JP5749930B2 - ペプチド含有動物細胞培養用培地 - Google Patents
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- JP5749930B2 JP5749930B2 JP2010535788A JP2010535788A JP5749930B2 JP 5749930 B2 JP5749930 B2 JP 5749930B2 JP 2010535788 A JP2010535788 A JP 2010535788A JP 2010535788 A JP2010535788 A JP 2010535788A JP 5749930 B2 JP5749930 B2 JP 5749930B2
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Description
(1)
セリン、チロシン及びシステインからなる群から選ばれる少なくとも2種以上のアミノ酸を含み、10個以下のアミノ酸からなるペプチドまたはその塩を含有する動物細胞培養用培地。
(2)上記(1)の動物細胞培養用培地であって、
(a)セリン、チロシン及びシステインを少なくとも合計33%以上含み、10個以下のアミノ酸からなるペプチドを含有する動物細胞培養用培地、または
(b)セリン、チロシン及びシステインからなるアミノ酸群から選ばれる2種のアミノ酸を少なくとも合計33%以上含み、10個以下のアミノ酸からなるペプチドを含有する動物細胞培養用培地。
(3)セリン、チロシン及びシステインからなるトリペプチドまたはその塩を含有する動物細胞培養用培地。
(4)セリン、チロシン及びシステインからなる群から選ばれる2種のアミノ酸からなるジペプチドまたはその塩を含有する動物細胞培養用培地。
(5)所望のタンパク質を産生する細胞を培養して当該タンパク質を製造する際に、培養液中に上記(1)〜(4)のいずれかに記載の動物細胞培養用培地を用いて培養することを特徴とする、細胞の培養方法。
(6)上記(1)〜(4)のいずれかに記載の動物細胞培養用培地を用いて所望のタンパク質を産生する細胞を培養して当該タンパク質を製造することを特徴とする、所望のタンパク質の製造方法。
(7)前記動物細胞培養用培地を、培養の開始時に使用するか、または流加もしくは連続方式で添加する、(5)または(6)に記載の方法。
(8)細胞を、回分培養法(batch culture)、繰り返し回分培養法(repeated batch culture)、流加培養法(fed-batch culture)、繰り返し流加培養法(repeated fed-batch culture)、連続培養法(continuous culture)、または、灌流培養法(perfusion culture)で培養する、(5)または(6)に記載の方法。
(9)細胞を流加培養法で培養する、上記(8)の方法。
(10)前記動物細胞培養用培地が、逐次的に複数回、又は連続的に、流加することによって培養液中に供給される、上記(9)の方法。
(11)細胞が所望のタンパク質をコードする遺伝子を導入したものである、(5)または(6)に記載の方法。
(12)所望のタンパク質が抗体である、上記(11)の方法。
(13)細胞が哺乳動物細胞である、(5)または(6)に記載の方法。
(14)哺乳動物細胞がCHO細胞である、上記(13)の方法。
(15)上記(6)の方法で製造されたタンパク質を有効成分とする医薬の製造方法。
(16)セリン、チロシン及びシステインからなる群から選ばれる少なくとも2種以上のアミノ酸を含み、2個または3個のアミノ酸からなるペプチドであって、
(a)セリン、チロシン及びシステインからなるペプチド、またはそれらの内一つまたは複数のアミノ酸が化学修飾されているペプチド、または
(b)セリン、チロシン及びシステインから選ばれる2種のアミノ酸からなるペプチド、またはそれらの内一つまたは複数のアミノ酸が化学修飾されているペプチド。
(17)培養液中に(16)に記載のペプチドを含有せしめることを特徴とする、培養中の動物細胞のタンパク質産生量をする増強する方法。
(18)上記(17)の方法であって、培養液中に(16)に記載のペプチドを約0.1mMから約25mM含有せしめることを特徴とする、前記方法。
(19)上記(16)に記載のペプチドからなる、動物細胞培養用無血清培地添加剤。
(20)上記(16)に記載のペプチドからなる、形質転換細胞のタンパク質産生量増強剤。
本発明に係る動物細胞培養用培地は、特定のアミノ酸を構成単位として含むアミノ酸数2〜10個のペプチドを含有することを特徴とする。そのような特定のアミノ酸として、セリン、チロシン及びシステインの3種のアミノ酸からなる群から選ばれる、少なくとも2種のアミノ酸残基が、本願発明を特徴付けるものである。
