JP2023502460A - Trem2抗体およびそれらの使用 - Google Patents
Trem2抗体およびそれらの使用 Download PDFInfo
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- JP2023502460A JP2023502460A JP2022529507A JP2022529507A JP2023502460A JP 2023502460 A JP2023502460 A JP 2023502460A JP 2022529507 A JP2022529507 A JP 2022529507A JP 2022529507 A JP2022529507 A JP 2022529507A JP 2023502460 A JP2023502460 A JP 2023502460A
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Abstract
Description
本発明の抗体を生成するために、抗体生殖系列、親和性成熟、脱免疫化、および創薬可能性の最適化を含む重要な操作が行われた。このような抗体は、ヒトTREM2に対する親和性が高く、免疫原性が低減し、ヒトの臨床試験に許容できる、または最適な開発可能性を備えたヒト抗体である。
本発明のTREM2抗体は、基本的に次のように発現および精製することができる。HEK293またはCHOなどの適切な宿主細胞は、最適な所定のHC:LCベクター比(1:3または1:2など)を使用して抗体を分泌するための発現系、またはHCおよびLCの両方をコードする単一のベクター系で、一過性でまたは安定的にトランスフェクトすることができる。抗体が分泌された公知組成培地は、多くの一般的に使用される技術のうちのいずれかを使用して精製されてもよい。例えば、培地は、リン酸緩衝生理食塩水(pH7.4)などの適合した緩衝液で平衡化された、Fabフラグメント用のMabSelect(登録商標)カラム(GE Healthcare)またはKappaSelectカラム(GE Healthcare)に適用され得る。カラムは、非特異的結合成分を除去するために洗浄され得る。
37℃での表面プラズモン共鳴法(SPR)を使用して、TREM2抗体の抗体1、参照抗体A、または参照抗体Bの抗原への結合速度および親和性を決定する。参照抗体Aは、PCT公開第2019/028292号において配列番号11、13、15、16、132、135、126によって示されるHCVR、ならびに配列番号20、22、23、25、144、131、および129によって示されるLCVRを含む。参照抗体Bは、PCT公開番号WO2016/023019においてそれぞれ配列番号412および413によって示されるHCVRおよびLCVRを含む。
抗体1がTREM2発現細胞に結合するかどうかを調べるために、結合実験を行う。BW5147.G.1.4細胞株は、ヒトTREM2およびそのアダプターDNAZアダプタータンパク質12(DAP12)を発現するように形質導入されている。結合を評価するために、抗体1の存在下で500,000個の細胞を、3倍、12点滴定を30μg/mlで開始し、37℃で30分間インキュベートする。抗体結合を、ヤギ抗ヒトIgG Alexa Fluor 647(Jackson Labs)を使用して検出する。平均蛍光強度(MFI)は、Accuri C6 Plusフローサイトメーター(BD Biosciences)を使用して測定する。
リガンドの存在下でのTREM2抗体媒介性NFAT活性化の影響を調べるために、ホスファチジルセリン(PS、Avanti脂質)をTREM2リガンドとして使用する。ウェルあたり1.5mMのPSを含有する96ウェルプレートを、室温で3時間乾燥させる。TREM2 NFATルシフェラーゼBW5147.G.14レポーター細胞(ウェルあたり400,000細胞)を、アイソタイプ対照抗体または抗体1の存在下でPSコーティングプレートにプレーティングし、5倍、8点滴定を30μg/mlで開始する。37℃で18時間インキュベートした後、Pierce Firefly ルシフェラーゼフラッシュアッセイキット(Thermo Fisher)およびEnvision 2105プレートリーダー(Perkin Elmer)を使用して発光を検出する。
