくは前記被験体の疾患、障害、または感染を治療するまたは予防するための、好ましくは予防接種および/または癌の治療または予防のための、あるいは請求項1〜12または14〜21のいずれか1項に記載の方法において、細胞表面に抗原分子または抗原分子の一部を発現させるための、組み合わせ製剤として、請求項1、6または8のいずれか1項に記載の抗原分子、請求項1または7に記載の光感作性薬剤、請求項1〜3のいずれか1項に記載のチェックポイント阻害剤、および場合によっては請求項4または5に記載のTLRリガンドを含む、製品。
- 被験体の免疫応答を刺激するのに用いられる、好ましくは前記被験体の疾患、障害、または感染を治療するまたは予防するための、好ましくは予防接種および/または癌の治療または予防のための、あるいは請求項1〜12または14〜21のいずれか1項に記載の方法において、細胞表面に抗原分子または抗原分子の一部を発現させる、キットであって、該キットは、
請求項1または7に記載の光感作性薬剤を含む第1の容器と、
請求項1、6または8のいずれか1項に記載の前記抗原分子を含む第2の容器と、
請求項1〜3のいずれか1項に記載のチェックポイント阻害剤を含む第3の容器と、場合によっては
請求項4または5に記載のTLRリガンドを含む第4の容器と、
を含む、キット。 - 被験体の免疫応答を引き起こす、好ましくは前記被験体の疾患、障害、または感染を治療するまたは予防する、好ましくは予防接種および/または癌の治療または予防のための、方法であって、該方法は、請求項14〜21のいずれか1項に記載の方法にしたがって細胞の集団を調製することと、その後に前記細胞を前記被験体に投与することとを含む、方法。
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