次に、本願のペプチド含有培地に含まれるペプチドについて詳細に説明する。本願のペプチド含有培地に含まれるペプチドは特定のアミノ酸残基の組合わせからなり、アミノ酸数が2〜10個の合成ペプチドもしくは組換えタンパク質由来ペプチドである。アミノ酸の組合わせとしては、上述の通り、セリン、チロシン及びシステインからなる群から選ばれる少なくとも2種以上を含むことが特徴である。また、本発明のペプチドには、セリン、チロシン及びシステイン以外に他のアミノ酸を含んでいてもよい。また、本発明のペプチドには、化学修飾されたアミノ酸を含んでいてもよい。具体的な態様としては、
(1)セリン、チロシン及びシステインからなる群から選ばれる少なくとも2種以上のアミノ酸を含み、10個以下のアミノ酸からなるペプチドまたはその塩;
(2)セリン、チロシン及びシステインを少なくとも合計33%以上含み、10個以下のアミノ酸からなるペプチドまたはその塩;または、
(3)セリン、チロシン及びシステインのアミノ酸群から選ばれる2種のアミノ酸を少なくとも合計33%以上含み、10個以下のアミノ酸からなるペプチドまたはその塩;
が挙げられる。
(4)セリン、チロシン及びシステインからなるトリペプチドまたはその塩;
(5)セリン、チロシン及びシステインからなる群から選ばれる2種のアミノ酸からなるジペプチドまたはその塩、
(6)セリン、チロシン及びシステインからなるトリペプチドの内一つまたは複数のアミノ酸が化学修飾されているペプチドまたはその塩;
(7)セリン、チロシン及びシステインから選ばれる2種のアミノ酸からなるペプチドの内一つまたは複数のアミノ酸が化学修飾されているペプチドまたはその塩;
が挙げられる。
本願のペプチド含有培地は、タンパク質を産生する動物細胞を培養対象とする際に効果が顕著である。
上述した細胞培養方法により動物細胞を培養することにより、タンパク質を高産生させることが可能となる。従って、本願のペプチド含有培地を用いて所望のタンパク質を産生する細胞を培養して、当該タンパク質を製造する方法も、本発明の一態様である。
本発明の方法により製造されたタンパク質又はポリペプチド(本発明のタンパク質とも称する)が医薬として利用可能な生物学的活性を有する場合には、そのようなタンパク質又はポリペプチドを医薬的に許容される担体又は添加剤と混合して製剤化することにより、医薬品を製造することができる。本発明のタンパク質及び本発明のタンパク質を有効成分とする医薬品も本発明の範囲に包含される。
本発明によるタンパク質の製造方法は、本願中で記載されたペプチドを培養液中に含有させることにより培養中の動物細胞のタンパク質産生量をする増強する方法、と言い換えることができる。従って、セリン、チロシン及びシステインの3種アミノ酸群から選ばれる少なくとも2種のアミノ酸により特徴付けられる本願発明のペプチドは、動物細胞培養用無血清培地添加剤、または形質転換細胞のタンパク質産生量増強剤として使用することができる。
培地組成及び調製法は以下の通りである。
初発培地:市販の動物細胞培養用培地を、溶解後濾過滅菌し初発培地とした。
流加培地:初発培地に用いた市販の動物細胞培養用培地を初発培地の3倍濃度となるよう溶解し,濾過滅菌後流加培地とした(Control)。さらにその流加培地に対し、トリペプチドを最終50 もしくは25 mM 含有するように添加した培地を濾過滅菌後、トリペプチド含有流加培地とした(それぞれ、50 mM Tripeptide;25 mM Tripeptide)。
トリペプチド:配列 Cys-Tyr-Serの化学合成されたトリペプチド。
細胞:ヒト化IgG(抗グリピカン-3抗体)産生CHO細胞株(国際公開第WO 2006/006693号パンフレットを参照)。
培地組成及び調製法は以下の通りである。
初発培地:市販の動物細胞培養用培地を、溶解後濾過滅菌し初発培地とした。
流加培地:初発培地に用いた市販の動物細胞培養用培地を初発培地の3倍濃度となるよう溶解し,濾過滅菌後流加培地とした(Control)。さらにその流加培地に対し、ジペプチドを最終50 mM 含有するように添加した培地を濾過滅菌後、ジペプチド含有流加培地とした(Dipeptide)。
ジペプチド:配列 Cys-Tyrの化学合成されたジペプチド。
細胞:ヒト化IgG(抗グリピカン-3抗体)産生CHO細胞株(国際公開第WO 2006/006693号パンフレットを参照)。
以下の参考例1〜3は本発明者らの未公開先願であるPCT/JP2008/058046に記載の高濃度アミノ酸含有培地による培養を示す。
培地組成及び調製法は以下の通りである。
初発培地:市販の動物細胞培養用培地を溶解後濾過滅菌した。
流加培地:初発培地に用いる動物細胞培養用培地を初発培地に対し3倍濃度とし溶解後、セリン50mM、システイン塩酸塩一水和物1.8mM、チロシン14.5mMを加え、塩酸によりpHを培地成分が全て溶解するまで落とし(pH1.5付近)、培地成分が全て溶解していることを確認後濾過滅菌した。
細胞:ヒト化IgG(抗グリピカン-3抗体)産生CHO細胞株(国際公開WO 2006/006693号パンフレットを参照)。
培地組成及び調製法は以下の通りである。
初発培地:市販の動物細胞培養用培地を溶解後濾過滅菌した。
