JP2020522266A - 非対称なch2−ch3領域の変異を有する、操作された多重特異性抗体及び他の多量体タンパク質 - Google Patents
非対称なch2−ch3領域の変異を有する、操作された多重特異性抗体及び他の多量体タンパク質 Download PDFInfo
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Abstract
Description
本願は、EFS−Webを介して提出された配列表を含み、その全容を参照により本明細書に援用する。ASCIIテキストファイルは、2018年5月29日に作成され、ファイル名はJBI5124WOPCT_ST25.txtであり、そのサイズは164キロバイトである。
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域をコードするポリヌクレオチドを含むか、
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域と、307、309及び311位に野生型アミノ酸残基を有する第2のCH2−CH3領域とをコードするポリヌクレオチドを含むか、又は
配列番号27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、87、88又は91のポリヌクレオチド配列を含む、単離されたポリヌクレオチドも提供する。
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域をコードする単離されたポリヌクレオチド、
配列番号27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、87、88又は91のポリヌクレオチド配列を有する、単離されたポリヌクレオチド、
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域と、307、309及び311位に野生型アミノ酸残基を有する第2のCH2−CH3領域とをコードするポリヌクレオチドを含む、単離されたポリヌクレオチド、又は
配列番号27及び47、それぞれ、
配列番号28及び47、それぞれ、
配列番号29及び47、それぞれ、
配列番号30及び47、それぞれ、
配列番号31及び48、それぞれ、
配列番号32及び48、それぞれ、
配列番号33及び48、それぞれ、
配列番号34及び48、それぞれ、
配列番号35及び49、それぞれ、
配列番号36及び49、それぞれ、
配列番号37及び49、それぞれ、
配列番号38及び49、それぞれ、
配列番号39及び50、それぞれ、
配列番号40及び50、それぞれ、
配列番号41及び50、それぞれ、
配列番号42及び50、それぞれ、
配列番号43及び51、それぞれ、
配列番号44及び51、それぞれ、
配列番号45及び51、それぞれ、
配列番号46及び51、それぞれ、
配列番号87及び89、それぞれ、
配列番号87及び90、それぞれ、
配列番号88及び89、それぞれ、
配列番号88及び90、それぞれ、
配列番号92及び89、それぞれ、又は
配列番号92及び90、それぞれ、を有する単離されたポリヌクレオチドを含むベクターも提供する。
多重特異性抗体が発現される条件下で本発明の宿主細胞を培養することと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性抗体を精製することと、を含む、方法も提供する。
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311R を有する第1の重鎖と第1の軽鎖とを含む第1の親抗体を与えることと、
307、309及び311位に野生型アミノ酸残基を有する第2の重鎖と第2の軽鎖とを含む第2の親抗体を与えることと、
第1の親抗体と第2の親抗体とを試料中で接触させることと、
試料をインキュベートすることと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性抗体を精製することとを含む方法も提供する。
配列番号2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、52、53又は56のCH2−CH3領域を含む抗体重鎖をコードするか、又は
配列番号27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、87、88又は91のポリヌクレオチド配列を有する、ポリヌクレオチドも提供する。
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域を含む第1の親タンパク質を与えることと、
307、309及び311位に野生型アミノ酸残基を有する第2のCH2−CH3領域を含む第2の親タンパク質を与えることと、
第1の親タンパク質と第2の親タンパク質とを試料中で接触させることと、
試料をインキュベートすることと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性タンパク質を精製することと、を含む、方法も提供する。
本明細書及び添付の「特許請求の範囲」において使用されるとき、単数形「a」、「an」及び「the」は、内容によってそうでない旨が明確に断られない限り、複数の指示対象を包含する。したがって、例えば、「細胞」と言った場合には、2個以上の細胞の組み合わせなどが含まれる。
VDNKFNKEQQNAFYEILHLPNLNEEQRNAFIQSLKDDPSQSANLLAEAKKLNDAQAPK
FNMQCQRRFYEALHDPNLNEEQRNAKIKSIRDDC
VDNKFNKEQQNAFYEILHLPNLNEEQRNAFIQSLKDDPSQSANLLAEAKKLNDAQAPK
FNMQQQRRFYEALHDPNLNEEQRNAKIKSIRDD
本発明は、プロテインAリガンドクロマトグラフィーを用いた精製を容易とする多重特異性抗体及びCH2−CH3領域に非対称の変異を有する他の多量体CH2−CH3領域含有タンパク質、それらをコードするポリヌクレオチド、ベクター及び宿主細胞、並びにそれらを製造する及び使用する方法を提供するものである。
それぞれ、F405L及びK409R、
それぞれ、野生型及びF405L/R409K、
それぞれ、T366W及びT366S/L368A/Y407V、
それぞれ、T366Y/F405A及びT394W/Y407T、
それぞれ、T366W/F405W及びT394S/Y407A、
それぞれ、F405W/Y407A及びT366W/T394S、
それぞれ、L351Y/F405A/Y407V及びT394W、
それぞれ、T366I/K392M/T394W及びF405A/Y407V、
それぞれ、T366L/K392M/T394W及びF405A/Y407V、
それぞれ、L351Y/Y407A及びT366A/K409F、
それぞれ、L351Y/Y407A及びT366V/K409F、
それぞれ、Y407A及びT366A/K409F、
それぞれ、D399K/E356K及びK409D/K392D、又は
それぞれ、D399K/E356K/E357K及びK409D/K392D/K370である。
ラーゼIia)、TP53、TPM1、TPM2、TRADD、TRAF1、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、TREM1、TREM2、TRPC6、TSLP、TWEAK、VEGF、VEGFB、VEGFC、バーシカン、VHLC5、VISTA、VLA−4、XCL1(リンホタクチン)、XCL2(SCM−1b)、XCR1(GPR5/CCXCR1)、YY1、及びZFPM2である。
