JP6657392B2 - 二重特異性抗ヒトcd20/ヒトトランスフェリン受容体抗体及び使用方法 - Google Patents
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- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/522—CH1 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/66—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Description
a)(完全長)抗体軽鎖及び(完全長)抗体重鎖の対を二つ含み、(完全長)重鎖及び(完全長)軽鎖の対のそれぞれにより形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)(完全長)抗体の一の重鎖の任意のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片
を含む二重特異性抗体であって、
(完全長)抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け)を含み、
(完全長)抗体重鎖のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EUインデックスに従って番号付け)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン1(CH1)が互いに置き換えわるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体である、二重特異性抗体である。
a)さらなるFab断片に融合している(完全長)重鎖は、C末端重鎖アミノ酸残基としてトリペプチドLSPを有し、そのプロリンが、さらなるFab断片の、又はペプチド結合を介してペプチド性リンカーの第一のアミノ酸残基に直接融合し、
b)さらなるFab断片に融合していない(完全長)重鎖が、C末端重鎖アミノ酸残基として、トリペプチドLSP又はSPG又はPGKを有する
a)ヒトサブクラスIgG1の完全長抗体、
b)ヒトサブクラスIgG4の完全長抗体、
c)変異L234A、L235A及びP329Gを有するヒトサブクラスIgG1の完全長抗体、
d)変異S228P、L235E及びP329Gを有するヒトサブクラスIgG4の完全長抗体、
e)両方の重鎖中に変異L234A、L235A及びP329Gを、一方の重鎖中に変異i)T366W、及びii)S354C又はY349Cを、それぞれの他方の重鎖中に変異i)T366S、L368A及びY407V、並びにii)Y349C又はS354Cを有するヒトサブクラスIgG1の完全長抗体、
f)両方の重鎖中に変異S228P、L235E、P329Gを、一方の重鎖中に変異i)T366W、及びii)S354C又はY349Cを、それぞれの他方の重鎖中に変異i)T366S、L368A及びY407V、並びにii)Y349C又はS354Cを有するヒトサブクラスIgG4の完全長抗体、
g)両方の重鎖中に変異L234A、L235A、P329G、I253A、H310A及びH435Aを、一方の重鎖中に変異i)T366W、及びii)S354C又はY349Cを、それぞれの他方の重鎖中に変異i)T366S、L368A及びY407V、並びにii)Y349C又はS354Cを有するヒトサブクラスIgG1の完全長抗体、又は
h)両方の重鎖中に変異L234A、L235A、P329G、M252Y、S254T及びT256Eを、一方の重鎖中に変異i)T366W、及びii)S354C又はY349Cを、それぞれの他方の重鎖中に変異i)T366S、L368A及びY407V、並びにii)Y349C又はS354Cを有するヒトサブクラスIgG1の完全長抗体、又は
i)両方の重鎖中に変異L234A、L235A、P329G、H310A、H433A及びY436Aを、一方の重鎖中に変異i)T366W、及びii)S354C又はY349Cを、それぞれの他方の重鎖中に変異i)T366S、L368A及びY407V、並びにii)Y349C又はS354Cを有するヒトサブクラスIgG1の完全長抗体である。
(完全長)抗体は、両方の重鎖中に変異L234A、L235A及びP329Gを、一の重鎖中に変異T366W及びS354Cを、それぞれの他の重鎖中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1の(完全長抗体)であり、
さらなるFab断片は、変異T366Wを含む重鎖のC末端、又は変異T366S、L368A及びY407Vを含む重鎖のC末端に融合している。
i)70%以上の配列番号01に対する配列同一性を有する軽鎖、
ii)70%以上の配列番号02に対する配列同一性を有する重鎖、
iii)70%以上の配列番号03に対する配列同一性を有する軽鎖、及び
iv)70%以上の配列番号04に対する配列同一性を有する重鎖Fab断片
を含み、ここで、
配列番号01はアミノ酸配列
DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
を有し、
配列番号02はアミノ酸配列
QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
を有し、
配列番号03はアミノ酸配列
AIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
を有し、
配列番号04はアミノ酸配列
QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
を有する。
a)各結合部位が第一の抗原に特異的に結合する、第一及び第二のFab断片、
b)結合部位が第二の抗原に特異的に結合し、可変軽鎖ドメイン(VL)及び可変重鎖ドメイン(VH)が互いに置き換えられるようにドメインクロスオーバーを含む、第三のFab断片、
c)第一のFc領域ポリペプチド及び第二のFc領域ポリペプチドを含むFc領域、
を含み、
第一及び第二のFab断片がそれぞれ、重鎖断片及び完全長軽鎖を含み、
第一のFab断片の重鎖断片のC末端が、第一のFc領域ポリペプチドのN末端に融合しており、
第二のFab断片の重鎖断片のC末端が、第三のFab断片の可変軽鎖ドメインのN末端に融合し、第三のFab断片の重鎖定常ドメイン1のC末端が、第二のFc領域ポリペプチドのN末端に融合しており、
第一及び第二のFab断片の完全長抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け。)を含み、
第一及び第二のFab断片の重鎖断片のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EUインデックスに従って番号付け。)を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体である、
二重特異性抗体である。
a)ヒトサブクラスIgG1のFc領域ポリペプチド、
b)ヒトサブクラスIgG4のFc領域ポリペプチド、
c)変異L234A、L235A及びP329Gを有するヒトサブクラスIgG1のFc領域ポリペプチド、
d)変異228P、L235E及びP329Gを有するヒトサブクラスIgG4のFc領域ポリペプチド、
