JP7284156B2 - 細菌またはListeria株の凍結乾燥のための組成物および方法 - Google Patents
細菌またはListeria株の凍結乾燥のための組成物および方法 Download PDFInfo
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Description
本出願は、2017年9月19日に出願された米国特許出願番号第62/560,318号の利益を主張するものであり、この出願は、その全体があらゆる目的で参照により本明細書に組み込まれる。
ファイル519152SEQLIST.txtに記載の配列表は、89.2キロバイトであり、2018年8月24日に作成したものであり、これにより参照により本明細書に組み込まれる。
凍結乾燥は、溶液から溶媒を除去して、液体より安定しており、高温での保管が容易である固体または粉末を形成するプロセスある。フリーズドライとしても公知の凍結乾燥は、凍結、続いて昇華を含む。結果として生じる凍結乾燥物は、冷凍せずにまたは液体より高温で保管することができ、このことにより、物質の保管および輸送コストが削減され、製品に必要とされる保管スペースも低減される。凍結乾燥は、製品の重量を低減させることもでき、したがって、同様に、出荷および関連コストが削減される。凍結乾燥は、様々な生体分子の保存および保管に特に有用である。なぜなら、凍結乾燥は、それらの保管寿命を延ばすからである。
細菌またはListeria株、例えばListeria monocytogenes、の凍結乾燥のための方法および組成物が提供される。一態様では、細菌またはListeria株を含む凍結乾燥された組成物を生産するための方法が提供される。一部のそのような方法は、緩衝液を含む製剤中の細菌またはListeria株を含む組成物を提供するステップと、組成物を凍結ステップにおいて冷却するステップと、冷却された組成物を一次乾燥ステップにおいて真空および第1の温度上昇に曝露するステップと、一次乾燥ステップからの組成物を二次乾燥ステップにおいて真空および第2の温度上昇に曝露するステップとを含むことができ、それによって凍結乾燥された組成物が生産される。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
Listeria株を含む凍結乾燥された組成物を生産する方法であって、
(a)緩衝液とスクロースとを含む製剤中においてListeria株を含む組成物を提供するステップ、
(b)ステップ(a)で提供された組成物を凍結ステップにおいて約-32℃~約-80℃の間の保持温度で冷却するステップ、
(c)ステップ(b)により生産された組成物を一次乾燥ステップにおいて約-10℃~約-30℃の間の保持温度で真空に曝露するステップ、および
(d)ステップ(c)により生産された組成物を二次乾燥ステップにおいて約-5℃~約25℃の間の保持温度で真空に曝露するステップ
を含み、それによって凍結乾燥された組成物を生産する方法。
(項目2)
ステップ(a)の前に、前記Listeria株を低下した温度に曝露することにより前記Listeria株においてストレス応答が誘導される、項目1に記載の方法。
(項目3)
ステップ(a)の前に、前記Listeria株を低下した温度に曝露することにより前記Listeria株においてストレス応答が誘導されない、項目1に記載の方法。
(項目4)
ステップ(a)における前記組成物に使用される前記Listeria株が、ステップ(a)の前に解凍される凍結されたListeria株である、前記いずれかの項目に記載の方法。
(項目5)
解凍される前記凍結されたListeria株の濃度が、1ミリリットル当たり約1×10 9 ~約1×10 10 コロニー形成単位(CFU)の間である、項目4に記載の方法。
(項目6)
前記凍結されたListeria株が、約2℃~約37℃で解凍される、項目4または5に記載の方法。
(項目7)
前記凍結されたListeria株が、約20℃~約37℃で解凍される、項目6に記載の方法。
(項目8)
前記凍結されたListeria株が、約32℃および約37℃で解凍される、項目7に記載の方法。
(項目9)
前記凍結されたListeria株が、約37℃で解凍される、項目8に記載の方法。
(項目10)
前記凍結されたListeria株が、8時間以下の間、解凍される、項目4~9のいずれか一項に記載の方法。
(項目11)
前記凍結されたListeria株が、解凍後24時間以下の間、約2℃~約8℃で保持される、項目4~10のいずれか一項に記載の方法。
(項目12)
ステップ(a)における前記組成物に使用される前記Listeria株が、ステップ(a)の前に新鮮培養される、項目1~3のいずれか一項に記載の方法。
(項目13)
前記緩衝液が、リン酸緩衝液である、前記いずれかの項目に記載の方法。
(項目14)
前記製剤が、約1%~約5% w/v スクロースを含む、前記いずれかの項目に記載の方法。
(項目15)
前記製剤が、約2%~約3% w/v スクロースを含む、項目14に記載の方法。
(項目16)
前記製剤が、約2.5% w/v スクロースを含む、項目15に記載の方法。
(項目17)
前記製剤が、1ミリリットル当たり約1×10 9 ~約1×10 10 コロニー形成単位(CFU)のListeriaを含む、前記いずれかの項目に記載の方法。
(項目18)
前記製剤が、トレハロース、グルタミン酸一ナトリウム(MSG)および組換えヒト血清アルブミン(rHSA)のうちの1つまたは複数を含まない、前記いずれかの項目に記載の方法。
(項目19)
前記製剤が、トレハロース、MSG、またはrHSAを含まない、項目18に記載の方法。
(項目20)
前記凍結ステップ(b)における前記保持温度が、約-40℃~約-50℃の間である、前記いずれかの項目に記載の方法。
(項目21)
前記凍結ステップ(b)における前記保持温度が、約-45℃である、項目20に記載の方法。
(項目22)
前記凍結ステップ(b)が、温度を毎分約1℃の速度で前記保持温度に低下させることを含む、前記いずれかの項目に記載の方法。
(項目23)
前記凍結ステップ(b)における前記冷却が、約2時間~約4時間の冷却である、前記いずれかの項目に記載の方法。
(項目24)
前記凍結ステップ(b)における前記冷却が、前記組成物を約2時間、前記保持温度で保持することを含む、前記いずれかの項目に記載の方法。
(項目25)
前記一次乾燥ステップ(c)における前記保持温度が、約-12℃~約-22℃の間である、前記いずれかの項目に記載の方法。
(項目26)
前記一次乾燥ステップ(c)における前記保持温度が、約-17℃~約-19℃の間である、項目25に記載の方法。
(項目27)
前記一次乾燥ステップ(c)における前記保持温度が、約-18℃である、項目26に記載の方法。
(項目28)
前記一次乾燥ステップ(c)が、温度を毎分約1℃の速度で前記保持温度に上昇させることを含む、前記いずれかの項目に記載の方法。
(項目29)
前記一次乾燥ステップ(c)が、約25時間~約35時間である、前記いずれかの項目に記載の方法。
(項目30)
前記一次乾燥ステップ(c)の終了が、前記組成物が保持温度に達した約12~約16時間後である、前記いずれかの項目に記載の方法。
(項目31)
前記一次乾燥ステップ(c)が、約0.09mbarの真空圧である、前記いずれかの項目に記載の方法。
(項目32)
前記二次乾燥ステップ(d)における前記保持温度が、約-5℃~約20℃の間である、前記いずれかの項目に記載の方法。
(項目33)
前記二次乾燥ステップ(d)における前記保持温度が、約-5℃~約5℃の間である、項目32に記載の方法。
(項目34)
前記二次乾燥ステップ(d)における前記保持温度が、約0℃である、項目33に記載の方法。
(項目35)
前記二次乾燥ステップ(d)が、温度を毎分約0.2℃の速度で前記保持温度に上昇させることを含む、前記いずれかの項目に記載の方法。
(項目36)
前記二次乾燥ステップ(d)が、約1時間~約10時間である、前記いずれかの項目に記載の方法。
(項目37)
前記二次乾燥ステップ(d)が、前記組成物を約2時間~約6時間、前記保持温度で保持することを含む、前記いずれかの項目に記載の方法。
(項目38)
前記二次乾燥ステップ(d)が、前記組成物を約5時間~約6時間、前記保持温度で保持することを含む、項目37に記載の方法。
(項目39)
前記二次乾燥ステップ(d)が、約0.09mbarの真空圧である、前記いずれかの項目に記載の方法。
(項目40)
前記凍結乾燥された組成物中の残留水分が、約1%~約5%の間である、前記いずれかの項目に記載の方法。
(項目41)
前記凍結乾燥された組成物中の前記残留水分が、約2%~約4%の間である、項目40に記載の方法。
(項目42)
前記凍結乾燥された組成物中の前記残留水分が、少なくとも約2.5%である、前記いずれかの項目に記載の方法。
(項目43)
前記凍結乾燥された組成物中の前記残留水分が、少なくとも約3%である、項目42に記載の方法。
(項目44)
前記凍結乾燥された組成物が、約-20℃~約4℃の間で約12カ月保管された後、少なくとも約60%の生存率を示す、前記いずれかの項目に記載の方法。
(項目45)
