JP7021083B2 - 免疫応答を誘導するための方法および手段 - Google Patents
免疫応答を誘導するための方法および手段 Download PDFInfo
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Description
該対象に第1組成物の投与後に第2組成物を投与することを含み、
第1組成物および第2組成物は各々、(i)危険シグナル;および(ii)医薬的に許容される担体を含み、
第1組成物および第2組成物は相乗的な免疫応答を誘導する時間の範囲内に投与される。
第1容器は(i)危険シグナル;および(ii)医薬的に許容される担体を含む第1組成物を含有し;および第2容器は(i)危険シグナル;および(ii)医薬的に許容される担体を含む第2組成物を含有し、および
好ましくは該キットは第1組成物および第2組成物が、相乗的な免疫応答が誘導される時間の範囲内に投与されるという指示をさらに含む。
下記において、定義は提供され、本発明の全ての態様に適用される。
純水または低塩溶液(好ましくは50mM未満の電解質)を使用しておよそ5mg/ml未満、よくて1mg/ml以下の濃度にプロタミンおよびRNAを希釈する工程、
該2つの溶液を混合する工程、および
次いで適宜最終処方物が5%糖を含有するように(すなわちおよそ300mOsm/Lのオスモル濃度)糖含有溶液を加える工程、
を含む。
5%糖の塩フリーまたは低塩(好ましくは50mM未満の電解質)溶液を用いて、およそ5mg/ml未満、よくて1mg/ml以下の濃度にプロタミンおよびRNAを希釈する工程、および
該2つの溶液を混合する工程(最終処方物は5%糖を含有する。すなわちオスモル濃度はおよそ300mOsm/L)、
を含む。
RNAを合成し精製する。ついで生成物を凍結乾燥し、0.5mg/mlで純水に再懸濁させる。プロタミンIPEX 5000を純水で28倍に希釈し、およそ0.5mg/mlの低塩のプロタミンの溶液を得る。1体積のRNAを1体積のプロタミンと混合する。直ちに強力に混合する(例えばピペットでのアップダウンやボルテックス)。当該処方物を10分間室温に置き、ついで適量の40%グルコースで最終濃度5%グルコースとなるようにさらに希釈する。溶液を、RNA(およびプロタミンの)濃度が10μg/70μLになるように、5%グルコースでさらに希釈する。マウスに、140μLのプロタミン-RNA溶液の静脈内注射を1回行うか、または70μLの該溶液の静脈内注射を2回(2または4または5または6時間あけて)行う。
それらの条件において、図1に示すとおり、当該2回の注射が2または4時間あけて(最大5時間あけて)行われたときに、インターフェロンα(TNFαではなく)の相乗的な産生が該(最終)注射から3時間後に採取した血清中に検出される。
実施例1と同一のプロタミン-RNAの処方物を用いて、70μLの静脈内投与を2時間あけて行い、第2注射から3時間後に血清を採取するダブル注射スケジュールにより、図2に示すとおり、インターフェロンαの相乗的な産生はIFNARに依存すると見られる(それはIFNAR-1欠損マウスでは認められない)。このことは精製または組換えI型インターフェロンと同様に機能性生物(機能性I型インターフェロン受容体を有する)におけるI型インターフェロンのインデューサー(弱くとも)は当該生物を(インターフェロン産生の観点から)プロタミン-RNA粒子の第2注射に対して強く反応するように感作させることができることを示唆する。
実施例1の70μLのプロタミン-RNA粒子は、同量のプロタミン-RNA粒子の第1注射、または他の危険シグナル:例えば非メチル化DNA(「CpG ODN」)またはイミキモド(図3において両方)またはdsRNA(図4);の注射の2時間後にそれらが投与されたとき、強力に(相乗的に)インターフェロン産生を誘導する。したがって、相乗的なI型インターフェロン産生を得るために、プロタミン-RNA粒子はもう一つの危険シグナルの後に(または前に)注射されることができる。