流加培地:初発培地に用いる動物細胞培養用培地を初発培地に対し3倍濃度とし溶解後、セリン50mM、システイン塩酸塩一水和物1.8mM、チロシン14.5mMを加え、塩酸によりpHを培地成分が全て溶解するまで落とし(pH1.5付近)、培地成分が全て溶解していることを確認後濾過滅菌した。
細胞:タウリントランスポーター遺伝子を導入したヒト化IgG産生CHO細胞株(国際公開WO2007/119774パンフレットを参照)。
培地組成及び調製法は以下の通りである。
初発培地:市販の動物細胞培養用培地を溶解後濾過滅菌した。
流加培地(Ser,Cys,Tyr):初発培地に用いる動物細胞培養用培地を初発培地に対し3倍濃度とし溶解後、セリン50mM、システイン塩酸塩一水和物1.8mM、チロシン14.5mMを加え、塩酸によりpHを培地成分が全て溶解するまで落とし(pH1.5付近)、培地成分が全て溶解していることを確認後濾過滅菌した。
流加培地(Ser,Cys):初発培地に用いる動物細胞培養用培地を初発培地に対し3倍濃度とし溶解後、セリン50mM、システイン塩酸塩一水和物1.8mMを加え、塩酸によりpHを培地成分が全て溶解するまで落とし(pH1.0付近)、培地成分が全て溶解していることを確認後濾過滅菌した。
流加培地(Ser,Tyr):初発培地に用いる動物細胞培養用培地を初発培地に対し3倍濃度とし溶解後、セリン50mM、チロシン14.5mMを加え、塩酸によりpHを培地成分が全て溶解するまで落とし(pH1.0付近)、培地成分が全て溶解していることを確認後濾過滅菌した。
流加培地(Cys,Tyr):初発培地に用いる動物細胞培養用培地を初発培地に対し3倍濃度とし溶解後、システイン塩酸塩一水和物1.8mM、チロシン14.5mMを加え、塩酸によりpHを培地成分が全て溶解するまで落とし(pH1.0付近)、培地成分が全て溶解していることを確認後濾過滅菌した。
細胞:タウリントランスポーター遺伝子を導入したヒト化IgG産生CHO細胞株。
Claims (17)
- セリン、チロシン及びシステインからなる群から選ばれる少なくとも2種以上のアミノ酸を含み、10個以下のアミノ酸からなるペプチドまたはその塩を0.1〜100mMの培養液濃度で含有する動物細胞培養用培地であって、前記ペプチドの構成単位のアミノ酸がセリン、チロシン、システイン以外の他のアミノ酸を含まない、動物細胞培養用培地。
- セリン、チロシン及びシステインからなるトリペプチドまたはその塩を0.1〜100mMの培養液濃度で含有する動物細胞培養用培地。
- セリン、チロシン及びシステインからなる群から選ばれる2種のアミノ酸からなるジペプチドまたはその塩を0.1〜100mMの培養液濃度で含有する動物細胞培養用培地。
- 所望のタンパク質を産生する細胞を培養して当該タンパク質を製造する際に、培養液中に請求項1〜3のいずれかに記載の動物細胞培養用培地を用いて培養することを特徴とする、細胞の培養方法。
- 請求項1〜3のいずれかに記載の動物細胞培養用培地を用いて所望のタンパク質を産生する細胞を培養して当該タンパク質を製造することを特徴とする、所望のタンパク質の製造方法。
- 前記動物細胞培養用培地を、培養の開始時に使用するか、または流加もしくは連続方式で添加する、請求項4または5に記載の方法。
- 細胞を、回分培養法(batch culture)、繰り返し回分培養法(repeated batch culture)、流加培養法(fed-batch culture)、繰り返し流加培養法(repeated fed-batch culture)、連続培養法(continuous culture)、または、灌流培養法(perfusion culture)で培養する、請求項4または5に記載の方法。
- 細胞を流加培養法で培養する、請求項7に記載の方法。
- 前記動物細胞培養用培地が、逐次的に複数回、又は連続的に、流加することによって培養液中に供給される、請求項8記載の方法。
- 細胞が所望のタンパク質をコードする遺伝子を導入したものである、請求項4または5に記載の方法。
- 所望のタンパク質が抗体である、請求項10記載の方法。
- 細胞が哺乳動物細胞である、請求項4〜11のいずれかに記載の方法。
- 哺乳動物細胞がCHO細胞である、請求項12記載の方法。
- 培養中の動物細胞のタンパク質産生量を増強する方法であって、該方法は、培養液中にセリン、チロシン及びシステインからなる群から選ばれる少なくとも2種以上のアミノ酸を含み、セリン、チロシン、システイン以外の他のアミノ酸を含まない、10個以下のアミノ酸からなるペプチドを0.1〜100mMの培養液濃度で含有せしめることを特徴とする、前記方法。
- 培養液中に前記ペプチドを約0.1mMから約25mM含有せしめることを特徴とする、請求項14に記載の方法。
- 請求項14に記載のペプチドからなる、動物細胞培養用無血清培地添加剤。
- 請求項14に記載のペプチドからなる、形質転換細胞のタンパク質産生量増強剤。
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