前記凍結乾燥された組成物が、約-20℃~約4℃の間で約12カ月保管された後、少なくとも約75%の生存率を示す、項目44に記載の方法。
(項目46)
前記凍結乾燥された組成物が、約-20℃~約4℃の間で約12カ月保管された後、少なくとも約80%の生存率を示す、項目45に記載の方法。
(項目47)
前記Listeria株が、組換えListeria monocytogenes株である、前記いずれかの項目に記載の方法。
(項目48)
前記Listeria株が、組換えListeria monocytogenes株であり、
前記緩衝液が、リン酸緩衝液であり、
前記製剤が、約2%~約3% w/v スクロースを含み、
前記製剤が、トレハロース、MSG、またはrHSAを含まず、
前記製剤が、1ミリリットル当たり約1×10 9 ~約1×10 10 コロニー形成単位(CFU)のListeriaを含み、
前記凍結ステップ(a)における前記保持温度が、約-40℃~約-50℃の間であり、
前記一次乾燥ステップ(c)における前記保持温度が、-17℃~-19℃の間であり、
前記二次乾燥ステップ(d)における前記保持温度が、-1℃~1℃の間であり、
前記凍結乾燥された組成物中の前記残留水分が、約2.5%~約4%の間である、
前記いずれかの項目に記載の方法。
(項目49)
ステップ(a)における前記組成物に使用される前記Listeria株が、ステップ(a)の前に解凍される凍結されたListeria株であり、
解凍される前記凍結されたListeria株の濃度が、1ミリリットル当たり約1×10 9 ~約1×10 10 コロニー形成単位(CFU)の間であり、
前記凍結されたListeria株が、約37℃で解凍され、
前記凍結されたListeria株が、8時間以下の間、解凍され、
前記凍結されたListeria株が、解凍後24時間以下の間、約2℃~約8℃で保持される、
項目48に記載の方法。
(項目50)
前記Listeria株が、融合ポリペプチドをコードする第1のオープンリーディングフレームを含む核酸を含む組換えListeria株であり、前記融合ポリペプチドが、疾患関連抗原ペプチドに融合されたPEST含有ペプチドを含む、前記いずれかの項目に記載の方法。
(項目51)
前記組換えListeria株が、prfA中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、D133V PrfA突然変異タンパク質をコードする第2のオープンリーディングフレームを含む、項目50に記載の方法。
(項目52)
前記組換えListeria株が、actA、dalおよびdat中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、アラニンラセマーゼ酵素またはD-アミノ酸アミノトランスフェラーゼ酵素をコードする第2のオープンリーディングフレームを含み、前記PEST含有ペプチドが、LLOのN末端断片である、項目50に記載の方法。
(項目53)
(1)Listeria株と、(2)リン酸緩衝液と、(3)スクロースとを含む、Listeria株の凍結乾燥用の製剤。
(項目54)
前記Listeria株が、前記Listeria株を低下した温度に曝露することによりストレス応答が誘導された株である、項目53に記載の製剤。
(項目55)
前記Listeria株が、凍結されたListeriaストックからである、項目53または54に記載の製剤。
(項目56)
前記Listeria株が、新鮮培養されたListeriaストックからである、項目53または54に記載の製剤。
(項目57)
約1%~約5% w/v スクロースを含む、項目53~56のいずれか一項に記載の製剤。
(項目58)
約2%~約3% w/v スクロースを含む、項目57に記載の製剤。
(項目59)
約2.5% w/v スクロースを含む、項目58に記載の製剤。
(項目60)
トレハロース、グルタミン酸一ナトリウム(MSG)および組換えヒト血清アルブミン(rHSA)のうちの1つまたは複数を含まない、項目53~59のいずれか一項に記載の製剤。
(項目61)
トレハロース、MSG、またはrHSAを含まない、項目60に記載の製剤。
(項目62)
前記Listeria株が、組換えListeria monocytogenes株である、項目53~61のいずれか一項に記載の製剤。
(項目63)
前記Listeria株が、組換えListeria monocytogenes株であり、
前記製剤が、約2%~約3% w/v スクロースを含み、
前記製剤が、トレハロース、MSG、またはrHSAを含まない、
項目53~62のいずれか一項に記載の製剤。
(項目64)
前記Listeria株が、融合ポリペプチドをコードする第1のオープンリーディングフレームを含む核酸を含む組換えListeria株であり、前記融合ポリペプチドが、疾患関連抗原ペプチドに融合されたPEST含有ペプチドを含む、項目53~63のいずれか一項に記載の製剤。
(項目65)
前記組換えListeria株が、prfA中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、D133V PrfA突然変異タンパク質をコードする第2のオープンリーディングフレームを含む、項目64に記載の製剤。
(項目66)
前記組換えListeria株が、actA、dalおよびdat中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、アラニンラセマーゼ酵素またはD-アミノ酸アミノトランスフェラーゼ酵素をコードする第2のオープンリーディングフレームを含み、前記PEST含有ペプチドが、LLOのN末端断片である、項目64に記載の製剤。
(項目67)
項目1~52のいずれか一項に記載の方法により生産される、凍結乾燥された組成物。
(項目68)
Listeria株と、リン酸緩衝液と、スクロースとを含む、凍結乾燥された組成物。
(項目69)
トレハロース、グルタミン酸一ナトリウム(MSG)および組換えヒト血清アルブミン(rHSA)のうちの1つまたは複数を含まない、項目68に記載の凍結乾燥された組成物。
(項目70)
トレハロース、MSG、またはrHSAを含まない、項目69に記載の凍結乾燥された組成物。
(項目71)
前記凍結乾燥された組成物中の前記残留水分が、約1%~約5%の間である、項目67~70のいずれか一項に記載の凍結乾燥された組成物。
(項目72)
前記凍結乾燥された組成物中の前記残留水分が、約2%~約4%の間である、項目71に記載の凍結乾燥された組成物。
(項目73)
前記凍結乾燥された組成物中の前記残留水分が、少なくとも約2.5%である、項目67~72のいずれか一項に記載の凍結乾燥された組成物。
(項目74)
前記凍結乾燥された組成物中の前記残留水分が、少なくとも約3%である、項目73に記載の凍結乾燥された組成物。
(項目75)
凍結乾燥された組成物中の前記残留水分が、少なくとも約2.5%である、Listeria株を含む凍結乾燥された組成物。
(項目76)
約-20℃~約4℃の間で約12カ月保管された後、少なくとも約60%の生存率を示す、項目67~75のいずれか一項に記載の凍結乾燥された組成物。
(項目77)
約-20℃~約4℃の間で約12カ月保管された後、少なくとも約75%の生存率を示す、項目76に記載の凍結乾燥された組成物。
(項目78)
約-20℃~約4℃の間で約12カ月保管された後、少なくとも約80%の生存率を示す、項目77に記載の凍結乾燥された組成物。
(項目79)
前記Listeria株が、組換えListeria monocytogenes株である、項目67~78のいずれか一項に記載の凍結乾燥された組成物。
(項目80)
前記Listeria株が、組換えListeria monocytogenes株であり、
前記凍結乾燥された組成物が、トレハロース、MSG、またはrHSAを含まず、
前記凍結乾燥された組成物中の前記残留水分が、2.5%~4%の間である、
項目67~79のいずれか一項に記載の凍結乾燥された組成物。
(項目81)
前記Listeria株が、融合ポリペプチドをコードする第1のオープンリーディングフレームを含む核酸を含む組換えListeria株であり、前記融合ポリペプチドが、疾患関連抗原ペプチドに融合されたPEST含有ペプチドを含む、項目67~80のいずれか一項に記載の凍結乾燥された組成物。
(項目82)
前記組換えListeria株が、prfA中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、D133V PrfA突然変異タンパク質をコードする第2のオープンリーディングフレームを含む、項目81に記載の凍結乾燥された組成物。
(項目83)
前記組換えListeria株が、actA、dalおよびdat中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、アラニンラセマーゼ酵素またはD-アミノ酸アミノトランスフェラーゼ酵素をコードする第2のオープンリーディングフレームを含み、前記PEST含有ペプチドが、LLOのN末端断片である、項目81に記載の凍結乾燥された組成物。
(項目84)
凍結されたListeria株を凍結乾燥用に調製する方法であって、前記凍結されたListeria株を約20℃~約37℃の間の温度で解凍するステップを含む方法。
