JP6965350B2 - 糖タンパク質再構築のためのエンドグリコシダーゼ変異体及びその使用方法 - Google Patents
糖タンパク質再構築のためのエンドグリコシダーゼ変異体及びその使用方法 Download PDFInfo
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- Enzymes And Modification Thereof (AREA)
Description
式中、R1は、β−1, 4−結合を介して結合した−H又はN−アセチルグルコサミンであり、R2及びR3は、同一又は異なり、それぞれ独立して
からなる群より選択される。
ステップAにおいて、細菌性α−フコシダーゼの存在又は非存在下でエンドグリコシダーゼ(野生型EndoS2)を用いて異質的N−グリカンを担持した天然又は組換えコアフコシル化又は非フコシル化治療用IgG又はIgG−Fc断片を処理することで、2つの還元末端GlcNAc残基の間の結合を加水分解し、コアフコシル化又は非フコシル化GlcNAc−IgGアクセプターを形成する。
ステップBにおいて、活性化オリゴ糖供与体の形態である広範囲の所定オリゴ糖構成単位をコアフコシル化又は非フコシル化GlcNAc−IgGに移転して、化膿レンサ球菌EndoS2変異体を用いたトランスグリコシル化により天然β−1,4−結合を再構成することにより、所定オリゴ糖を再構築コアフコシル化又は非フコシル化IgG又はそのFc断片に結合する。
からなる群より選択される。
ここで、R1は、β−1, 4−結合を介して結合した−H又はN−アセチルグルコサミンであり、R2及びR3は、同一又は異なり、それぞれ独立して、
からなる群より選択される。
ペプチド、治療用タンパク質及びインタクトIgG又はそのFc断片の糖鎖工学のためのEndoS2変異体の調製
9
9
式中、R1は、β−1,4結合を介して結合した−H又はN−アセチルグルコサミンであり、R2及びR3は、同一又は異なり、それぞれ独立して
からなる群より選択される。
FcγRIIIAと糖鎖改変リツキシマブとの結合
糖鎖改変リツキシマブのADCC活性
抗CD20抗体の糖鎖工学の方法
ここで、R1は、β−1,4結合を介して結合した−H又はN−アセチルグルコサミンであり、R2及びR3は、同一又は異なり、それぞれ独立して
からなる群より選択される。
医薬製剤
治療への使用
材料及び方法
市販のリツキシマブを用いたGlcNAc-リツキシマブの調製。
グリカン−オキサゾリンの調製
EndoS2及びその変異体の加水分解活性のアッセイ
SCT−オキサゾリンを供与体基質として用いたEndoS2及びその変異体のトランスグリコシル化活性のアッセイ
EndoS2変異体を用いた種々のグリカンオキサゾリンを含むGlcNAc−リツキシマブに対するトランスグリコシル化
ELISAによりFcγIIA受容体に対するリツキシマブの再構築グライコフォームの親和性を調べた。
糖鎖改変抗CD20抗体のADCC活性
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Claims (11)
- 野生型EndoS2(配列番号1)に1以上の変異を含むエンドグリコシダーゼS2(EndoS2)の変異体であって、
前記1以上の変異は、残基T138、D226、T227及び/又はT228にあり、前記EndoS2の変異体は、加水分解活性が野生型EndoS2よりも低く、トランスグリコシル化活性が野生型EndoS2よりも高い、エンドグリコシダーゼS2(EndoS2)の変異体。 - 前記1以上の変異は、T138D、T138E、T138F、T138H、T138K、T138L、T138M、T138N、T138Q、T138R、T138V、T138W、D226Q、T227Q及びT228Qからなる群より選択される、請求項1に記載のEndoS2の変異体。
- 前記変異体は、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号3、配列番号4又は配列番号5に示される配列を含む、請求項1に記載のEndoS2の変異体。
- 活性化オリゴ糖を糖タンパク質アクセプターに結合することを含む、請求項1〜3のいずれか1項に記載のEndoS2の変異体を用いた工学的に改造された糖タンパク質の製造方法。
- 前記活性化オリゴ糖は、グリカンオキサゾリンである、請求項4に記載の方法。
- 前記糖タンパク質アクセプターは、GlcNAc単糖を含む請求項4に記載の方法。
- 前記糖タンパク質アクセプターは、非フコシル化GlcNAc−受容体である、請求項4に記載の方法。
- 前記糖タンパク質アクセプターは、グリコペプチド、糖タンパク質、抗体、又はその断片である、請求項4に記載の方法。
- 前記糖タンパク質アクセプターは、コアフコシル化又は非フコシル化GlcNAC−IgGアクセプター又はその断片である、請求項4に記載の方法。
- 前記GlcNAC−IgGアクセプターは、セツキシマブ、リツキシマブ、ムロモナブ−CD3、アブシキシマブ、ダクリズマブ、バシリキシマブ、パリビズマブ、インフリキシマブ、トラスツズマブ、ゲムツズマブオゾガミシン、アレムツズマブ、イブリツモマブチウキセタン、アダリムマブ、オマリズマブ、トシツモマブ、1−131トシツモマブ、エファリズマブ、ベバシズマブ、パニツムマブ、ペルツズマブ、ナタリズマブ、エタネルセプト、IGN101、ボロシキシマブ、抗CD80 mAb、抗CD23 mAb、CAT−3888、CDP−791、エラプトズマブ、MDX−010、MDX−060、MDX−070、マツズマブ、CP−675,206、CAL、SGN−30、ザノリムマブ、アデカツムマブ、オレゴボマブ、ニモツズマブ、ABT−874、デノスマブ、AM 108、AMG 714、フォントリズマブ、ダクリズマブ、ゴリムマブ、CNTO 1275、オクレリズマブ、HuMax−CD20、ベリムマブ、エプラツズマブ、MLN1202、ビジリズマブ、トシリズマブ、オクレリズマブ、セルトリズマブペゴル、エクリズマブ、ペキセリズマブ、アブシキシマブ、ラニビジムマブからなる群より選択されるモノクローナル抗体に由来する、請求項10に記載の方法。
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