e)両方のFc領域ポリペプチド中に変異L234A、L235A及びP329Gを、一のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれの他のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1のFc領域ポリペプチド、
f)両方のFc領域ポリペプチド中にS228P、L235E及びP329Gを、一のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれの他のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG4のFc領域ポリペプチド、
g)両方のFc領域ポリペプチド中に変異L234A、L235A、P329G、I253A、H310A及びH435Aを、一のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれの他のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1のFc領域ポリペプチド、又は
h)両方のFc領域ポリペプチドに変異L234A、L235A、P329G、M252Y、S254T及びT256Eを、一のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれ他のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1のFc領域ポリペプチド、又は
i)両方のFc領域ポリペプチド中に変異L234A、L235A、P329G、H310A、H433A及びY436Aを、一のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれ他のFc領域ポリペプチド中に変態T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1のFc領域ポリペプチドである。
i)少なくとも70%、又は少なくとも80%、又は少なくとも90%、又は95%以上の配列番号14に対する配列同一性を有する軽鎖、
ii)少なくとも70%、又は少なくとも80%、又は少なくとも90%、又は95%以上の配列番号15に対する配列同一性を有する重鎖、
iii)少なくとも70%、又は少なくとも80%、又は少なくとも90%、又は95%以上の配列番号16に対する配列同一性を有する交差抗体鎖、
iv)少なくとも70%、又は少なくとも80%、又は少なくとも90%、又は95%以上の配列番号17に対する配列同一性を有する修飾された重鎖
を含み、ここで、
配列番号14はアミノ酸配列
DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
を有し、
配列番号15はアミノ酸配列
QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
を有し、
配列番号16はアミノ酸配列
QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
を有し、
配列番号17はアミノ酸配列
QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDGGGGSGGGGSAIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
を有する。
a)二重特異性抗体が産生されるように、本明細書で報告される宿主細胞を培養すること
b)細胞又は培養媒体から二重特異性抗体を回収し、それにより、本明細書で報告される二重特異性抗体を産生すること
「血液脳関門」又は「BBB」は、脳毛細血管内皮細胞原形質膜内の密着結合によって形成される末梢循環と脳及び脊髄との間の生理的関門を指し、脳への分子(尿素(60ダルトン)のような非常に小さな分子さえも含む。)の輸送を制限する密着した関門を生じる。脳内のBBB、脊髄内の血液脊髄関門、及び網膜内の血液網膜関門は、CNS内の近接する毛細血管関門であり、本明細書ではまとめて血液脳関門又はBBBと称する。BBBはまた、血液CSF関門(脈絡叢)を包含し、この関門は、毛細管内皮細胞ではなく上衣細胞からなる。
− FcγRI(CD64)は、高い親和性を有するモノマーIgGを結合し、マクロファージ、単球、好中球及び好酸球上で発現すること。アミノ酸残基E233−G236、P238、D265、N297、A327及びP329(KabatのEUインデックスに従い番号付け。)の少なくとも一のFc領域IgGにおける改変は、FcγRIへの結合を減少させる。IgG1及びIgG4に置換される、233〜236位のIgG2残基は、FcγRIへの結合を103倍減少させ、抗体−感受性化赤血球に対するヒト単球応答を削減した(Armour, K.L., et al., Eur. J. Immunol. 29(1999)2613-2624)。
− FcγRII(CD32)は、中程度から低い親和性で複合体化したIgGに結合し、広く発現している。この受容体は、二のサブタイプ、FcγRIIA及びFcγRIIBに分けることができる。FcγRIIAは、殺傷に関与する多くの細胞(例えば、マクロファージ、単球、好中球)に見られ、殺傷プロセスを活性化することができるようである。FcγRIIBは、阻害過程で役割を果たすようであり、B-細胞、マクロファージ、及びマスト細胞及び好酸球で見られる。それは、B細胞上では、更なる免疫グロブリンの産生及び例えばIgEクラスへのアイソタイプスイッチングを抑制するよう機能するようである。マクロファージ上では、FcγRIIBは、FcγRIIAを通じて媒介されるような、食作用を阻害するよう作用する。好酸球及びマスト細胞上では、B型は、その分離した受容体へのIgE結合を通じたこれらの細胞の活性化を抑制するのを助けうる。FcγRIIAへの減少した結合は、例えば、アミノ酸残基E233−G236、P238、D265、N297、A327、P329、D270、Q295、A327、R292及びK414(KabatのEUインデックスに従い番号付け。)の少なくとも一の変異を有するIgGFc領域を含む抗体で見られる。
− FcγRIII(CD16)は、中程度から低い親和性でIgGに結合し、二種類で存在する。FcγRIIIAは、NK細胞、マクロファージ、好酸球並びにいくつかの単球及びT細胞上で見られ、ADCCを媒介する。FcγRIIIBは、好中球で多く発現する。FcγRIIIAへの減少した結合は、例えば、アミノ酸残基E233−G236、P238、D265、N297、A327、P329、D270、Q295、A327、S239、E269、E293、Y296、V303、A327、K338及びD376(KabatのEUインデックスに従い番号付け。)の少なくとも一の変異を有するIgGFc領域を含む抗体で見られる。
(a)アミノ酸残基26〜32(L1)、50〜52(L2)、91〜96(L3)、26〜32(H1)、53〜55(H2)、及び96〜101(H3)に生じる超可変ループ(Chothia, C. and Lesk, A.M., J. Mol. Biol. 196(1987)901-917);
(b)アミノ酸残基24〜34(L1)、50〜56(L2)、89〜97(L3)、31〜35b(H1)、50〜65(H2)、及び95〜102(H3)に生じるCDR(Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD(1991), NIH Publication 91-3242.);