(項目85)
前記温度が、約32℃~約37℃の間である、項目84に記載の方法。
(項目86)
前記温度が、約37℃である、項目85に記載の方法。
(項目87)
前記凍結されたListeria株が、8時間以下の間、解凍される、項目84~86のいずれか一項に記載の方法。
(項目88)
前記凍結されたListeria株が、解凍後24時間以下の間、約2℃~約8℃で保持される、項目84~87のいずれか一項に記載の方法。
(項目89)
前記凍結されたListeria株が、緩衝液とスクロースとを含む製剤中において解凍される、項目84~88のいずれか一項に記載の方法。
(項目90)
前記製剤が、約1%~約5% w/v スクロースを含む、項目89に記載の方法。
(項目91)
前記製剤が、約2%~約3% w/v スクロースを含む、項目90に記載の方法。
(項目92)
前記製剤が、約2.5% w/v スクロースを含む、項目91に記載の方法。
(項目93)
前記製剤が、トレハロース、グルタミン酸一ナトリウム(MSG)および組換えヒト血清アルブミン(rHSA)のうちの1つまたは複数を含まない、項目89~92のいずれか一項に記載の方法。
(項目94)
前記製剤が、トレハロース、MSG、またはrHSAを含まない、項目93に記載の方法。
(項目95)
前記Listeria株が、組換えListeria monocytogenes株である、項目89~94のいずれか一項に記載の方法。
(項目96)
前記Listeria株が、組換えListeria monocytogenes株であり、
前記製剤が、約2%~約3% w/v スクロースを含み、
前記製剤が、トレハロース、MSG、またはrHSAを含まない、
項目89~95のいずれか一項に記載の方法。
本明細書において同じ意味で使用される用語「タンパク質」、「ポリペプチド」および「ペプチド」は、コードされたおよびコードされていないアミノ酸、ならびに化学的にまたは生化学的に修飾または誘導体化されたアミノ酸を含む、任意の長さのポリマー形態のアミノ酸を指す。これらの用語は、修飾ペプチド骨格を有するポリペプチドなどの、修飾されたポリマーを含む。
詳細な説明
I.大要
II.細菌またはListeriaの凍結乾燥
A.細菌またはListeriaのプレコンディショニング
B.細菌またはListeria凍結乾燥製剤
C.凍結ステップ
D.一次乾燥ステップ
E.二次乾燥ステップ
F.凍結乾燥された細菌またはListeriaの保管および復元
III.組換え細菌またはListeria株
A.組換え融合ポリペプチドを含む、または組換え融合ポリペプチドをコードする核酸を含む細菌またはListeria株
B.細菌またはListeria株の弱毒化
(1)細菌およびListeria株を弱毒化する方法
(2)弱毒化細菌およびListeria株を相補する方法
IV.組換え融合ポリペプチド
A.抗原ペプチド
(1)リステリオリジンO(LLO)
(2)ActA
C.組換え融合ポリペプチドをコードする免疫療法構築物の生成
V.免疫原性組成物、医薬組成物およびワクチン
VI.治療方法
VII.キット
実施形態の列挙
配列の簡単な説明
代表的な原薬調製および凍結乾燥サイクル
ADXS-HER2およびADXS-HPV(最終液体薬物製品)のための典型的な現在の保管温度は、-80℃であり、このことは、コールドチェーン(cold chain)メンテナンスを妨げ、サプライチェーンの課題を課す。コールドチェーンは、薬物製品有効性を保証し、潜在的な患者リスクを回避するために常に厳密に保たれなくてはならないことから、凍結状態でのListeria monocytogenes最終薬物製品(液体)の保管は不便である。HER2/Neu融合タンパク質により形質転換された弱毒化組換えListeria monocytogenes(Lm)であるADXS-HER2は、HER2発現がんを標的とするように開発されているLm Technology(商標)免疫療法製品候補である。Axalimogene filolisbac(ADXS-HPV)は、HPV関連がんの処置のために開発されたLm Technology(商標)免疫療法候補である。これは、HPV関連腫瘍を標的とする融合タンパク質Lm-LLO-E7を分泌する、生きた弱毒化Listeria monocytogenesに基づく免疫療法である。コールドチェーンは、薬物有効性を保証し、潜在的な患者リスクを回避するために常に保たれなくてはならないことから、凍結液体状態での最終薬物製品の保管は不便である。コールドチェーンを維持しつつ、-20℃での薬物製品の長期保管を支持する凍結乾燥(lyo)サイクルの開発は、有益となるであろう。したがって、薬物製品の長期保管を支持する凍結乾燥サイクルを開発するための試験を行った。
ADXS-HPV液体凍結された製剤のための原薬プロセス概要
2.1.1.WP5-Lyo1
2.1.2.WP7-Lyo2
2.2.残留水分目標
2.2.1.WP5-Lyo3
2.3 安定性における最適残留水分の評価
2.3.1 WP7-Lyo4
2.4.凍結乾燥前のストレス処理の評価
2.4.1.WP7-Lyo5
2.5.凍結乾燥前の温度シフトの評価
2.5.1.WP7-Lyo6
2.6.低下した一次乾燥棚温度および低下した凍結温度の評価
2.6.1.WP7-Lyo7
2.7.保持時間試験
2.7.1.WP7-Lyo8
2.8.増加させた一次乾燥棚温度の評価
2.8.1.WP7-Lyo9
2.9 増加させた一次乾燥温度(-18℃)におけるプラス/マイナス温度シフトの比較
2.9.1.WP7-Lyo10
2.10.-18℃の一次乾燥温度における温度シフトなしの安定性試験、および生物活性決定
2.10.1.WP7-Lyo11
2.11.新鮮vs.異なる解凍による凍結材料の安定性試験
2.11.1.WP7-Lyo12
2.11.2.WP7-Lyo13
2.12.製品の提示
2.12.1.WP7-Lyo14
2.13 バッチ規模
2.15.要約
(実施例3)
Listeria monocytogenesのための凍結乾燥パラメーターの再現およびさらなる最適化
3.1.比較の基盤として以前の凍結乾燥サイクルを再現する
3.2.二次乾燥棚温度の関数として残留水分含量を試験する
3.3.改変された凍結ステップを評価する
3.4.改変された凍結ステップおよび一次乾燥温度を評価する
3.5.解凍手順(37℃解凍)を評価する
3.6.異なる細菌目標濃度を評価する(WP7)
(a)OD10:F1000:規定通りの、届けられたBDSの使用、
(b)OD2:F0200:31.37ml BDS + 118.63ml製剤緩衝液、および
(c)OD0.65:F0065:10.20ml BDS + 139.80ml製剤緩衝液。
ADXSプラットフォーム製造プロセスを使用して、HER2材料を提供した(実施例7を参照)。
パラメーター 細胞ペレット
量 800mL(体積による
OD600(未加工の材料) 10.05
細胞/mL 1.69×1010
生存率 98.45%
凍結乾燥の前、凍結乾燥の後、ならびに1、2および3日間の加速された条件(30℃)で、VCCを解析した。凍結乾燥の後、および3日間の加速された条件で、残留水分を解析した。凍結乾燥の前、凍結乾燥の後、ならびに1、2および3日間の加速された条件(30℃)において、MFIおよびRMMを解析した。
3.7.2Rバイアル提示を評価する(WP8)
3.8 大規模生産(WP7)
(実施例4)
薬物製品の凍結乾燥、および凍結乾燥された薬物製品の長期室温安定性
4.1 ADXS11-001パイロットバッチ
4.1.1 材料と方法
4.3 結論
(実施例5)
原薬を凍結/解凍し、連続的に加工された材料に匹敵する結果を得る能力
5.1 WP7、サイクル3
5.2 材料と方法
5.5 フリーズドライされた製品の光学的評価
5.6 ケーキ重量の決定
5.9 共振式質量測定(アルキメデス)
5.10 カール・フィッシャー滴定
・ A1300(13の目標OD600):1E+10CFU/mL
・ A0085(0.85の目標OD600):1E+09CFU/mL
・ B1300(13の目標OD600):1E+10CFU/mL
・ B0085(0.85の目標OD600):1E+09CFU/mL
APC(Ireland、Dublin)は、各製剤の試料によりフローサイトメトリーを再度行った。VCCおよび%生細胞結果を図62および表27に提示する。
(実施例6)
凍結乾燥前の凍結原薬の解凍における温度および時間の効果
6.1 バルク原薬の凍結解凍(FT)
6.2 DS容器(バッグvs.ボトル)の評価
6.3 DS解凍温度およびDS濃度の評価
(実施例7)
例示的な凍結乾燥条件
7.1 製剤
7.3 凍結乾燥サイクル
7.4 ADXS DSプラットフォームプロセス説明
7.6 原薬プロセスフロー図
7.7 薬物製品プロセスフロー図
Claims (45)
- Listeria株を含む凍結乾燥された組成物を生産する方法であって、
(a)緩衝液とスクロースとを含む製剤中においてListeria株を含む組成物を提供するステップであって、
前記Listeria株が、Listeria monocytogenes株であり、
前記製剤が、1%~5% w/v スクロースを含む、ステップ、
