JP7491843B2 - グループbアデノウイルス含有製剤 - Google Patents
グループbアデノウイルス含有製剤 Download PDFInfo
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- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000000316 virotherapy Methods 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
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- A61K35/761—Adenovirus
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- A61K9/08—Solutions
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
1.グループBアデノウイルスに適した液体製剤であって、
a)複製可能グループBアデノウイルスなどのグループBアデノウイルスと、
b)15~25%v/vのグリセロール、(例えば、17~20%v/v)、例えば、16、17、18、19、20、21%v/vのグリセロールと、
c)0.1~1.6%v/vのエタノール、例えば、1%v/vのエタノールまたは1.4%もしくは1.5%v/vのエタノールなどの0.1~1.5%v/vのエタノールと、
d)緩衝液と、を含み、
製剤のpHが、8.0~9.6の範囲内にあり、例えば、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4または9.5、例えば、8.5~9.5、特に、8.5~9.0、より具体的には、pH8.5、8.6、8.7、8.8または8.9である、製剤。
a)15~20%v/vのグリセロールと、
b)1~1.5%v/vのエタノールと、
c)0.2~0.3mMのメチオニンと、
d)10~20mMのアルギニンと、
e)メグルミンなどの緩衝液と、
f)任意に、0.1~0.2%v/vのポリソルベート80と、を含み、
製剤のpHが、8.0~9.5の範囲内にあり、例えば、pH8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9または9.0などの8.0~9.0、特に8.0のpHである、項1~15のいずれか1つに記載の製剤。
a)20%v/vのグリセロールと、
b)1.4~1.5%v/vのエタノールと、
c)0.25mMのメチオニンと、
d)15mMのアルギニンと、
e)メグルミンなどの緩衝液と、を含み、
製剤のpHが、8.0~9.5の範囲内にあり、例えば、pH8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9または9.0などの8.0~9.0、特に8.0のpHである、項26に記載の製剤。
a)20%v/vのグリセロールと、
b)1%v/vのエタノールと、
c)0.115%v/vのポリソルベート80と、
d)0.15mMのメチオニンと、
e)10mMのアルギニンと、
f)メグルミンなどの緩衝液と、を含み、
製剤のpHが、8.0~9.5の範囲内にあり、例えば、pH8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9または9.0などの8.5~9.5、特に9.0のpHである、項1~15のいずれか1つに記載の製剤。
5’ITR-B1-BA-B2-BX-BB-BY-B3-3’ITR
式中、
B1が結合であるか、またはE1A、E1BもしくはE1A-E1Bを含み、
BAが、-E2B-L1-L2-L3-E2A-L4を含み、
B2が結合であるか、またはE3を含み、
BXが結合、または制限部位、1つ以上の導入遺伝子、もしくはその両方を含むDNA配列であり、
BBがL5を含み、
BYが結合、または制限部位、1つ以上の導入遺伝子、もしくはその両方を含むDNA配列であり、
B3が結合であるか、またはE4を含み、
BXまたはBYの少なくとも一方が結合ではない、項1~28のいずれか1つに記載の製剤。
a)スプライスアクセプター配列(例えば、短いスプライスアクセプター配列CAGG、配列番号1または配列番号2)と、