図5に示すとおり、株化肺転移を有するマウスは、「相乗的」注射プロトコル(2回、2時間あけて、実施例1のとおりに製造された70μLのプロタミン-RNA粒子の静脈内注射)を2サイクル(1週間あけて)行って治療した場合には、腫瘍形成の遅延を示した。「バルク」プロトコル(実施例1の140μLのプロタミン-RNA粒子の1回静脈内注射)2サイクル(1週間あけて)行って治療した場合には示さなかった。従って、プロタミン-RNA粒子による効果的な抗ガン性免疫を引き起こすためには数時間(6未満)のダブル注射スケジュールが必要である。
[請求項1]
対象に第2組成物を第1組成物の投与後に投与することを含む、該対象において免疫反応を誘導するための方法であって、
第1組成物および第2組成物は各々(i)危険シグナル;および(ii)医薬的に許容される担体を含み、
相乗的な免疫反応が誘導される時間内に第1組成物および第2組成物が投与される、
該方法。
[請求項2]
該時間が約6時間である、請求項1に記載の方法。
[請求項3]
該危険シグナルがToll様受容体アゴニストであり、および/または該危険シグナルがI型インターフェロンを誘導する、請求項1または2に記載の方法。
[請求項4]
該Toll様受容体アゴニストが、RNAを含む粒子(該RNAはカチオン性ポリマーまたは脂質またはカチオン性ポリマーおよび脂質の両方と会合(associate)する);二本鎖RNA;CpGモチーフを含む非メチル化DNA;イミキモド;およびレシキモドからなる群から選択される、請求項3に記載の方法。
[請求項5]
該カチオン性ポリマーがプロタミン、ポリエチレンイミン、ポリ-L-リジン、ポリ-L-アルギニン、およびヒストンからなる群から選択される、請求項4に記載の方法。
[請求項6]
該粒子がRNAおよびプロタミンを含む、請求項5に記載の方法。
[請求項7]
該プロタミン-RNA粒子が約10nm~約990nm、約10nm~約750nm、約10nm~約450nm、約50nm~約450nm、約50nm~約100nm、または約90nm~約110nmのサイズを有するプロタミン-RNAナノ粒子である、請求項6に記載の方法。
[請求項8]
該プロタミン-RNAナノ粒子が約16:1~約1:2、約8:1~約1:2、または約4:1~約1:2のポリカチオン:RNAの質量比を有する、請求項7に記載の方法。
[請求項9]
第1組成物中および/または第2組成物中の該危険シグナルがプロタミン-RNAナノ粒子である、請求項1~8のいずれか1項に記載の方法。
[請求項10]
該粒子中に含まれる該RNAがオリゴヌクレオチドまたはメッセンジャーRNAである請求項4~9のいずれか1項に記載の方法。
[請求項11]
該粒子中に含まれる該RNAが、少なくとも1つのUヌクレオチドまたは少なくとも1つのGヌクレオチド、または少なくとも1つのUヌクレオチドおよび少なくとも1つのGヌクレオチドを含む、請求項4~10のいずれか1項に記載の方法。
[請求項12]
該粒子中に含まれる該RNAが修飾RNAである、請求項4~11のいずれか1項に記載の方法。
[請求項13]
該時間が約5時間、約4時間、約3時間、約2時間、約1時間、または約30分である、請求項1~12のいずれか1項に記載の方法。
[請求項14]
該誘導される免疫反応が、第1組成物および第2組成物の両方の投与後に該対象から得られた血清中のI型インターフェロン発現において、該組成物の一方のみの投与と比較した、少なくとも2倍、少なくとも3倍、少なくとも4倍、少なくとも5倍、少なくとも6倍、少なくとも7倍、少なくとも8倍、少なくとも9倍、または少なくとも10倍の増加として検出され、該I型インターフェロンは好ましくはインターフェロンαである、請求項1~13のいずれか1項に記載の方法。
[請求項15]
該誘導される免疫反応が、該組成物の一方のみの投与と比較して、第1組成物および第2組成物の両方の投与後に該対象から得られた血清中のTNFα発現の増加および減少を示さない、請求項1~14のいずれか1項に記載の方法。
[請求項16]
第1組成物および/または第2組成物が抗原をさらに含む、請求項1~15のいずれか1項に記載の方法。
[請求項17]
第1容器および第2容器を含むキットであって、
第1容器は(i)危険シグナル;および(ii)医薬的に許容される担体を含む第1組成物を含み;および