(b)ステップ(a)で提供された組成物を凍結ステップにおいて-32℃~-80℃の間の保持温度で冷却するステップ、
(c)ステップ(b)により生産された組成物を一次乾燥ステップにおいて-10℃~-30℃の間の保持温度で真空に曝露するステップ、および
(d)ステップ(c)により生産された組成物を二次乾燥ステップにおいて-5℃~25℃の間の保持温度で真空に曝露するステップ
を含み、それによって凍結乾燥された組成物を生産し、前記凍結乾燥された組成物中の残留水分が、1%~5%の間である、
方法。 - ステップ(a)の前に、前記Listeria株を0℃~4℃の温度に曝露することにより前記Listeria株においてストレス応答が誘導される、請求項1に記載の方法。
- ステップ(a)の前に、前記Listeria株を0℃~4℃の温度に曝露することにより前記Listeria株においてストレス応答が誘導されない、請求項1に記載の方法。
- ステップ(a)における前記組成物に使用される前記Listeria株が、ステップ(a)の前に解凍される凍結されたListeria株である、請求項1~3のいずれか1項に記載の方法。
- 解凍される前記凍結されたListeria株の濃度が、1ミリリットル当たり1×109~1×1010コロニー形成単位(CFU)の間である、請求項4に記載の方法。
- 前記凍結されたListeria株が、2℃~37℃で解凍される、請求項4または5に記載の方法。
- 前記凍結されたListeria株が、20℃~37℃で解凍される、請求項6に記載の方法。
- 前記凍結されたListeria株が、32℃~37℃で解凍される、請求項7に記載の方法。
- 前記凍結されたListeria株が、37℃で解凍される、請求項8に記載の方法。
- 前記凍結されたListeria株が、8時間以下の間、解凍される、
請求項4~9のいずれか1項に記載の方法。 - 前記凍結されたListeria株が、解凍後24時間以下の間、2℃~8℃で保持される、請求項4~10のいずれか1項に記載の方法。
- ステップ(a)における前記組成物に使用される前記Listeria株が、ステップ(a)の前に新鮮培養される、請求項1~3のいずれか1項に記載の方法。
- 前記緩衝液が、リン酸緩衝液である、請求項1~12のいずれか1項に記載の方法。
- 前記製剤が、2%~3% w/v スクロースを含む、請求項1~13のいずれか1項に記載の方法。
- 前記製剤が、2.5% w/v スクロースを含む、請求項14に記載の方法。
- 前記製剤が、1ミリリットル当たり1×109~1×1010コロニー形成単位(CFU)のListeriaを含む、前記いずれかの請求項1~15のいずれか1項に記載の方法。
- 前記製剤が、トレハロース、グルタミン酸一ナトリウム(MSG)および組換えヒト血清アルブミン(rHSA)のうちの1つまたは複数を含まない、請求項1~16のいずれか1項に記載の方法。
- 前記製剤が、トレハロースも、MSGも、rHSAも含まない、請求項17に記載の方法。
- 前記凍結ステップ(b)における前記保持温度が、-40℃~-50℃の間である、請求項1~18のいずれか1項に記載の方法。
- 前記凍結ステップ(b)における前記保持温度が、-45℃である、請求項19に記載の方法。
- 前記凍結ステップ(b)が、温度を毎分1℃の速度で前記保持温度に低下させることを含む、請求項1~20のいずれか1項に記載の方法。
- 前記凍結ステップ(b)における前記冷却が、2時間~4時間の冷却である、請求項1~21のいずれか1項に記載の方法。
- 前記凍結ステップ(b)における前記冷却が、2時間の冷却である、請求項22に記載の方法。
- 前記一次乾燥ステップ(c)における前記保持温度が、-12℃~-22℃の間である、
請求項1~23のいずれか1項に記載の方法。 - 前記一次乾燥ステップ(c)における前記保持温度が、-17℃~-19℃の間である、請求項24に記載の方法。
- 前記一次乾燥ステップ(c)における前記保持温度が、-18℃である、請求項25に記載の方法。
- 前記一次乾燥ステップ(c)が、温度を毎分1℃の速度で前記保持温度に上昇させることを含む、請求項1~26のいずれか1項に記載の方法。
- 前記一次乾燥ステップ(c)が、25時間~35時間である、請求項1~27のいずれか1項に記載の方法。
- 前記一次乾燥ステップ(c)の終了が、前記組成物が保持温度に達した12~16時間後である、請求項1~28のいずれか1項に記載の方法。
- 前記一次乾燥ステップ(c)が、0.09mbarの真空圧である、請求項1~29のいずれか1項に記載の方法。
- 前記二次乾燥ステップ(d)における前記保持温度が、-5℃~20℃の間である、請求項1~30のいずれか1項に記載の方法。
- 前記二次乾燥ステップ(d)における前記保持温度が、-5℃~5℃の間である、請求項31に記載の方法。
- 前記二次乾燥ステップ(d)における前記保持温度が、0℃である、請求項32に記載の方法。
- 前記二次乾燥ステップ(d)が、温度を毎分0.2℃の速度で前記保持温度に上昇させることを含む、請求項1~33のいずれか1項に記載の方法。
- 前記二次乾燥ステップ(d)が、1時間~10時間である、請求項1~34のいずれか1項に記載の方法。
- 前記二次乾燥ステップ(d)が、前記組成物を2時間~6時間、前記保持温度で保持することを含む、請求項1~35のいずれか1項に記載の方法。
- 前記二次乾燥ステップ(d)が、前記組成物を5時間~6時間、前記保持温度で保持することを含む、請求項1~36のいずれか1項に記載の方法。
- 前記二次乾燥ステップ(d)が、0.09mbarの真空圧である、請求項1~37のいずれか1項に記載の方法。
- 前記凍結乾燥された組成物中の前記残留水分が、2%~4%の間である、請求項1~38のいずれか1項に記載の方法。
- 前記凍結乾燥された組成物中の前記残留水分が、少なくとも2.5%である、請求項39に記載の方法。
- 前記凍結乾燥された組成物中の前記残留水分が、少なくとも3%である、請求項40に記載の方法。
- 前記凍結乾燥された組成物が、
-20℃~4℃の間で12カ月保管された後、少なくとも60%の生存率
を示す、請求項1~41のいずれか1項に記載の方法。 - 前記緩衝液が、リン酸緩衝液であり、
前記製剤が、2%~3% w/v スクロースを含み、
前記製剤が、トレハロースも、MSGも、rHSAも含まず、
前記製剤が、1ミリリットル当たり1×109~1×1010コロニー形成単位(CFU)のListeriaを含み、
前記凍結ステップ(b)における前記保持温度が、-40℃~-50℃の間であり、
前記一次乾燥ステップ(c)における前記保持温度が、-17℃~-19℃の間であり、
前記二次乾燥ステップ(d)における前記保持温度が、-1℃~1℃の間であり、
前記凍結乾燥された組成物中の前記残留水分が、2.5%~4%の間である、
請求項1~42のいずれか1項に記載の方法。 - ステップ(a)における前記組成物に使用される前記Listeria株が、ステップ(a)の前に解凍される凍結されたListeria株であり、
解凍される前記凍結されたListeria株の濃度が、1ミリリットル当たり1×109~1×1010コロニー形成単位(CFU)の間であり、
前記凍結されたListeria株が、37℃で解凍され、
前記凍結されたListeria株が、8時間以下の間、解凍され、
前記凍結されたListeria株が、解凍後24時間以下の間、2℃~8℃で保持される、
請求項43に記載の方法。 - 前記Listeria株が、融合ポリペプチドをコードする第1のオープンリーディングフレームを含む核酸を含む組換えListeria株であり、前記融合ポリペプチドが、疾患関連抗原ペプチドに融合されたPEST含有ペプチドを含み、ここで、
(I)前記組換えListeria株が、prfA中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、D133V PrfA突然変異タンパク質をコードする第2のオープンリーディングフレームを含む、または
(II)前記組換えListeria株が、actA、dalおよびdat中の欠失または不活性化突然変異を含む弱毒化Listeria monocytogenes株であり、前記核酸が、エピソームプラスミドにあり、アラニンラセマーゼ酵素またはD-アミノ酸アミノトランスフェラーゼ酵素をコードする第2のオープンリーディングフレームを含み、前記PEST含有ペプチドが、LLOのN末端断片である、
請求項1~44のいずれか1項に記載の方法。
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Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9012141B2 (en) | 2000-03-27 | 2015-04-21 | Advaxis, Inc. | Compositions and methods comprising KLK3 of FOLH1 antigen |