b)内部リボソーム進入配列または高い自己切断効率の2Aペプチドと、
c)コザック配列と、
d)それらの組み合わせと、から選択される調節エレメントをさらに含む、項29~34のいずれか1つに記載の製剤。
一実施形態では、BXは、制限部位、例えば、1または2などの1、2、3または4つの制限部位を含む。一実施形態では、BXは、少なくとも1つの導入遺伝子、例えば、1または2つの導入遺伝子を含む。一実施形態では、BXは少なくとも1つの導入遺伝子、例えば、1または2つの導入遺伝子、および1つ以上の制限部位、例えば2または3つの制限部位を含み、特に、遺伝子、または遺伝子を含むDNA配列がゲノムから特異的に切除および/または置換されることを可能にするように、制限部位が、それ/それらを挟む。あるいは、制限部位が各遺伝子を挟んでもよく、例えば2つの導入遺伝子がある場合、遺伝子が選択的に切除および/または置換されることを確実にするために3つの異なる制限部位が必要とされる。一実施形態では、1つ以上の、例えば全ての導入遺伝子が導入遺伝子カセットの形態である。
現在開示されている製剤は、生理的pHを超えるアルカリ性pHを有する。特定のpHへの所与の溶液の緩衝は、例えば、トリス、リジン、強酸(例えば、HCl)または弱酸(例えば、酢酸またはマレイン酸)、強塩基(例えば、NaOH)または弱塩基(例えば、アンモニア)を含む酸/塩基系を含む、当該技術分野で既知の日常的な技術を使用して行うことができる。
本開示による製剤の患者レシピエントは、ヒトまたは家畜などの動物であってもよい。一実施形態では、患者は成人などのヒトである。
本開示の製剤は、さらなる癌療法、例えば、化学療法と組み合わせて使用されてもよい。
配列番号1:スプライスアクセプター(SA)。配列番号2:分岐スプライスアクセプター(BSA)。配列番号3:内部リボソーム侵入配列(IRES)。配列番号4:ポリアデニル化配列。
配列番号:5 EnAdゲノムのbp28166-28366に対応するBX DNA配列。配列番号6:EnAdゲノムのbp29345-29379に対応し、これを含むBY DNA配列。配列番号7:リーダー配列。配列番号8:リーダー配列。配列番号9:P2Aペプチド。配列番号10:F2Aペプチド。配列番号11:E2A ペプチド。配列番号12:2Aペプチド。配列番号13:EnAdゲノム。配列番号14:NG-73ウイルスゲノム配列。配列番号15:NG-74ウイルスのゲノム配列。配列番号16:NG-76ウイルスゲノム配列。配列番号17:NG-77ウイルスゲノム配列。配列番号18:NG-78ウイルスゲノム配列。
配列番号19:NG-92ウイルスゲノム配列。配列番号20:NG-95ウイルスゲノム配列。配列番号21:NG-96ウイルスのゲノム配列。配列番号22:NG-97ウイルスゲノム配列。配列番号23:NG-134ウイルスゲノム配列。配列番号24:NG-135ウイルスゲノム配列。配列番号25:領域BYに挿入されたサイトカインTNFaをコードする導入遺伝子カセットからなるNG-139ウイルスゲノム配列。配列番号26:領域BYに挿入された抗VEGF全長抗体をコードする導入遺伝子カセットからなるウイルスゲノム配列。導入遺伝子カセットには、SSA、5´リーダーを有するab重鎖配列、SSA、およびab軽鎖配列が含まれる。配列番号27:領域BYに挿入された抗VEGF全長抗体をコードする導入遺伝子カセットからなるウイルスゲノム配列。配列番号28:BY領域に挿入された抗VEGF全長抗体をコードする導入遺伝子カセットからなるNG-165ウイルスゲノム配列。配列番号29:BY領域に挿入された、C末端His6タグを有する抗VEGFScFvをコードする導入遺伝子カセットからなるNG-167ウイルスゲノム配列。配列番号:30:領域BYに挿入された抗PD-L1全長抗体をコードする導入遺伝子カセットからなるNG-177ウイルスゲノム配列。配列番号31:BXおよびBY領域に挿入された固有の制限部位を有するEnAdゲノムからなるNG-185ウイルスゲノム配列。配列番号32:領域BYに挿入された抗PD-L1全長抗体をコードする導入遺伝子カセットからなるNG-190ウイルスゲノム配列。配列番号33:領域BYに挿入された腫瘍関連抗原NY-ESO-1をコードする導入遺伝子カセットからなるNG-217ウイルスゲノム配列。