JP2022058436A - 抗rankl抗体およびその使用 - Google Patents
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
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- 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
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
本発明の例示的な抗体は、本質的に以下のように発現および精製される。配列番号15(配列番号1の例示的な重鎖をコードする)および配列番号16(配列番号2の例示的な軽鎖をコードする)で示されるポリヌクレオチド配列を含有するグルタミン合成酵素(GS)発現ベクターを使用して、エレクトロポレーションにより、チャイニーズハムスター細胞株(CHO、GSノックアウト)にトランスフェクトする。発現ベクターは、SV Early(シミアンウイルス(Simian Virus)40E)プロモーターおよびGS遺伝子をコードする。GSの発現は、CHO細胞によって必要とされるアミノ酸であるグルタミンの生化学的合成を可能にする。トランスフェクション後、細胞について50μM L-メチオニンスルホキシミン(MSX)を用いてバルク選択を行う。MSXによるGSの阻害を用いて、選択のストリンジェンシーを高める。発現ベクターcDNAが宿主細胞ゲノムの転写活性領域に組み込まれた細胞を、CHO野生型細胞に対して選択することができる。トランスフェクトされたプールを低密度でプレーティングして、安定した発現細胞のクローンに近い成長(close-to-clonal outgrowth)を可能にする。マスターウェルを抗体発現についてスクリーニングし、次いで無血清懸濁培地中でスケールアップして、産生に使用する。
BIAcore(登録商標)2000機器を用いて、結合親和性を測定する。すべての測定を25℃で行う。2μg/mLの実施例1の例示的な抗体をHBS-EP緩衝液(150mM塩化ナトリウム、3mM EDTA、0.005%(w/v)界面活性剤P-20、および10mM HEPES、pH7.4)に溶解する。プロテインAを、アミン結合キットを用いて、500応答単位(Rus)のレベルでCM4センサーチップのフローセル1~4に固定化する。
ヒトRANKおよびNF-kB駆動型ルシフェラーゼレポーターを安定して共発現するHEK293細胞を使用して、実施例1の例示的な抗体がRANKL活性を中和する能力を評価する。このHEK293細胞モデルにおいて、RANKは、ヒトRANKLによって結合されたときにNF-kBシグナル伝達を誘導し、これによりルシフェラーゼ発光がもたらされる。実施例1の例示的な抗体によるRANKへのRANKL結合の中和は、ルシフェラーゼ発光の低下によって測定される。
実施例1の例示的な抗体がRANKLタンパク質に結合する場所を決定するために、水素重水素交換質量分析(Hydrogen deuterium exchange with mass spectrometry)(HDXMS)を行う。この方法を用いて、いくつかの抗体のエピトープをマッピングすることに成功している(Obungu et. al. 2009 Biochemistry,48:7251-60 Lu et. al. 2005 Biochemistry44:11106-14)。
20~22週齢のインタクトなC57/B6雌マウス(Charles River)を、12時間の明/暗サイクルで、22℃で食餌(0.72% Caおよび0.61% P、ビタミンD 0.99IU/gを含むTD 2014、Teklad、Madison、WI)および水に自由にアクセスできるようにして維持する。
卵巣摘出したマウスモデルを用いて、インビボでの骨量密度に対する効果を評価する。20週齢の雌C57/B6マウス(Harlan、Indianapolis、IN)を卵巣摘出し(または偽手術した対照群)、12時間の明/暗サイクルで、22℃で食餌(0.72% Caおよび0.61% P、ビタミンD 0.99IU/gを含むTD 2014、Teklad、Madison、WI)および水に自由にアクセスできるようにして維持する。骨減少症は、卵巣摘出したマウスを6週間にわたり骨量を喪失させることによって、マウスにおいて確立される。
精巣摘出したマウスモデルを用いて、骨量密度および骨塩含量に対するインビボでの効果を評価する。16週齢の雄C57/B6マウス(Harlan、Indianapolis、IN)を精巣摘出し(またはビヒクル対照群、n=6)、12時間の明/暗サイクルで、22℃で食餌(0.72% Caおよび0.61% Pを含むTD 2014、Vit.D 0.99IU/g、Teklad、Madison、WI)および水に自由にアクセスできるようにして維持する。骨減少症は、マウスを6週間にわたり骨量を喪失させることによって、精巣摘出したマウスにおいて確立される。
配列
例示的なHC(配列番号1)