MA41644A (fr) | 2015-03-03 | 2018-01-09 | Advaxis Inc | Compositions à base de listeria comprenant un système d'expression de minigènes codant pour des peptides, et leurs procédés d'utilisation |
EP3548623A4 (en) | 2016-11-30 | 2020-11-25 | Advaxis, Inc. | IMMUNOGENIC COMPOSITIONS TARGETING RECURRENT CANCER MUTATIONS AND THEIR USE PROCEDURES |
CN111356760A (zh) | 2017-09-19 | 2020-06-30 | 阿德瓦希斯公司 | 细菌或李斯特菌菌株的冻干组合物和方法 |
US11738075B2 (en) * | 2018-03-20 | 2023-08-29 | National Research Council Of Canada | Method for lyophilizing live vaccine strains of Francisella tularensis |
CN110106114A (zh) * | 2019-05-10 | 2019-08-09 | 上海市计量测试技术研究院(中国上海测试中心、华东国家计量测试中心、上海市计量器具强制检定中心) | 一种用于单增李斯特菌标准物质的冻干保护剂及冻干保存方法和应用 |
CN112048545B (zh) * | 2020-09-10 | 2022-11-18 | 上海创宏生物科技有限公司 | 一种冻干保护剂、pcr扩增试剂及其冻干方法和应用 |
US20230407240A1 (en) * | 2020-10-24 | 2023-12-21 | Kula Bio, Inc. | Minimal footprint high density fermentation of plant byproducts |
CN113287601A (zh) * | 2021-05-20 | 2021-08-24 | 江苏康进医疗器材有限公司 | 一种适用于超低温冻存的立体多腔细胞袋 |
WO2024086605A1 (en) * | 2022-10-18 | 2024-04-25 | Takeda Vaccines, Inc. | Dengue vaccine formulation |
US20240148654A1 (en) * | 2022-11-07 | 2024-05-09 | Southwest Research Institute | Lyophilized and stabilized live attenuated formulated vaccine against tularemia |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013177473A (ja) | 2007-05-18 | 2013-09-09 | Medimmune Llc | 凍結乾燥フォームによる生物活性材料の防腐 |
JP2014171423A (ja) | 2013-03-08 | 2014-09-22 | Nissin Foods Holdings Co Ltd | 凍結乾燥菌試料およびその製造方法 |
WO2016105510A2 (en) | 2014-12-26 | 2016-06-30 | Conjugon, Inc. | Methods and compositions for growth, storage, and use of bacterial preparations for wound and surface treatments |
Family Cites Families (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4205132A (en) | 1978-07-17 | 1980-05-27 | Microlife Technics, Inc. | Lyophilization of bacteria |
US4751180A (en) | 1985-03-28 | 1988-06-14 | Chiron Corporation | Expression using fused genes providing for protein product |
US4935233A (en) | 1985-12-02 | 1990-06-19 | G. D. Searle And Company | Covalently linked polypeptide cell modulators |
US5830702A (en) | 1990-10-31 | 1998-11-03 | The Trustees Of The University Of Pennsylvania | Live, recombinant listeria monocytogenes and production of cytotoxic T-cell response |
US8114414B2 (en) | 1994-11-08 | 2012-02-14 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treatment of cervical cancer |
US8956621B2 (en) | 1994-11-08 | 2015-02-17 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treatment of cervical dysplasia |
US20070264279A1 (en) | 1994-11-08 | 2007-11-15 | Claudia Gravekamp | Compositions and methods comprising a MAGE-b antigen |
US7662396B2 (en) | 2001-03-26 | 2010-02-16 | The Trustees Of The University Of Pennsylvania | Compositions and methods for enhancing the immunogenicity of antigens |
US7794729B2 (en) | 1994-11-08 | 2010-09-14 | The Trustees Of The University Of Pennsylvania | Methods and compositions for immunotherapy of cancer |
US8791237B2 (en) | 1994-11-08 | 2014-07-29 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treatment of non-hodgkins lymphoma |
US6051237A (en) | 1994-11-08 | 2000-04-18 | The Trustees Of The University Of Pennsylvania | Specific immunotherapy of cancer using a live recombinant bacterial vaccine vector |
US7820180B2 (en) | 2004-09-24 | 2010-10-26 | The Trustees Of The University Of Pennsylvania | Listeria-based and LLO-based vaccines |
WO1998012332A1 (en) | 1996-09-17 | 1998-03-26 | Chiron Corporation | Compositions and methods for treating intracellular diseases |
US6099848A (en) | 1997-11-18 | 2000-08-08 | The Trustees Of The University Of Pennsylvania | Immunogenic compositions comprising DAL/DAT double-mutant, auxotrophic, attenuated strains of Listeria and their methods of use |
GB9726555D0 (en) | 1997-12-16 | 1998-02-11 | Smithkline Beecham Plc | Vaccine |
DE60021760T2 (de) | 1999-12-09 | 2006-06-08 | Chiron Corp., Emeryville | Verfahren zur verabreichung von wirkstoffen in das zentrale nervensystem oder lymphsystem |
US9012141B2 (en) | 2000-03-27 | 2015-04-21 | Advaxis, Inc. | Compositions and methods comprising KLK3 of FOLH1 antigen |
