JP2022036962A - 抗ninj-1抗体及びその使用 - Google Patents
抗ninj-1抗体及びその使用 Download PDFInfo
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Abstract
Description
[技術的課題]
そこで、本発明者らは、ヒトのNINJ-1タンパク質又は、そのタンパク質の同族結合部位のみに特異的に結合する抗体を開発するために研究する中で、本発明で開示する特有のCDR配列構成を有する抗体とその断片が、他の生物由来のNINJ-1タンパク質(特に、マウスNINJ-1タンパク質)とは交差反応性を示さず、ヒトのNINJ-1タンパク質のみに特異的に結合することを確認して本発明を完成した。
前記のような目的を達成するために、ヒト由来のNINJ-1(Ninjurin-1)タンパク質に特異的に結合する抗体又はその断片を提供する。
配列番号1で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号2で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号3で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び配列番号4で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号5で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号6で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含む抗体でもあり、
配列番号7で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号8で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号9で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び配列番号10で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号11で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号12で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含む抗体でもあって、
配列番号13で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号14で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号15で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び配列番号16で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号17で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号18で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含む抗体でもあり、
配列番号19で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号20で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号21で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び配列番号22で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号23で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号24で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含む抗体でもある。
前記細胞又はその培養した培養培地から前記ポリペプチドを回収する段階を含む、ヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片の生産方法を提供する。
したがって、本発明は、ヒトのNINJ-1に特異的に結合する抗体又はその断片を提供する。本発明に係る抗体又はその断片は、ヒトのNINJ-1に対する結合親和性と結合特異性が極めて高く、タンパク質間の類似性が高い他の生物由来のNINJ-1タンパク質(特に、マウスNINJ-1タンパク質)とは交差反応性を示さないのが特徴である。したがって、NINJ-1タンパク質と関連する疾患の診断だけでなく、NINJ-1タンパク質が関与する病理状態の抑制において正確性、高感度等にかなりの利点を提供する。特に、本発明で提供される抗体は、免疫細胞とヒトの大脳内皮細胞との間の付着を抑制する効果が顕著で、多発性硬化症の治療効果がある。
ヒトのNINJ-1タンパク質のP26-N37領域を利用した抗体同定
ヒトのNINJ-1(Ninjurin-1、配列番号25)のP26-N37領域に特異的な抗体を発掘するために、ヒトのscFvライブラリに基づいて、ファージディスプレイ(Phage display)技術を利用して、次のような実験を実施した。前記P26-N37領域の断片ペプチドを以下でHBAg1と称す。
前記<1-1>の3次バイオパニングで回収されたファージを、宿主細胞(ER2537、NEB)に感染させた後、LB固体培地上でコロニー95個を選別した後、液体培地で、常温で、700rpmで培養した。その後、各ウェルに最終濃度が1mMになるようにIPTG(Isopropyl β-D-1-thiogalactopyranoside)を処理した後、30℃で12乃至16時間、200rpmで培養した。培養液を3000rpmで20分間遠心分離して上澄み液を除去した後、TESバッファーを通した浸透圧細胞溶解法を通じて、細胞内ファージ粒子を得た。事前にストレプタビジン(streptavidin)が塗布された96ウェルプレートThermo scientific、Cat No. 436014)に10ug/mlの濃度のHBAg1又はPBS(Phosphate buffered saline、対照群(Control))でコーティングしたプレートに回収したファージ粒子を50ulずつ入れて、常温で1時間反応させた。その後、ホースラディッシュペルオキシダーゼ(horseradish peroxidase)が結合された抗HA(hemagglutinin)二次抗体(Santa cruz biotechnology)を入れて、再び常温で1時間反応させた後、TMB溶液を用いた発色反応を5分間誘導した後、1N H2SO4溶液で反応を停止させ、430nmでの吸光度を測定した。
NINJ-1の組換えタンパク質の発現及び精製