(c)アミノ酸残基27c〜36(L1)、46〜55(L2)、89〜96(L3)、30〜35b(H1)、47〜58(H2)、及び93−101(H3)に生じる抗原コンタクト(MacCallum et al., J. Mol. Biol. 262(1996)732-745);並びに
(d)HVRアミノ酸残基46〜56(L2)、47〜56(L2)、48〜56(L2)、49〜56(L2)、26〜35(H1)、26〜35b(H1)、49〜65(H2)、93〜102(H3)、及び94〜102(H3)を含む、(a)、(b)、及び/又は(c)の組み合わせ
を含む。
分率X/Yの100倍
ここで、Xは配列アラインメントプログラムALIGN−2により、AとBのそのプログラムのアラインメントにおいて同一であるとして一致したスコアのアミノ酸残基の数であり、YはBの全アミノ酸残基数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと異なる場合、AのBに対する%アミノ酸配列同一性は、BのAに対する%アミノ酸配列同一性とは異なることは理解されるであろう。特に断らない限り、本明細書で使用されるすべての%アミノ酸配列同一性値は、ALIGN−2コンピュータプログラムを使用して、直前の段落で説明したように得られる。
一態様において、本発明は、一つには、本明細書で報告される二重特異性抗ヒトCD20/ヒトトランスフェリン受容体抗体が改善された特性を有するという発見に基づいている。ある実施態様において、二重特異性抗ヒトCD20/ヒトトランスフェリン受容体抗体が提供される。本明細書で報告される抗体は、例えば、パーキンソン病又は多発性硬化症の診断又は治療に有用である。
一態様において、本発明は、ヒトCD20及びヒトトランスフェリン受容体に結合する単離された二重特異性抗体を提供する。抗体は、(完全長)コア抗体及び特定のドメインが交差して変化している融合したFab断片から成る二重特異性抗体である。したがって、結果として生じる二重特異性抗体は不斉である。それゆえ、二重特異性抗体は、いわゆるノブ変異(HCknob)を有する第一の重鎖及びいわゆるホール変異(HChole)を有する第二の重鎖を使用したノブ・イントゥー・ホールと呼ばれるヘテロ二量体化技術を使用して産生される。
a)それぞれ、完全長抗体軽鎖及び完全長抗体重鎖の二対を含み、完全長重鎖及び完全長軽鎖のそれぞれの対により形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)完全長抗体の一の重鎖のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片を含み、
完全長抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け。)を含み、
完全長抗体重鎖のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EUインデックスに従って番号付け。)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、軽鎖可変ドメイン(VL)及び重鎖可変ドメイン(VH)が互いに置き換えられるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体である、
二重特異性抗体である。
a)それぞれ、完全長抗体軽鎖及び完全長抗体重鎖の二対を含み、完全長重鎖及び完全長軽鎖のそれぞれの対により形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)完全長抗体の一の重鎖のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片を含み、
完全長抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け。)を含み、
完全長抗体重鎖のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EUインデックスに従って番号付け。)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン1(CH1)が互いに置き換えられるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体である、
二重特異性抗体である。
a)それぞれ、完全長抗体軽鎖及び完全長抗体重鎖の二対を含み、完全長重鎖及び完全長軽鎖のそれぞれの対により形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)完全長抗体の一の重鎖のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン1(CH1)が互いに置き換えられるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体である、
二重特異性抗体である。
a)第一の抗原に特異的に結合する第一の抗体に由来する第一の軽鎖及び第一の重鎖;並びに
b)第二の抗原に特異的に結合する第二の抗体に由来する第二の軽鎖及び第二の重鎖を含み、
第二の軽鎖において、定常ドメインCLは第二の重鎖の定常ドメインCH1で置き換えられ、
第二の重鎖において、定常ドメインCH1は第二の軽鎖の定常ドメインCLで置き換えられ、
i)第一の軽鎖の定常ドメインCLにおいて、124及び123位のアミノ酸(Kabatに従って番号付け。)は、K、R及びHより選択されるアミノ酸によって互いに独立して置換され;第一の重鎖の定常ドメインCH1において、147及び213位のアミノ酸(KabatのEUインデックスに従って番号付け。)は、E又はDより選択されるアミノ酸によって互いに独立して置換されるか;又は
ii)第二の重鎖の定常ドメインCLにおいて、124及び123位のアミノ酸(Kabatに従って番号付け。)は、K、R及びHより選択されるアミノ酸によって互いに独立して置換され;第二の軽鎖の定常ドメインCH1において、147及び213位のアミノ酸(KabatのEUインデックスに従って番号付け。)は、E又はDより選択されるアミノ酸によって互いに独立して置換される
二重特異性抗体である。
a)それぞれ、完全長抗体軽鎖及び完全長抗体重鎖の二対を含み、完全長重鎖及び完全長軽鎖のそれぞれの対により形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)完全長抗体の一の重鎖のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片
を含み、
完全長抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け。)を含み、
完全長抗体重鎖のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EU indexに従って番号付け。)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン1(CH1)が互いに置き換えられるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体である、
二重特異性抗体である。
a)それぞれ、完全長抗体軽鎖及び完全長抗体重鎖の二対を含み、完全長重鎖及び完全長軽鎖のそれぞれの対により形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)完全長抗体の一の重鎖のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片