EP1303299B1 (en) | 2000-03-29 | 2010-07-28 | The Trustees of The University of Pennsylvania | Use of prokaryotic pest-like peptides for enhancing immunogenicity of antigens |
US6855320B2 (en) | 2000-03-29 | 2005-02-15 | The Trustees Of The University Of Pennsylvania | Fusion of non-hemolytic, truncated form of listeriolysin O to antigens to enhance immunogenicity |
US7700344B2 (en) | 2001-03-26 | 2010-04-20 | The Trustees Of The University Of Pennsylvania | Compositions and methods for enhancing the immunogenicity of antigens |
US8771702B2 (en) | 2001-03-26 | 2014-07-08 | The Trustees Of The University Of Pennsylvania | Non-hemolytic LLO fusion proteins and methods of utilizing same |
CA2486980A1 (en) | 2002-05-29 | 2003-12-11 | The Regents Of The University Of California | Attenuated listeria spp. and methods for using the same |
AU2004204751A1 (en) | 2003-01-09 | 2004-07-29 | The Trustees Of The University Of Pennsylvania | Compositions, methods and kits for enhancing the immunogenicity of a bacterial vaccine vector |
JP4545151B2 (ja) | 2003-02-06 | 2010-09-15 | シーラス コーポレイション | 非食細胞中への侵入について減弱化されているリステリア、そのリステリアを含むワクチン、およびそれらの使用法 |
CA2577306A1 (en) | 2004-08-13 | 2006-02-16 | The Trustees Of The University Of Pennsylvania | Methods for constructing antibiotic resistance free vaccines |
US7858097B2 (en) | 2004-08-13 | 2010-12-28 | The Trustees Of The University Of Pennsylvania | Antibiotic resistance free Listeria strains and methods for constructing and using same |
US7855064B2 (en) | 2004-08-13 | 2010-12-21 | The Trustees Of The University Of Pennsylvania | Antibiotic resistance free vaccines and methods for constructing and using same |
US20060121053A1 (en) * | 2004-10-18 | 2006-06-08 | Pamela Sweeney | High cell density process for growth of Listeria |
WO2007061848A2 (en) * | 2005-11-17 | 2007-05-31 | The Trustees Of The University Of Pennsylvania | Methods for producing, growing, and preserving listeria vaccine vectors |
US7935804B2 (en) | 2006-03-01 | 2011-05-03 | Aduro Biotech | Engineered Listeria and methods of use thereof |
US7665238B2 (en) | 2006-04-03 | 2010-02-23 | S.C. Johnson & Son, Inc. | Air freshener with holder |
AU2007266675B2 (en) * | 2006-05-28 | 2012-09-06 | Cipla-Medpro (Pty) Ltd | Probiotic strain and antimicrobial peptide derived therefrom |
EP2061800B1 (en) | 2006-08-15 | 2015-07-29 | The Trustees of the University of Pennsylvania | Compositions comprising hmw-maa and fragments thereof, and methods of use thereof |
US8268326B2 (en) | 2006-08-15 | 2012-09-18 | The Trustees Of The University Of Pennsylvania | Compositions comprising HMW-MAA and fragments thereof, and methods of use thereof |
WO2008130551A2 (en) | 2007-04-16 | 2008-10-30 | The Trustees Of The University Of Pennsylvania | Antibiotic resistance free listeria strains and methods for constructing and using same |
US20140234370A1 (en) | 2009-11-11 | 2014-08-21 | Advaxis, Inc. | Compositions and methods for prevention of escape mutation in the treatment of her2/neu over-expressing tumors |
US9017660B2 (en) | 2009-11-11 | 2015-04-28 | Advaxis, Inc. | Compositions and methods for prevention of escape mutation in the treatment of Her2/neu over-expressing tumors |
US20120135033A1 (en) | 2008-05-19 | 2012-05-31 | Anu Wallecha | Multiple delivery system for heterologous antigens |
US9650639B2 (en) | 2008-05-19 | 2017-05-16 | Advaxis, Inc. | Dual delivery system for heterologous antigens |
EP2288379A4 (en) | 2008-05-19 | 2012-08-08 | Advaxis | DOUBLE RELEASE SYSTEM FOR HETEROLOGIST ANTIGENE |
US20150366955A9 (en) | 2009-11-11 | 2015-12-24 | Advaxis, Inc. | Compositions and methods for prevention of escape mutation in the treatment of her2/neu over-expressing tumors |
US8795686B2 (en) * | 2008-11-07 | 2014-08-05 | Serum Institute Of India | Stable, dried rotavirus vaccine, compositions and process for preparation thereof |
ES2637068T3 (es) | 2009-03-04 | 2017-10-10 | The Trustees Of The University Of Pennsylvania | Composiciones que comprenden factores angiogénicos y métodos de uso de las mismas |