本発明の多重特異性抗体に更なるFc変異を導入することにより、エフェクター機能及び薬物動態特性を調節することができる。従来の免疫機能では、抗体−抗原複合体と免疫系の細胞との相互作用の結果、エフェクター機能、例えば、抗体依存性細胞障害、及び食作用から免疫調整性シグナル、例えば、リンパ球の増殖及び抗体の分泌の制御に及ぶ広範な応答が生じる。これらの相互作用はすべて、抗体又は免疫複合体のFc領域の、特化した細胞表面受容体への結合を介して開始される。抗体及び免疫複合体によって誘発される細胞応答の多様性は、Fc受容体の構造的異種性に起因する。すなわち、FcγRI(CD64)FcγRIIa(CD32A)及びFcγRIII(CD16)は、活性化性Fcγ受容体(すなわち、免疫系を増強)であり、FcγRIIb(CD32B)は、阻害性Fcγ受容体である(すなわち、免疫系の減弱)。FcRn受容体への結合は、抗体の半減期を調節する。
親多重特異性抗体と比較して変化したアミノ酸配列を有する本発明の操作された多重特異性抗体は、標準的なクローニング及び発現技術を用いて作製することができる。例えば、部位特異的変異誘発又はPCR介在変異誘発を行って変異(複数可)を導入することができ、抗体の結合又は他の対象とする特性に対する影響を、周知の方法及び本明細書の実施例で述べる方法を用いて評価することができる。
治療用抗体の免疫原性は、注入反応のリスク増大及び治療応答の期間短縮に関連している(Baert et al.,(2003)N Engl J Med 348:602−08)。宿主において治療用抗体が免疫応答を誘導する程度は、抗体のアロタイプによって部分的に決定され得る(Stickler et al.,(2011)Genes and Immunity 12:213−21)。抗体のアロタイプは、抗体の定常領域配列における特定の位置のアミノ酸配列の変異に関連する。
本発明の多重特異性抗体は、標準的な分子生物学技術を使用し、親抗体のFabアーム交換を促進することで作製することができる。本発明の多重特異性抗体は、プロテインAリガンド親和性クロマトグラフィーを用いて精製することができる。
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1の重鎖又はそのフラグメントと第1の軽鎖とを含む第1の親抗体を与えることと、
307、309及び311位に野生型アミノ酸残基を有する第2の重鎖又はそのフラグメントと第2の軽鎖とを含む第2の親抗体を与えることと、
第1の親抗体と第2の親抗体とを試料中で接触させることと、
試料をインキュベートすることと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性抗体を精製することとを含む、方法も提供する。
変異T307P/L309Qを有する第1の重鎖又はそのフラグメントと第1の軽鎖とを含む第1の親抗体を与えることと、
307及び309位に野生型アミノ酸残基を有する第2の重鎖又はそのフラグメントと第2の軽鎖とを含む第2の親抗体を与えることと、
第1の親抗体と第2の親抗体とを試料中で接触させることと、
試料をインキュベートすることと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性抗体を精製することとを含む、方法も提供する。
変異T307P/V309Qを有する第1の重鎖又はそのフラグメントと第1の軽鎖とを含む第1の親抗体を与えることと、
307及び309位に野生型アミノ酸残基を有する第2の重鎖又はそのフラグメントと第2の軽鎖とを含む第2の親抗体を与えることと、
第1の親抗体と第2の親抗体とを試料中で接触させることと、
試料をインキュベートすることと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性抗体を精製することとを含む、方法も提供する。
変異T307P/L309Q/Q311Rを有する第1の重鎖又はそのフラグメントと第1の軽鎖とを含む第1の親抗体を与えることと、
307、309及び311位に野生型アミノ酸残基を有する第2の重鎖又はそのフラグメントと第2の軽鎖とを含む第2の親抗体を与えることと、
第1の親抗体と第2の親抗体とを試料中で接触させることと、
試料をインキュベートすることと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性抗体を精製することとを含む、方法も提供する。
変異T307P/V309Q/Q311Rを有する第1の重鎖又はそのフラグメントと第1の軽鎖とを含む第1の親抗体を与えることと、
307、309及び311位に野生型アミノ酸残基を有する第2の重鎖又はそのフラグメントと第2の軽鎖とを含む第2の親抗体を与えることと、
第1の親抗体と第2の親抗体とを試料中で接触させることと、
試料をインキュベートすることと、
プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性抗体を精製することとを含む、方法も提供する。
本明細書で特定される変異は、多量体タンパク質が、非対称のQ311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311R変異を有するCH2−CH3領域をそれぞれが有する少なくとも2個のポリペプチド鎖を有するものである限り、任意の多量体タンパク質をその親タンパク質から単離するために使用することができる。
それぞれF405L及びK409R、
それぞれ、野生型及びF405L/R409K、
それぞれ、T366W及びT366S/L368A/Y407V、
それぞれ、T366Y/F405A及びT394W/Y407T、
それぞれ、T366W/F405W及びT394S/Y407A、
それぞれ、F405W/Y407A及びT366W/T394S、
それぞれ、L351Y/F405A/Y407V及びT394W、
それぞれ、T366I/K392M/T394W及びF405A/Y407V、
それぞれ、T366L/K392M/T394W及びF405A/Y407V、
それぞれ、L351Y/Y407A及びT366A/K409F、
それぞれ、L351Y/Y407A及びT366V/K409F、
それぞれ、Y407A及びT366A/K409F、
それぞれ、D399K/E356K及びK409D/K392D、又は
それぞれ、D399K/E356K/E357K及びK409D/K392D/K370である。
それぞれ、配列番号2及び22、
それぞれ、配列番号3及び22、
それぞれ、配列番号4及び22、
それぞれ、配列番号5及び22、
それぞれ、配列番号6及び23、
それぞれ、配列番号7及び23、
それぞれ、配列番号8及び23、
それぞれ、配列番号9及び23、
それぞれ、配列番号10及び24、
それぞれ、配列番号11及び24、
それぞれ、配列番号12及び24、
それぞれ、配列番号13及び24、
それぞれ、配列番号14及び25、
それぞれ、配列番号15及び25、
それぞれ、配列番号16及び25、
それぞれ、配列番号17及び25、
それぞれ、配列番号18及び26、
それぞれ、配列番号19及び26、
それぞれ、配列番号20及び26、
それぞれ、配列番号21及び26、
それぞれ、配列番号52及び54、
それぞれ、配列番号52及び55、
それぞれ、配列番号53及び54、
それぞれ、配列番号53及び55、
それぞれ、配列番号56及び54、又は、
それぞれ、配列番号56及び55のアミノ酸配列を有する。
本発明はまた、本発明の多量体タンパク質のCH2−CH3領域、抗体重鎖、抗体軽鎖、又はポリペプチドのいずれかをコードする単離されたポリヌクレオチドも提供する。
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域をコードするポリヌクレオチドを含むか、
変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域と、307、309及び311位に野生型アミノ酸残基を有する第2のCH2−CH3領域とをコードするポリヌクレオチドを含むか、又は