配列番号34:領域BYに挿入された腫瘍関連抗原NY-ESO-1をコードする導入遺伝子カセットからなるNG-220ウイルスゲノム配列。配列番号35:領域BYに挿入された、C末端His6タグを有する抗PD-L1ScFvをコードする導入遺伝子カセットを持つEnAdゲノムからなるNG-221ウイルスゲノム配列。配列番号36:領域BYに挿入された抗CTLA-4全長抗体をコードする導入遺伝子カセットからなるNG-242ウイルスゲノム配列。配列番号37:領域BXに挿入された抗VEGFScFvをコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-257ウイルスゲノム配列。配列番号38:領域BYに挿入された抗VEGF全長抗体をコードする導入遺伝子カセットからなるNG258ウイルスゲノム配列。配列番号39:領域BYに挿入された抗VEGFScFvおよび抗PD-L1ScFvをコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-272ウイルスゲノム配列。配列番号40:領域BYに挿入されたヨウ化ナトリウム共輸送体(NIS)をコードする導入遺伝子カセットからなるNG-280ウイルスゲノム配列。配列番号41:領域BXに挿入された抗VEGFScFvをコードする導入遺伝子カセットおよび領域BYに挿入された抗PD-L1ScFvをコードする第2の導入遺伝子カセットを有するEnAdゲノムを含むNG-281ウイルスゲノム配列。配列番号42:領域BYに挿入されたTリンパ球活性化抗原CD80をコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-330ウイルスゲノム配列。導入遺伝子カセットには、5´SSA、ヒトCD80cDNA配列、および3´ポリ(A)配列が含まれる。配列番号43:領域BYに挿入されたIFNαおよびCD80をコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-343ウイルスゲノム配列。導入遺伝子カセットには、5´SSA、IFNαcDNA配列、P2Aペプチド、CD80cDNA配列、および3´ポリ(A)配列が含まれる。配列番号44:NG-641ゲノム。配列番号45:領域BYに挿入されたFlt3リガンド、MIP1αおよびIFNαをコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-345ウイルスゲノム配列。導入遺伝子カセットには、5´SSA、Flt3リガンドcDNA配列、P2Aペプチド配列、MIP1αcDNA配列、T2Aペプチド配列、IFNαcDNA配列、および3´ポリ(A)配列が含まれる。配列番号46:領域BYに挿入されたFlt3リガンド、MIP1αおよびCD80をコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-346ウイルスゲノム配列。導入遺伝子カセットには、5´SSA、Flt3リガンドcDNA配列、P2Aペプチド配列、MIP1αcDNA配列、T2Aペプチド配列、CD80cDNA配列、3´ポリ(A)配列が含まれる。配列番号47:領域BYに挿入されたIFNα、MIP1αおよびCD80をコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-347ウイルスゲノム配列。導入遺伝子カセットには、5´SSA、IFNαcDNA配列、P2Aペプチド配列、MIP1αcDNA配列、T2Aペプチド配列、CD80cDNA配列、および3´ポリ(A)配列が含まれる。配列番号48:領域BYに挿入された膜アンカー型の単鎖Fv抗ヒトCD3eキメラ形態をコードする導入遺伝子カセットとTリンパ球活性化抗原CD80を有するEnAdゲノムを含むNG-348ウイルスゲノム配列。導入遺伝子カセットには、5´SSA、膜アンカー型抗CD3εcDNA配列、P2Aペプチド、ヒトCD80cDNA配列および3´ポリ(A)配列を含まれる。配列番号49:領域BYに挿入された、C端末V5タグを有する単鎖Fv抗ヒトCD3eの膜アンカー型キメラ形態をコードする導入遺伝子カセットとTリンパ球活性化抗原CD80を有するEnAdゲノムを含むNG-348Aウイルスゲノム配列。導入遺伝子カセットには、5´SSA、膜アンカー型抗CD3εcDNA配列、V5タグ、P2Aペプチド、ヒトCD80cDNA配列および3´ポリ(A)配列が含まれる。