JP6967221B2 - 非天然アミノ酸導入抗体 - Google Patents
非天然アミノ酸導入抗体 Download PDFInfo
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- JP6967221B2 JP6967221B2 JP2017535557A JP2017535557A JP6967221B2 JP 6967221 B2 JP6967221 B2 JP 6967221B2 JP 2017535557 A JP2017535557 A JP 2017535557A JP 2017535557 A JP2017535557 A JP 2017535557A JP 6967221 B2 JP6967221 B2 JP 6967221B2
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Description
本出願は、日本特許出願2015−162160号(2015年8月19日出願)に基づく優先権を主張しており、この内容は本明細書に参照として取り込まれる。
[技術分野]
本発明は、ヒトIgG抗体の定常領域において、少なくとも1つのリジン誘導体を含むモノクローナル抗体または該抗体断片に関する。また本発明は、該リジン誘導体が化学修飾された修飾化抗体または該修飾化抗体断片に関する。
(1) 抗体の定常領域に、N6-((ベンジルオキシ)カルボニル)-L-リジン誘導体(以下、Z-リジン誘導体)を少なくとも1つ含む、モノクローナル抗体または該抗体断片。
(2) 前記抗体の定常領域が、ヒト、ラット、ラビットおよびマウスから選ばれる抗体の定常領域である、(1)に記載のモノクローナル抗体または該抗体断片。
(3) 前記抗体の定常領域が、抗体の重鎖定常領域および軽鎖定常領域からなる群より選ばれる少なくとも1つの定常領域である、(1)または(2)に記載のモノクローナル抗体または該抗体断片。
(4) 前記抗体の定常領域が、CH1領域、κ鎖定常領域およびλ鎖定常領域からなる群より選ばれる少なくとも1つの定常領域である、(1)〜(3)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
(5) 下記a)〜c)からなる群より選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である、(1)〜(4)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
a) KabatらによるEUインデックス(以下、EUインデックス)において、ヒトIgG抗体の重鎖の118、120、121、127、129、131、133、135、152、159、169、173、174、177、180、190、199、205および210番目のアミノ酸残基。
b) EUインデックスにおいて、ヒト抗体のκ鎖の110、112、119、138、141、145、147、149、153、154、155、158、161、167、169、180、183、184、191、195、197、205、207、210および211番目のアミノ酸残基。
c) EUインデックスにおいて、ヒト抗体のλ鎖の110、119、125、127、129、143、147、160、161、165、166、172、173、180、187、189、191、195、205、207、210、および215番目のアミノ酸残基。
(6) EUインデックスにおいて、ヒトIgG抗体の重鎖の131、177および199番目ならびにヒト抗体のκ鎖の155、191および197番目からなる群より選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である、(1)〜(5)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
(7) 少なくとも1つのZ-リジン誘導体が修飾されている、(1)〜(6)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
(8) 前記修飾が、Z-リジン誘導体と反応性を有する分子による化学修飾である、(7)に記載のモノクローナル抗体または該抗体断片。
(9) 前記Z-リジン誘導体と反応性を有する分子が、親水性高分子、両親媒性高分子および機能性分子からなる群より選ばれる少なくとも1つの分子である、(8)に記載のモノクローナル抗体または該抗体断片。
(10) 前記Z-リジン誘導体と反応性を有する分子が、PEG、抗原結合分子、薬物および蛍光化合物からなる群より選ばれる少なくとも1つの分子である、(8)または(9)に記載のモノクローナル抗体または該抗体断片。
(11) 前記抗原結合分子がモノクローナル抗体または該抗体断片である、(10)に記載のモノクローナル抗体または該抗体断片。
(12) 前記抗体断片が、Fab、Fab’、(Fab’)2、一本鎖抗体(scFv)、二量体化V領域(diabody)、ジスルフィド安定化V領域(dsFv)およびCDRを含むペプチドからなる群より選ばれる抗体断片である、(1)〜(11)のいずれか1つに記載の抗体断片。
(13) 前記モノクローナル抗体が遺伝子組換え抗体である、(1)〜(12)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
(14) 前記遺伝子組換え抗体がマウス抗体、ラット抗体、ラビット抗体、キメラ抗体、ヒト化抗体またはヒト抗体である、(13)に記載のモノクローナル抗体または該抗体断片。
(15) (1)〜(14)のいずれか1つに記載のモノクローナル抗体または該抗体断片をコードする塩基配列を有する核酸。
(16) (15)に記載の核酸を含有するベクター。
(17) (16)に記載のベクターを含む形質転換細胞。
(18) 前記細胞が原核細胞または真核細胞である、(17)に記載の形質転換細胞。
(19) (17)または(18)に記載の形質転換細胞を培地中で培養し、培養物から抗体または該抗体断片を採取することを含む、(1)〜(14)のいずれか1つに記載のモノクローナル抗体または該抗体断片の製造方法。
(20) (1)〜(14)のいずれか1つに記載のモノクローナル抗体または該抗体断片を含む組成物。
(21) 抗体の定常領域に、N6-(((トランス-シクロオクト-2-エン-1-イル)オキシ)カルボニル)-L-リジン(以下、TCO*-Lys)およびN6-((ビシクロ[6.1.0]ノン-4-イン-9-イルメトキシ)カルボニル)-L-リジン(以下、BCN-Lys)からなる群より選ばれる少なくとも1つのリジン誘導体を含むモノクローナル抗体または該抗体断片。
(22) 抗体の定常領域が、ヒト、ラット、ラビットおよびマウスから選ばれる抗体の定常領域である、(21)に記載のモノクローナル抗体または該抗体断片。
(23) 抗体の定常領域が、抗体の重鎖定常領域および軽鎖定常領域からなる群より選ばれる少なくとも1つの定常領域である、(21)または(22)に記載のモノクローナル抗体または該抗体断片。
(24) 抗体の定常領域が、CH1領域、κ鎖定常領域およびλ鎖定常領域からなる群より選ばれる少なくとも1つの定常領域である、(21)〜(23)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
(25) 下記a)〜c)からなる群より選ばれる少なくとも1つのアミノ酸残基がリジン誘導体である、(21)〜(24)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
a) KabatらによるEUインデックス(以下、EUインデックス)において、ヒトIgG抗体の重鎖の118、120、121、127、129、131、133、135、152、159、169、173、174、177、180、190、199、205および210番目のアミノ酸残基。
b) EUインデックスにおいて、ヒト抗体のκ鎖の110、112、119、138、141、145、147、149、153、154、155、158、161、167、169、180、183、184、191、195、197、205、207、210および211番目のアミノ酸残基。
c) EUインデックスにおいて、ヒト抗体のλ鎖の110、119、125、127、129、143、147、160、161、165、166、172、173、180、187、189、191、195、205、207、210、および215番目のアミノ酸残基。
(26) 少なくとも1つのリジン誘導体が修飾されている、(21)〜(25)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
(27) 前記修飾が、リジン誘導体と反応性を有する分子による化学修飾である、(26)に記載のモノクローナル抗体または該抗体断片。
(28) 前記リジン誘導体と反応性を有する分子が、親水性高分子、両親媒性高分子および機能性高分子からなる群より選ばれる少なくとも1つの分子である、(27)に記載のモノクローナル抗体または該抗体断片。