配列番号27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、87、88又は91のポリヌクレオチド配列を含む、単離されたポリヌクレオチドも提供する。
本発明はまた、本発明の多重特異性抗体又は多量体タンパク質と、製薬上許容される担体とを含む医薬組成物も提供する。治療用途では、本発明の多重特異性抗体又は多量体タンパク質は、製薬上許容される担体中に活性成分として有効量の本発明の多重特異性抗体又は多量体タンパク質を含有する医薬組成物として調製することができる。「担体」とは、活性化合物と共に投与される希釈剤、補助剤、賦形剤、又はビヒクルを指す。このようなビヒクルは、水、及び石油、動物、植物又は合成物由来のものを含む油、例えば、落花生油、大豆油、鉱油、ゴマ油などの液体であってよい。例えば、0.4%生理食塩水及び0.3%グリシンを用いることができる。これらの溶液は滅菌され、一般には粒子状物質を含まない。これらは、通常の周知の滅菌技術(例えば、濾過)によって滅菌することができる。この組成物は、生理学的条件に近づけるために必要とされる医薬的に許容される補助物質、例えばpH調整剤及び緩衝剤、安定化剤、増粘剤、潤滑剤及び着色剤等を含有することができる。そのような医薬製剤中の本発明の多重特異性抗体又は多量体タンパク質の濃度は幅広く異なってもよく、即ち約0.5重量%未満から、通常は少なくとも約1重量%まで、最大で15又は20重量%までであってよく、また、選択される特定の投与方法に従って、必要とされる用量、流体体積、粘度等に主に基づいて選択される。好適なビヒクル、及び他のヒトタンパク質、例えばヒト血清アルブミンを含む製剤は、例えば、Remington:The Science and Practice of Pharmacy,21st Edition,Troy,D.B.ed.,Lipincott Williams and Wilkins,Philadelphia,PA 2006,Part 5,Pharmaceutical Manufacturing pp691−1092に記載され、特にpp.958−989を参照されたい。
FcRn及びプロテインAのZドメインは、CH2ドメインとCH3ドメインとの界面でFcに結合し、Fc上の同じ残基の多くと接触する。マウスIgG2a/bは、ヒトIgG1よりも弱くZドメインに結合するのに対してFcRnにはいずれも結合することから、マウスIgG2aのCH2ドメインでは保存されていない位置が、ヒトIgG1のCH2ドメインのZドメイン結合界面で特定された。図1Aは、ヒトIgG1のCH2ドメインとマウスIgG2aのCH2ドメインの残基305と315との間のアラインメントを示す。305、307、309、314及び315位の残基がヒト配列とマウス配列とで異なっていたことから、ヒトIgG1に逆変異T307P及び/又はL309Qを導入することによって、FcRnとの相互作用に影響を及ぼすことなく、プロテインAとの結合性が低下した操作されたIgG1変異体が生じるものと仮定された。ヒトIgG1のバリン305はCH2ドメインのβ鎖内に位置し、プロテインAともFcRnとも相互作用しない。ロイシン314及びアスパラギン315は、ヒトIgGとマウスIgGとで異なっているが、それらの相違は保存的である(例えば、ヒトIgGのL314は、マウスIgGでは別の疎水性残基L/M314に変わっており、N315はマウスIgGでは別の極性残基S315に変わっている)。したがって、307及び309位における変化が、ヒトIgG1のプロテインA及びFcRnとの相互作用に最も大きな影響を及ぼすものと推論された。
変異T307A、Q311A、Q311K、Q311E、T307P/L309Q又はT307P/L309Q/Q311Rを、標準的な分子生物学的手法を用いて異なる単一特異性抗体の両方の重鎖に遺伝子操作により導入した。
配列番号68 gp120−R HC
QVQLVQSGAEVKKPGASVKVSCQASGYRFSNFVIHWVRQAPGQRFEWMGWINPYNGNKEFSAKFQDRVTFTADTSANTAYMELRSLRSADTAVYYCARVGPYSWDDSPQDNYYMDVWGKGTTVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EIVLTQSPGTLSLSPGERATFSCRSSHSIRSRRVAWYQHKPGQAPRLVIHGVSNRASGISDRFSGSGSGTDFTLTITRVEPEDFALYYCQVYGASSYTFGQGTKLERKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
DIVMTQSPDSLAVSLGERATINCRASQSVDYNGISYMHWYQQKPGQPPKLLIYAASNPESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQIIEDPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHADWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHKDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHRDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHHDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLPVQHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLPVQHRDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARLYGFTYGFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMDSRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QVQLVESGGGVVQPGRSRRLSCAASGFTFSRYTMHWVRQAPGKGLEWVAVISFDGSNKYYVGSVKGRFTISRDNSENTLYLQVNILRAEDTAVYYCAREARGSYAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
EVQLVESGGGVVQPGGSLSLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSNKKYADSVKGRFTISRDNSENTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EVQLVESGGGVVQPGGSLSLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSNKKYADSVKGRFTISRDNSENTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHRDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EVQLVESGGGVVQPGGSLSLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSNKKYADSVKGRFTISRDNSENTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLPVQHRDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EVQLVESGGGVVQPGGSLSLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSNKKYADSVKGRFTISRDNSENTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHRDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EVQLVESGGGVVQPGGSLSLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMSYDGSNKKYADSVKGRFTISRDNSENTLYLQMNSLRAEDTAVYYCARDRGIAAGGNYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLPVQHRDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