を含み、
完全長抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け。)を含み、
完全長抗体重鎖のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EUインデックスに従って番号付け。)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン1(CH1)が互いに置き換えられるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体であり、
ヒトCD20結合部位が、配列番号18のアミノ酸配列に対して少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、又は100%の配列同一性を有する重鎖可変ドメイン(VH)配列と、配列番号19のアミノ酸配列に対して、少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、又は100%の配列同一性を有する軽鎖可変ドメイン(VL)とを含み、
ヒトトランスフェリン受容体結合部位が、配列番号20のアミノ酸配列に対して少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、又は100%の配列同一性を有する重鎖可変ドメイン(VH)配列と、配列番号21のアミノ酸配列に対して、少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、又は100%の配列同一性を有する軽鎖可変ドメイン(VL)とを含む、
二重特異性抗体である。
i)少なくとも70%、少なくとも80%、少なくとも90%、又は95%以上の配列番号01に対する配列同一性を有する軽鎖、
ii)少なくとも70%、少なくとも80%、少なくとも90%、又は95%以上の配列番号02に対する配列同一性を有する重鎖、
iii)少なくとも70%、少なくとも80%、少なくとも90%、又は95%以上の配列番号03に対する配列同一性を有する軽鎖、及び
iv)少なくとも70%、少なくとも80%、少なくとも90%、又は95%以上の配列番号04に対する配列同一性を有する重鎖Fab断片
を含み、ここで、
配列番号01はアミノ酸配列
DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
を有し、
配列番号02はアミノ酸配列
QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
を有し、
配列番号03はアミノ酸配列
AIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
を有し、
配列番号04はアミノ酸配列
QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
を有する。
a)それぞれ、完全長抗体軽鎖及び完全長抗体重鎖の二対を含み、完全長重鎖及び完全長軽鎖のそれぞれの対により形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)完全長抗体の一の重鎖のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片を含み、
完全長抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け。)を含み、
完全長抗体重鎖のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EU indexに従って番号付け。)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン1(CH1)が互いに置き換えられるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体であり、
ヒトCD20結合部位が、配列番号18のアミノ酸配列を有する重鎖可変ドメイン(VH)と、配列番号19のアミノ酸配列を有する軽鎖可変ドメイン(VL)とを含み、
ヒトトランスフェリン受容体結合部位が、配列番号20のアミノ酸配列を有する重鎖可変ドメイン(VH)と、配列番号21のアミノ酸配列を有する軽鎖可変ドメイン(VL)とを含む、
二重特異性抗体である。
a)それぞれ、完全長抗体軽鎖及び完全長抗体重鎖の二対を含み、完全長重鎖及び完全長軽鎖のそれぞれの対により形成される結合部位が第一の抗原に特異的に結合し、完全長抗体が、それぞれ、CH1、CH2及びCH3ドメインを含む、二の完全長重鎖のFc領域ポリペプチドにより形成されるFc領域を含み、
b)完全長抗体の一の重鎖のC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片を含み、
完全長抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け。)を含み、
完全長抗体重鎖のそれぞれが、第一の定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EU indexに従って番号付け。)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン 1(CH1)が互いに置き換えられるように、ドメイン交差を含み、
第一の抗原がヒトCD20であり、第二の抗原がヒトトランスフェリン受容体であり、
ヒトCD20結合部位が、配列番号18のアミノ酸配列を有する重鎖可変ドメイン(VH)と、配列番号19のアミノ酸配列を有する軽鎖可変ドメイン(VL)とを含み、
ヒトトランスフェリン受容体結合部位が、配列番号20のアミノ酸配列を有する重鎖可変ドメイン(VH)と、配列番号21のアミノ酸配列を有する軽鎖可変ドメイン(VL)とを含み、
Fc領域ポリペプチドが
a)ヒトサブクラスIgG1のFc領域ポリペプチド、
b)ヒトサブクラスIgG4のFc領域ポリペプチド、
c)変異L234A、L235A及びP329Gを有するヒトサブクラスIgG1のFc領域ポリペプチド、
d)変異228P、L235E及びP329Gを有するヒトサブクラスIgG4のFc領域ポリペプチド、
e)両方のFc領域ポリペプチド中に変異L234A、L235A及びP329Gを、一方のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれの他方のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1のFc領域ポリペプチド、
f)両方のFc領域ポリペプチド中にS228P及びP329Gを、一方のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれの他方のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG4のFc領域ポリペプチド、
g)両方のFc領域ポリペプチド中に変異L234A、L235A、P329G、I253A、H310A及びH435Aを、一方のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれの他方のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1のFc領域ポリペプチド、又は