(29) 前記リジン誘導体と反応性を有する分子が、PEG、抗原結合分子、薬物および蛍光化合物からなる群より選ばれる少なくとも1つの分子である、(27)または(28)に記載のモノクローナル抗体または該抗体断片。
(30) 前記抗原結合分子がモノクローナル抗体または該抗体断片である、(29)に記載のモノクローナル抗体または該抗体断片。
(31) 前記抗体断片が、Fab、Fab’、(Fab’)2、一本鎖抗体(scFv)、二量体化V領域(diabody)、ジスルフィド安定化V領域(dsFv)およびCDRを含むペプチドからなる群より選ばれる抗体断片である、(21)〜(30)のいずれか1つに記載の抗体断片。
(32) 前記モノクローナル抗体が遺伝子組換え抗体である、(21)〜(31)のいずれか1つに記載のモノクローナル抗体または該抗体断片。
(33) 前記遺伝子組換え抗体がマウス抗体、ラット抗体、ラビット抗体、キメラ抗体、ヒト化抗体またはヒト抗体である、(32)に記載のモノクローナル抗体または該抗体断片。
(34) (21)〜(33)のいずれか1つに記載のモノクローナル抗体または該抗体断片をコードする塩基配列を有する核酸。
(35) (34)に記載の核酸を含有するベクター。
(36) (35)に記載のベクターを含む形質転換細胞。
(37) (36)に記載の形質転換細胞を培地中で培養し、培養物から抗体または該抗体断片を採取することを含む、(21)〜(33)のいずれか1つに記載のモノクローナル抗体または該抗体断片の製造方法。
(38) (21)〜(33)のいずれか1つに記載のモノクローナル抗体または該抗体断片を含む組成物。
(39) Z-リジン誘導体がアジド-Z-リジン、エチニル-Z-リジン、アミノ-Z-リジンおよびホルミル-Z-リジンから選ばれる少なくとも1つである(1)〜(13)に記載のモノクローナル抗体または該抗体断片。
(40) Z-リジン誘導体がアジド-Z-リジンまたはエチニル-Z-リジンの少なくともいずれか1つである(1)〜(13)に記載のモノクローナル抗体または該抗体断片。
(41) Z-リジン誘導体がアジド-Z-リジンである(1)〜(13)に記載のモノクローナル抗体または該抗体断片。
アジド-Z-リジンの中でも、オルト-アジド-Z-リジンまたはメタ-アジド-Z-リジンが好ましく、エチニル-Z-リジンの中でも、オルト-エチニル-Z-リジンまたはメタ-エチニル-Z-リジンが好ましく、アミノ-Z-リジンの中でも、オルト-アミノ-Z-リジンまたはメタ-アミノ-Z-リジンが好ましく、ホルミル-Z-リジンの中でも、オルト-ホルミル-Z-リジンまたはメタ-ホルミル-Z-リジンが好ましい。
Z-リジン誘導体がアジド-Z-リジンであるときには、本発明の抗体および該抗体断片は、抗体の定常領域において、少なくとも1つのアジド-Z-リジンを含むことにより、部位特異的な化学修飾を高効率かつ簡便に行うことが可能となる。
Z-リジン誘導体がエチニル-Z-リジンであるときには、本発明の抗体および該抗体断片は、抗体の定常領域において、少なくとも1つのエチニル-Z-リジンを含むことにより、部位特異的な化学修飾を簡便に行うことが可能となる。
Z-リジン誘導体がアミノ-Z-リジンであるときには、本発明の抗体および該抗体断片は、抗体の定常領域において、少なくとも1つのアミノ-Z-リジンを含むことにより、部位特異的な化学修飾を行うことが可能となる。
Z-リジン誘導体がホルミル-Z-リジンであるときには、本発明の抗体および該抗体断片は、抗体の定常領域において、少なくとも1つのホルミル-Z-リジンを含むことにより、部位特異的な化学修飾を行うことが可能となる。
TCO*-Lys及びBCN-Lysの化学構造を、表2に示す。
(a)KabatらによるEUインデックス(以下、EUインデックス)において、ヒトIgG抗体の重鎖の118、120、121、127、129、131、133、135、152、159、169、173、174、177、180、190、199、205および210番目から選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である抗体または該抗体断片。
(b)EUインデックスにおいて、ヒトIgG抗体の重鎖の118、127、129、131、133、135、159、173、174、177、180, 199、205および210番目から選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である抗体または該抗体断片。
(c)EUインデックスにおいて、ヒト抗体のκ鎖の110、112、119、138、141、145、147、149、153、154、155、158、161、167、169、180、183、184、191、195、197、205、207、210および211番目から選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である抗体または該抗体断片。
(d)EUインデックスにおいて、ヒト抗体のκ鎖の110、112、119、138、145、149、153、155、158、161、167、169、183、184、191、195、197、205、207、210および211番目から選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である抗体または該抗体断片。
(e)EUインデックスにおいて、ヒト抗体のλ鎖の110、119、125、127、129、143、147、160、161、165、166、172、173、180、187、189、191、195、205、207、210および215番目から選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である抗体または抗体断片。
(f)EUインデックスにおいて、ヒト抗体のλ鎖の110、125、143、160、161、165、166、172、173、180、191、205、210、および215番目から選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体である抗体または抗体断片。
(g)EUインデックスにおいて、ヒトIgG抗体の重鎖の131、177および199番目ならびにヒト抗体のκ鎖の155、191および197番目からなる群より選ばれる少なくとも1つのアミノ酸残基がZ−リジン誘導体である抗体または抗体断片。
(a)KabatらによるEUインデックス(以下、EUインデックス)において、ヒトIgG抗体の重鎖の118、120、121、127、129、131、133、135、152、159、169、173、174、177、180、190、199、205および210番目から選ばれる少なくとも1つのアミノ酸残基がTCO*-LysまたはBCN-Lysである抗体または該抗体断片。
(b)EUインデックスにおいて、ヒト抗体のκ鎖の110、112、119、138、141、145、147、149、153、154、155、158、161、167、169、180、183、184、191、195、197、205、207、210および211番目から選ばれる少なくとも1つのアミノ酸残基がTCO*-LysまたはBCN-Lysである抗体または該抗体断片。
(c)EUインデックスにおいて、ヒト抗体のλ鎖の110、119、125、127、129、143、147、160、161、165、166、172、173、180、187、189、191、195、205、207、210および215番目から選ばれる少なくとも1つのアミノ酸残基がTCO*-LysまたはBCN-Lysである抗体または抗体断片。
(d)EUインデックスにおいて、ヒトIgG抗体の重鎖の121および131番目ならびにヒト抗体のκ鎖の169番目からなる群より選ばれる少なくとも1つのアミノ酸残基がTCO*-LysまたはBCN-Lysである抗体または抗体断片。
放射性標識化合物としては、診断用または治療用用途に使用される核種であればよく、例えば、3H、14C、32P、33P、35S、51Cr、57CO、18F、153Gd、159Gd、64Cu、68Ge、166Ho、115In、113In、112In、111In、131I、125I、123I、121I、140La、177Lu、54Mn、99Mo、103Pd、142Pr、149Pm、186Re、188Re、211At、105Rh、97Ru、153Sm、47Sc、75Se、85Sr、99Tc、201Ti、113Sn、117Sn、133Xe、169Yb、175Yb、90Yおよび65Zn等、または上述の核種を含む化合物が挙げられる。放射性標識化合物は、クロラミンT法などによって抗体に直接結合させることができる。また、放射性標識化合物をキレートする物質を抗体に結合させてもよい。キレート剤としては例えば、DOTA、PA-DOTA、TRITAおよびDTPA等が挙げられ、キレート剤によって修飾された抗体、キレート剤を介して放射性標識化合物が標識された修飾化抗体も本発明の抗体に含まれる。