QVQLVESGGGVVQPGRSRRLSCAASGFTFSRYTMHWVRQAPGKGLEWVAVISFDGSNKYYVGSVKGRFTISRDNSENTLYLQVNILRAEDTAVYYCAREARGSYAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Zドメインに対する単一特異性IgG1変異体の結合
表8に示すようなFc変異を有する単一特異性抗RSV抗体を実験に使用した。
311位における導入された単一位置変異体(Q311R、Q311A、Q311K及びQ311H)のいずれにおいても、単一特異性抗体のFcRnとの相互作用は阻害されなかった。Q311R変異は、FcRnとの結合能力をある程度向上させ、この変異が血清中半減期を延長させる可能性を示唆した。RSV−L[TLQ]は、RSV−Lと比較した場合に同様の親和性でFcRnに結合した。非対称F405L Q311R(bsRSV−L[Q311R])又はF405L/T307P/L309Q/Q311R変異(bsRSV−L[TLQ])を有する二重特異性IgG1抗体も、野生型IgG1と比較して同等の親和性でFcRnに結合した。図2Aは、Q311R、Q311A、Q311K又はQ311H変異を有するIgG1変異体のFcRnに対する競合結合の用量反応曲線を示す。図2Bは、対称(例えば、単一特異性mAbとしてRSV−L、RSV−L[Q311R]、RSV−L[TLQ])又は非対称(例えば、二重特異性mAbとしてbsRSV−L[Q311R]、bsRSV−L[TLQ])のQ311R又はT307P/L309Q/Q311R変異のいずれかを有するIgG1変異体のFcRnに対する競合結合の用量反応曲線を示す。I253D変異は、FcRnとの相互作用を阻害することが知られており、これをネガティブコントロールとして用いた。
T307A、Q311A、Q311K、Q311R、Q311H、T307P/L309Q及びT307P/L309Q/Q311R変異を、単一特異性の親抗RSV抗体又は抗gp120抗体に遺伝子操作により導入した。Fabアーム交換を用いて二重特異性抗RSV/gp120抗体を作製するため、親抗体を、F405L変異(抗RSV mAb)又はK409R変異(抗gp120 mAb)を有するように更に操作した。これらの変異がZドメイン及びFcRnとの結合をどの程度調節するかを評価した。
両方のアームに変異を有する各親mAbについて、1mgを1mLのmAbSelect sureカラム(GE Healthcare)にロードし、1×PBS(pH 7.2)〜50mMクエン酸塩(pH 3.5)までの30mLの勾配を用いて1mL/分で溶出した。280nmの吸光度及びpHをモニターした。ピーク最大でのpH値を用いて分取実験用の溶出pHを決定した。
α−スクリーンアッセイを用いてFcRnとの結合をインビトロで評価した。これらのアッセイでは、ビオチン化IgGをストレプトアビジンでコーティングしたドナービーズに結合させ、Hisタグ化したFcRnをNiコーティングしたアクセプタービーズに結合させた。2つのタンパク質間の結合によって発光シグナルが生じた。標識されていない野生型又は変異体IgGを使用して結合を競合させたところ、シグナルは用量依存的に低下した。mAbを、SureLINK Chromophoric Biotin Labeling kit(KPL Inc.)を使用して製造業者のプロトコールに従ってビオチン化した。Hisタグ化したFcRnをSino Biologicalから購入した。0.05%(w/v)ウシ血清アルブミン(BSA)及び0.01%(w/v)Tween−20を添加した、pH 6.0に調整した1×PBS中でアッセイを行った。1μg/mLのビオチン化した野生型IgG1を、ストレプトアビジンを結合させたドナービーズに結合させ、0.2μg/mLのHisタグ化したFcRnを、ニッケルを結合させたアクセプタービーズに結合させた。競合Abを0.4mg/mLで調製し、各点で3倍に連続希釈した。EnVisionプレートリーダー(Perkin Elmer)を使用して520〜620nmの発光を記録した。Prism6.01ソフトウェア(GraphPad Software,Inc.)及び上記に述べたような4パラメータ競合モデルを用いた当てはめ(Vafa et al.,Methods 65:114−126,2014)を用いて、データを分析した。
CH2−CH3界面における変異は、Fcの構造を変化させ、Fcの動力学を高め、熱安定性を低下させ、Fcγ受容体との相互作用を変化させることが報告されている(Majumdar et al.,MAbs 7:84−95,2015)。Q311R又はT307P/L309Q/Q311R変異がFcの構造に同様の影響を有するかどうかを調べるため、これらの変異を有する抗体を、Fcγ受容体に結合する能力及びそれらの熱安定性に関して評価した。
αスクリーンアッセイを使用し、若干の改変を行った実施例2に述べたプロトコールを用いて、IgG1変異体のFcγRへの結合を評価した。C末端Hisタグを有するFcγRの可溶性細胞外ドメインをR&D Systemsより購入した。0.05%(w/v)ウシ血清アルブミン(BSA)及び0.01%(w/v)Tween−20を添加した、1×PBS(pH 7.2)中でアッセイを行った。1μg/mLのビオチン化した野生型IgG1を、ストレプトアビジンを結合させたドナービーズに結合させ、Hisタグ化したFcγRを、ニッケルを結合させたアクセプタービーズに結合させた。FcγRIについては、野生型IgG1よりも弱く受容体に結合したビオチン化IgG1−L234A/L235A変異体を使用してシグナルウインドウを大きくした。使用したFcγRの濃度は、200ng/mL(FcγRI及びFcγRIIIa)、10ng/mL(FcγRIIa)、又は14ng/mL(FcγRIIb)とした。競合Abを0.4mg/mLで調製し、各点で3倍に連続希釈した。
二重特異性抗体への非対称的Q311R又はT307P/L309Q/Q311R変異の導入によって、親単一特異性mAbからの二重特異性抗体の精製が容易となった。
親抗体としてRSV−L[TLQ]及びgp120−Rを、二重特異性としてbsRSV−L[TLQ]mAbを実験に使用した。
上清中での交差材料から作製された二重特異性抗体に非対称Q311R又はT307P/L309Q/Q311Rを導入することによって、親抗体から作製された二重特異性抗体の精製が容易となった。
親mAbとしてRSV−L[Q311R]又はRSV−L[TLQ]とgp120−RとをExpi293細胞で発現させ、抗体力価を決定した(Octet,ForteBio)。二重特異性抗体bsRSV−L[Q311R]及びbsRSV−L[TLQ]を作製するため、等ミリグラム量のRSV−L[Q311R]及びgp120−R、又はRSV−L[TLQ]及びgp120−Rを含有する培養上清同士を加え合わせ、2−メルカプトエチルアミンを最終濃度75mMにまで添加した後、31℃で5時間インキュベートし、1×DPBS(pH 7.4)中に重点的に透析することにより、0.2mg/mLの最終タンパク質濃度でFabアーム交換反応を行った(Labrijn Aran F,Meesters Joyce I et al.2014)。透析後、タンパク質を1mLのmAbSelect Sureカラム(GE)にかけ、pH段階勾配を用いて溶出した。