QVQLVQSGAEVKKPGSSVKVSCKASGYAFTNYYIEWVRQAPGQGLEWMGVINPGWGDTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARRDTAHGYYALDPWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
例示的なLC(配列番号2)
DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWDYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
例示的なHCVR(配列番号3)
QVQLVQSGAEVKKPGSSVKVSCKASGYAFTNYYIEWVRQAPGQGLEWMGVINPGWGDTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARRDTAHGYYALDPWGQGTTVTVSS
例示的なLCVR(配列番号4)
DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWDYPLTFGGGTKVEIK
例示的なHC(配列番号5)
QVQLQQSGAELVRPGTSVKVSCKASGYAFTNYYIEWLKQRPGQGLEWIGVINPGWGDTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVFFCARRDTRHGYYALDYWGQGTSVTVSSAKTTPPSVYPLAPGTALKSNSMVTLGCLVKGYFPEPVTVTWNSGALSSGVHTFPAVLQSGLYTLTSSVTVPSSTWPSQTVTCNVAHPASSTKVDKKIVPRNCGGDCKPCICTGSEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISQDDPEVHFSWFVDDVEVHTAQTRPPEEQFNSTFRSVSELPILHQDWLNGRTFRCKVTSAAFPSPIEKTISKPEGRTQVPHVYTMSPTKEEMTQNEVSITCMVKGFYPPDIYVEWQMNGQPQENYKNTPPTMDTDGSYFLYSKLNVKKEKWQQGNTFTCSVLHEGLHNHHTEKSLSHSPG
例示的なLC(配列番号6)
DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNDYPLTFGAGTRLEIKRADAAPTVSIFPPSTEQLATGGASVVCLMNNFYPRDISVKWKIDGTERRDGVLDSVTDQDSKDSTYSMSSTLSLSKADYESHNLYTCEVVHKTSSSPVVKSFNRNEC
例示的なHCVR(配列番号7)
QVQLQQSGAELVRPGTSVKVSCKASGYAFTNYYIEWLKQRPGQGLEWIGVINPGWGDTNYNEKFKGKATLTADKSSSTAYMQLSSLTSDDSAVFFCARRDTRHGYYALDYWGQGTSVTVSS
例示的なLCVR(配列番号8)
DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNDYPLTFGAGTRLEIK
例示的なHCDR1(配列番号9)
KASGYAFTNYYIE
例示的なHCDR2(配列番号10)
VINPGWGDTNYNEKFKG
例示的なHCDR3(配列番号11)
ARRDTXHGYYALDX
6位のXはAlaまたはArgであり、14位のXはProまたはTyrである。
例示的なLCDR1(配列番号12)
KASQNVGTNVA
例示的なLCDR2(配列番号13)
YSASYRYS
例示的なLCDR3(配列番号14)
QQYXDYPLT
4位のXはTrpまたはAsnである。
配列番号1のHCタンパク質をコードする例示的なDNA(配列番号15)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGCTACGCCTTCACCAACTACTATATCGAGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGTGATCAACCCCGGCTGGGGCGACACGAACTACAACGAGAAGTTCAAGGGCAGAGTCACCATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGACGCGATACGGCTCACGGCTACTACGCCCTTGATCCGTGGGGCCAAGGAACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGGCCGCCGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGT
配列番号2のLCをコードする例示的なDNA(配列番号16)