マクロファージにおけるTREM2活性化に対する抗体1の影響を調べるために、
マクロファージを、抗体1またはアイソタイプ対照抗体の存在下または非存在下で、PDAPP脳組織切片(TREM2の生理学的内因性リガンドを含む)上で培養する。
インビボでのタウ媒介性神経変性中のミクログリア活性化状態に対する抗体1の影響を評価するために、抗体1を7ヵ月齢の雌rTg4510P301Lタウトランスジェニックマウスにゼロ日目に投与し、3倍、6点滴定を体重1グラムあたりの300mgで開始した。7日目に、マウスを犠牲にし、RNA分析のために脳組織を採取する。TREM2依存性遺伝子であるClec7aは、Taqman qPCRアッセイを使用して海馬で測定し、相対的発現をハウスキーピング遺伝子Hprtに対して正規化する。
抗体1の免疫原性の可能性を調べるために、主要組織適合遺伝子複合体関連ペプチドプロテオミクス(MAPP)アッセイを行う。10人の正常なヒトドナーからの初代ヒト樹状細胞を、抗CD14ビーズおよび磁気分離器でCD14陽性細胞を分離することにより、バフィーコートから調製する。CD14陽性細胞を1ウェルあたり5×106細胞でプレーティングし、10%ウシ胎仔血清を含有する完全RPMI培地で、20ng/ml IL-4および40ng/ml GM-CSFとともに37℃、かつ5%CO2で3日間インキュベートすることにより、未成熟樹状細胞に分化させた。4日後(4日目)に培地を交換し、3μMの抗体を含有する新鮮な培地を細胞に添加する。5日目に、5μg/mlのLPSを添加して、細胞を成熟樹状細胞に形質転換する。6日目に、細胞を、プロテアーゼ阻害剤を含む1mLのRIPA緩衝液に溶解し、溶解物を-80℃で凍結する。
抗体1LCDR1(配列番号1)
RASQAIRDDLG
抗体1LCDR2(配列番号2)
YAASSLQS
抗体1LCDR3(配列番号3)
LQNYNYPHT
抗体1HCDR1(配列番号4)
GFSFNTYWIG
抗体1CDR2(配列番号5)
IIYPGDQDIRYSPSFQG
抗体1HCDR3(配列番号6)
ARYGRYIYGYGGYHGMDV
抗体1LCVR(配列番号7)
DIQMTQSPSSLSASVGDRVTITCRASQAIRDDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQNYNYPHTFGQGTKLEIK
抗体1HCVR(配列番号8)
EVQLVQSGAEVKKPGESLKISCKGSGFSFNTYWIGWVRQMPGKGLEWMGIIYPGDQDIRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYGRYIYGYGGYHGMDVWGQGTTVTVSS
抗体1LC(配列番号9)
DIQMTQSPSSLSASVGDRVTITCRASQAIRDDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQNYNYPHTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
抗体1HC(配列番号10)
EVQLVQSGAEVKKPGESLKISCKGSGFSFNTYWIGWVRQMPGKGLEWMGIIYPGDQDIRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARYGRYIYGYGGYHGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
ヒトECD TREM2-His(配列番号11)
HNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFPPTSHHHHHH
マウスECD TREM2-His(配列番号12)
LNTTVLQGMAGQSLRVSCTYDALKHWGRRKAWCRQLGEEGPCQRVVSTHGVWLLAFLKKRNGSTVIADDTLAGTVTITLKNLQAGDAGLYQCQSLRGREAEVLQKVLVEVLEDPLDDQDAGDLWVPEESSSFEGAQVEHSTSRNQETSFPPTSHHHHHH
ウサギECD TREM2-HIS(配列番号13)