本発明の非天然アミノ酸を含む抗体または該抗体断片は、モレキュラー・クローニング第2版、カレント・プロトコールズ・イン・モレキュラー・バイオロジー、Antibodies, A Laboratory manual, Cold Spring Harbor Laboratory (1988)、Monoclonal Antibodies:principles and practice, Third Edition, Acad. Press (1993)、Antibody Engineering, A Practical Approach, IRL Press at Oxford University Press (1996)等に記載された方法を用いて製造することができる。例えば、以下に記載する本発明の非天然アミノ酸を含む抗体または該抗体断片の発現ベクターを適当な宿主細胞に導入し、得られた形質転換体を非天然アミノ酸を添加した培地中で培養し、該培養物から精製することにより、本発明の非天然アミノ酸を含む抗体または該抗体断片を製造することができる。
(1)抗体または該抗体断片の発現ベクターの構築
本発明の非天然アミノ酸を含む抗体または該抗体断片の発現ベクターは、その目的に応じて、または該発現ベクターを導入すべき宿主細胞に適したものを適宜選択し、使用することができる。
抗体のVLおよびVHをコードするcDNAは以下のようにして取得することができる。
任意の抗体を産生する抗体産生細胞またはハイブリドーマ細胞から抽出したmRNAを鋳型として用い、cDNAを合成する。合成したcDNAをファージまたはプラスミド等のベクターに挿入してcDNAライブラリーを作製する。
分泌シグナル配列を含む抗体のVLおよびVHの完全なアミノ酸配列に関しては、既知の抗体のVLおよびVHのアミノ酸配列[Sequences of Proteins of Immunological Interest, US Dept. Health and Human Services (1991)]と比較することにより、分泌シグナル配列の長さおよびN末端アミノ酸配列を推定でき、更には抗体が属するサブグループを知ることができる。また、VLおよびVHの各CDRのアミノ酸配列についても、同様の方法で見出すことができる。
上述1-(3)で取得した抗体のV領域アミノ酸配列が、非ヒト抗体のV領域の場合は、その抗体のVLおよびVHの配列を用いてヒト型キメラ抗体を作製することができる。1-(1)に記載の抗体または該抗体断片の発現用ベクターのCLおよびCHをコードする遺伝子の上流に、ヒト以外の動物の抗体のVLおよびVHをコードするcDNAを挿入し、ヒト型キメラ抗体または該抗体断片の発現ベクターを構築することができる。
ヒト化抗体のVLおよびVHをコードするcDNAは、以下のようにして構築することができる。まず、目的のヒト以外の動物の抗体のVLおよびVHのCDRを移植するヒト抗体のVLおよびVHのFRのアミノ酸配列を選択する。
ヒト化抗体は、ヒト以外の動物の抗体のVLおよびVHのCDRのみをヒト抗体のVLおよびVHのFRに移植しただけでは、その抗原結合活性は元のヒト以外の動物の抗体に比べて低下してしまうことが知られている[BIO/TECHNOLOGY, 9, 266 (1991)]。
1-(1)に記載の抗体または該抗体断片の発現用ベクターのヒト抗体のCLおよびCHをコードする遺伝子の上流に、1-(5)および1-(6)で構築したヒト化抗体のVLおよびVHをコードするcDNAを挿入し、ヒト化抗体または該抗体断片の発現ベクターを構築することができる。
本発明の非天然アミノ酸を含む抗体または該抗体断片は、前記1.で作製した本発明の抗体または該抗体断片の発現ベクターを適当な宿主細胞に導入して得られた形質転換体を、目的の非天然アミノ酸を添加した培地で培養して培養物中に本発明の非天然アミノ酸を含む抗体または該抗体断片を生成蓄積させ、該培養物から精製することにより取得することができる。
本発明における宿主細胞が原核細胞である場合、遺伝子組換え抗体を生産させることができる原核細胞であれば、いかなる細胞でも用いることができる。該原核細胞としては、例えば、大腸菌、枯草菌、サルモネラ菌、セレチア属およびシュードモナス属等が挙げられ、中でも、大腸菌が好ましい。
原核細胞培養用培地としては、例えば、LB培地(Becton, Dickinson and Company社製)、NZYM GIT培地(日本製薬社製)、Terrific Broth培地(Applichem社製)、SOB培地(Applichem社製)、SOC培地(Ampliqon社製)、またはこれら培地にアンピシリン等の各種抗生物質を添加した培地等が挙げられる。
本発明において、宿主細胞が真核細胞である場合、遺伝子組換え抗体を生産させることができる真核細胞であれば、いかなる細胞でも用いることができる。具体的には、動物細胞、酵母細胞、昆虫細胞および植物細胞などが挙げられる。
本発明の非天然アミノ酸を含む抗体または該抗体断片の製造方法は、無細胞タンパク質合成系(無細胞発現系ともいう)を採用することもできる。無細胞タンパク質合成系とは、タンパク質の翻訳に必要なタンパク質因子を細胞抽出液として取り出し、試験管内で目的とするタンパク質を合成させる系である。様々な生物種に由来する抽出液を利用して無細胞系を構成することができ、例えば、大腸菌や好熱性細菌等の細菌、小麦胚芽、ウサギ網状赤血球、マウスL細胞、エールリッヒ腹水癌細胞、HeLa細胞、CHO細胞および出芽酵母等の、高いタンパク質合成活性の状態の真核細胞、および原核細胞の抽出液を用いることができる(Clemens, M. J., Transcription and Translation - A Practical Approach, (1984), pp. 231-270, Henes, B.D. et al. eds., IRL Press, Oxford)。
本発明において、各種非天然アミノ酸はWO2013/068874、WO2014/004639、WO2014/044872およびWO2014/124258などに記載する方法に準じて合成することができる。または市販の非天然アミノ酸を使用することができる。
化合物(a-2)は、化合物(a-1)及び1〜20当量の酸クロリド化剤を、溶媒中、必要により、1〜50当量の添加剤存在下、-20℃と用いる溶媒の沸点の間の温度で、5分間から72時間反応することにより製造することができる。
化合物(a-1)は、市販品として得られるか、又は公知の方法[例えば、実験化学講座、第5版、16巻、p.1、丸善株式会社(2005年)など]もしくはそれらに準じた方法により得ることができる。
酸クロリド化剤は、例えばホスゲン、トリホスゲン、トリクロロメチルクロロホルメートなどがあげられる。
溶媒としては、ジクロロメタン、クロロホルム、1,2-ジクロロエタン、トルエン、アセ卜ニ卜リル、ジエチルエ一テル、テ卜ラヒドロフラン(THF)、1,2-ジメトキシエタン(DME)、ジオキサン、N,N-ジメチルホルムアミド(DMF)、N.N-ジメチルアセ卜アミド(DMA)、N-メチルピロリドン(NMP)、ピリジンなどがあげられ、これらは単独でまたは混合して用いられる。
添加剤としては、ピリジン、トリエチルアミン、N,N-ジイソプロピルエチルアミン、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(DBU)、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなどがあげられる。
化合物(a-4)は、化合物(a-2)及び1〜10当量の化合物(a-3)を、溶媒中、必要により、1〜50当量の添加剤存在下、-20℃と用いる溶媒の沸点の間の温度で、5分間から72時間反応することにより製造することができる。
化合物(a-3)は、市販品として得られるか、又は公知の方法[例えば、Amino Acid, Peptides and Proteins in Organic Chemistry, Volume 4, Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis、Andrew B. Hughes、2011年、ISBN: 978-3-527-32103-2など]もしくはそれらに準じた方法により得ることができる。
溶媒としては、ジクロロメタン、クロロホルム、1,2-ジクロロエタン、トルエン、アセ卜ニ卜リル、酢酸エチル、ジエチルエ一テル、THF 、DME、ジオキサン、DMF、DMA、NMP、ピリジン、水などがあげられ、これらは単独でまたは混合して用いられる。
添加剤としては、ピリジン、トリエチルアミン、N,N-ジイソプロピルエチルアミン、DBU、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなどがあげられる。
化合物(I)は、化合物(a-4)を、溶媒中、1〜50当量の添加剤存在下、-20℃と用いる溶媒の沸点の間の温度で、5分間から72時間反応することにより製造することができる。
溶媒としては、ジクロロメタン、クロロホルム、1,2-ジクロロエタン、トルエン、アセ卜ニ卜リル、酢酸エチル、ジエチルエ一テル、THF、DME、ジオキサン、DMF、DMA、NMP、ピリジン、水などがあげられ、これらは単独でまたは混合して用いられる。