EP2498808A4 (en) | 2009-11-11 | 2014-01-08 | Advaxis | COMPOSITIONS AND METHOD FOR PREVENTING FLUID MUTATIONS IN THE TREATMENT OF TUMORS WITH HER2 / NEW OVEREXPRESSION |
US10016617B2 (en) | 2009-11-11 | 2018-07-10 | The Trustees Of The University Of Pennsylvania | Combination immuno therapy and radiotherapy for the treatment of Her-2-positive cancers |
US20110223187A1 (en) | 2010-02-15 | 2011-09-15 | Vafa Shahabi | Live listeria-based vaccines for central nervous system therapy |
US20110305724A1 (en) | 2010-04-19 | 2011-12-15 | Yvonne Paterson | Immunotherapeutic, anti-tumorigenic compositions and methods of use thereof |
WO2012138377A2 (en) | 2010-10-01 | 2012-10-11 | Trustees Of The University Of Pennsylvania | The use of listeria vaccine vectors to reverse vaccine unresponsiveness in parasitically infected individuals |
CN103687611A (zh) * | 2011-03-11 | 2014-03-26 | 阿德瓦希斯公司 | 基于李斯特菌属的佐剂 |
KR20140134695A (ko) | 2012-03-12 | 2014-11-24 | 어드박시스, 인크. | 리스테리아 백신 치료 후 억제 세포 기능 저해 |
SI2800811T1 (sl) | 2012-05-25 | 2017-10-30 | The Regents Of The University Of California | Postopki in sestavki za RNA usmerjeno modifikacijo tarčne DNA in za RNA usmerjeno modulacijo prepisovanja |
US10093894B2 (en) | 2012-08-20 | 2018-10-09 | Chr. Hansen A/S | Method for optimizing a process for freeze drying a bacteria-containing concentrate |
WO2014106123A1 (en) | 2012-12-27 | 2014-07-03 | Aduro Biotech, Inc. | Signal peptide fusion partners facilitating listerial expression of antigenic sequences and methods of preparation and use thereof |
MX2015008944A (es) | 2013-01-15 | 2016-06-21 | Teva Pharma | Proceso de liofilizacion. |
BR112016019057A2 (pt) | 2014-02-18 | 2017-10-10 | Advaxis Inc | método de induzir uma resposta imune contra uma doença em um indivíduo |
MX2016011114A (es) | 2014-02-25 | 2017-02-20 | Advaxis Inc | Composiciones y metodos para el tratamiento de tumores que sobreexpresan her2/neu. |
SG11201607213QA (en) | 2014-03-05 | 2016-09-29 | Advaxis Inc | Methods and compositions for increasing a t-effector cell to regulatory t cell ratio |
KR102491332B1 (ko) | 2014-04-24 | 2023-01-27 | 어드박시스, 인크. | 재조합 리스테리아 백신 균주 및 그 생산 방법 |
MA39942A (fr) | 2014-05-02 | 2017-03-08 | Univ Pennsylvania | Immunothérapie et radiothérapie combinées pour le traitement de cancers positifs à her-2 |
WO2016011362A1 (en) | 2014-07-18 | 2016-01-21 | Advaxis, Inc. | Listeria-based immunogenic compositions for eliciting anti-tumor responses |
AU2015289533B2 (en) | 2014-07-18 | 2021-04-01 | Advaxis, Inc. | Combination of a PD-1 antagonist and a Listeria-based vaccine for treating prostate cancer |
WO2016011320A1 (en) | 2014-07-18 | 2016-01-21 | Advaxis, Inc. | Bivalent listeria-based delivery system of heterologous antigens |
AU2015289529A1 (en) | 2014-07-18 | 2017-02-09 | Advaxis, Inc. | Recombinant listeria strain expressing heterologous antigen fusion proteins and methods of use thereof |
US10010593B2 (en) | 2014-10-14 | 2018-07-03 | The Trustees Of The University Of Pennsylvania | Recombinant Listeria vaccine strains and methods of using the same in cancer immunotherapy |
MA41217A (fr) | 2014-12-19 | 2017-10-24 | Advaxis Inc | Polythérapies ayant des souches de listeria recombinées |
US20160220652A1 (en) | 2015-02-03 | 2016-08-04 | Advaxis, Inc. | Methods of using recombinant listeria vaccine strains in disease immunotherapy |
WO2016126876A2 (en) | 2015-02-03 | 2016-08-11 | Advaxis, Inc. | Listeria-based adjuvants |
WO2016126878A2 (en) | 2015-02-03 | 2016-08-11 | The Trustees Of The University Of Pennsylvania | Listeria-based immunomodulation |
MA41644A (fr) | 2015-03-03 | 2018-01-09 | Advaxis Inc | Compositions à base de listeria comprenant un système d'expression de minigènes codant pour des peptides, et leurs procédés d'utilisation |
WO2016154412A2 (en) | 2015-03-26 | 2016-09-29 | The Trustees Of The University Of Pennsylvania | Combination of a pd-1 antagonist and a listeria based vaccine for treating pancreatic cancer |