第2容器は(i)危険シグナル;および(ii)医薬的に許容される担体を含む第2組成物を含み;および
好ましくは該キットは相乗的な免疫反応が誘導される時間内に第1組成物および第2組成物が投与されるとの説明をさらに含む;
キット。
[請求項18]
対象における免疫反応の誘導における使用のための第1組成物および第2組成物であって、
第2組成物は第1組成物の投与後に投与され、
第1組成物および第2組成物は各々(i)危険シグナル;および(ii)医薬的に許容される担体を含み、
相乗的な免疫反応が誘導される時間内に第1組成物および第2組成物が投与される、
第1組成物および第2組成物。
[請求項19]
治療的使用のための第1組成物および第2組成物の使用であって、
第2組成物は第1組成物の投与後に投与され、
第1組成物および第2組成物は各々(i)危険シグナル;および(ii)医薬的に許容される担体を含み、
相乗的な免疫反応が誘導される時間内に第1組成物および第2組成物が投与される、
使用。
[請求項20]
該治療的使用がガン治療である、請求項19に記載の使用。
Claims (11)
- インターフェロンαレベルの高まりに反映される免疫応答を誘導する方法に使用するための、危険シグナルおよび医薬的に許容される担体を含む組成物であって、
該組成物は第1組成物として対象に投与され、および、該方法はインターフェロンα産生に対する相乗効果が誘導されるように第1組成物の投与後6時間の時間以内に第2組成物を対象に投与することを含み、
第1組成物は、(i)RNAおよびプロタミンを含む粒子を含む危険シグナル;および(ii)医薬的に許容される担体を含み、
第2組成物は、(i)RNAおよびプロタミンを含む粒子;二本鎖RNA;CpGモチーフを含む非メチル化DNA;およびイミキモドからなる群から選択される危険シグナル;および(ii)医薬的に許容される担体を含み、
該誘導される免疫反応が、該組成物の一方のみの投与と比較して、第1組成物および第2組成物の両方の投与後に該対象から得られた血清中のTNFα発現の増加を示さない、
組成物。 - 該プロタミン-RNA粒子が10nm~990nm、10nm~750nm、10nm~450nm、50nm~450nm、50nm~100nm、または90nm~110nmの範囲のサイズを有するプロタミン-RNAナノ粒子である、請求項1に記載の組成物。
- 該プロタミン-RNAナノ粒子が16:1~1:2、8:1~1:2、または4:1~1:2の範囲のポリカチオン:RNAの質量比を有する、請求項2に記載の組成物。
- 第1組成物中および/または第2組成物中の該危険シグナルがプロタミン-RNAナノ粒子である、請求項1~3のいずれか1項に記載の組成物。
- 該粒子中に含まれる該RNAがオリゴヌクレオチドまたはメッセンジャーRNAである請求項1~4のいずれか1項に記載の組成物。
- 該粒子中に含まれる該RNAが、少なくとも1つのUヌクレオチドまたは少なくとも1つのGヌクレオチド、または少なくとも1つのUヌクレオチドおよび少なくとも1つのGヌクレオチドを含む、請求項1~5のいずれか1項に記載の組成物。
- 該粒子中に含まれる該RNAが修飾RNAである、請求項1~6のいずれか1項に記載の組成物。
- 該時間が5時間以下、4時間以下、3時間以下、2時間以下、1時間以下、または30分である、請求項1~7のいずれか1項に記載の組成物。
- 該誘導される免疫反応が、第1組成物および第2組成物の両方の投与後に該対象から得られた血清中のI型インターフェロンα発現において、該組成物の一方のみの投与と比較した、少なくとも2倍、少なくとも3倍、少なくとも4倍、少なくとも5倍、少なくとも6倍、少なくとも7倍、少なくとも8倍、少なくとも9倍、または少なくとも10倍の増加によって検出される、請求項1~8のいずれか1項に記載の組成物。
- 第1組成物および/または第2組成物が抗原をさらに含む、請求項1~9のいずれか1項に記載の組成物。
- 該免疫応答が疾患の進行を防止、減速、または抑制するために誘導され、該疾患が好ましくはガン疾患またはウイルス感染である、請求項1~10のいずれか1項に記載の組成物。
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