添加剤としては、保護基であるPの種類に応じて適切なものを選択することができ、より具体的には、例えば、プロテクティブ・グル一ブス・イン・オ一ガニック・シンセシス第 3 版(Protective Groups in Organic Synthe sis, third edit ion)、グリ一ン(T. W. Greene)著、John Wiley & Sons Inc . (1999年)などに記載の脱保護反応に必要な添加剤などがあげられる。例えば、PがBocである場合には、塩酸などの酸が好ましい。
なお、上記各製造法における中間体、及び目的化合物は、有機合成化学で常用される分離精製法、例えば、濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマ卜グラフィ一等に付して単離精製することができる。また、中間体においては特に精製することなく次の反応に供することも可能である。
化合物(I)の塩を取得したいとき、化合物(I)が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、化合物(I)を適当な溶媒に溶解又は懸濁し、酸又は塩基を加えることにより塩を形成させて単離、精製すればよい。
本発明の非天然アミノ酸を含む修飾化抗体または該修飾化抗体断片は、上述の本発明の非天然アミノ酸を含む抗体または該抗体断片に含まれる少なくとも1つのアミノ酸残基、非天然アミノ酸残基または糖鎖を、化学修飾または遺伝子工学的手法で修飾することにより、作製することができる。化学修飾は[抗体工学入門、地人書館(1994)Kolb et al., Angew Chem Int Ed Engl. 40. 2004-21, 2001]に記載された方法で行うことができ、遺伝子工学的手法としては、組換えタンパク質発現ベクターを適当な宿主細胞へ導入して発現させる等の方法が挙げられるが、これらの方法に限定されない。
反応性(%)=[波長495 nmのエリア面積値/(Alexa488のモル吸光係数×上記の式で得られた抗体または該抗体断片の濃度(M))/抗体または該抗体断片1分子あたりの非天然アミノ酸の分子数]×100
反応性(%)=[波長495 nmのエリア面積値/ (Fluoresceinのモル吸光係数×上記式により算出される抗体または該抗体断片の濃度(M))/抗体または該抗体断片1分子あたりの非天然アミノ酸の分子数]×100
反応性(%)=[波長550 nmのエリア面積値/ (Cy3のモル吸光係数×上記式で算出される抗体または該抗体断片の濃度(M))/抗体または該抗体断片1分子あたりの非天然アミノ酸の分子数]×100
本発明の非天然アミノ酸を含む抗体または該抗体断片のエフェクター活性を制御する方法としては、例えば、抗体の定常領域の297番目のアスパラギン(Asn)に結合するN結合複合型糖鎖の還元末端に存在するN−アセチルグルコサミン(GlcNAc)にα-1,6結合するフコース(コアフコースともいう)の量を制御する方法(国際公開第2005/035586号、国際公開第2002/31140号、国際公開第00/61739号)および抗体のFc領域のアミノ酸残基を改変することで制御する方法などが挙げられる。本発明の非天然アミノ酸を含む抗体にはいずれの方法を用いても、エフェクター活性を制御することができる。
更に、上述の方法を組み合わせて、一つの抗体に使用することにより、抗体のエフェクター活性が制御された抗体を取得することができる。
精製した本発明の非天然アミノ酸を含む抗体または該抗体断片の活性評価は、以下のように行うことができる。
本発明の非天然アミノ酸を含む抗体または該抗体断片は、例えば診断薬、治療剤等の医薬等への使用が可能である。
非天然アミノ酸・オルト-アジド-Z-リジン(以下、o-Az-Z-Lysと記載する)導入抗体を作製するために、大腸菌W3110株(ATCC)を親株宿主細胞として、遺伝子組換え大腸菌(以下、W3110RF-Zero株と記載する)を下記の方法で作製した。
抗Her2ヒト化抗体(IgG1、κ)のFabであるTrastuzumab-Fabについて、CH1およびCκのLys残基をo-Az-Z-Lysに置換したo-Az-Z-Lys導入Trastuzumab-Fabを、以下に記載する方法で作製した。
(1)大腸菌用のo-Az-Z-Lys導入Fabの基本発現ベクターの構築
大腸菌用o-Az-Z-Lys導入Fabの基本発現ベクターとしては、市販ベクターpFLAG-CTS (SIGMA社製)を利用した。pFLAG-CTSのlacリ
プレッサー遺伝子lacIの直下流に、文献[Mukai et al, Biochem Biophys Res Commun 411, 757-761, 2011]記載の方法に準じて、ピロリジンtRNA(以下、Pyl tRNA、tRNAPylとも記載する)の塩基配列およびピロリジルtRNA合成酵素(以下Pyl RSとも記載する)をコードする塩基配列を挿入した。以下、当該発現ベクターをpFLAG-CTS PylTSと記載する。Pyl tRNAの塩基配列およびPyl RSをコードする塩基配列としては、Methanosarcina mazei由来の野生型Pyl tRNAをコードする塩基配列(配列番号1)、およびMethanosarcina mazei由来のPyl RS の変異体(Y306A/Y384F)[Yanagisawa et al, Chem Biol., 15, 1187-1197, 2008]のアミノ酸配列(配列番号8)をコードする塩基配列を使用した。
(2-1)野生型Trastuzumab-Fabの発現ベクターの構築
Trastuzumab-Fabをコードする塩基配列は、Proc.Natl.Acad. Sci. U.S.A., 89, 4285(1992)に記載されるTrastuzumabのFabの軽鎖領域のアミノ酸配列(配列番号2)とFabの重鎖領域のアミノ酸配列(配列番号3)をもとにして設計した。
軽鎖、重鎖ともに、Tacプロモーターとシャイン・ダルガノ配列からなる塩基配列(配列番号4)の支配下に、PelB分泌シグナル(配列番号5)に連結させた。
表3に記載した各o-Az-Z-Lys導入Trastuzumab-Fabの発現ベクターを以下に記載する方法で作製した。
Trastuzumab-Fab発現ベクターは、(2-1)、(2-2)で得られたベクター(配列番号9-23および26-62の塩基配列をそれぞれ含むベクター)を制限酵素EcoRIとSalIにて処理し、目的の軽鎖の塩基配列が挿入されたpFLAG-CTS PylTSへ、目的の重鎖塩基配列を挿入して構築した。
o-Az-Z-Lys導入Trastuzumab-Fabを調製するために、実施例2にて構築した大腸菌用Trastuzumab-Fab発現ベクターを、実施例1で作製したW3110 RF-zero株に導入した。
各種Trastuzumab-Fab発現ベクターを10 ng/μLとなるように滅菌蒸留水に懸濁した。3μLの該DNA溶液を50μLのコンピテントセルに加えて穏やかに混和し、エッペンドルフチューブに分注し氷上に30分間保持した。続いて、42 ℃のウォーターバスに30秒間保持した後、再度氷上に2 分間静置した。
実施例3で得られた各o-Az-Z-Lys導入Trastuzumab-FabとAlexa488 DIBOとの反応性を、以下に記載する方法で測定した。当該反応には、クリックケミストリーを用いた。
反応性(%)=[波長495 nmのエリア面積値/ ( 71,000×Fab濃度(M))]×100
ここで、67980はTrastuzumab-Fabのモル吸光係数、71,000はAlexa488のモル吸光係数である。
実施例4で得られた結果より、高効率での化学修飾が可能なo-Az-Z-Lys導入抗体-Fabを作製できるo-Az-Z-Lys導入部位を見出すため、以下に記載する実験を行った。
実施例5で作製したベクターを用いて、実施例3と同様にo-Az-Z-Lys導入Trastuzumab-Fab、およびCixutumumab-Fabを調製した。
実施例6で得られたo-Az-Z-Lys導入Trastuzumab-Fabおよびo-Az-Z-Lys導入Cixutumumab-FabとAlexa488 DIBOとの反応性を、実施例4と同様に測定した。Cixutumumab-Fabのモル吸光係数としては、74820を用いた。o-Az-Z-Lys導入FabとAlexa488との反応は、クリックケミストリーを用いた。
実施例3、6で作製した各o-Az-Z-Lys導入Trastuzumab-Fabと野生型Trastuzumab-Fabとの抗原結合活性を以下に記載する方法で測定した。
実施例6で作製した各o-Az-Z-Lys導入Cixutumumab-Fabと野生型Cixutumumab-Fabとの抗原結合活性を実施例8と同様の方法で測定した。
表3〜5に記載する各種o-Az-Z-Lys導入Trastuzumab-Fabのうち、6ヶ所のo-Az-Z-Lys導入部位を表7に記載した。Trastuzumab-Fab以外のFabを用いて、表7に記載する部位にo-Az-Z-Lysを導入した各種Fabを作製し、反応性を測定した。