WO2016183361A1 (en) | 2015-05-13 | 2016-11-17 | Advaxis, Inc. | Immunogenic listeria-based compositions comprising truncated acta-antigen fusions and methods of use thereof |
EP3302574A4 (en) | 2015-05-26 | 2018-10-17 | Advaxis, Inc. | Personalized delivery vector-based immunotherapy and uses thereof |
AU2016281958A1 (en) | 2015-06-24 | 2018-02-15 | Advaxis, Inc. | Manufacturing device and process for personalized delivery vector-based immunotherapy |
CA2998857A1 (en) * | 2015-09-15 | 2017-03-23 | Anu Wallecha | Manufacturing method of an immunotherapeutic formulation comprising a recombinant listeria strain |
WO2017048850A1 (en) | 2015-09-15 | 2017-03-23 | Advaxis, Inc. | Listeria-based immunogenic compositions and methods of use thereof in cancer prevention and treatment |
MA42845A (fr) | 2015-09-17 | 2018-07-25 | Advaxis Inc | Souches vaccinales de listeria de recombinaison et méthodes d'utilisation desdites souches dans l'immunothérapie anticancéreuse |
US20180280487A1 (en) | 2015-10-14 | 2018-10-04 | Advaxis, Inc. | Recombinant listeria vaccine strains and methods of using the same in cancer immunotherapy |
WO2017085691A1 (en) | 2015-11-20 | 2017-05-26 | Advaxis, Inc. | Manufacturing device and method of an immunotherapeutic formulation comprising a recombinant listeria strain |
MA44087A (fr) | 2015-12-16 | 2018-10-24 | Advaxis Inc | Immunothérapie basée sur la listéria et ses méthodes d'utilisation |
AU2017211387A1 (en) | 2016-01-27 | 2018-08-16 | Advaxis, Inc. | Personalized delivery vector-based immunotherapy and uses thereof |
CA3029235A1 (en) | 2016-07-05 | 2018-01-11 | Advaxis, Inc. | Listeria-based immunogenic compositions comprising wilms tumor protein antigens and methods of use thereof |
US20200061167A1 (en) | 2016-11-07 | 2020-02-27 | Advaxis, Inc. | Combination of listeria-based vaccine with anti-ctla-4 or anti-cd137 antibodies |
WO2018102585A1 (en) | 2016-11-30 | 2018-06-07 | Advaxis, Inc. | Personalized immunotherapy in combination with immunotherapy targeting recurrent cancer mutations |
EP3548623A4 (en) | 2016-11-30 | 2020-11-25 | Advaxis, Inc. | IMMUNOGENIC COMPOSITIONS TARGETING RECURRENT CANCER MUTATIONS AND THEIR USE PROCEDURES |
TW201833323A (zh) | 2017-01-05 | 2018-09-16 | 美商艾法西斯公司 | 重組李斯特菌屬疫苗菌株及在癌症免疫治療中使用該菌株之方法 |
WO2019006401A2 (en) | 2017-06-30 | 2019-01-03 | Advaxis, Inc. | LISTERIA-BASED IMMUNOGENIC COMPOSITIONS COMPRISING HETERICCLIENT WILMS TUMOR PROTEIN ANTIGENS AND METHODS OF USE THEREOF |
CN111356760A (zh) | 2017-09-19 | 2020-06-30 | 阿德瓦希斯公司 | 细菌或李斯特菌菌株的冻干组合物和方法 |
WO2019094607A2 (en) | 2017-11-08 | 2019-05-16 | Advaxis, Inc. | Immunogenic heteroclitic peptides from cancer-associated proteins and methods of use thereof |
WO2019157098A1 (en) | 2018-02-06 | 2019-08-15 | Advaxis, Inc. | Compositions comprising a recombinant listeria strain and an anti-ccr8 antibody and methods of use |
AU2019231783B2 (en) | 2018-03-09 | 2023-11-16 | Advaxis, Inc. | Compositions and methods for evaluating attenuation and infectivity of Listeria strains |
US20210239681A1 (en) | 2018-04-27 | 2021-08-05 | Advaxis, Inc. | Compositions and methods for evaluating potency of listeria-based immunotherapeutics |
-
2018
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- 2023-05-18 JP JP2023082143A patent/JP2023096115A/ja active Pending
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013177473A (ja) | 2007-05-18 | 2013-09-09 | Medimmune Llc | 凍結乾燥フォームによる生物活性材料の防腐 |
JP2014171423A (ja) | 2013-03-08 | 2014-09-22 | Nissin Foods Holdings Co Ltd | 凍結乾燥菌試料およびその製造方法 |
WO2016105510A2 (en) | 2014-12-26 | 2016-06-30 | Conjugon, Inc. | Methods and compositions for growth, storage, and use of bacterial preparations for wound and surface treatments |
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KR20200044982A (ko) | 2020-04-29 |
EP3684912A1 (en) | 2020-07-29 |
CN111356760A (zh) | 2020-06-30 |
US20220062181A1 (en) | 2022-03-03 |
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AU2018336988B2 (en) | 2023-06-22 |
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US11179339B2 (en) | 2021-11-23 |
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