h)両方のFc領域ポリペプチドに変異L234A、L235A、P329G、M252Y、S254T及びT256Eを、一方のFc領域ポリペプチド中に変異T366W及びS354Cを、それぞれ他方のFc領域ポリペプチド中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1のFc領域ポリペプチド、又は
i)両方の重鎖中に変異L234A、L235A、P329G、H310A、H433A及びY436Aを、一方の重鎖中に変異i)T366W、及びii)S354C又はY349Cを、それぞれの他方の重鎖中に変異i)T366S、L368A及びY407V、並びにii)Y349C又はS354Cを有するヒトサブクラスIgG1の完全長抗体である
二重特異性抗体である。
ある実施態様において、本明細書で提供される抗体はキメラ抗体である。特定のキメラ抗体は、例えば、米国特許第4816567号、及びMorrison, S.L. et al., Proc. Natl. Acad. Sci. USA 81(1984)6851−6855)に記載されている。一例において、キメラ抗体は、非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、又はサル等の非ヒト霊長類由来の可変領域)とヒト定常領域とを含む。更なる例において、キメラ抗体は、クラス又はサブクラスが親抗体のものから変更されている「クラススイッチ」抗体である。キメラ抗体は、その抗原結合断片を含む。
ある実施態様において、本明細書で提供される抗体は、ヒト抗体である。ヒト抗体は、当技術分野において既知の様々な技術を用いて生産することができる。ヒト抗体は、一般的に、van Dijk, M.A. and van de Winkel, J.G., Curr. Opin. Pharmacol. 5(2001)368−374及びLonberg, N., Curr. Opin. Immunol. 20(2008)450−459に記載されている。
ある実施態様において、本明細書で提供される二重特異性抗体のアミノ酸配列変異体が企図される。例えば、抗体の結合親和性及び/又は他の生物学的特性を改善することが望まれる。抗体のアミノ酸配列変異体は、抗体をコードするヌクレオチド配列に適切な修飾を導入することにより、又はペプチド合成により調製することができる。このような改変は、例えば、抗体のアミノ酸配列内の残基からの欠失、及び/又は残基への挿入、及び/又は残基の置換を含む。最終コンストラクトが所望の特性、例えば、抗原結合を有していることを条件として、欠失、挿入、及び置換の任意の組み合わせを、最終構築物に到達させるために作製することができる。
ある実施態様では、一又は複数のアミノ酸置換を伴う抗体変異体が提供される。置換変異体の目的の部位は、HVR及びFRを含む。保存的置換は、「好ましい置換」と題して表1に示す。より実質的な変更は、「例示的置換」と題して表1に示し、アミノ酸側鎖のクラスを参照して下記にさらに説明する。アミノ酸置換は、目的の抗体に導入することができ、その産物は、所望の活性、例えば、抗原結合の保持/改善、免疫原性の低下、又はADCC又はCDCの改善についてスクリーニングされる。
表
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性の親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖配向に影響する残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe
ある実施態様において、本明細書で提供される二重特異性抗体は、抗体がグリコシル化される程度を上昇又は低下させるように改変される。グリコシル化部位の抗体への付加又は欠失は、一又は複数のグリコシル化部位が創出又は削除されるようにアミノ酸配列を改変することにより、簡便に達成することができる。
ある実施態様において、一又は複数のアミノ酸修飾を、本明細書で提供される二重特異性抗体のFc領域に導入し、それによりFc領域変異体を生成することができる。Fc領域変異体は、一又は複数のアミノ酸位置でアミノ酸修飾(例えば置換)を含むヒトFc領域配列(例えばヒトIgG1、IgG2、IgG3又はIgG4のFc領域)を含みうる。
ある実施態様において、抗体の一又は複数の残基がシステイン残基で置換されているシステイン操作抗体、例えば「チオMAb」を作製することが望ましい場合がある。特定の実施態様において、置換される残基が抗体の接近可能な部位で生じる。これらの残基をシステインで置換することによって、反応性チオール基が抗体の接近可能部位に配置され、抗体を他の部分、例えば薬物部分又はリンカー−薬剤部分にコンジュゲートさせ、本明細書中でさらに記載されるように免疫コンジュゲートを作るために使用することができる。特定の実施態様では、以下の残基のうちのいずれかの一又は複数がシステインで置換される:軽鎖のV205(Kabatの番号付け);重鎖のA118(EU番号付け);及び重鎖Fc領域のS400(EU番号付け)。システイン改変抗体は、例えば、米国特許第7521541号に記載のように生成されうる。
ある実施態様において、本明細書で提供される二重特異性抗体は、当技術分野で知られており、容易に入手可能なさらなる非タンパク質部分を含むようにさらに修飾することができる。抗体の誘導体化に適した部分は、限定されるものではないが、水溶性ポリマーを含む。水溶性ポリマーの非限定的な例は、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールのコポリマー、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ−1,3−ジオキソラン、ポリ−1,3,6−トリオキサン、エチレン/無水マレイン酸コポリマー、ポリアミノ酸(ホモポリマー又はランダムコポリマーのいずれか)、及びデキストラン又はポリ(n−ビニルピロリドン)ポリエチレングリコール、プロピレングリコールホモポリマー、ポリプロピレン(prolypropylene)オキシド/エチレンオキシドコポリマー、ポリオキシエチル化ポリオール(例えばグリセロール)、ポリビニルアルコール、並びにそれらの混合物を含む(ただし、これらに限定されない)。ポリエチレングリコールプロピオンアルデヒドは、水中でのその安定性のために製造上の利点を有しうる。ポリマーは、任意の分子量であってよく、分枝状でも非分枝状でもよい。抗体に付着するポリマーの数は変化してもよく、一を超えるポリマーが付着する場合、それらは同じか又は異なる分子であってよい。一般的に、誘導体化に使用されるポリマーの数及び/又はタイプは、改善されるべき抗体の特定の特性又は機能、その抗体誘導体が限定条件の下での治療に使用されるかどうかを含めた(ただし、これらに限定されない)考慮事項に基づいて決定することができる。
抗体は、例えば米国特許第4816567号に記載されているような組み換え方法及び組成物を用いて製造される。一実施態様では、本明細書に記載される二重特異性抗ヒトCD20/ヒトトランスフェリン受容体抗体をコードする単離された核酸が提供される。さらなる実施態様において、そのような核酸を含む一又は複数のベクター(例えば発現ベクター)が提供される。さらなる実施態様では、そのような核酸を含む宿主細胞が提供される。一実施態様において、宿主細胞は、真核生物細胞、例えばチャイニーズハムスター卵巣(CHO)細胞、又はリンパ系細胞(例えば、Y0、NS0、Sp20細胞)である。一実施態様において、上述のように、抗体の発現に適した条件下で、抗体をコードする核酸を含む宿主細胞を培養することと、任意選択的に宿主細胞(又は宿主細胞培地)から抗体を回収することとを含む、二重特異性抗ヒトCD20/ヒトトランスフェリン受容体抗体を作製する方法が提供される。
