JP2020517275A - タンパク質の純度及び抗原に対する親和性が向上したポリペプチド、その抗体または抗原結合断片との複合体、及びこれらの製造方法 - Google Patents
タンパク質の純度及び抗原に対する親和性が向上したポリペプチド、その抗体または抗原結合断片との複合体、及びこれらの製造方法 Download PDFInfo
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- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
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- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
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- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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Classifications
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
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Abstract
Description
i)以下の一般式1の23番目のアミノ酸TがNに置換されるか、
ii)以下の一般式1の54番目のアミノ酸SがAに置換されるか、または
iii)以下の一般式1の23番目のアミノ酸Tと、54番目のアミノ酸Sが各々N及びAに置換されて真核細胞内で生産時、グリコシレーション(glycosylation)が防止されて、タンパク質の純度及びターゲット抗原に対する親和性(affinity)が向上することを特徴とするポリペプチドを提供する:
(一般式1)
VDX3KX5X6KEX9X10X11AX13X14EIX17X18LPNLTX24X25QX27X28AFIX32X33LX35DDPSQSX42X43LLX46EAKKLNDSQAPK;
前記一般式1で、各々のX3、X5、X6、X9、X10、X11、X13、X14、X17、X18、X24、X25、X27、X28、X32、X33、X35、X42、X43、及びX46は独立的な任意のアミノ酸残基であって、
X3は、A及びNから選択され、
X5は、F及びYから選択され、
X6は、A及びNから選択され、
X9は、A、B、C、E、G、H、K、L、M、S、T、V、及びQから選択され、
X10は、A、B、F、G、H、K、L、M、P、Q、R、S、T、V、W、及びYから選択され、
X11は、A、B、C、D、E、F、G、H、I、K、L、M、N、P、Q、R、V、W、及びYから選択され、
X13は、C、D、F、G、H、I、L、P、Q、S、T、及びVから選択され、
X14は、A、C、D、E、F、H、I、K、L、M、N、P、Q、R、S、T、V、W、及びYから選択され、
X17は、A、B、E、F、G、H、I、L、M、P、Q、R、T、V、W、及びYから選択され、
X18は、A、D、E、F、G、H、I、K、L、N、R、S、T、V、W、及びYから選択され、
X24は、A、C、D、E、F、G、I、K、L、M、N、P、Q、R、S、T、V、及びWから選択され、
X25は、A、C、D、E、G、H、I、K、L、M、N、Q、R、S、T、V、W、及びYから選択され、
X27は、A、C、G、H、I、K、L、M、P、Q、R、S、T、V、及びWから選択され、
X28は、A、B、E、F、G、I、K、L、M、N、P、Q、R、S、T、V、及びYから選択され、
X32は、A、D、F、G、I、L、M、N、Q、R、S、T、V、Wから選択され、
X33は、K、Sから選択され、
X35は、A、D、E、F、G、H、I、K、L、M、P、Q、R、S、T、V、W、及びYから選択され、
X42は、A及びSから選択され、
X43は、A、C、及びSから選択され、