前記実施例1で得られたscFv候補が、実際にヒトのNINJ-1タンパク質のP26-N37領域に構造的結合ができるのか、又はNINJ-1の細胞外ドメインの部分の結合が可能であるかを確認するために、ヒトのNINJ-1(hNinjurin-1、NM_004148.3、72..284、配列番号26)又はマウスのNINJ-1(MusNINJ-1、NM_013610.2、17..229、配列番号27)の遺伝子のうち、細胞外ドメインの部分に転写終止コドン2つを含む塩基配列を、pGEX-4T-1発現ベクター(GST-tagを含んでいるベクター、GE healthcare Life Sciences)内のクローニング部位BamHIとXhoIの間に入れて、それぞれの組換えタンパク質発現ベクターを作製した。具体的な塩基配列は図3Aに示し、具体的なクローニング領域は、図3Bに図示して、それぞれの発現ベクターをpGST/huNINJ1とpGST/musNINJ1と命名した。前記発現ベクターを大腸菌DH5a(enzynomics)に形質導入して培養した。Midiprep後、DNA塩基配列確認を通じて、GST/huNINJ-1及びGST/musNINJ-1の挿入の有無を最終的に確認した。
前記実施例<2-1>で製作された発現ベクターpGST/huNINJ-1又はpGST/musNINJ-1が形質転換された大腸菌DH5aを、Midiprepして、十分なプラスミドDNAを回収した後、大腸菌(E.coli)上で組換えタンパク質の発現及び精製のために、次のように実験を実施した。pGST/huNINJ-1又はpGST/musNINJ-1プラスミドDNAを利用して、大腸菌BL21DE3をそれぞれ形質転換させて、LG培地で培養した後、単一コロニーを、アンピシリン(ampicillin)が含まれた5ml LB液状培地で、OD600値が0.6から0.8になるように培養した。その後、0mM、0.5mM、1mMのIPTGを処理して37℃で3時間培養した後、10分間8000rpmで遠心分離して、細胞だけを回収した。細胞液にSDS-PAGEを実施して、クマシー溶液(coomassie stain; Sigma Aldrich)を処理して発現を確認した(図4A)。
GST/huNINJ-1及びGST/musNINJ-1のELISAを通じた親和度測定
ヒトの抗NINJ-1抗体の生産用発現ベクターの製造及び抗体の生産
HBAg1に対するヒトの抗-NINJ-1 IgGの親和度測定
正常細胞基盤の抗NINJ-1 IgGスクリーニング
NINJ-1の診断特異性を確認
本発明の抗-NINJ-1 IgG処理後大脳血管内皮細胞及び免疫細胞の付着抑制能分析
Collagen I Rat tail Proteinを、50ug/mlの濃度で96ウェルプレートにコーティングした後、各ウェルに1.0x104個のhCMEC/D3細胞株を72時間37℃、5%CO2の環境で培養した後、16時間200IU/mlのTNFαとIFNγ又は1ug/ml濃度のPMAを処理した。その後、マグネシウムとカルシウムが含まれていないDPBSで2回洗浄して、細胞に残存する炎症誘導物質を除去した後、10μg/ml濃度の各抗体を、そのウェルに入れて反応させた。この過程が完了すると、もう一度DPBSで2回洗浄して残存する抗体を除去した後、免疫細胞として、緑色蛍光タンパク質(Green fluorescent protein)を発現するU937細胞株(lymphoblast、リンパ球)を1.0x104個を入れて90分間37℃、5%CO2の環境で付着を誘導した後、DPBSで3回洗浄した。全ての過程はリアルタイム細胞イメージ分析器(IncuCyte(商標) ZOOM)を利用して、緑色で標識された細胞の数を測定した。そして、各ウェルについて、最終的に残った細胞の数を初期細胞数で分けた後、PMA(Sigma Aldrich)処理したものを基準に標準化した。
Claims (22)
- ヒト由来のNINJ-1(Ninjurin-1)タンパク質に特異的に結合する抗体又はその断片。
- 前記抗体又はその断片は、配列番号25で表示されるヒト由来のNINJ-1タンパク質配列の中で、26番目のアミノ酸乃至37番目のアミノ酸の領域に特異的に結合することを特徴とする請求項1記載のヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片。
- 前記抗体又はその断片は、配列番号1で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号2で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号3で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び
配列番号4で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号5で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号6で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含むことを特徴とする請求項2記載のヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片。 - 前記抗体又は断片は、配列番号7で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号8で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号9で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び
配列番号10で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号11で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号12で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含むことを特徴とする請求項2記載のヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片。 - 前記抗体又は断片は、配列番号13で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号14で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号15で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び
配列番号16で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号17で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号18で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含むことを特徴とする請求項2記載のヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片。 - 前記抗体又は断片は、配列番号19で表示されるアミノ酸配列を含む相補性決定部位(CDR)L1、配列番号20で表示されるアミノ酸配列を含む相補性決定部位(CDR)L2及び配列番号21で表示されるアミノ酸配列を含む相補性決定部位(CDR)L3を含む抗体軽鎖可変領域(VL);及び