配列番号50:NG-350Aゲノム配列、配列番号51:領域BYに挿入された単鎖Fv抗ヒトCD3eの膜アンカー型キメラ形態をコードする導入遺伝子カセットを有するEnAdゲノムを含むNG-420ウイルスゲノム配列。導入遺伝子カセットには、5´SSA、膜アンカー型抗CD3εcDNA配列および3´ポリ(A)配列が含まれる。配列番号52:領域BYに挿入された単鎖Fv抗ヒトCD3eの膜アンカー型キメラ形態をコードする導入遺伝子カセットとC端末V5タグを有するEnAdゲノムを含むNG-420Aウイルスゲノム配列。導入遺伝子カセットには、5´SSA、膜アンカー型抗CD3εcDNA配列、V5タグ配列および3´ポリ(A)配列が含まれる。配列番号53:NG-601(EnAd-CMV-EpCANBiTE)。配列番号54:NG-602(EnAd-SA-EpCANBiTE)。配列番号55:NG-605(EnAd-CMV-FAPBiTE)。配列番号56:NG-606(EnAd-SA-FAPBiTE)。配列番号57:NG-611ゲノム。配列番号58:NG-612ゲノム。配列番号59:NG-613ゲノム。配列番号60:NG-614ゲノム。配列番号61:NG-615ゲノム。配列番号62:NG-616ゲノム。配列番号63:NG-617ゲノム。配列番号64:NG-618ゲノム。配列番号65:NG-640ゲノム。
グループBアデノウイルス製剤の安定性に対するpHの影響を決定する実験を行った。異なる緩衝液、すなわち、炭酸塩/重炭酸塩、ジエタノールアミン、Gly-NaCl、HEPE、メグルミン、ホウ酸ナトリウムおよびTris緩衝液を試験した。各緩衝液を、異なるpH値の範囲、すなわち、8.0、8.5、9.0、9.5、10.0で製造した。各緩衝液には、グリセロール、エタノール、アルギニン、メチオニンおよびポリソルベートも含まれていた。EnAdを各緩衝液に懸濁し、製剤を4℃で保存した。各製剤から試料を定期的に採取し、各製剤中のアデノウイルスの安定性を、HPLCを使用して試料中のウイルスDNAの濃度を測定することにより測定した。DNAの濃度が低いほど、ウイルス分解のレベルが高く、したがって、安定性が低いことを強く示していた。
一連の実験を行って、グリセロールが製剤に含まれた場合のグループBアデノウイルス製剤の安定性への影響を判定した。3つの濃度、すなわち、9%、14%、20%で決定的スクリーニング計画(Definitive Screening Design(DSD))を使用して組み合わせて、グリセロールをスクリーニングした。結果を、SAS JMP統計ソフトウェアを使用して分析した。DSDデータに基づいて、モデルを作成した。各製剤は10mMのHEPESも含んでいた。アデノウイルスを各製剤に懸濁し、製剤を4℃で17週間の期間保存した。製剤の安定性を、HPLCを使用して、試料のウイルスDNA濃度を測定することにより、0週目、7週目、17週目に評価した。
エタノール/アルギニン/メチオニン/ポリソルベートが製剤から除かれている場合のグループBアデノウイルス製剤の安定性への影響を判定するために、一連の実験を行った。異なる範囲の緩衝液、すなわち、HEPES5mM、メグルミン10mM、TRIS10mMおよびGly-NaCl10mMを試験した。いずれかのエタノール、アルギニン、メチオニンまたはポリソルベートを含む製剤はなかった。グループBアデノウイルスを各製剤に懸濁し、製剤を4℃で9ヶ月間保存した。製剤の安定性および効力は、それぞれHPLCおよびMTS(細胞を溶解するアデノウイルスの能力を評価する細胞生存率アッセイ)により、3ヶ月間隔、すなわち、0ヶ月、3ヶ月、6ヶ月、9ヶ月でそれぞれ評価された。
実施例3の結果に続いて、4℃での長期間(24ヶ月間)保存中のグループBアデノウイルス製剤の安定性に対するエタノール、アルギニンおよびメチオニンの各々の相対的影響を判定する試みにおいて、さらなる実験を行った。
この実施例では、4℃での長期間(20ヶ月間)保存中のアデノウイルス製剤の安定性に関するポリソルベートの重要性を評価する実験の結果について説明する。
この実施例では、25℃での短期間(11週間)保存中にグループBアデノウイルス製剤中で使用した場合の異なる緩衝液の安定性を比較する実験の結果について説明している。