GACATCCAGATGACCCAGTCTCCATCCTCTCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAAGGCCAGCCAGAATGTGGGCACCAACGTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGCGCCAGCTACAGATACAGCGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAGCAGTACTGGGACTACCCCCTGACCTTCGGCGGAGGGACCAAGGTGGAGATCAAACGGACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC
RANKL細胞外ドメイン(配列番号17)
MSKLEAQPFAHLTINATDIPSGSHKVSLSSWYHDRGWAKISNMTFSNGKLIVNQDGFYYLYANICFRHHETSGDLATEYLQLMVYVTKTSIKIPSSHTLMKGGSTKYWSGNSEFHFYSINVGGFFKLRSGEEISIEVSNPSLLDPDQDATYFGAFKVRDID
Claims (10)
- 軽鎖可変領域(LCVR)および重鎖可変領域(HCVR)を含む、ヒトRANKLに結合する抗体であって、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、前記LCDR1のアミノ酸配列が配列番号12であり、前記LCDR2のアミノ酸配列が配列番号13であり、前記LCDR3のアミノ酸配列が配列番号14であり、前記HCDR1のアミノ酸配列が配列番号9であり、前記HCDR2のアミノ酸配列が配列番号10であり、前記HCDR3のアミノ酸配列が配列番号11である、抗体。
- a.配列番号11で示されるアミノ酸配列の6位のXaaがAlaであり、
b.配列番号11で示されるアミノ酸配列の14位のXaaがProであり、
c.配列番号14で示されるアミノ酸配列の4位のXaaがTrpである、
請求項1に記載の抗体。 - a.配列番号11で示されるアミノ酸配列の6位のXaaがArgであり、
b.配列番号11で示されるアミノ酸配列の14位のXaaがTyrであり、
c.配列番号14で示されるアミノ酸配列の4位のXaaがAsnである、
請求項1に記載の抗体。 - 軽鎖可変領域(LCVR)および重鎖可変領域(HCVR)を含む、ヒトRANKLに結合する抗体であって、前記LCVRのアミノ酸配列が配列番号4または配列番号8であり、前記HCVRのアミノ酸配列が配列番号3または配列番号7である、抗体。
- 前記LCVRのアミノ酸配列が配列番号4であり、前記HCVRのアミノ酸配列が配列番号3である、請求項4に記載の抗体。
- 前記LCVRのアミノ酸配列が配列番号8であり、前記HCVRのアミノ酸配列が配列番号7である、請求項4に記載の抗体。
- 軽鎖(LC)および重鎖(HC)を含み、前記LCのアミノ酸配列が配列番号2または配列番号6であり、前記HCのアミノ酸配列が配列番号1または配列番号5である、ヒトRANKLに結合する抗体。
- 前記LCのアミノ酸配列が配列番号2であり、前記HCのアミノ酸配列が配列番号1である、請求項7に記載の抗体。
- 前記LCのアミノ酸配列が配列番号6であり、前記HCのアミノ酸配列が配列番号5である、請求項7に記載の抗体。
- 請求項1~9のいずれか一項に記載の抗体、および1つ以上の薬学的に許容される担体、希釈剤、または賦形剤を含む、医薬組成物。
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PCT/US2017/057543 WO2018080914A1 (en) | 2016-10-28 | 2017-10-20 | Anti-rankl antibodies and uses thereof |
JP2019516460A JP7246306B2 (ja) | 2016-10-28 | 2017-10-20 | 抗rankl抗体およびその使用 |
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IL266059A (en) | 2019-06-30 |
JP7246306B2 (ja) | 2023-03-27 |
EP3532501A1 (en) | 2019-09-04 |
US10913799B2 (en) | 2021-02-09 |
CN109890845B (zh) | 2022-07-01 |
CA3038850A1 (en) | 2018-05-03 |
BR112019006127A2 (pt) | 2019-06-18 |
KR20190052137A (ko) | 2019-05-15 |
WO2018080914A1 (en) | 2018-05-03 |
MX2019004862A (es) | 2019-08-12 |
JP2020500836A (ja) | 2020-01-16 |
US20190284289A1 (en) | 2019-09-19 |
EA201990557A1 (ru) | 2019-09-30 |
CN109890845A (zh) | 2019-06-14 |
AU2017351026A1 (en) | 2019-03-21 |
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