Fabアーム交換の代わりに共通軽鎖技術を利用して作製された二重特異性抗体を精製するうえで、Q311R又はT307P/L309Q/Q311R変異を利用することの有用性を評価した。
親抗体TNF−[Q311R]、TNF−[TLQ]及びaVb5(表8を参照)を実験で使用した。親の抗TNF抗体と抗αVβV抗体とは共通の軽鎖を共有しており、したがって、これらのmAbを実験で使用することにより、軽鎖のミスペアリングによって生じ得るmAb種を最小限に抑えた。
Tg32系ヘミ接合体マウスを用いて、選択された抗体のPK特性を調べた。これらの実験では、RSV−Lは約7日の半減期を有していた。Q311R又はT307P/L309Q/Q311R変異のいずれかを有するホモ二量体の親Ab(抗体RSV−L[Q311R]及びRSV−L[TLQ])はどちらも、少なくとも野生型mAbと同程度の長さの半減期を有した(それぞれ約7日及び9日)。これらの変異は、二重特異性抗体に非対称に導入された場合にも血清中半減期にほとんど影響を及ぼさなかった。bsRSV−L[Q311R]及びbsRSV−L[TLQ]は、それぞれ11/1±3.6日及び4.8±2.0日の血清中半減期を有していた。RSV−Lの血清中半減期は7.0±3.9日であり、RSV−L[TLQ]の半減期は9.0±4.0日であり、RSV−L[Q311R]の血清中半減期は6.7±3.4日であった。I253D変異体AbはFcRnに結合せず、この実験のコントロールとして使用した。
Tg32系ヘミ接合体マウス(Jackson Laboratoriesストック番号014565)を抗体の薬物動態(PK)試験に使用した。これらのマウスは、FcRnのヒトαミクログロブリンサブユニットの形質転換体であり、したがってヒトにおける血清中半減期の予測に役立つ(Petkova et al.,Int Immunol 18:1759−1769,2006)。マウスに、尾静脈を介して、2mg/kgの用量の試験Abを各群4匹の動物に静脈内注射した。1h、1d、3d、7d、14d及び21dの時点を取った。示した時点で、CO2麻酔下のマウスの後眼窩静脈叢から連続採血を行い、最後の血液は心臓穿刺により採血した。室温で30分後に、血液試料を3,000×gで15分間遠心し、分析用の血清を採取した。
Claims (79)
- 単離された多重特異性抗体であって、変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R、又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域と、307、309及び311位に野生型アミノ酸残基を有する第2のCH2−CH3領域とを含み、残基の番号付けはEUインデックスに従う、単離された多重特異性抗体。
- 前記抗体が、IgG1、IgG2又はIgG4アイソタイプである、請求項1に記載の単離された多重特異性抗体。
- 前記第2のCH2−CH3領域と比較して、前記第1のCH2−CH3領域のプロテインAリガンドに対する結合が低下している、請求項1又は2に記載の単離された多重特異性抗体。
- 前記プロテインAリガンドが、黄色ブドウ球菌のプロテインA、Zドメイン又はYドメインを含む、請求項3に記載の単離された多重特異性抗体。
- 前記Zドメインが、配列番号1のアミノ酸配列を有する、請求項4に記載の単離された多重特異性抗体。
- 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域に非対称の安定化変異を更に含む、請求項1〜5のいずれか一項に記載の単離された多重特異性抗体。
- 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域における、又は前記第2のCH2−CH3領域及び前記第1のCH2−CH3領域における、前記非対称の安定化変異が、
a)それぞれ、F405L及びK409R、
b)それぞれ、野生型及びF405L/R409K、
c)それぞれ、T366W及びT366S/L368A/Y407V、
d)それぞれ、T366Y/F405A及びT394W/Y407T、
e)それぞれ、T366W/F405W及びT394S/Y407A、
f)それぞれ、F405W/Y407A及びT366W/T394S、
g)それぞれ、L351Y/F405A/Y407V及びT394W、
h)それぞれ、T366I/K392M/T394W及びF405A/Y407V、
i)それぞれ、T366L/K392M/T394W及びF405A/Y407V、
j)それぞれ、L351Y/Y407A及びT366A/K409F、
k)それぞれ、L351Y/Y407A及びT366V/K409F、
l)それぞれ、Y407A及びT366A/K409F、
m)それぞれ、D399K/E356K及びK409D/K392D、又は
n)それぞれ、D399K/E356K/E357K及びK409D/K392D/K370
である、請求項6に記載の単離された多重特異性抗体。 - 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域が、
a)それぞれ、配列番号2及び22、
b)それぞれ、配列番号3及び22、
c)それぞれ、配列番号4及び22、
d)それぞれ、配列番号5及び22、
e)それぞれ、配列番号6及び23、
f)それぞれ、配列番号7及び23、
g)それぞれ、配列番号8及び23、
h)それぞれ、配列番号9及び23、
i)それぞれ、配列番号10及び24、
j)それぞれ、配列番号11及び24、
k)それぞれ、配列番号12及び24、
l)それぞれ、配列番号13及び24、
m)それぞれ、配列番号14及び25、
n)それぞれ、配列番号15及び25、
o)それぞれ、配列番号16及び25、
p)それぞれ、配列番号17及び25、
q)それぞれ、配列番号18及び26、
r)それぞれ、配列番号19及び26、
s)それぞれ、配列番号20及び26、
t)それぞれ、配列番号21及び26、
u)それぞれ、配列番号52及び54、
v)それぞれ、配列番号52及び55、
w)それぞれ、配列番号53及び54、
x)それぞれ、配列番号53及び55、
y)それぞれ、配列番号56及び54、又は
z)それぞれ、配列番号56及び55
のアミノ酸配列を有する、請求項1〜7のいずれか一項に記載の単離された多重特異性抗体。 - 前記単離された多重特異性抗体が、FcγR又はFcRnに対する前記抗体の結合を調節する少なくとも1つの変異を更に含む、請求項1〜8のいずれか一項に記載の単離された多重特異性抗体。
- FcγR又はFcRnに対する前記抗体の結合を調節する前記少なくとも1つの変異が、L234A、F234A、V234A、L235A、G237A、P238S、H268A、V309L、A330A、P331S、L234A/L235A、F234A/L235A、V234A/L235A、V234A/G237A/P238S/H268A/V309L/A330S/P331S、L234A/L235A/G237A/P238S/H268A/A330S/P331S、S239D/I332E、S298A/E333A/K334A、F243L/R292P/Y300L、F243L/R292P/Y300L/P396L、F243L/R292P/Y300L/V305I/P396L、G236A/S239D/I332E、S267E、S267E/L328F、S267E/I332E又はM252Y/S254T/T256Eである、請求項9に記載の単離された多重特異性抗体。
- 第1の軽鎖及び第2の軽鎖を含む、請求項1〜10のいずれか一項に記載の単離された多重特異性抗体。