o-Az-Z-Lys導入Trastuzumab-Fab を用いて、リンカーを介してFabを二量体化できるか検討した。実施例2、3と同様の方法で、表7で示した6ヶ所の部位それぞれにo-Az-Z-Lysを導入した6種類のo-Az-Z-Lys導入Trastuzumab-Fabを作製し、以下に記載する方法で同種のFabを二量体化したFabホモダイマーを作製した。
Trastuzumab-Fabに複数のo-Az-Z-Lysが導入されたFabを作製し、その反応性を測定した。表8に記載するTAGコドンを導入した塩基配列を用いて、複数箇所のコドンをamberコドンに置換したTrastuzumab-Fab発現ベクターを実施例2と同様の方法で作製した。得られたFab発現ベクターを実施例1で作製した3110 RF-zero株に導入し、実施例3と同様の方法で、各種o-Az-Z-Lys導入Fabを取得した。
反応性(%)=[波長495 nmのエリア面積値/ ( 71,000×上記式で算出されるFab濃度(M))/Fab1分子あたりの非天然アミノ酸の分子数]×100
実施例3および実施例12にて作製した1ヶ所または2ヶ所にo-Az-Z-Lysが導入されたTrastuzumab-FabをMertansine(DM1-SH)と反応させて、Trastuzumab-Fabの化学修飾体を作製し、その細胞傷害活性を測定した。
Trastuzumab IgG抗体において、表7に記載する部位にそれぞれo-Az-Z-Lysを導入した6種類のIgG抗体を作製し、Alexa488との反応性を測定した。
反応性(%)=[波長495 nmのエリア面積値/ ( 71,000×上記式で算出される抗体濃度(M))/2]×100
参考例2〜7に従い合成した各種Z-Lys誘導体、Lys誘導体BCN-Lys(SciChem社製)またはTCO*-Lys(SciChem社製)を導入したTrastuzumab-Fabを以下に記載する方法で作製し、その反応性を測定した。作製した各種非天然アミノ酸導入Trastuzumab-Fabを表10に記載した。
反応性(%)=[波長495 nmのエリア面積値/ ( 70,000×上記式で算出されるFab濃度(M))]×100
ここで70,000はFluoresceinのモル吸光係数である。また、67980はTrastuzumab-Fabのモル吸光係数である。
反応性(%)=[波長550 nmのエリア面積値/ ( 150,000×Fab濃度(M))]×100
ここで150,000はCy3のモル吸光係数である。また、67980はTrastuzumab-Fabのモル吸光係数である。
参考例8に従い合成したm-formyl-Z-Lysを導入したTrastuzumab-Fabを、実施例15と同様の方法で作製した。作製したm-formyl-Z-Lys導入Fabや、抗体作成に使用した塩基配列を表11に記載した。
得られたm-formyl-Z-Lys導入Fabを質量分析した結果、実測値と理論分子量が一致し、1分子のTrasutuzumab-Fabに1分子のm-formyl-Z-Lysが導入されたことが確認できた。
N6-{[(2-アジドベンジル)オキシ]カルボニル}-L-リジン塩酸塩(オルト-アジド-Z-リジン塩酸塩)
(2-アミノフェニル)メタノールを原料に用いて、文献記載(Bioconjugate Chem. 2016, 27, 198)のmAzZLys合成方法と同様の手法により、オルト-アジド-Z-リジン塩酸塩を取得した。
ESIMS m/z: 322(M ‐ HCl)+; 1H NMR (400 MHz, DMSO-d6, D2O,δ): 1.23-1.45 (m, 4H), 1.68-1.82 (m, 2H), 2.97-3.01 (m, 2H), 3.57-3.60 (m, 1H), 4.95 (s, 2H), 7.18-7.24 (m, 1H), 7.31-7.47 (m, 3H).
N6-{[(3-アジドベンジル)オキシ]カルボニル}-L-リジン塩酸塩(メタ-アジド-Z-リジン塩酸塩)
文献記載(Bioconjugate Chem. 2016, 27, 198)のmAzZLys合成方法に従い、メタ-アジド-Z-リジン塩酸塩を取得した。
N6-{[(4-アジドベンジル)オキシ]カルボニル}-L-リジン塩酸塩(パラ-アジド-Z-リジン塩酸塩)
(4-アミノフェニル)メタノールを原料に用いて、文献記載(Bioconjugate Chem. 2016, 27, 198)のmAzZLys合成方法と同様の手法により、パラ-アジド-Z-リジン塩酸塩を取得した。
ESIMS m/z: 322(M ‐ HCl)+; 1H NMR (400 MHz, DMSO-d6, D2O,δ): 1.22-1.44 (m, 4H), 1.58-1.78 (m, 2H), 2.94-3.02 (m, 2H), 3.24-3.28 (m, 1H), 4.97 (s, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H).
N6-{[(2-エチニルベンジル)オキシ]カルボニル}-L-リジン塩酸塩(オルト-エチニル-Z-リジン塩酸塩)
(工程1)
市販の(2-ヨードフェニル)メタノール(75.0 g, 0.321 mol)をトリエチルアミン(1 L)に溶解し、エチニルトリメチルシラン(34.7 g, 0.353 mol)及びビストリフェニルホスフィン-塩化パラジウム(II)(4.51 g, 6.40 mmol)を加え、窒素雰囲気下室温で10分撹拌した。反応混合物にヨウ化銅(I)(0.61 g, 3.20 mmol)を加え、室温で2時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/石油エーテル=5/95〜10/90)で精製し、{2-[(トリメチルシリル)エチニル]フェニル}メタノール(60 g, 92%)を得た。
ESIMS m/z: 205(M + H)+.
工程1で得られた{2-[(トリメチルシリル)エチニル]フェニル}メタノール(36.0 g, 0.176 mol)をテトラヒドロフラン(THF)(350 mL)に溶解し、氷冷下、ホスゲン(20%トルエン溶液, 174 mL, 0.352 mol)を加え、室温で16時間撹拌した。反応混合物を減圧濃縮し、2-[(トリメチルシリル)エチニル]ベンジル カルボノクロリデートの粗生成物(47.0 g)を得た。得られた粗生成物はそのまま次工程へ用いた。
工程2で得られた2-[(トリメチルシリル)エチニル]ベンジル カルボノクロリデートの粗生成物(47.0 g, 0.158 mol)をTHF(500 mL)に溶解し、2-[(トリメチルシリル)エチニル]ベンジル カルボノクロリデートの溶液を得た。市販の(tert-ブトキシカルボニル)-L-リジン(39.0 g, 0.158 mol)を1 mol/L NaOH水溶液(470 mL)及びTHF(250 mL)に溶解し、(tert-ブトキシカルボニル)-L-リジンの溶液を得た。上記2-[(トリメチルシリル)エチニル]ベンジル カルボノクロリデートの溶液を、氷冷下10分かけて、上記(tert-ブトキシカルボニル)-L-リジンの溶液に滴下し、室温で2時間撹拌した。反応混合物を冷却し、ジエチルエーテルを加え、水で抽出した。得られた水層に、pHが1〜2になるように1 mol/L塩酸水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をTHF(85 L)に溶解し、氷冷下、1 mol/L テトラブチルアンモニウムフルオリド溶液(28 mL)を加え、室温で2時間撹拌した。反応混合物に1 mol/L 塩酸水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン/メタノール=98/2〜97/3)で精製し、N2-(tert-ブトキシカルボニル)-N6-{[(2-エチニルベンジル)オキシ]カルボニル}-L-リジン(16.0 g, 2段階トータル収率22%)を得た。
ESIMS m/z: 405(M + H)+.
工程3で得られたN2-(tert-ブトキシカルボニル)-N6-{[(2-エチニルベンジル)オキシ]カルボニル}-L-リジン(16.0 g, 0.039 mol)を1,4-ジオキサン(30 mL)に溶解し、塩酸-ジオキサン溶液(30 mL)をゆっくり滴下し、室温で16時間撹拌した。反応混合物の溶媒を減圧留去し、得られた残渣をジエチルエーテルでリスラリー精製し、オルト-エチニル-Z-リジン塩酸塩(11.8 g, 99%)を得た。
ESIMS m/z: 305(M ‐ HCl)+; 1H NMR (400 MHz, DMSO-d6, D2O,δ): 1.28-1.50 (m, 4H), 1.71-1.86 (m, 2H), 2.97-3.01 (m, 2H), 3.85-3.90 (m, 1H), 4.37 (S, 1H), 5.14 (s, 2H), 7.34-7.47 (m, 3H), 7.52-7.54 (m, 1H).
