JP7235256B2 - 重症熱性血小板減少症候群ウイルスの外膜糖タンパク質に結合する抗体及びその用途 - Google Patents
重症熱性血小板減少症候群ウイルスの外膜糖タンパク質に結合する抗体及びその用途 Download PDFInfo
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Description
本発明は、重症熱性血小板減少症候群(Severe Fever with Thrombocytopenia Syndrome、SFTS)の病原体である重症熱性血小板減少症候群ウイルス(Severe Fever with Thrombocytopenia Syndrome Virus、SFTSV)を検出または診断し、SFTSを治療するために使用されるSFTSVの外膜糖タンパク質に特異的に結合する抗体に関する。
重症熱性血小板減少症候群(SFTS)は新種のダニ媒介感染病疾患であり、主にフタトゲチマダニ(Haemaphysalis longicornis)またはタカサゴキララマダニ(Amblyomma testudinarium)類によって媒介される重症熱性血小板減少症候群ウイルス(SFTSV)によって発生する。2009年中国でSFTSが最初報告され、2012年日本及び韓国でも疾患及びウイルスが報告されている。SFTSの主な症状は発熱、腹痛、吐逆、嘔吐、血小板減少症または白血球減少症などであり、重度の場合、多発性臓器不全が発生して死亡に至ることもある。SFTSは、中国、日本または韓国で毎年発生しているが、致死率が非常に高く、春から夏までの期間に主に発生する。SFTSVの野生宿主としてはセスジネズミが有力であり、中国の主要発病地ではヤギ、牛、犬またはニワトリなどの家畜から血清抗体が高い比率で発見されたことから、家畜が宿主の役割をする可能性もあると推定される。感染者の体液を媒介にしたヒト-ヒト感染が報告されているが、SFTSを効果的に治療できると証明された治療剤または予防法は未だない。
〔発明が解決しようとする課題〕
本発明は、SFTSVを効果的に検出または診断してSFTSを治療できる抗体を提供することを目的とする。また、本発明は、SFTSV、特にSFTSVの外膜糖タンパク質に特異的に結合する抗体を提供することを他の目的とする。
上記の課題を達成するため、本発明は、SFTSV、特にその外膜糖タンパク質に特異的に結合する新規な抗体を提供する。また、本発明は、前記抗体を使用してSFTSVを効果的に検出、分離または精製する方法を提供する。また、本発明は、前記抗体を使用してSFTSを効果的に予防または治療する方法を提供する。
本発明の抗体は、SFTSVの外膜糖タンパク質GcまたはGnに特異的に結合可能であるため、本発明の抗体を使用することでSFTSVを効果的に検出または診断でき、SFTSを治療することができる。
〔図1〕抗体クローンAb1~Ab10のアミノ酸配列を示した図である。
以下、本発明の理解を助けるために実施例などを挙げて詳しく説明する。しかし、本発明による実施例は多くの他の形態に変形でき、本発明の範囲が後述される実施例によって限定されると解釈されてはならない。本発明の実施例は当業界で平均的な知識を持つ者に本発明をより完全に説明するために提供されるものである。
アフリカミドリザル腎臓由来のVero細胞を韓国細胞株銀行から購入し、2%熱不活性化されたウシ胎児血清(Gibco)及びペニシリン-ストレプトマイシン(Gibco)を補充したロズウェルパーク記念研究所(Roswell Park Memorial Institute(RPMI))-1640培地(Welgene)で5%二酸化炭素雰囲気、37℃で培養した。
本実験で使用されたSFTSウイルスは、ソウル大学病院に入院して2012年に死亡した63歳女性患者の血清サンプルから分離したKF358691である[Kim KH、Yi J、Kim G、Choi SJ、Jun KI、Kim NH、et al.Severe fever with thrombocytopenia syndrome、South Korea、2012.Emerging infectious diseases.2013;19(11):1892-4.]。分離したウイルスをVero細胞の単一層に接種して5%二酸化炭素雰囲気、37℃で培養した。ウイルスをVero細胞で増殖させ、すべての実験はウイルス培養第三継代数(viral passage)で行われた。Reed-Muench法を用いてVero細胞で50%組織培養物感染投与量(TCID50)を滴定した。