- 前記第1の軽鎖及び前記第2の軽鎖が同じアミノ酸配列を有する、請求項11に記載の単離された多重特異性抗体。
- 前記単離された多重特異性抗体が、2つ以上の抗原に結合する、請求項1〜12のいずれか一項に記載の単離された多重特異性抗体。
- 前記2つの抗原が、PD1、CD27、CD28、NKP46、ICOS、GITR、OX40、CTLA4、LAG3、TIM3、KIRa、CD73、CD39、IDO、BTLA、VISTA、TIGIT、CD96、CD30、HVEM、DNAM−1、LFA、腫瘍抗原、EGFR、cMet、FGFR、ROR1、CD123、IL1RAP、FGFR、メソテリン、CD3、T細胞受容体、CD32b、CD32a、CD16a、CD16b、NKG2D、NKP46、CD28、CD47、DLL、CD8、CD89、HLA、B細胞受容体、又はCD137のうちのいずれか2つである、請求項13に記載の単離された多重特異性抗体。
- 二重特異性抗体である、請求項1〜14のいずれか一項に記載の単離された多重特異性抗体。
- 請求項1〜15のいずれか一項に記載の単離された多重特異性抗体を含む、医薬組成物。
- a)変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する前記第1のCH2−CH3領域をコードするポリヌクレオチドを含み、
b)変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する前記第1のCH2−CH3領域と、307、309及び311位に野生型アミノ酸残基を有する前記第2のCH2−CH3領域とをコードするポリヌクレオチドを含み、
c)配列番号27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、87、88又は91のポリヌクレオチド配列を含む、単離されたポリヌクレオチド。 - a)変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する前記第1のCH2−CH3領域をコードする前記単離されたポリヌクレオチドと、
b)配列番号27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、87、88又は91のポリヌクレオチド配列を有する、前記単離されたポリヌクレオチドと、
c)変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する前記第1のCH2−CH3領域と、307、309及び311位に野生型アミノ酸残基を有する前記第2のCH2−CH3領域とをコードするポリヌクレオチドを含む、前記単離されたポリヌクレオチドと、
d)
i)配列番号27及び47、それぞれ、
ii)配列番号28及び47、それぞれ、
iii)配列番号29及び47、それぞれ、
iv)配列番号30及び47、それぞれ、
v)配列番号31及び48、それぞれ、
vi)配列番号32及び48、それぞれ、
vii)配列番号33及び48、それぞれ、
viii)配列番号34及び48、それぞれ、
ix)配列番号35及び49、それぞれ、
x)配列番号36及び49、それぞれ、
xi)配列番号37及び49、それぞれ、
xii)配列番号38及び49、それぞれ、
xiii)配列番号39及び50、それぞれ、
xiv)配列番号40及び50、それぞれ、
xv)配列番号41及び50、それぞれ、
xvi)配列番号42及び50、それぞれ、
xvii)配列番号43及び51、それぞれ、
xviii)配列番号44及び51、それぞれ、
xix)配列番号45及び51、それぞれ、
xx)配列番号46及び51、それぞれ、
xxi)配列番号87及び89、それぞれ、
xxii)配列番号87及び90、それぞれ、
xxiii)配列番号88及び89、それぞれ、
xxiv)配列番号88及び90、それぞれ、
xxv)配列番号92及び89、それぞれ、又は
xxvi)配列番号92及び90それぞれ、
を有する前記単離されたポリヌクレオチドと
を含む、ベクター。 - 請求項18に記載のベクターを含む、宿主細胞。
- 前記宿主細胞が、ハイブリドーマ、骨髄腫、SP2/0、NS0、U266、CHO、CHO−K1SV、CHO−K1、DG44又はHek293である、請求項19に記載の宿主細胞。
- 請求項1に記載の単離された多重特異性抗体を製造する方法であって、
a)前記多重特異性抗体が発現される条件下で請求項19に記載の宿主細胞を培養することと、
b)プロテインAリガンド親和性クロマトグラフィーを使用して前記多重特異性抗体を精製することと、を含む、方法。 - 変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1の重鎖又はそのフラグメントと、307、309及び311位に野生型アミノ酸残基を有する第2の重鎖又はそのフラグメントとを含む、単離された多重特異性抗体を製造する方法であって、
a)前記変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311R を有する前記第1の重鎖又はそのフラグメントと第1の軽鎖とを含む第1の親抗体を与えることと、
b)307、309及び311位に野生型アミノ酸残基を有する前記第2の重鎖又はそのフラグメントと第2の軽鎖とを含む第2の親抗体を与えることと、
c)前記第1の親抗体と前記第2の親抗体とを試料中で接触させることと、
d)前記試料をインキュベートすることと、
e)プロテインAリガンド親和性クロマトグラフィーを使用して前記多重特異性抗体を精製することと、を含む、方法。 - 前記単離された多重特異性抗体が、前記第1の重鎖又はそのフラグメント及び前記第2の重鎖又はそのフラグメントに非対称の安定化変異を更に有する、請求項22に記載の方法。
- 前記第1の重鎖若しくはそのフラグメント及び前記第2の重鎖若しくはそのフラグメントにおける、又は前記第2の重鎖若しくはそのフラグメント及び前記第1の重鎖若しくはそのフラグメントにおける、前記非対称の安定化変異が、
a)それぞれ、F405L及びK409R、
b)それぞれ、野生型及びF405L/R409K、
c)それぞれ、T366W及びT366S/L368A/Y407V、
d)それぞれ、T366Y/F405A及びT394W/Y407T、
e)それぞれ、T366W/F405W及びT394S/Y407A、
f)それぞれ、F405W/Y407A及びT366W/T394S、
g)それぞれ、L351Y/F405A/Y407V及びT394W、
h)それぞれ、T366I/K392M/T394W及びF405A/Y407V、
i)それぞれ、T366L/K392M/T394W及びF405A/Y407V、
j)それぞれ、L351Y/Y407A及びT366A/K409F、
k)それぞれ、L351Y/Y407A及びT366V/K409F、
l)それぞれ、Y407A及びT366A/K409F、
m)それぞれ、D399K/E356K及びK409D/K392D、又は
n)それぞれ、D399K/E356K/E357K及びK409D/K392D/K370
である、請求項23に記載の方法。 - 前記単離された多重特異性抗体が、IgG1、IgG2又はIgG4アイソタイプである、請求項22〜24のいずれか一項に記載の方法。
- 前記第1の軽鎖及び前記第2の軽鎖が同じアミノ酸配列を有する、請求項22〜25のいずれか一項に記載の方法。
- 前記第1の親抗体及び前記第2の親抗体が、精製抗体として与えられる、請求項22〜25のいずれか一項に記載の方法。
- 前記第1の親抗体及び前記第2の親抗体が、前記第1の親抗体及び前記第2の親抗体を発現する細胞から回収された細胞培地中で与えられる、請求項22〜26のいずれか一項に記載の方法。
- 工程d)において還元剤が添加される、請求項22に記載の方法。