配列番号22で表示されるアミノ酸配列を含む相補性決定部位(CDR)H1、配列番号23で表示されるアミノ酸配列を含む相補性決定部位(CDR)H2及び配列番号24で表示されるアミノ酸配列を含む相補性決定部位(CDR)H3を含む抗体重鎖可変領域(VH)を含むことを特徴とする請求項2記載のヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片。 - 前記断片は、二重特異性抗体、Fab、Fab'、F(ab)2、F(ab')2、Fv、及びscFvからなる群から選ばれる断片であることを特徴とする請求項1記載のヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片。
- 請求項1記載の抗体又はその断片を符号化するポリヌクレオチド。
- 請求項8記載のポリヌクレオチドを含むベクター。
- 請求項9記載のベクターを含む細胞。
- 請求項10記載の細胞をポリヌクレオチドが発現される条件下で培養して軽鎖及び重鎖の可変領域を含むポリペプチドを生産する段階;及び
前記細胞又はこれを培養した培養培地から前記ポリペプチドを回収する段階を含む、ヒトのNINJ-1タンパク質に特異的に結合する抗体又はその断片の生産方法。 - 請求項1記載の抗体又はその断片を試料と接触させる段階;及び
前記抗体又はその断片を検出する段階を含む、ヒトのNINJ-1特異的検出方法。 - 請求項1記載の抗体又はその断片を有効成分として含む多発性硬化症の予防又は治療用薬学的組成物。
- 請求項1記載の抗体又はその断片を有効成分として含むがんの予防及び治療用薬学的組成物。
- 前記組成物は、がんの転移(cancer metastasis)を抑制することを特徴とする請求項14記載の薬学的組成物。
- 前記がんは、大腸癌、肺癌、肝臓癌、胃癌、食道癌、膵臓癌、胆嚢癌、腎臓癌、膀胱癌、前立腺癌、精巣癌、子宮頸部癌、子宮内膜癌、絨毛癌、卵巣癌、乳癌、甲状腺癌、脳腫瘍、頭頸部癌、悪性黒色腫、リンパ腫、再生不良性貧血からなる群から選ばれたものであることを特徴とする請求項14又は請求項15記載の組成物。
- 多発性硬化症の予防及び治療用製剤を製造するための請求項1記載の抗体又はその断片の使用。
- 請求項1記載の抗体又はその断片を有効成分として含む組成物の有効量を、これを必要とする個体に投与することを特徴とする多発性硬化症の予防及び治療方法。
- がん転移阻害用製剤を製造するための請求項1記載の抗体又はその断片の使用。
- 請求項1記載の抗体又はその断片を有効成分として含む組成物の有効量を、これを必要とする個体に投与することを特徴とするがん転移阻害方法。
- がんの予防及び治療用製剤を製造するための請求項1記載の抗体又はその断片の使用。
- 請求項1記載の抗体又はその断片を有効成分として含む組成物の有効量を、これを必要とする個体に投与することを特徴とするがんの予防及び治療方法。
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US6140117A (en) * | 1996-07-24 | 2000-10-31 | Washington University | Ninjurin |
KR100998276B1 (ko) * | 2008-12-09 | 2010-12-03 | 서울대학교산학협력단 | Ninjurin1 발현 또는 활성 억제제를 함유하는 염증성 질환 예방 및 치료용 조성물 |
KR101484405B1 (ko) | 2013-08-14 | 2015-01-19 | 서울대학교산학협력단 | Ninjurin1 결핍 유래의 강박증 예방 또는 치료용 약학적 조성물 |
-
2017
- 2017-08-28 CN CN201780066566.6A patent/CN109890844B/zh active Active
- 2017-08-28 WO PCT/KR2017/009377 patent/WO2018038583A1/ko unknown
- 2017-08-28 EP EP17844003.8A patent/EP3517547A4/en not_active Ceased
- 2017-08-28 KR KR1020170108711A patent/KR102497298B1/ko active IP Right Grant
- 2017-08-28 JP JP2019511526A patent/JP7138883B2/ja active Active
- 2017-08-28 US US16/328,522 patent/US11286296B2/en active Active
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2021
- 2021-11-16 JP JP2021186235A patent/JP7316592B2/ja active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140037640A1 (en) * | 2008-12-09 | 2014-02-06 | Snu R&Db Foundation | Composition comprising expression or activity inhibitors of ninjurin1 for the prevention and treatment of inflammatory disease |
US8703711B2 (en) * | 2009-06-09 | 2014-04-22 | Val-Chum, Limited Partnership | Ninjurin-1 modulation and uses thereof |
WO2014095916A1 (en) * | 2012-12-18 | 2014-06-26 | Sanofi | Ninjurin-1 as therapeutic target for brain tumor |
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EP3517547A4 (en) | 2020-07-08 |
JP7316592B2 (ja) | 2023-07-28 |
CN109890844A (zh) | 2019-06-14 |
JP2019533431A (ja) | 2019-11-21 |
EP3517547A1 (en) | 2019-07-31 |
KR20180023875A (ko) | 2018-03-07 |
JP7138883B2 (ja) | 2022-09-20 |
US20190248878A1 (en) | 2019-08-15 |
WO2018038583A1 (ko) | 2018-03-01 |
CN109890844B (zh) | 2022-09-27 |
US11286296B2 (en) | 2022-03-29 |
KR102497298B1 (ko) | 2023-02-07 |
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