安定性を示す方法のより幅広いパネルを用いて、加速条件でのスクリーニング方法を使用して特定された条件が4℃の長期間保存に変換されることを確認する実験を行った。一連の異なる緩衝液、すなわち、pH8.0のメグルミン、pH8.5のメグルミン、pH9.0のメグルミン、pH8.5のTRIS、およびGly-NaClをすべて10mMで試験した。製剤のすべてが、20%のグリセロール、1.4%のエタノール、15mMのアルギニン、0.25mMのメチオニンを含んでいた。グループBアデノウイルス製剤は、4℃および-80℃の両方で12ヶ月の期間保存された。4°Cで保存された製剤の安定性および効力は、AEX-HPLC(ウイルス濃度)、MTS(アデノウイルスが細胞を溶解する能力を評価する細胞生存率アッセイ)、および感染力アッセイ(細胞に感染し、かつ複製を開始するアデノウイルスの能力を評価する)によって評価された。12ヶ月後、-80℃および4℃で保存された試料は、同じ方法を使用して一緒に分析された。
Claims (12)
- グループBアデノウイルスに適した液体製剤であって、
a)複製可能なグループBアデノウイルスなどのグループBアデノウイルスと、
b)15~25%v/vのグリセロール、例えば、16、17、18、19、20、21%v/vのグリセロールと、
c)0.1~1.5%v/vのエタノール、例えば、1%v/vのエタノールなどの0.2~1%v/vのエタノールと、
d)0.01~0.3mMのメチオニン、例えば、0.25mMのメチオニンと、
e)緩衝液と、
を含み、
前記製剤のpHが、8.0~9.6の範囲内にあり、例えば、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4または9.5であり、
前記製剤が糖を含まない、製剤。 - 前記製剤が静脈内投与用である、請求項1に記載の製剤。
- 前記製剤がゆっくりとした注射による投与用である、請求項2に記載の製剤。
- 前記製剤が注入による投与用である、請求項2に記載の製剤。
- 界面活性剤、例えば、非イオン性界面活性剤をさらに含む、請求項1~4のいずれか一項に記載の製剤。
- ポリソルベート、例えば、0.05~0.15%のポリソルベート20、40、60、または80などのポリソルベート20、40、60、または80をさらに含む、請求項5に記載の製剤。
- 前記製剤が、ポリソルベート80、例えば、0.115%のポリソルベート80などの0.05~0.15%のポリソルベート80を含む、請求項6に記載の製剤。
- アルギニン、例えば、15mMのアルギニンなどの5~20mMのアルギニンをさらに含む、請求項1~7のいずれか一項に記載の製剤。
- 前記緩衝液が、メグルミン、グリシン(Gly-NaClなど)、TRISおよびそれらの2つ以上の組み合わせから選択される、請求項1~8のいずれか一項に記載の製剤。
- 前記製剤がメグルミン緩衝液を含む、請求項9に記載の製剤。
- 前記製剤がHEPES緩衝液を含まない、請求項1~10のいずれか一項に記載の製剤。
- 前記製剤が、
a)15~20%v/vのグリセロールと、
b)1~1.5%v/vのエタノールと、
c)0.1~0.2%v/vのポリソルベート80と、
d)0.2~0.3mMのメチオニンと、
e)10~20mMのアルギニンと、
f)メグルミンなどの緩衝液と、を含み、
前記製剤のpHが、pH8などの8.0~9.6の範囲内のpHである、請求項1~11のいずれか一項に記載の製剤。
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CA3088350A1 (en) | 2019-08-08 |
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GB201801614D0 (en) | 2018-03-14 |
PH12020551057A1 (en) | 2021-08-23 |
BR112020014248A2 (pt) | 2020-12-15 |
MX2020007495A (es) | 2020-11-12 |
JP2021512054A (ja) | 2021-05-13 |
ZA202003615B (en) | 2021-09-29 |
US11998580B2 (en) | 2024-06-04 |
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