NTTVFQGVAGQSLRVSCPYDSATHWGRRKAWCRQLGEEGPCERVVSTHSWWLLSFLKRRNGSTAITDDALGGTLTVTLRDLQAQDAGVYQCQSLQGREASTLQKILVEVLTEPLEHEHAGDFWVPEESGSFEDPPVERSSSRSPSEGEPSFPPASGGGGQHHHHHH
ラットECD TREM2-His(配列番号14)
NTTVLQGVAGQSLRVSCTYDALRHWGRRKAWCRQLAEEGPCQRVVSTHGVWLLAFLRKQNGSTVITDDTLAGTVTITLRNLQAGDAGLYQCQSLRGREAEVLQKVVVEVLEDPLDDQDAGDLWVPEESESFEGAQVEHSTSRSQSGGGGQHHHHHH
カニクイザルECD TREM2-His(配列番号15)
HNTTVFQGVEGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRRNGSTAITDDTLGGTLTITLRNLQPHDAGFYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWVPGESESFEDAHVEHSISRPSQGSHLPSCLSKEGGGGQHHHHHH
Claims (20)
- 軽鎖可変領域(LCVR)と重鎖可変領域(HCVR)とを含み、前記LCVRが、相補性決定領域(CDR)LCDR1、LCDR2、およびLCDR3を含み、前記HCVRが、CDR HCDR1、HCDR2およびHCDR3を含み、LCDR1が、配列番号1によって示されるアミノ酸配列を有し、LCDR2が、配列番号2によって示されるアミノ酸配列を有し、LCDR3が、配列番号3によって示されるアミノ酸配列を有し、HCDR1が、配列番号4によって示されるアミノ酸配列を有し、HCDR2が、配列番号5によって示されるアミノ酸配列を有し、HCDR3が、配列番号6によって示されるアミノ酸配列を有する、TREM2に結合する抗体。
- 前記LCVRが、配列番号7によって示されるアミノ酸配列を有し、前記HCVRが、配列番号8によって示されるアミノ酸配列を有する、請求項1に記載の抗体。
- 前記抗体が、LCおよびHCを含み、前記LCが、配列番号9によって示されるアミノ酸配列を有し、前記HCが、配列番号10によって示されるアミノ酸配列を有する、請求項1または2に記載の抗体。
- 請求項1~3のいずれか一項に記載の抗体と、1つまたはそれ以上の薬学的に許容される担体、希釈剤または賦形剤とを含む、医薬組成物。
- 神経変性疾患の治療に使用するための、請求項4に記載の医薬組成物。
- 前記神経変性疾患が、アルツハイマー病、進行性脳性麻痺、多発性硬化症、ALS、または前頭側頭型認知症である、請求項5に記載の使用のための医薬組成物。
- 外傷性脳損傷の治療に使用するための、請求項4に記載の使用のための医薬組成物。
- 神経変性疾患または外傷性脳損傷を有する患者を治療するための方法であって、有効量の請求項1~3のいずれか一項に記載の抗体を前記患者に投与することを含む、方法。
- 前記患者が、神経変性疾患を有する、請求項8に記載の方法。
- 前記神経変性疾患が、アルツハイマー病、進行性脳性麻痺、多発性硬化症、ALS、または前頭側頭型認知症である、請求項9に記載の方法。
- 前記患者が、外傷性脳損傷を有する、請求項8に記載の方法。
- 療法において使用するための、請求項1~3のいずれか一項に記載の抗体。
- 神経変性疾患または外傷性脳損傷の治療において使用するための、請求項1~3のいずれか一項に記載の抗体。
- 神経変性疾患の前記治療のための、請求項13に記載の使用のための抗体。
- 前記神経変性疾患が、アルツハイマー病、進行性脳性麻痺、多発性硬化症、ALS、または前頭側頭型認知症である、請求項14に記載の使用のための抗体。
- 外傷性脳損傷の治療のための、請求項13に記載の使用のための抗体。
- 神経変性疾患または外傷性脳損傷の治療のための薬剤の製造における、請求項1~3のいずれか一項に記載の抗体の使用。
- 神経変性疾患の治療のための薬剤の製造における、請求項17に記載の使用。
- 前記神経変性疾患が、アルツハイマー病、進行性脳性麻痺、多発性硬化症、ALS、外傷性脳損傷、または前頭側頭型認知症である、請求項18に記載の使用。
- 外傷性脳損傷の治療のための薬剤の製造における、請求項17に記載の使用。
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