- 前記還元剤が、2−メルカプトエチルアミン(2−MEA)、ジチオトレイトール(DTT)、ジチオエリスリトール(DTE)、グルタチオン、トリス(2−カルボキシエチル)ホスフィン(TCEP)、L−システイン又はβ−メルカプトエタノールである、請求項29に記載の方法。
- 2−MEAが、約10mM〜約100mMの濃度で存在する、請求項30に記載の方法。
- 2−MEAが、約25mM〜約75mMの濃度で存在する、請求項31に記載の方法。
- 工程d)が、約20℃〜約37℃の温度で約90分〜約6時間行われる、請求項22に記載の方法。
- プロテインAリガンド親和性クロマトグラフィーが、pH勾配を用いる、請求項22〜33のいずれか一項に記載の方法。
- 前記pH勾配が、約pH7.0〜約3.0である、請求項34に記載の方法。
- 前記pH勾配が、約pH4.6〜約3.4である、請求項34に記載の方法。
- 多量体抗体が、約pH 4.4〜約pH 4.1で溶出する、請求項34〜46のいずれか一項に記載の方法。
- プロテインAリガンド親和性クロマトグラフィーが、クエン酸塩緩衝液を用いる、請求項34〜37のいずれか一項に記載の方法。
- 前記多重特異性抗体が、二重特異性抗体である、請求項22〜38のいずれか一項に記載の方法。
- 同じアミノ酸配列を有する2個の重鎖又はそのフラグメントと2個の軽鎖又はそのフラグメントとを含む、単離された抗体であって、前記2個の重鎖が、変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有し、残基の番号付けはEUインデックスに従う、単離された抗体。
- 前記2個の重鎖又はそのフラグメントが、変異F405L、K409R、F405L/R409K、T366W又はT366S/L368A/Y407Vを更に有する、請求項40に記載の単離された抗体。
- 前記抗体が、IgG1、IgG2又はIgG4アイソタイプである、請求項40又は41に記載の単離された抗体。
- 配列番号2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、52、53又は56の重鎖CH2−CH3領域を含む、請求項40〜42のいずれか一項に記載の単離された抗体。
- a)配列番号2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、52、53又は56の前記CH2−CH3領域を含む抗体重鎖をコードするか、又は
b)配列番号27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、87、88又は91の前記ポリヌクレオチド配列を含む、ポリヌクレオチド。 - 請求項44に記載のポリヌクレオチドを含む、ベクター。
- 請求項45に記載のベクターを含む、宿主細胞。
- 請求項40に記載の単離された抗体を製造する方法であって、前記抗体が発現される条件下で、請求項46に記載の宿主細胞を培養することを含む、方法。
- 第1のポリペプチドと第2のポリペプチドとを含む多量体タンパク質であって、前記第1のポリペプチドが、変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域を含み、前記第2のポリペプチドが、307、309及び311位に野生型アミノ酸残基を有する第2のCH2−CH3領域を含み、残基の番号付けはEUインデックスに従う、多量体タンパク質。
- 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域が、IgG1、IgG2又はIgG4アイソタイプである、請求項48に記載の多量体タンパク質。
- 前記第2のCH2−CH3領域と比較して、前記第1のCH2−CH3領域のプロテインAリガンドに対する結合が低下している、請求項48又は49に記載の多量体タンパク質。
- 前記プロテインAリガンドが、黄色ブドウ球菌のプロテインA、Zドメイン又はYドメインを含む、請求項50に記載の多量体タンパク質。
- 前記Zドメインが、配列番号1のアミノ酸配列を有する、請求項51に記載の多量体タンパク質。
- 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域に非対称の安定化変異を更に有する、請求項48〜52のいずれか一項に記載の多量体タンパク質。
- 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域における、又は前記第2のCH2−CH3領域及び前記第1のCH2−CH3領域における、前記非対称の安定化変異が、
a)それぞれ、F405L及びK409R、
b)それぞれ、野生型及びF405L/R409K、
c)それぞれ、T366W及びT366S/L368A/Y407V、
d)それぞれ、T366Y/F405A及びT394W/Y407T、
e)それぞれ、T366W/F405W及びT394S/Y407A、
f)それぞれ、F405W/Y407A及びT366W/T394S、
g)それぞれ、L351Y/F405A/Y407V及びT394W、
h)それぞれ、T366I/K392M/T394W及びF405A/Y407V、
i)それぞれ、T366L/K392M/T394W及びF405A/Y407V、
j)それぞれ、L351Y/Y407A及びT366A/K409F、
k)それぞれ、L351Y/Y407A及びT366V/K409F、
l)それぞれ、Y407A及びT366A/K409F、
m)それぞれ、D399K/E356K及びK409D/K392D、又は
n)それぞれ、D399K/E356K/E357K及びK409D/K392D/K370
である、請求項53に記載の多量体タンパク質。 - 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域が、
a)それぞれ、配列番号2及び22、
b)それぞれ、配列番号3及び22、
c)それぞれ、配列番号4及び22、
d)それぞれ、配列番号5及び22、
e)それぞれ、配列番号6及び23、
f)それぞれ、配列番号7及び23、
g)それぞれ、配列番号8及び23、
h)それぞれ、配列番号9及び23、
i)それぞれ、配列番号10及び24、
j)それぞれ、配列番号11及び24、
k)それぞれ、配列番号12及び24、
l)それぞれ、配列番号13及び24、
m)それぞれ、配列番号14及び25、
n)それぞれ、配列番号15及び25、
o)それぞれ、配列番号16及び25、
p)それぞれ、配列番号17及び25、
q)それぞれ、配列番号18及び26、
r)それぞれ、配列番号19及び26、
s)それぞれ、配列番号20及び26、
t)それぞれ、配列番号21及び26、
u)それぞれ、配列番号52及び54、
v)それぞれ、配列番号52及び55、
w)それぞれ、配列番号53及び54、
x)それぞれ、配列番号53及び55、
y)それぞれ、配列番号56及び54、又は
z)それぞれ、配列番号56及び55
のアミノ酸配列を有する、請求項48〜54のいずれか一項に記載の多量体タンパク質。 - 前記第1のCH2−CH3領域及び/又は前記第2のCH2−CH3領域が異種タンパク質に結合されている、請求項48〜55のいずれか一項に記載の多量体タンパク質。
- 前記異種タンパク質が、ペプチド、受容体の細胞外ドメイン、リガンドの細胞外ドメイン、分泌タンパク質、scFv、Fab、重鎖可変領域(VH)、軽鎖可変領域(VL)、フィブロネクチンIII型ドメイン及び/又はファイノマーである、請求項56に記載の多量体タンパク質。
- 前記異種タンパク質が、前記第1のCH2−CH3領域及び/又は前記第2のCH2−CH3領域のN末端又はC末端に、必要に応じてリンカーを介して結合される、請求項57に記載の多量体タンパク質。
- 前記リンカーが、配列番号57、58、59、60、61、62、63、64、65、66、67、92、93、94、95、96、97又は98のアミノ酸配列を有する、請求項68に記載の多量体タンパク質。