本実験で使用されたSFTSウイルス糖タンパク質のアミノ酸配列は既に報告されている[Kim KH、Yi J、Kim G、Choi SJ、Jun KI、Kim NH、et al.Severe fever with thrombocytopenia syndrome、South Korea、2012.Emerging infectious diseases.2013;19(11):1892-4.]。SFTSウイルス糖タンパク質をコーディングするDNA鎖を得るため、配列番号171のSFTSウイルス糖タンパク質のアミノ酸配列(GenBank Accession No:AGT98506、Gn糖タンパク質に対してアミノ酸20-452、Gc糖タンパク質に対してアミノ酸563-1035)に相応するヒトコドン最適化されたDNA配列を合成した(GenScript)。
Ficoll-Paque溶液(GE Healthcare)を使用してSFTSから回復した患者の末梢血単核細胞を収集した。全体RNAをTRIzol試薬(Invitrogen)を使用して分離し、オリゴ(dT)プライミング(priming)と共に、SuperScriptIII第一鎖cDNA合成キット(Invitrogen)を使用して全体RNAからcDNAを合成した。前記cDNAを使用して、pComb3XSSファージミド(phagemid)ベクター使用してヒト単鎖可変切片(scFv)抗体のファージディスプレイライブラリを製作した。そして[Barbas CF、Burton DR、Scott JK、Silverman GJ.Phage display:a laboratory manual:CSHL Press;2004.]に記載されたように、ライブラリからscFvクローンを選択するために4ラウンドのバイオパニングを行った。バイオパニングの各ラウンド毎に、組換えSFTSウイルス糖タンパク質GcまたはGnヒトIgG1 Fc領域融合タンパク質(Gc-Fc、Gn-Fc)3μgを、メーカーの指示に従って5×106個の磁気性ダイナビーズ(Dynabeads)M-270エポキシビーズ(Invitrogen)のコーティングに使用した。そして、タンパク質と結合されたビーズはバイオパニング手順で使用した。
SFTSウイルス糖タンパク質に結合する個別的な抗体クローンを選択するため、バイオパニングの最後のラウンドからファージクローンを選択し、ファージ酵素免疫分析法のためにscFv-ディスプレイファージを製造した。マイクロタイタープレート(Corning)を一晩中4℃でウェル当り100ngの組換えGc、GnヒトIgk鎖定常領域融合タンパク質(Gc-Ck、Gn-Ck)でコーティングした。前記ウェルを37℃で1時間、100μlのPBS内3%(w/v)BSAで遮断し、37℃で2時間ファージを含む50μlの培養物上清液で培養して、150μlのPBS内0.05%(v/v)Tween20で3回洗浄した。その後、遮断バッファー(1:5000)に希釈された50mlのホースラディッシュペルオキシダーゼ(HRP)-結合された抗M13抗体(GE Healthcare)を各ウェルに添加し、プレートを37℃で1時間培養した。150μlの0.05%PBSTで3回洗浄した後、50μlの2,2-アジノ-ビス-3-エチルベンゾチアゾリン-6-スルホン酸(ABTS)基質溶液(Pierce)を各ウェルに添加して室温で30分間培養した。その後、各ウェルの吸光度をマイクロプレートリーダー(Labsystems)を使用して405nmで測定した。
SFTSウイルス特異的scFv-Fc融合抗体(100μl/ml)を系列希釈して0.01μl/mlまで10倍ずつ減少させた。各濃度のscFvsを100 TCID50 SFTSウイルス(菌株KF358691)の同じ体積に混合し、37℃で1時間培養した。その後、前記ウイルス-抗体混合物を8-ウェル共焦点顕微鏡チャンバ内のVero細胞の単一層に移し、37℃で1時間培養した。ウイルス-抗体混合物を除去した後、サンプルを5%二酸化炭素雰囲気、37℃で、2%FBS及び抗生剤が含まれたRPMI-1640培地で培養した。8-ウェル共焦点顕微鏡チャンバ内のVero細胞は免疫蛍光分析(IFA)のために使われた。すべての実験は3回行われ、相対的な中和効果は陽性対照群としてMAb4-5[Xiling Guo et al.A human antibody neutralizing SFTS virus、an emerging hemorrhagic fever virus、2013.Clin.Vaccine Immunol.2013;20(9):1426-32).]及び陰性対照群として抗ニューカッスル病ウイルス(NDV)抗体と比べてそれぞれ測定した。