N6-{[(3-エチニルベンジル)オキシ]カルボニル}-L-リジン塩酸塩(メタ-エチニル-Z-リジン塩酸塩)
(工程1)
市販の(3-ヨードフェニル)メタノール(75.0 g, 0.321 mol)を用いて、参考例4の工程1と同様にして、{3-[(トリメチルシリル)エチニル]フェニル}メタノール(60.0 g, 91%)を得た。
ESIMS m/z: 205(M + H)+.
工程1で得られた{3-[(トリメチルシリル)エチニル]フェニル}メタノール(60 g, 0.293 mol)をメタノール(1 L)に溶解し、炭酸カリウム(20.3 g, 0.146 mol)を加え、室温で3時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/石油エーテル=30/70〜40/60)で精製し、(3-エチニルフェニル)メタノール(33 g, 83%)を得た。
ESIMS m/z: 133(M + H)+.
工程2で得られた(3-エチニルフェニル)メタノール(33.0 g, 0.249 mol)を用いて、参考例4の工程2と同様にして、3-エチニルベンジル カルボノクロリデートの粗生成物(40.0 g)を得た。得られた粗生成物はそのまま次工程へ用いた。
工程3で得られた3-エチニルベンジル カルボノクロリデートの粗生成物(40 g, 0.205 mol)をTHF(50 mL)に溶解し、3-エチニルベンジル カルボノクロリデートの溶液を得た。市販の(tert-ブトキシカルボニル)-L-リジン(50.4 g, 0.205 mol)を1 mol/L NaOH水溶液(500 mL)及びTHF(200 mL)に溶解し、(tert-ブトキシカルボニル)-L-リジンの溶液を得た。上記3-エチニルベンジル カルボノクロリデートの溶液を、氷冷下10分かけて、上記(tert-ブトキシカルボニル)-L-リジンの溶液に滴下し、室温で2時間撹拌した。反応混合物を冷却し、ジエチルエーテルを加え、水で抽出した。得られた水層に、pHが1〜2になるように1 mol/L塩酸水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン/メタノール=98/2〜97/3)で精製し、N2-(tert-ブトキシカルボニル)-N6-{[(3-エチニルベンジル)オキシ]カルボニル}-L-リジン(20 g, 2段階トータル収率25%)を得た。
ESIMS m/z: 405(M + H)+.
工程4で得られたN2-(tert-ブトキシカルボニル)-N6-{[(3-エチニルベンジル)オキシ]カルボニル}-L-リジン(17.0 g, 0.042 mol)を用いて、参考例4の工程4と同様にして、メタ-エチニル-Z-リジン塩酸塩(11.1 g, 87%)を得た。
ESIMS m/z: 305(M ‐ HCl)+; 1H NMR (400 MHz, DMSO-d6, D2O,δ): 1.28-1.50 (m, 4H), 1.70-1.85 (m, 2H), 2.97-3.01 (m, 2H), 3.83-3.90 (m, 1H), 4.21 (S, 1H), 5.01 (s, 2H), 7.28-7.47 (m, 4H).
N6-{[(4-エチニルベンジル)オキシ]カルボニル}-L-リジン塩酸塩(パラ-エチニル-Z-リジン塩酸塩)
(工程1)
市販の4-エチニルベンズアルデヒド(5.00 g, 38.5 mmol)をエタノール(100 mL)に溶解し、氷冷下、水素化ホウ素ナトリウム(4.40 g, 116 mmol)を加え、0℃で2分間撹拌した。反応混合物に塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/石油エーテル=20/80)で精製し、(4-エチニルフェニル)メタノール(5.00 g, 100%)を得た。
ESIMS m/z: 133(M + H)+.
工程1で得られた(4-エチニルフェニル)メタノール(7.80 g, 58.7 mmol)をジクロロメタン(100 mL)に溶解し、室温でピリジン(10 mL)及び市販の4-ニトロフェニルクロロホルメート(11.8 g, 58.7 mmol)を加え、終夜撹拌した。反応混合物に水を加え、ジクロロメタンで抽出した。有機層を水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去することで、4-エチニルベンジル (4-ニトロフェニル)カルボナートの粗生成物(17.5 g)を得た。得られた粗生成物はそのまま次工程へ用いた。
工程2で得られた4-エチニルベンジル (4-ニトロフェニル)カルボナート(7.50 g, 25.0 mmol)をTHF(100 mL)に溶解し、ジイソプロピルエチルアミン(6.40 g, 50.0 mmol)及び市販の(tert-ブトキシカルボニル)-L-リジン(6.20 g, 25.0 mmol)を加え、室温で終夜撹拌した。反応混合物にpHが3になるように4 mol/L 塩酸水溶液を加え、ジクロロメタンで抽出した。有機層を水及び飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン/メタノール=98/2〜97/3)で精製し、N2-(tert-ブトキシカルボニル)-N6-{[(4-エチニルベンジル)オキシ]カルボニル}-L-リジン(4.00 g, 2段階トータル収率40%)を得た。
ESIMS m/z: 405(M + H)+.
工程3で得られたN2-(tert-ブトキシカルボニル)-N6-{[(4-エチニルベンジル)オキシ]カルボニル}-L-リジン(3.40 g, 8.30 mmol)を塩酸-酢酸エチル溶液(25 mL)に溶解し、室温で2時間撹拌した。反応混合物を減圧濃縮し、得られた残渣を逆層分取クロマトグラフィーで精製し、パラ-エチニル-Z-リジン塩酸塩(1.30 g, 50%)を得た。
ESIMS m/z: 305(M ‐ HCl)+; 1H NMR (300 MHz, DMSO-d6,δ): 1.26-1.50 (m, 4H), 1.70-1.84 (m, 2H), 2.94-3.04 (m, 2H), 3.80-3.90 (m, 1H), 4.20 (s, 1H), 5.02 (s, 2H), 7.28-7.38 (m, 3H), 7.47 (d, J = 8.1 Hz, 2H), 8.20-8.36 (br, 3H).
N6-{[(3-アミノベンジル)オキシ]カルボニル}-L-リジン塩酸塩(メタ-アミノ-Z-リジン塩酸塩)
(工程1)
市販の(3-アミノフェニル)メタノール(3.24 g, 26.3 mmol)を用いて、文献記載(Chem. Mater. 2011, 23, 4844.)の合成方法と同様の手法により、tert-ブチル [3-(ヒドロキシメチル)フェニル]カルバメート(7 g, quant.)を得た。
ESIMS m/z: 224(M + H)+.
工程1で得られたtert-ブチル [3-(ヒドロキシメチル)フェニル]カルバメート(1.49 g, 6.70 mmol)を用いて、参考例6の工程2と同様にして、tert-ブチル [3-({[(4-ニトロフェノキシ)カルボニル]オキシ}メチル)フェニル]カルバメートの粗生成物(2.35 g)を得た。得られた粗生成物はそのまま次工程へ用いた。
工程2で得られたtert-ブチル [3-({[(4-ニトロフェノキシ)カルボニル]オキシ}メチル)フェニル]カルバメートの粗生成物(2.35 g)を用いて、参考例6の工程3と同様にして、N2-(tert-ブトキシカルボニル)-N6-[({3-[(tert-ブトキシカルボニル)アミノ]ベンジル}オキシ)カルボニル]-L-リジン(2.90 g, 2段階トータル収率87%)を得た。
ESIMS m/z: 496(M + H)+.
工程3で得られたN2-(tert-ブトキシカルボニル)-N6-[({3-[(tert-ブトキシカルボニル)アミノ]ベンジル}オキシ)カルボニル]-L-リジン(2.80 g, 5.65 mmol)を用いて、参考例4の工程4と同様にして、メタ-アミノ-Z-リジン塩酸塩(1.15 g, 70%)を得た。
ESIMS m/z: 296(M ‐ HCl)+;1H NMR (400 MHz, DMSO-d6,δ):1.24-1.42 (m, 4H), 1.62-1.80 (m, 2H), 2.50 (br s, 2H), 2.93-3.01 (m, 2H), 3.59 (t, J = 5.6 Hz, 1H), 4.84 (s, 2H), 6.42-6.53 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 5.6 Hz, 1H).