- 前記多量体タンパク質が抗体である、請求項48に記載の多量体タンパク質。
- 前記抗体が、多重特異性、二重特異性又は単一特異性である、請求項60に記載の多量体タンパク質。
- 2個、3個又は4個のポリペプチド鎖を含む、請求項48〜61のいずれか一項に記載の多量体タンパク質。
- 請求項48〜62のいずれか一項に記載の多量体タンパク質を含む、医薬組成物。
- 変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する第1のCH2−CH3領域と、307、309及び311位に野生型アミノ酸残基を有する第2のCH2−CH3領域とを含む単離された多量体タンパク質を製造する方法であって、
a)前記変異Q311R、Q311K、T307P/L309Q、T307P/V309Q、T307P/L309Q/Q311R又はT307P/V309Q/Q311Rを有する前記第1のCH2−CH3領域を含む第1の親タンパク質を与えることと、
b)307、309及び311位に前記野生型アミノ酸残基を有する前記第2のCH2−CH3領域を含む第2の親タンパク質を与えることと、
c)前記第1の親タンパク質と前記第2の親タンパク質とを試料中で接触させることと、
d)前記試料をインキュベートすることと、
e)プロテインAリガンド親和性クロマトグラフィーを使用して多重特異性タンパク質を精製することとを含む、前記方法。 - 前記多量体タンパク質が、前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域に非対称の安定化変異を更に有する、請求項64に記載の方法。
- 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域における、又は前記第2のCH2−CH3領域及び前記第1のCH2−CH3領域における、前記非対称の安定化変異が、
a)それぞれ、F405L及びK409R、
b)それぞれ、野生型及びF405L/R409K、
c)それぞれ、T366W及びT366S/L368A/Y407V、
d)それぞれ、T366Y/F405A及びT394W/Y407T、
e)それぞれ、T366W/F405W及びT394S/Y407A、
f)それぞれ、F405W/Y407A及びT366W/T394S、
g)それぞれ、L351Y/F405A/Y407V及びT394W、
h)それぞれ、T366I/K392M/T394W及びF405A/Y407V、
i)それぞれ、T366L/K392M/T394W及びF405A/Y407V、
j)それぞれ、L351Y/Y407A及びT366A/K409F、
k)それぞれ、L351Y/Y407A及びT366V/K409F、
l)それぞれ、Y407A及びT366A/K409F、
m)それぞれ、D399K/E356K及びK409D/K392D、又は
n)それぞれ、D399K/E356K/E357K及びK409D/K392D/K370
である、請求項65に記載の方法。 - 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域が、IgG1、IgG2又はIgG4アイソタイプである、請求項64〜66のいずれか一項に記載の方法。
- 前記第1のCH2−CH3領域及び前記第2のCH2−CH3領域が、
a)それぞれ、配列番号2及び22、
b)それぞれ、配列番号3及び22、
c)それぞれ、配列番号4及び22、
d)それぞれ、配列番号5及び22、
e)それぞれ、配列番号6及び23、
f)それぞれ、配列番号7及び23、
g)それぞれ、配列番号8及び23、
h)それぞれ、配列番号9及び23、
i)それぞれ、配列番号10及び24、
j)それぞれ、配列番号11及び24、
k)それぞれ、配列番号12及び24、
l)それぞれ、配列番号13及び24、
m)それぞれ、配列番号14及び25、
n)それぞれ、配列番号15及び25、
o)それぞれ、配列番号16及び25、
p)それぞれ、配列番号17及び25、
q)それぞれ、配列番号18及び26、
r)それぞれ、配列番号19及び26、
s)それぞれ、配列番号20及び26、
t)それぞれ、配列番号21及び26、
u)それぞれ、配列番号52及び54、
v)それぞれ、配列番号52及び55、
w)それぞれ、配列番号53及び54、
x)それぞれ、配列番号53及び55、
y)それぞれ、配列番号56及び54、又は
z)それぞれ、配列番号56及び55
のアミノ酸配列を有する、請求項64〜67のいずれか一項に記載の方法。 - 前記第1のCH2−CH3領域及び/又は前記第2のCH2−CH3領域が異種タンパク質に結合されている、請求項64〜68のいずれか一項に記載の方法。
- 前記異種タンパク質が、ペプチド、受容体の細胞外ドメイン、リガンドの細胞外ドメイン、分泌タンパク質、scFv、Fab、重鎖可変領域(VH)、軽鎖可変領域(VL)、フィブロネクチンIII型ドメイン及び/又はファイノマーである、請求項69に記載の方法。
- 前記異種タンパク質が、前記第1のCH2−CH3領域及び/又は前記第2のCH2−CH3領域のN末端又はC末端に、必要に応じてリンカーを介して結合される、請求項69又は70に記載の方法。
- 前記リンカーが、配列番号57、58、59、60、61、62、63、64、65、66、67、92、93、94、95、96、97又は98のアミノ酸配列を有する、請求項71に記載の方法。
- 前記第1の親タンパク質及び前記第2の親タンパク質が、精製タンパク質として与えられる、請求項64〜72のいずれか一項に記載の方法。
- 前記第1の親タンパク質及び前記第2の親タンパク質が、前記第1の親タンパク質及び前記第2の親タンパク質を発現する細胞から回収された細胞培地中で与えられる、請求項64〜72のいずれか一項に記載の方法。
- 工程d)において還元剤が添加される、請求項64に記載の方法。
- 前記還元剤が、2−メルカプトエチルアミン(2−MEA)、ジチオトレイトール(DTT)、ジチオエリスリトール(DTE)、グルタチオン、トリス(2−カルボキシエチル)ホスフィン(TCEP)、L−システイン又はβ−メルカプトエタノールである、請求項75に記載の方法。
- 2−MEAが、約10mM〜約100mMの濃度で存在する、請求項76に記載の方法。
- 2−MEAが、約25mM〜約75mMの濃度で存在する、請求項76に記載の方法。
- 工程d)が、約25℃〜約37℃の温度で約90分〜約6時間にわたって行われる、請求項64に記載の方法。
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WO2018224951A3 (en) | 2019-02-14 |
US11149094B2 (en) | 2021-10-19 |
MX2019014576A (es) | 2020-07-29 |
AU2018281045A1 (en) | 2019-12-12 |
CN110785185A (zh) | 2020-02-11 |
KR20200014379A (ko) | 2020-02-10 |
US20180346605A1 (en) | 2018-12-06 |
RU2019144115A3 (ja) | 2022-02-10 |
CN110785185B (zh) | 2024-05-24 |
WO2018224951A2 (en) | 2018-12-13 |
EP3634486A2 (en) | 2020-04-15 |
CA3065171A1 (en) | 2018-12-13 |
BR112019025583A2 (pt) | 2020-06-16 |
EP3634486A4 (en) | 2021-03-31 |
RU2019144115A (ru) | 2021-07-09 |
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