相対的な中和効果は免疫蛍光分析(IFA)を使用して測定した。Ab10、MAb4-5(陽性対照群)、抗NDV(陰性対照群)があるか又はないウイルス-抗体混合物で処理されたか又は処理されていない細胞を2日間培養した。前記細胞を室温で1時間リン酸塩バッファー食塩水(PBS)で4%パラホルムアルデヒドで固定させた。スライドを1%ウシ血清アルブミン(BSA)内の0.1%トリトンX-100で遮断及び透過させた後、一晩中4℃で抗SFTSウイルス糖タンパク質GnクローンAb6抗体(5μl/ml)とともに培養した。細胞を洗浄してフルオレセインイソチオシアネート(FITC)-結合された抗ヒトIgG(Pierce)で室温で1時間培養した。4’,6-ジアミジノ-2-フェニルインドール二塩酸塩(DAPI)は核を染色するのに使用した。サンプルを共焦点顕微鏡(Leica、Buffalo Grove、IL、USA)で実験した。蛍光信号強度はコンピューター補助Leica application suite advanced fluorescence(LAS AF)を使用して測定した。顕微鏡写真は×10/0.3レンズを使用して各スライドの5ヶ所領域で撮影し、分析のために3つの中間値を使用した。405nm青色ダイオードレーザーでDAPI信号を設定し、アルゴンイオンレーザーでAlexa 488を調整した。
ヒトscFvライブラリを組換えSFTSウイルス糖タンパク質に対してバイオパニングした。4ラウンドのパニングの後、抗体クローンを酵素結合免疫吸着分析法(ELISA)を通じてスクリーニングした。10個のクローン(Gcに対してAb1~5及びGnに対してAb6~10)がELISAを通じてSFTSウイルスを認識することが示された。前記ELISA分析の結果を図2に示し、各抗体クローンのアミノ酸配列を図1に示した。
SFTSウイルスに対して精製されたscFv-hFc抗体の中和活性は、Vero細胞で実験した。実験した10個のクローン(Ab1~Ab10)のうち、Ab10が最も強い中和活性を見せた。Ab10 scFv-hFc抗体(100μl/ml)を0.01μl/mlで10倍ずつ希釈し、100 TCID50 SFTSウイルス(KF358691菌株)に対して滴定した。SFTSV感染の免疫蛍光分析結果及び蛍光強度測定結果を図3に示した。
Claims (11)
- 重症熱性血小板減少症候群ウイルス(SFTSV)の外膜糖タンパク質Gnに特異的に結合する抗体であって、以下を含む抗体:
配列番号105の軽鎖相補性決定領域1(LCDR1)、配列番号125の軽鎖相補性決定領域2(LCDR2)、配列番号145の軽鎖相補性決定領域3(LCDR3)、配列番号110の重鎖相補性決定領域1(HCDR1)、配列番号130の重鎖相補性決定領域2(HCDR2)、及び、配列番号150の重鎖相補性決定領域3(HCDR3)。 - 前記抗体は、以下を含む、請求項1に記載の抗体:
配列番号85のアミノ酸配列を含む軽鎖、及び、配列番号90のアミノ酸配列を含む重鎖。 - 配列番号85のポリペプチドをコーディングするヌクレオチド配列;並びに、
配列番号90のポリペプチドをコーディングするヌクレオチド配列
を含む核酸。 - 請求項3に記載の核酸を含むベクター。
- 請求項4に記載のベクターを含む宿主細胞。
- 請求項1に記載の抗体を含むSFTSV診断または検出用組成物。
- 請求項1に記載の抗体を含むSFTSV診断または検出用キット。
- 請求項1に記載の抗体を含む薬学的組成物。
- SFTSを予防または治療するために用いられる、請求項8に記載の薬学的組成物。
- SFTSVを診断、予防または治療するために用いられる、請求項1に記載の抗体。
- 請求項1に記載の抗体を用いた、SFTSV診断用組成物の製造方法。
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KR102504884B1 (ko) * | 2019-07-23 | 2023-02-28 | 와이-클론 메디컬 사이언시스 컴퍼니 리미티드 | Sftsv에 결합 가능한 나노 항체 및 이의 응용 |
CN110437332B (zh) * | 2019-08-20 | 2020-03-06 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | 一种抗病毒感染的sftsv蛋白结合分子 |
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US20190112360A1 (en) | 2019-04-18 |
CN109071637A (zh) | 2018-12-21 |
KR20210019491A (ko) | 2021-02-22 |
KR20190123816A (ko) | 2019-11-01 |
US20210171611A1 (en) | 2021-06-10 |
KR102039189B1 (ko) | 2019-11-01 |
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