N6-{[(3-ホルミルベンジル)オキシ]カルボニル}-L-リジン塩酸塩(メタ-ホルミル-Z-リジン塩酸塩)
(工程1)
市販の(3-ヨードフェニル)メタノール(1.00 g, 4.25 mmol)をTHF(15 mL)に溶解し、メシチレン(0.3 mL, 2.12 mmol)、トリエチルアミン(0.6 mL, 4.25 mmol)及びトリエチルシラン(1.3 mL, 8.40 mmol)を加え、室温で5分間撹拌した。反応混合物に[1,1′-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.700 g, 1.06 mmol)を加え、一酸化炭素封入下(70 psi)、100℃で16時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/石油エーテル=5/95)で精製し、3-(ヒドロキシメチル)ベンズアルデヒド(512 mg, 88%)を得た。
ESIMS m/z: 137(M + H)+.
工程1で得られた3-(ヒドロキシメチル)ベンズアルデヒド(510 mg, 3.75 mmol)を用いて、参考例4の工程2と同様にして、3-ホルミルベンジル カルボノクロリデートの粗生成物(410 mg)を得た。得られた粗生成物はそのまま次工程へ用いた。
工程2で得られた3-ホルミルベンジル カルボノクロリデートの粗生成物(410 mg)を用いて、参考例5工程4と同様にして、N2-(tert-ブトキシカルボニル)-N6-{[(3-ホルミルベンジル)オキシ]カルボニル}-L-リジン(540 mg, 2段階トータル収率66%)を得た。
ESIMS m/z: 409 (M + H)+.
工程3で得られたN2-(tert-ブトキシカルボニル)-N6-{[(3-ホルミルベンジル)オキシ]カルボニル}-L-リジン(540 mg, 1.32 mmol)を用いて、参考例4の工程4と同様にして、メタ-ホルミル-Z-リジン塩酸塩(130 mg, 29%)を得た。
ESIMS m/z: 309(M ‐ HCl)+;1H NMR (400 MHz, DMSO-d6,δ):1.30-1.50 (m, 4H), 1.70-1.85 (m, 2H), 2.90-3.10 (m, 2H), 3.85 (br s, 1H), 5.10 (s, 2H), 7.33 (t, J = 5.2 Hz, 1H), 7.55-7.75 (m, 2H), 7.80-7.94 (m, 2H), 8.28 (br s, 2H), 10.02 (s, 1H), 13.8 (br s, 1H).
配列番号3-人工配列の説明:Trastuzumab-Fab重鎖領域のアミノ酸配列
配列番号4-人工配列の説明:Tacプロモーターとシャイン・ダルガノ配列からなる塩基配列
配列番号5-人工配列の説明:PelB分泌シグナルをコードする塩基配列
配列番号6-人工配列の説明:Trastuzumab-Fab軽鎖領域をコードする塩基配列
配列番号7-人工配列の説明:Trastuzumab-Fab重鎖領域をコードする塩基配列
配列番号8-人工配列の説明:Methanosarcina mazei由来のPyl RS の変異体(Y306A/Y384F)のアミノ酸配列
配列番号9-人工配列の説明:軽鎖κ鎖 126Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号10-人工配列の説明:軽鎖κ鎖 145Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号11-人工配列の説明:軽鎖κ鎖 149Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号12-人工配列の説明:軽鎖κ鎖 169Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号13-人工配列の説明:軽鎖κ鎖 183Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号14-人工配列の説明:軽鎖κ鎖 188Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号15-人工配列の説明:軽鎖κ鎖 190Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号16-人工配列の説明:軽鎖κ鎖 207Lys部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号17-人工配列の説明:重鎖CH1 121Lys部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号18-人工配列の説明:重鎖CH1 133Lys部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号19-人工配列の説明:重鎖CH1 147Lys部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号20-人工配列の説明:重鎖CH1 205Lys部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号21-人工配列の説明:重鎖CH1 210Lys部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号22-人工配列の説明:重鎖CH1 213Lys部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号23-人工配列の説明:重鎖CH1 214Lys部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号24-人工配列の説明:重鎖CH1 118Ala部位へamberコドンを挿入したTrastuzumab-Fab重鎖可変領域および定常領域の塩基配列
配列番号25-人工配列の説明:重鎖CH1 119Ser部位へamberコドンを挿入したTrastuzumab-Fab重鎖可変領域および定常領域の塩基配列
配列番号26-人工配列の説明:重鎖CH1 162Ala部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号27-人工配列の説明:重鎖CH1 176Ser部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号28-人工配列の説明:軽鎖κ鎖119Pro部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号29-人工配列の説明:軽鎖κ鎖138Asn部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号30-人工配列の説明:軽鎖κ鎖141Pro部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号31-人工配列の説明:軽鎖κ鎖147Gln部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号32-人工配列の説明:軽鎖κ鎖155Gln部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号33-人工配列の説明:軽鎖κ鎖158Asn部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号34-人工配列の説明:軽鎖κ鎖161Glu部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号35-人工配列の説明:軽鎖κ鎖167Asp部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号36-人工配列の説明:軽鎖κ鎖180Thr部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号37-人工配列の説明:軽鎖κ鎖191Val部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号38-人工配列の説明:軽鎖κ鎖195Glu部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号39-人工配列の説明:軽鎖κ鎖197Thr部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号40-人工配列の説明:軽鎖κ鎖210Asn部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号41-人工配列の説明:軽鎖κ鎖211Arg部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号42-人工配列の説明:軽鎖κ鎖110Val部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号43-人工配列の説明:軽鎖κ鎖112Ala部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号44-人工配列の説明:軽鎖κ鎖153Ala部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号45-人工配列の説明:軽鎖κ鎖154Leu部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号46-人工配列の説明:軽鎖κ鎖184Ala部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号47-人工配列の説明:軽鎖κ鎖205Val部位へamberコドンを挿入したTrastuzumab-Fab軽鎖定常領域の塩基配列
配列番号48-人工配列の説明:重鎖CH1 120Thr部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号49-人工配列の説明:重鎖CH1 127Pro部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号50-人工配列の説明:重鎖CH1 131Ser部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号51-人工配列の説明:重鎖CH1 135Thr部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号52-人工配列の説明:重鎖CH1 148Asp部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号53-人工配列の説明:重鎖CH1 152Glu部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号54-人工配列の説明:重鎖CH1 159Asn部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号55-人工配列の説明:重鎖CH1 169Thr部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号56-人工配列の説明:重鎖CH1 173Val部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号57-人工配列の説明:重鎖CH1 177Ser部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号58-人工配列の説明:重鎖CH1 180Tyr部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号59-人工配列の説明:重鎖CH1 190Ser部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号60-人工配列の説明:重鎖CH1 199Ile部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号61-人工配列の説明:重鎖CH1 129Ala部位へamberコドンを挿入したTrastuzumab-Fab重鎖定常領域の塩基配列
配列番号62-人工配列の説明:重鎖CH1 174Leu部位へamberコドンを挿入したTrastuzumab-Fab重鎖領域の塩基配列