特定の実施態様では、本明細書において提供される二重特異性抗ヒトCD20/ヒトトランスフェリン受容体抗体のいずれもが、生物学的試料中のCD20の存在を検出するために有用である。本明細書で使用する「検出(する)」という用語は、定量的又は定性的検出を包含する。特定の実施態様では、生物学的サンプルは細胞又は組織を含む。
本発明はまた、本明細書で報告される、一又は複数の細胞傷害性剤、例えば化学療法剤若しくは薬物、増殖阻害剤、毒素(例えばタンパク質毒素、細菌、真菌、植物若しくは動物起源の酵素的に活性な毒素又はその断片)又は放射性同位体にコンジュゲートした二重特異性抗ヒトCD20/ヒトトランスフェリン受容体抗体を含むイムノコンジュゲートを提供する。
本明細書で報告される抗ヒトCD20/ヒトトランスフェリン受容体抗体又はイムノコンジュゲートの薬学的製剤は、所望の度合いの純度を有するこのような抗体を、一又は複数の任意選択的な薬学的に許容される担体と混合することによって(Remington’s Pharmaceutical Sciences 16th edition, Osol, A.(ed.)(1980))、凍結乾燥製剤又は水溶液の形態に調製される。通常、薬学的に許容される担体は、用いられる用量及び濃度で受容者に対して非毒性であり、限定されるものではないが、リン酸塩、クエン酸塩、及び他の有機酸等のバッファー;アスコルビン酸及びメチオニンを含む酸化防止剤;防腐剤(例えばオクタデシルジメチオルベンジルアンモニウムクロリド、ヘキサメトニウムクロリド、ベンザルコニウムクロリド、ベンゼトニウムクロリド、フェノール、ブチル又はベンジルアルコール、メチル又はプロピルパラベンなどのアルキルパラベン、カテコール、レゾルシノール、シクロヘキサノール、3−ペンタノール、及びm−クレゾール);低分子量(約10残基未満)のポリペプチド;血清アルブミン、ゼラチン又は免疫グロブリン等のタンパク質;ポリビニルピロリドンなどの親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン又はリジン等のアミノ酸;グルコース、マンノース又はデキストリンを含む単糖類、二糖類、及びその他の糖質;EDTAなどのキレート剤;スクロース、マンニトール、トレハロース又はソルビトール等の糖;ナトリウムなどの塩形成対イオン;金属錯体(例えばZn−タンパク質錯体);及び/又はポリエチレングリコール(PEG)などの非イオン性界面活性剤を含む。本明細書における例示的な薬学的に許容される担体は、可溶性の中性活性ヒアルロニダーゼ糖タンパク質(sHASEGP)などの介在性薬物分散剤、例えばrhuPH20(HYLENEX(登録商標)、Baxter International, Inc.)などのヒト可溶性PH−20ヒアルロニダーゼ糖タンパク質をさらに含む。特定の典型的なsHASEGP及び使用法は、rhuPH20を含み、米国特許出願公開第2005/0260186号及び同第2006/0104968に記載されている。一態様では、sHASEGPは、コンドロイチナーゼなどの一又は複数の追加的グルコサミノグリカナーゼと組み合わせられる。
本明細書で提供される二重特異性抗ヒトCD20/ヒトトランスフェリン受容体抗体のいずれかが、治療方法に使用されうる。
本明細書で報告される別の態様では、上述した疾患の治療、予防、及び/又は診断に有用な材料を含有する製造品が提供される。製造品は、容器と容器上の又は容器に付随するラベル又は添付文書を含む。好適な容器は、例としてボトル、バイアル、シリンジ、IV輸液バッグなどを含む。容器はガラス又はプラスチックなどの様々な材料から形成されうる。容器は、疾患の治療、予防、及び/又は診断に効果的である、単独の又は別の組成物と併用の組成物を収容し、滅菌のアクセスポートを有しうる(例えば、容器は皮下注射針で貫通可能なストッパーを有する静脈内溶液バッグ又はバイアルであってもよい)。該組成物中の少なくとも一の活性剤は、本明細書で報告される抗体である。ラベル又は添付文書は、該組成物が特定の疾患の治療のために使用されることを示す。さらに、製造品は、(a)本明細書で報告される抗体を含む組成物を中に収容する第一の容器、及び(b)さらなる細胞傷害性剤又はその他の治療剤含む組成物を中に収容する第二の容器を含んでもよい。本実施態様における製造品は、組成物が特定の病態を治療するために使用され得ることを示す添付文書を更に含んでもよい。或いは、又は加えて、製造品は、薬学的に許容可能な緩衝液、例えば注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンガー溶液及びデキストロース溶液を含む第二(又は第三)の容器を更に含んでもよい。製造品は、他のバッファー、希釈剤、フィルタ、針、及びシリンジを含めた、商業的及び使用者の観点から望ましいその他の材料をさらに含んでもよい。
ヒト免疫グロブリンの軽鎖及び重鎖のヌクレオチド配列に関する一般情報は以下に与えられている:Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD(1991)。抗体鎖のアミノ酸は、Kabat(Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD(1991))に従い、番号付けられ、参照される。
標準的な方法を使用して、Sambrook, J. et al., Molecular Cloning:A laboratory manual;Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989に記載されているようにDNAを操作した。分子生物学的試薬を、製造元の指示に従って使用した。
所望の遺伝子セグメントを、化学合成により作製したオリゴヌクレオチドから調製した。特異的な制限エンドヌクレアーゼ切断部位に隣接する長い遺伝子セグメントを、PCR増幅を含むオリゴヌクレオチドのアニーリング及びライゲーションによって組み立て、その後示された制限部位を介してクローニングした。サブクローニングされた遺伝子断片のDNA配列を、DNA配列決定によって確認した。遺伝子合成断片は、Geneart(Regensburg, Germany)の所定の仕様に従って整理した。
DNA配列は、MediGenomix GmbH(Martinsried, Germany)又はSequiServe GmbH(Vaterstetten, Germany)で実施された二本鎖配列決定により決定した。
GCG(Genetics Computer Group, Madison, Wisconsin)のソフトウェアパッケージバージョン10.2及びInfomax’s Vector NT1 Advanceスイートバージョン8.0を、配列作成、マッピング、分析、注釈及び説明に使用した。
記載される二重特異性抗体の発現に関して、CMVイントロンAプロモーターの有無を問わないcDNA機構又はCMVプロモーターを含むゲノム機構のいずれかに基づく一過性発現に対する発現プラスミド(例えばHEK293細胞中)が適用されうる。
− 大腸菌においてこのプラスミドの複製を可能にする複製開始点、及び
− 大腸菌にアンピシリン耐性を付与するs−ラクタマーゼ遺伝子
を含有する。
− 5’末端の固有の制限部位
− ヒトサイトメガロウイルスからの前早期エンハンサー及びプロモーター
− cDNA機構の場合のイントロンA配列
− ヒト抗体遺伝子に由来する5’−非翻訳領域