X46は、D、E、及びSから選択される。
i)以下の一般式2の23番目のアミノ酸TがNに置換されるか、
ii)以下の一般式2の54番目のアミノ酸SがAに置換されるか、
または、iii)以下の一般式2の23番目のアミノ酸Tと、54番目のアミノ酸Sが各々N及びAに置換されて真核細胞内で生産時、グリコシレーション(glycosylation)が防止されて、タンパク質の純度及びターゲット抗原に対する親和性(affinity)が向上することを特徴とするポリペプチドを提供する:
(一般式2)
AEAKYAKEX9X10X11AIX17X18LPNLTX24X25QX27X28AFIX32X33LX35DDPSQSX42X43LLX46EAKKLNDSQAPK;
前記一般式2で、各々のX9、X10、X11、X13、X14、X17、X18、X24、X25、X27、X28、X32、X33、X35、X42、X43、及びX46は独立的な任意のアミノ酸残基であって、前記一般式1で定義したものと同一な意味を有する。
X9は、E、G、及びMから選択され、
X10は、A、F、H、K、Q、R、S、W、及びYから選択され、
X11は、A、D、E、F、H、I、K、L、M、N、Q、R、S、T、V、及びYから選択され、
X13は、C、D、F、G、H、I、L、P、Q、S、T、及びVから選択され、
X14は、F、H、I、K、L、M、N、R、S、T、V、W、及びYから選択され;
X17は、A、B、E、F、G、H、I、L、M、P、Q、R、T、V、W、及びYから選択され、
X18は、A、I、K、L、M、N、R、S、T、及びVから選択され;
X24は、A、I、T、及びVから選択され、
X25は、D、E、G、H、K、N、Q、R、S、及びTから選択され;
X27は、I、L、M、R、T、及びVから選択され;
X28は、A、S、T、及びVから選択され;
X32は、I、M、Q、S、T、V、及びWから選択され;
X33は、K、Sから選択され、
X35は、F、L、M、S、V、及びYから選択できる。
(1)Fab断片、これはVL−CLチェーン及びVH−CH1チェーンを有する一価断片である;(2)Fab'断片、これは重鎖ヒンジ領域(hinge region)を有しているFab断片である;(3)F(ab')2断片、これは重鎖ヒンジ領域により連結された、例えば、ヒンジ領域での二硫化結合により連結されたFab'の二合体である;(5)Fv断片、これは抗体の単一幹(arm)のVL及びVHを有する最小限の抗体断片である;(6)単一チェーンFv(scFv)断片、これはペプチドリンカーにより連結されたscFvのVH及びVLドメインの単一ポリペプチドチェーンである;(7)(scFv)2、これは2つのVHドメイン及び2つのVLドメインを含み、これらは二硫化結合による2つのVHドメインを通じて連結されている;及び(8)ドメイン抗体、これは特異的に抗原に結合する抗体単一可変領域(VHまたはVL)ポリペプチドでありうる。
ここで、前記n、m、及びpは独立的に、
nは、1乃至7の整数であり;
mは、0乃至7の整数であり;
nとmの和は、8以下の整数であり;及び
pは、1乃至7の整数である。
(a)前記ポリペプチドをコーディングする核酸を発現ベクターに挿入させるステップ;
(b)前記発現ベクターを宿主細胞に形質転換させるステップ;及び
(c)前記宿主細胞を培養してポリペプチドを収得するステップ。
(a)前記ポリペプチド(アフィボディ分子)と抗体または抗原結合断片が連結された複合体をコーディングする核酸を発現ベクターに挿入させるステップ;
(b)前記発現ベクターを真核細胞である宿主細胞に形質転換させるステップ;及び
(c)前記宿主細胞を培養してポリペプチド複合体を収得するステップ。
(a)本発明は、真核細胞内で生産されてもグリコシレーションが防止されてタンパク質の純度及びIL−6に対する親和性が向上するポリペプチド(アフィボディ分子)を提供する。
〔図面の簡単な説明〕
図1は、本発明のグリコシレーションが発生しないように突然変異を誘導するために使われる発現ベクター(pcDNA3.3ベクター、invitrogen, cat. #. K8300-01)のベクターマップを示した図である。
序列目録第1序列のアミノ酸序列からなる、IL−6に特異的に結合するアフィボディタンパク質を、TNFに対する抗体(アダリムマブ、adalimumab;序列目録第5序列の重鎖及び第6序列の軽鎖を含み)と遺伝的に結合した二重抗体を動物細胞(HEK293F細胞)で生産するとグリコシレーションが発生して二重抗体タンパク質の分子量が一定でなく、多数個のバンドとして表れることを確認した(図2−4のLane 1 Parent参照)。前記序列目録第1序列のアミノ酸序列からなるアフィボディタンパク質の1次序列を分析した結果、21番目と52番目のアミノ酸位置のアスパラギン(Asn、N)でグリコシレーションが発生する可能性が予測された(Eisenhaber B & Eisenhaber F, 2010, Methods Mol Biol.)。
前記実施例1で製作した変異序列を用いた3種の二重抗体変異体とparent序列の二重抗体はHEK293F細胞を用いて生産した。
アフィボディタンパク質のグリコシレーションによる標的タンパク質に対する結合力変化を次のように分析した。
Claims (17)
- 以下の一般式1のアミノ酸序列を含むポリペプチドにおいて、
i)以下の一般式1の23番目のアミノ酸TがNに置換されるか、ii)以下の一般式2の54番目のアミノ酸SがAに置換されるか、またはiii)以下の一般式1の23番目のアミノ酸Tと、以下の一般式2の54番目のアミノ酸Sが各々N及びAに置換されて真核細胞内で生産時、グリコシレーション(glycosylation)が防止されて、タンパク質の純度及びターゲット抗原に対する親和性(affinity)が向上することを特徴とする、ポリペプチド:
(一般式1)
VDX3KX5X6KEX9X10X11AX13X14EIX17X18LPNLTX24X25QX27X28AFIX32X33LX35DDPSQSX42X43LLX46EAKKLNDSQAPK;
前記一般式1で、各々のX3、X5、X6、X9、X10、X11、X13、X14、X17、X18、X24、X25、X27、X28、X32、X33、X35、X42、X43、及びX46は独立的な任意のアミノ酸残基であって、
X3は、A及びNから選択され、
X5は、F及びYから選択され、
X6は、A及びNから選択され、
X9は、A、B、C、E、G、H、K、L、M、S、T、V、及びQから選択され、
X10は、A、B、F、G、H、K、L、M、P、Q、R、S、T、V、W、及びYから選択され、
X11は、A、B、C、D、E、F、G、H、I、K、L、M、N、P、Q、R、V、W、及びYから選択され、
X13は、C、D、F、G、H、I、L、P、Q、S、T、及びVから選択され、
X14は、A、C、D、E、F、H、I、K、L、M、N、P、Q、R、S、T、V、W、及びYから選択され、
X17は、A、B、E、F、G、H、I、L、M、P、Q、R、T、V、W、及びYから選択され、
X18は、A、D、E、F、G、H、I、K、L、N、R、S、T、V、W、及びYから選択され、
X24は、A、C、D、E、F、G、I、K、L、M、N、P、Q、R、S、T、V、及びWから選択され、
X25は、A、C、D、E、G、H、I、K、L、M、N、Q、R、S、T、V、W、及びYから選択され、
X27は、A、C、G、H、I、K、L、M、P、Q、R、S、T、V、及びWから選択され、
X28は、A、B、E、F、G、I、K、L、M、N、P、Q、R、S、T、V、及びYから選択され、
X32は、A、D、F、G、I、L、M、N、Q、R、S、T、V、Wから選択され、
X33は、K、Sから選択され、
X35は、A、D、E、F、G、H、I、K、L、M、P、Q、R、S、T、V、W、及びYから選択され、
X42は、A及びSから選択され、
X43は、A、C、及びSから選択され、
X46は、D、E、及びSから選択される。 - 以下の一般式2のアミノ酸序列を含むポリペプチドにおいて、
i)以下の一般式1の23番目のアミノ酸TがNに置換されるか、ii)以下の一般式2の54番目のアミノ酸SがAに置換されるか、またはiii)以下の一般式1の23番目のアミノ酸Tと、以下の一般式2の54番目のアミノ酸Sが各々N及びAに置換されて真核細胞内で生産時、グリコシレーション(glycosylation)が防止されて、タンパク質の純度及びターゲット抗原に対する親和性(affinity)が向上することを特徴とする、ポリペプチド:
(一般式2)
AEAKYAKEX9X10X11AIX17X18LPNLTX24X25QX27X28AFIX32X33LX35DDPSQSX42X43LLX46EAKKLNDSQAPK;
前記一般式2で、各々のX9、X10、X11、X13、X14、X17、X18、X24、X25、X27、X28、X32、X33、X35、X42、X43、及びX46は独立的な任意のアミノ酸残基であって、
X9は、A、B、C、E、G、H、K、L、M、S、T、V、及びQから選択され、
X10は、A、B、F、G、H、K、L、M、P、Q、R、S、T、V、W、及びYから選択され、
X11は、A、B、C、D、E、F、G、H、I、K、L、M、N、P、Q、R、V、W、及びYから選択され、
X13は、C、D、F、G、H、I、L、P、Q、S、T、及びVから選択され、
X14は、A、C、D、E、F、H、I、K、L、M、N、P、Q、R、S、T、V、W、及びYから選択され、
X17は、A、B、E、F、G、H、I、L、M、P、Q、R、T、V、W、及びYから選択され、
X18は、A、D、E、F、G、H、I、K、L、N、R、S、T、V、W、及びYから選択され、
X24は、A、C、D、E、F、G、I、K、L、M、N、P、Q、R、S、T、V、及びWから選択され、
X25は、A、C、D、E、G、H、I、K、L、M、N、Q、R、S、T、V、W、及びYから選択され、
X27は、A、C、G、H、I、K、L、M、P、Q、R、S、T、V、及びWから選択され、
X28は、A、B、E、F、G、I、K、L、M、N、P、Q、R、S、T、V、及びYから選択され、
X32は、A、D、F、G、I、L、M、N、Q、R、S、T、V、Wから選択され、
X33は、K、Sから選択され、
X35は、A、D、E、F、G、H、I、K、L、M、P、Q、R、S、T、V、W、及びYから選択され、
X42は、A及びSから選択され、
X43は、A、C、及びSから選択され、
X46は、D、E、及びSから選択される。 - 前記一般式1のX3、X5、X6、X9、X10、X11、X13、X14、X17、X18、X24、X25、X27、X28、X32、X33、X35、X42、X43、及びX46;及び
前記一般式2のX9、X10、X11、X17、X18、X24、X25、X27、X28、X32、X33、X35、X42、X43、及びX46は独立的な任意のアミノ酸残基であって;
X9は、E、G、及びMから選択され;
X10は、A、F、H、K、Q、R、S、W、及びYから選択され;
X11は、A、D、E、F、H、I、K、L、M、N、Q、R、S、T、V、及びYから選択され;
X13は、C、D、F、G、H、I、L、P、Q、S、T、及びVから選択され;
X14は、F、H、I、K、L、M、N、R、S、T、V、W、及びYから選択され;
X17は、A、B、E、F、G、H、I、L、M、P、Q、R、T、V、W、及びYから選択され;
X18は、A、I、K、L、M、N、R、S、T、及びVから選択され;
X24は、A、I、T、及びVから選択され;
X25は、D、E、G、H、K、N、Q、R、S、及びTから選択され;
X27は、I、L、M、R、T、及びVから選択され;
X28は、A、S、T、及びVから選択され;
X32は、I、M、Q、S、T、V、及びWから選択され;
X33は、K、Sから選択され;
X35は、F、L、M、S、V、及びYから選択されたことを特徴とする、請求項1または2に記載のポリペプチド。 - 前記ポリペプチドはターゲット抗原がIL−6(interleukin-6)であり、序列目録第2序列乃至第4序列のうち、いずれか1つのアミノ酸序列からなることを特徴とする、請求項2に記載のポリペプチド。
- i)請求項1乃至3のうち、いずれか一項のポリペプチド;及び
ii)抗体またはその抗原結合断片が連結されたポリペプチド複合体。 - 前記ii)抗体またはその抗原結合断片のターゲット抗原はアンギオジェニン(angiogenin 2、Ang−2)、血管表皮成長因子(vascular endothelial growth factor)、腫瘍壊死因子(tumor necrosis factor)、TNF−α、TNFSF11、TNFSF13、TNFSF13B、TNFSF14、TNFSF15、インシュリン−類似成長因子(insulin-like growth factor)、インターリューキン1α、インターリューキン1β、インターリューキン10、インターリューキン17A、インターリューキン12、インターリューキン23、インターリューキン33、顆粒大食細胞集落刺戟因子(granulocyte macrophage colony-stimulating factor)、顆粒球集落刺激因子(granulocyte colonystimulating factor)、高い−移動性グループタンパク質(high-mobility group protein)B1、脂質多糖類(lipopolysaccharide)、Toll−様受容体(toll-like receptor 4)、神経成長因子(nerve growth factor)、ケモカインC−Cモチーフリガンド(chemokine C-C motif ligand)19、ケモカインC−Cモチーフリガンド21、ケモカインC−X−Cモチーフリガンド4、及びインターフェロンアルファ(α)で構成される群から選択される抗原であることを特徴とする、請求項5に記載のポリペプチド複合体。
- 前記ii)抗体またはその抗原結合断片のターゲット抗原はTNF−αであることを特徴とする、請求項5に記載のポリペプチド複合体。
- 前記抗体またはその抗原結合断片は、アダリムマブ(adalimumab)、インフリキシマブ(infliximab)、ゴリムマブ(golimumab)、及びセルトリズマブペゴル(certolizumab pegol)、及びその抗原結合断片で構成されるグループから選択されるもの、例えばアダリムマブ(adalimumab)、インフリキシマブ(infliximab)、ゴリムマブ(golimumab)、及びセルトリズマブペゴル(certolizumabpegol)からなる群より選択される全長抗体であることを特徴とする、請求項5に記載のポリペプチド複合体。
- 前記抗体またはその抗原結合断片は序列目録第5序列のアミノ酸序列を含むことを特徴とする、請求項5に記載のポリペプチド複合体。
- 前記ポリペプチド複合体のi)ポリペプチドとii)抗体またはその抗原結合断片は少なくとも1つのリンカーで連結されたことを特徴とする、請求項5に記載のポリペプチド複合体。
- 前記リンカーは、一般式(GnSm)pまたは(SmGn)pと表示されるアミノ酸序列からなることを特徴とする、請求項10に記載のポリペプチド複合体:
前記n、m、及びpは独立的に、
nは、1乃至7の整数であり;
mは、0乃至7の整数であり;
nとmの和は、8以下の整数であり;及び
pは、1乃至7の整数である。 - 請求項1乃至3のうち、いずれか一項のポリペプチドをコーディングするヌクレオチド序列からなる、核酸。
- 請求項5のポリペプチド複合体をコーディングするヌクレオチド序列からなる、核酸。
- 次のステップを含むグリコシレーションが防止されてタンパク質の純度及び抗原に対する親和性が向上したポリペプチドの製造方法:
(a)請求項12の核酸を発現ベクターに挿入させるステップ;
(b)前記発現ベクターを宿主細胞に形質転換させるステップ;及び
(c)前記宿主細胞を培養してポリペプチドを収得するステップ。 - 前記宿主細胞は真核細胞であることを特徴とする、請求項14に記載の方法。
- 次のステップを含むグリコシレーションが防止されてタンパク質の純度及び抗原に対する親和性が向上したポリペプチド複合体の製造方法:
(a)請求項13の核酸を発現ベクターに挿入させるステップ;
(b)前記発現ベクターを真核細胞である宿主細胞に形質転換させるステップ;及び
(c)前記宿主細胞を培養してポリペプチド複合体を収得するステップ。 - 前記宿主細胞は真核細胞であることを特徴とする、請求項16に記載の方法。
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