配列番号63-人工配列の説明:Cixutumumab-Fab軽鎖領域のアミノ酸配列
配列番号64-人工配列の説明:Cixutumumab-Fab重鎖領域のアミノ酸配列
配列番号65-人工配列の説明:Cixutumumab-Fab軽鎖領域をコードする塩基配列
配列番号66-人工配列の説明:Cixutumumab-Fab重鎖領域をコードする塩基配列
配列番号67-人工配列の説明:軽鎖λ鎖110Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号68-人工配列の説明:軽鎖λ鎖129Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号69-人工配列の説明:軽鎖λ鎖149Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号70-人工配列の説明:軽鎖λ鎖156Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号71-人工配列の説明:軽鎖λ鎖166Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号72-人工配列の説明:軽鎖λ鎖172Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号73-人工配列の説明:軽鎖λ鎖187Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号74-人工配列の説明:軽鎖λ鎖207Lys部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号75-人工配列の説明:軽鎖λ鎖119Pro部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号76-人工配列の説明:軽鎖λ鎖125Leu部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号77-人工配列の説明:軽鎖λ鎖137Ser部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号78-人工配列の説明:軽鎖λ鎖160Glu部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号79-人工配列の説明:軽鎖λ鎖161Thr部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号80-人工配列の説明:軽鎖λ鎖165Ser部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号81-人工配列の説明:軽鎖λ鎖173Tyr部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号82-人工配列の説明:軽鎖λ鎖180Ser部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号83-人工配列の説明:軽鎖λ鎖189His部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号84-人工配列の説明:軽鎖λ鎖191Ser部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号85-人工配列の説明:軽鎖λ鎖195Gln部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号86-人工配列の説明:軽鎖λ鎖197Thr部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号87-人工配列の説明:軽鎖λ鎖205Val部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号88-人工配列の説明:軽鎖λ鎖210Ala部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号89-人工配列の説明:軽鎖λ鎖215Ser部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号90-人工配列の説明:軽鎖λ鎖127Ala部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号91-人工配列の説明:軽鎖λ鎖143Ala部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号92-人工配列の説明:軽鎖λ鎖147Ala部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号93-人工配列の説明:軽鎖λ鎖157Ala部位へamberコドンを挿入したCixutumumab-Fab軽鎖領域の塩基配列
配列番号94-人工配列の説明:Farletuzumab-FabのVLの塩基配列
配列番号95-人工配列の説明:Farletuzumab-FabのVHの塩基配列
配列番号96-人工配列の説明:Adalimumab-FabのVLの塩基配列
配列番号97-人工配列の説明:Adalimumab-FabのVHの塩基配列
配列番号98-人工配列の説明:Rituximab-FabのVLの塩基配列
配列番号99-人工配列の説明:Rituximab-FabのVHの塩基配列
配列番号100-人工配列の説明:Bevacizumab-FabのVLの塩基配列
配列番号101-人工配列の説明:Bevacizumab-FabのVHの塩基配列
配列番号102-人工配列の説明:抗体No.2またはNo.5の重鎖の塩基配列
配列番号103-人工配列の説明:抗体No.3またはNo.6の重鎖の塩基配列
配列番号104-人工配列の説明:Trastuzuzumabの軽鎖の塩基配列
配列番号105-人工配列の説明:Trastuzuzumabの重鎖の塩基配列
配列番号106-人工配列の説明:9コピーのU6-tRNAPylの塩基配列
配列番号107-人工配列の説明:Pyl RS (Y306A/Y384F)の変異体の塩基配列
Claims (29)
- 抗体の定常領域に、N6-((ベンジルオキシ)カルボニル)-L-リジン誘導体(以下、Z-リジン誘導体)を少なくとも1つ含む、モノクローナル抗体またはその抗原結合断片であって
EUインデックスにおいて、ヒトIgG抗体の重鎖の177番目ならびにヒト抗体のκ鎖の191および197番目からなる群より選ばれる少なくとも1つのアミノ酸残基がZ-リジン誘導体であり、
前記Z-リジン誘導体がオルト-アジド-Z-リジンである、前記モノクローナル抗体またはその抗原結合断片。 - 少なくとも1つのZ-リジン誘導体が修飾されている、請求項1に記載のモノクローナル抗体またはその抗原結合断片。
- 前記修飾が、Z-リジン誘導体と反応性を有する分子による化学修飾である、請求項2に記載のモノクローナル抗体またはその抗原結合断片。
- 前記Z-リジン誘導体と反応性を有する分子が、親水性高分子、両親媒性高分子および機能性分子からなる群より選ばれる少なくとも1つの分子である、請求項3に記載のモノクローナル抗体またはその抗原結合断片。
- 前記Z-リジン誘導体と反応性を有する分子が、PEG、抗原結合分子、薬物および蛍光化合物からなる群より選ばれる少なくとも1つの分子である、請求項3または4に記載のモノクローナル抗体またはその抗原結合断片。
- 前記抗原結合分子がモノクローナル抗体またはその抗原結合断片である、請求項5に記載のモノクローナル抗体またはその抗原結合断片。
- 前記抗原結合断片が、Fab、Fab’、(Fab’)2、一本鎖抗体(scFv)、二量体化V領域(diabody)、ジスルフィド安定化V領域(dsFv)およびCDRを含むペプチドからなる群より選ばれる抗原結合断片である、請求項1〜6のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片。
- 前記モノクローナル抗体が遺伝子組換え抗体である、請求項1〜7のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片。
- 前記遺伝子組換え抗体がマウス抗体、ラット抗体、ラビット抗体、キメラ抗体、ヒト化抗体またはヒト抗体である、請求項8に記載のモノクローナル抗体またはその抗原結合断片。
- 請求項1〜9のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片をコードする塩基配列を有する核酸。
- 請求項10に記載の核酸を含有するベクター。
- 請求項11に記載のベクターを含む形質転換細胞。
- 前記細胞が原核細胞または真核細胞である、請求項12に記載の形質転換細胞。
- 請求項12または13に記載の形質転換細胞を培地中で培養し、培養物から抗体またはその抗原結合断片を採取することを含む、請求項1〜9のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片の製造方法。
- 請求項1〜9のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片を含む組成物。
- 抗体の定常領域に、N6-(((トランス-シクロオクト-2-エン-1-イル)オキシ)カルボニル)-L-リジン(以下、TCO*-Lys)およびN6-((ビシクロ[6.1.0]ノン-4-イン-9-イルメトキシ)カルボニル)-L-リジン(以下、BCN-Lys)からなる群より選ばれる少なくとも1つのリジン誘導体を含むモノクローナル抗体またはその抗原結合断片であって、
EUインデックスにおいて、ヒトIgG抗体の重鎖の121番目のアミノ酸残基がTCO*-Lysである、および/または、ヒトIgG抗体の重鎖の131番目のアミノ酸残基がTCO*-LysまたはBCN-Lysである、前記モノクローナル抗体またはその抗原結合断片。 - 少なくとも1つのリジン誘導体が修飾されている、請求項16に記載のモノクローナル抗体またはその抗原結合断片。
- 前記修飾が、リジン誘導体と反応性を有する分子による化学修飾である、請求項17に記載のモノクローナル抗体またはその抗原結合断片。
- 前記リジン誘導体と反応性を有する分子が、親水性高分子、両親媒性高分子および機能性高分子からなる群より選ばれる少なくとも1つの分子である、請求項18に記載のモノクローナル抗体またはその抗原結合断片。
- 前記リジン誘導体と反応性を有する分子が、PEG、抗原結合分子、薬物および蛍光化合物からなる群より選ばれる少なくとも1つの分子である、請求項18または19に記載のモノクローナル抗体またはその抗原結合断片。
- 前記抗原結合分子がモノクローナル抗体またはその抗原結合断片である、請求項20に記載のモノクローナル抗体またはその抗原結合断片。
- 前記抗原結合断片が、Fab、Fab’、(Fab’)2、一本鎖抗体(scFv)、二量体化V領域(diabody)、ジスルフィド安定化V領域(dsFv)およびCDRを含むペプチドからなる群より選ばれる抗原結合断片である、請求項16〜21のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片。
- 前記モノクローナル抗体が遺伝子組換え抗体である、請求項16〜22のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片。
- 前記遺伝子組換え抗体がマウス抗体、ラット抗体、ラビット抗体、キメラ抗体、ヒト化抗体またはヒト抗体である、請求項23に記載のモノクローナル抗体またはその抗原結合断片。
- 請求項16〜24のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片をコードする塩基配列を有する核酸。
- 請求項25に記載の核酸を含有するベクター。
- 請求項26に記載のベクターを含む形質転換細胞。
- 請求項27に記載の形質転換細胞を培地中で培養し、培養物から抗体またはその抗原結合断片を採取することを含む、請求項16〜24のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片の製造方法。
- 請求項16〜24のいずれか1項に記載のモノクローナル抗体またはその抗原結合断片を含む組成物。
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