− 免疫グロブリン重鎖シグナル配列
− cDNAとして、又はエクソン−イントロン機構を有する核酸をコードするそれぞれの抗体鎖
− ポリアデニル化シグナル配列を有する3’非翻訳領域
− 終了配列、及び
− 3’末端の固有の制限部位。
Current Protocols in Cell Biology(2000), Bonifacino, J.S., Dasso, M., Harford, J.B., Lippincott−Schwartz, J. and Yamada, K.M.(eds.), John Wiley & Sons, Inc.に記載されるような標準的な細胞培養技術が使用される。
二重特異性抗体を一過性発現によって産生する。したがって、製造業者の指示に従いHEK293系(Invitrogen)を使用して、それぞれのプラスミドを有するトランスフェクションを行う。簡潔には、無血清FreeStyleTM293発現培地(Invitrogen)における振盪フラスコ中又は撹拌された培養槽中のいずれかで懸濁状態で成長するHEK293細胞(Invitrogen)を、それぞれの発現プラスミド及び293fectinTM又はフェクチン(Invitrogen)のミックスを用いてトランスフェクトする。2Lの振盪フラスコ(Corning)に関して、HEK293細胞を、600mL中1.0*106細胞/mLの密度で播種し、120rpm、8%CO2でインキュベートする。翌日、A)600μgの総プラスミドDNA(1μg/mL)を含む20mLのOpti−MEM媒体(Invitrogen)と、B)1.2mLの293フェクチン又はフェクチン(2μl/mL)が補充されている20mlのOpti−MEM媒体との約42mLの混合物で、約1.5*106細胞/mLの細胞密度で細胞をトランスフェクトする。グルコース消費に従って、発酵中にグルコース溶液を添加する。5〜10日後、分泌された抗体を含有する上清を採取し、抗体を上清から直接精製するか、又は上清を冷凍して、保存する。
精製された抗体及び誘導体のタンパク質濃度を、Pace, et al., Protein Science 4(1995)2411−1423に従って、アミノ酸配列に基づいて計算されたモル吸光係数を用いて、280nmにおける光学濃度(OD)を決定することにより決定した。
細胞培養上清中の抗体及び誘導体の濃度をプロテインAアガロースビーズ(Roche Diagnostics GmbH, Mannheim, Germany)を用いた免疫沈降法により推定した。したがって、60μLのプロテインAアガロースビーズを、TBS−NP40(150mMのNaCl及び1%Nonidet−P40が補充された50mMのTrisバッファー、pH7.5)中で3回洗浄した。続いて、1〜15mLの細胞培養上清を、事前平衡化したTBS−NP40中のプロテインAアガロースビーズに適用した。室温で1時間インキュベートした後、ビーズを、Ultrafree−MC−フィルターカラム(Amicon)上で、0.5mLのTBS−NP40で一回、0.5mLの2倍のリン酸緩衝生理食塩水(2xPBS、Roche Diagnostics GmbH, Mannheim, Germany)で二回、そして、0.5mLの100mMのNa−クエン酸バッファー(pH5.0)で簡潔に四回洗浄した。結合した抗体を、35μlのNuPAGE(登録商標)LDS試料バッファー(Invitrogen)を添加することにより溶出した。試料の半分をNuPAGE(登録商標)試料還元剤と組み合わせ、残りの半分を未還元のままにし、70℃で10分間加熱した。その結果として、5〜30μlを4〜12%のNuPAGE(登録商標)ビス−TrisSDS−PAGEゲル(Invitrogen)(非還元SDS−PAGEについてはMOPSバッファーを含み、還元SDS−PAGEについては、NuPAGE(登録商標)抗酸化剤ランニングバッファー添加剤(Invitrogen)を含むMESバッファーを含む。)に添加し、Coomassie Blueで染色した。
標準的なプロトコールを参照して、濾過された細胞培養上清から抗体を精製した。簡潔には、抗体を、プロテインA Sepharoseカラム(GE healthcare)に適用し、PBSで洗浄した。抗体の溶出をpH2.8で行い、その直後に中和した。凝集したタンパク質を、サイズ排除クロマトグラフィー(Superdex 200, GE Healthcare)により、PBS中又は150mMのNaCl(pH6.0)を含む20mMのヒスチジンバッファー中のモノマー抗体から分離させた。モノマー抗体画分をプールし、例えばMILLIPORE Amicon Ultra(30 MWCO)遠心濃縮機を使用して濃縮し(必要な場合)、−20℃又は−80℃で冷凍し、保存した。試料の一部を続くタンパク質分析、及び例えばSDS−PAGE、サイズ排除クロマトグラフィー(SEC)又は質量分析による分析的特徴付けに関して提供した。
製造元の指示に従って、NuPAGE(登録商標)Pre−Castゲルシステム(Invitrogen)を使用した。特に、10%又は4〜12%のNuPAGE(登録商標)Novex(登録商標)ビス−TRIS Pre−Castゲル(pH6.4)及びNuPAGE(登録商標)MES(還元ゲル、NuPAGE(登録商標)抗酸化剤ランニングバッファー添加剤を含む)又はMOPS(非還元ゲル)ランニングバッファーを使用した。
微小流体Labchip技術(PerkinElmer, USA)を使用するCE−SDSによって、純度及び抗体完全性を分析した。したがって、5μlの抗体溶液を、製造元の指示に従って、HT Protein Express Reagent Kitを使用して、CE−SDS分析のために調製し、HT Protein Express Chipを使用してLabChip GXIIシステム上で分析した。LabChip GX Softwareを使用して、データを分析した。
凝集及びオリゴマー状態の抗体の決定に関するサイズ排除クロマトグラフィー(SEC)を、HPLCクロマトグラフィーによって行った。簡潔には、プロテインA精製抗体を、Dionex Ultimate(登録商標)システム(Thermo Fischer Scientific)上、300mMのNaCl、50mMのKH2PO4/K2HPO4バッファー(pH7.5)中のTosoh TSKgel G3000SWカラムに、又は、Dionex HPLC−システム上、2倍のPBS中のSuperdex 200カラム(GE Healthcare)に適用した。UV吸光度により、及びピークエリアの統合により、溶出した抗体を定量化した。BioRad Gel Filtration Standard 151-1901が標準として機能した。
この切片は、正確な集合に重きを有する二重特異性抗体の特徴づけを説明する。予測される一次抗体を、脱グリコシル化されたインタクトな抗体の、及び特別な場合、脱グリコシル化/限定されたLysC消化抗体のエレクトロスプレーイオン化質量分析(ESI−MS)により分析した。
試料を三のアリコートに分け、それぞれ、20mMのHis/His*HCl、140mMのNaCl、pH6.0又はPBS中に再バッファーし、40℃(His/NaCl)又は37℃(PBS)で保存した。コントロール試料を−80℃で保存した。
20mMのヒスチジン/ヒスチジンクロリド、140mMのNaCl、pH6.0中、1mg/mLの濃度で試料を調製し、0.4μmフィルタを通じた遠心分離により、光学384ウェルプレートに移し、パラフィン油でカバーした。流体力学半径を、DynaPro Plate Reader(Wyatt)上、動的光散乱により繰り返し測定し、その一方、試料を0.05℃/分の速度で、25℃から80℃に加熱した。
発現及び精製
一般的な材料及び方法のセクションで記載されるように、二重特異性抗体を産生した。
in vitroでのトランスフェリン受容体への結合の決定
二重特異性抗体のマウストランスフェリン受容体への結合を、マウスX63.AG8−563骨髄腫細胞上FACS解析により試験する。Aβ抗体が、Ag8細胞へ非特異的に結合する特定の傾向を示す場合、特異的な結合は、20倍超の抗マウス−TfR抗体で共インキュベートにより定量化されうる。細胞を遠心分離により採取し、PBSで洗浄し、5×104細胞を100μLのRPMI/10%FCS中で、200nMの抗マウスTfR抗体を添加する又は添加しない、ポリペプチド融合体の1.5pMから10nMの希釈系列と、氷上で1.5時間インキュベートする。RPMI/10%のFCSで二回洗浄した後、細胞を、RPMI/19%のFCS中1:600の希釈で、Phycoerythrin(Jackson Immunoresearch)に結合したヤギ抗ヒトIgGで、氷上で1.5時間インキュベートする。細胞を再び洗浄し、RPMI/10%のFCSに再懸濁させ、Phycoerythrinの蛍光を、FACS−アレイ装置(Becton−Dickinson)上で測定する。
ヒトTfR-抗体相互作用に関する表面プラズモン共鳴をベースとする結合アッセイ
抗ヒトFab抗体(GE HEALTHCARE、カタログ番号28−9583−25)を用いて、供給業者のマニュアルに従い標準的なアミンカップリングケミストリーの手順を使用して前処理したC1センサチップ(GE Healthcare、カタログ番号BR1005−35)を備えたBIAcore B 4000(GE Healthcare)上で、結合実験を行った。
Claims (15)
- a)抗体軽鎖及び抗体重鎖の対を二つ含み、重鎖及び軽鎖の対のそれぞれにより形成される結合部位が第一の抗原に特異的に結合する、一の抗体と、
b)抗体の重鎖の一つのC末端に融合し、結合部位が第二の抗原に特異的に結合する、一のさらなるFab断片
とを含む二重特異性抗体であって、
抗体軽鎖のそれぞれが、定常軽鎖ドメイン(CL)において、123位でアミノ酸残基アルギニン(野生型グルタミン酸残基の代替;E123R変異)を、124位でアミノ酸残基リジン(野生型グルタミン残基の代替;Q124K変異)(Kabatに従って番号付け)を含み、
抗体重鎖のそれぞれが、第一定常重鎖ドメイン(CH1)において、147位でグルタミン酸残基(野生型リジン残基の代替;K147E変異)を、213位でグルタミン酸残基(野生型リジンアミノ酸残基の代替;K213E変異)(Kabat EU indexに従って番号付け)を含み、
第二の抗原に特異的に結合するさらなるFab断片が、定常軽鎖ドメイン(CL)及び定常重鎖ドメイン1(CH1)が互いに置き換わるように、ドメイン交差を含み、
第一の抗原がヒトCD20タンパク質であり、第二の抗原がヒトトランスフェリン受容体である、抗体。 - さらなるFab断片が、ペプチド性リンカーにより、重鎖のC末端に融合している、請求項1に記載の抗体。
- a)さらなるFab断片に融合している重鎖が、C末端重鎖アミノ酸残基として、トリペプチドLSPを有し、そのプロリンが、さらなるFab断片の、又はペプチド結合を介するペプチド性リンカーの第一のアミノ酸残基に直接融合し、
b)さらなるFab断片に融合していない重鎖が、C末端重鎖アミノ酸残基として、トリペプチドLSP又はSPG又はPGKを有する
請求項1又は2に記載の抗体。 - a)ヒトサブクラスIgG1の完全長抗体、又は
b)ヒトサブクラスIgG4の完全長抗体、又は
c)変異L234A、L235A及びP329Gを有するヒトサブクラスIgG1の完全長抗体
d)変異S228P、L235E及びP329Gを有するヒトサブクラスIgG4の完全長抗体
e)両方の重鎖中に変異L234A、L235A及びP329Gを、一方の重鎖中に変異T366W及びS354Cを、それぞれの他方の重鎖中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1の完全長抗体
f)両方の重鎖中に変異S228P及びP329Gを、一方の重鎖中に変異T366W及びS354Cを、それぞれの他方の重鎖中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG4の完全長抗体
g)両方の重鎖中に変異L234A、L235A、P329G、I253A、H310A及びH435Aを、一方の重鎖中に変異T366W及びS354Cを、それぞれの他方の重鎖中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1の完全長抗体
h)両方の重鎖中に変異L234A、L235A、P329G、M252Y、S254T及びT256Eを、一方の重鎖中に変異T366W及びS354Cを、それぞれの他方の重鎖中に変異T366S、L368A、Y407V及びY349Cを有するヒトサブクラスIgG1の完全長抗体、又は
i)両方の重鎖中に変異L234A、L235A、P329G、H310A、H433A及びY436Aを、一方の重鎖中に変異i)T366W、及びii)S354C又はY349Cを、それぞれの他方の重鎖中に変異i)T366S、L368A及びY407V、並びにii)Y349C又はS354Cを有するヒトサブクラスIgG1の完全長抗体である、
請求項1から3のいずれか一項に記載の抗体。 - 二重特異性抗体が、
i)配列番号01の配列を有する軽鎖、
ii)配列番号02の配列を有する重鎖、
iii)配列番号03の配列を有する軽鎖、及び
iv)配列番号04の配列を有する重鎖Fab断片
を含む、請求項1から4のいずれか一項に記載の抗体。 - 二重特異性抗体が、配列番号01のアミノ酸配列を有する軽鎖、配列番号02のアミノ酸配列を有する重鎖、配列番号03のアミノ酸配列を有する軽鎖、及び配列番号04のアミノ酸配列を含む抗体Fab断片を含む、請求項1から4のいずれか一項に記載の抗体。
- モノクローナルである、請求項1から6のいずれか一項に記載の抗体。
- 請求項1から7のいずれか一項に記載の抗体と、薬学的に許容される担体とを含む薬学的製剤。
- 医薬としての使用のための、請求項1から7のいずれか一項に記載の抗体。
- 多発性硬化症の治療のための、請求項1から7のいずれか一項に記載の抗体。
- 医薬の製造における、請求項1から7のいずれか一項に記載の抗体の使用。
- 医薬が多発性硬化症の治療を目的とする、請求項11に記載の使用。
- 医薬が、CD20を発現する脳隔離B細胞の枯渇を目的とする、請求項11に記載の使用。
- 多発性硬化症を有する個体を治療するための、請求項1から7のいずれか一項に記載の抗体の有効量を含む、医薬。
- 個体において、CD20を発現する脳隔離B細胞を枯渇させるための、請求項1から7のいずれか一項に記載の抗体の有効量を含む、医薬。
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JP7000473B2 (ja) | 2015-10-02 | 2022-02-04 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | 二重特異性抗ヒトcd20/ヒトトランスフェリン受容体抗体及び使用方法 |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |