JP6035332B2 - A型インフルエンザウイルス中和抗体及びその使用法 - Google Patents
A型インフルエンザウイルス中和抗体及びその使用法 Download PDFInfo
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Description
本発明による抗体は、当該技術分野において既知の任意の方法により製造することができる。例えば、ハイブリドーマ技術を用いモノクローナル抗体を製造するという一般的な手法は周知のものである(Kohler,G.and Milstein,C,.1975;Kozbar et al.1983)。一実施形態では、国際公開第2004/076677号に開示されているEBV不死化法が代わりに使用される。
形質転換したB細胞及び培養した単一の形質細胞は、所望の特異性又は機能をもつ抗体の産生についてスクリーニングすることができる。
上記の通り、本発明の抗体を使用して、それらの結合するエピトープのマッピングを行うことができる。本発明者らは、A型インフルエンザウイルスの感染を中和する抗体が、HA上に見られるエピトープに対するものであることを発見した。一実施形態では、抗体は、A型インフルエンザウイルスの第1群及び第2群亜型のうちの1つ以上の間で保存されている、HAのステム領域中の1つ以上のエピトープに対するものである。本発明の抗体が結合するエピトープは、直鎖(連続)型又は立体構造(非連続)型のものであってよい。一実施形態では、本発明の抗体及び抗体断片は、本明細書で開示される通りの、配列番号37、38、39又は40を含むポリペプチド領域に結合する。
本発明の不死化B細胞クローン又は培養した形質細胞は、以降で組み換え発現を行うために抗体遺伝子をクローン化するための核酸資源として使用することもできる。製薬用途では、例えば、安定性、再現性、培養のし易さなどといった理由から、B細胞又はハイブリドーマから発現させるよりも、組み換え資源から発現させる方が一般的である。
本発明は、本発明の抗体及び/又は抗体断片並びに/あるいはこのような抗体をコードしている核酸並びに/あるいは本発明の抗体により認識されるエピトープを含有している医薬組成物を提供する。医薬組成物には、投与を可能にするために製薬上許容可能な担体を含有させることもできる。担体は、それ自体が、組成物を受容する各個体にとって有害になるほど抗体産生を誘導することのないものであるべきであり、かつ非毒性のものであるべきである。好適な担体は、大型で、ゆっくりと代謝される巨大分子、例えば、タンパク質、ポリペプチド、リポソーム、多糖類、ポリ乳酸、ポリグリコール酸、高分子アミノ酸、アミノ酸コポリマー及び不活性なウイルス粒子などであってよい。
本発明の抗体及び抗体断片又はそれらの誘導体及び変異体は、A型インフルエンザウイルスの感染の処置、A型インフルエンザウイルスの感染予防、又はA型インフルエンザウイルスの感染診断に使用することができる。
用語「含む(comprising)」は、「含有する(including)」並びに「から構成される(consisting)」を包含し、例えば、Xを「含む(comprising)」組成物は、ほぼXから構成されてもよく、又は例えばX+Yなどのように何か他の追加成分を共に含有してもよい。
季節性インフルエンザワクチン(H1及びH3 HAを含有)に応答してヘテロ亜型抗体を産生できる個体を特定するため、我々は、ワクチン又は陰性対照のH5 HA(A/VN/1203/04)と結合する抗体の分泌能を増幅させるため、ワクチン接種から7日後に、循環している形質細胞をELISPOTによりスクリーニングした。顕著なことに、H5特異的形質細胞について試験した5名のドナーの内4名で未検出だったのに対し、1名のドナーでは、IgG分泌形質細胞の14%がH5に対して抗体を産生し、57%がワクチンに対する抗体を産生していた。ワクチン接種から7日後に採取した末梢血単核細胞(PBMCs)から、磁気マイクロビーズを使用し、続いてFACSAriaを使用してセルソーティングすることにより、CD138+形質細胞を単離した。限界数の形質細胞を、マイクロウェル培養プレートに播種した。組み換えH5又はH9 HAを抗原として使用し、及び破傷風トキソイドを陰性対照として使用し、ELISAを平行して3つ行い、培養上清を試験した。スクリーニングした4,928種の培養上清のうち、12種はH5に結合したもののH9 HAには結合せず、25種はH9に結合したもののH5 HAには結合せず、54種はH5及びH9の両方に結合した。54種の培養物のうち、最も高いODシグナルを有していた一部の培養物にRT−PCRを行い、2対のVH及びVL遺伝子を回収した。
抗体FI6変異体2及びFI28変異体1が結合する抗原性の部位を特定するため、我々は、まずマウスモノクローナル抗体のC179(HAステム領域の保存配列にマッピングされる)に対する結合阻害能について、これらの抗体を試験した(Y.Okuno,et al.,J Virol 67,2552(1993))。FI6変異体2及びFI28変異体1のいずれもが、リコンビナントなH5 VN/1203/04 HAに対するC179の結合を完全に阻害したことから、これらの抗体が認識するエピトープがオーバーラップしていることが示唆された。対照的に、FI6変異体2及びFI28変異体1は、H5N1免疫ドナーから単離された一連のH5特異的抗体とは競合せず、HAの球状頭部中の異なるエピトープを認識する(C.P.Simmons et al.,PLoS Med 4,e178(2007);S.Khurana et al.,PLoS Med 6,e1000049(2009))。欠陥をもつエスケープ変異体をスクリーニングし、FI6変異体2エピトープのマッピングを試みたところ、このエピトープには、ウイルスに対する適応性を損なわずに容易に変異を起こすことはできないことが示唆された。
哺乳類細胞における産生性を向上させ、不要な体細胞変異及び望ましくない特性を排除するために、FI6変異体2のVH及びVLの変異体を数種類合成した。VH及びVL遺伝子を、それぞれIgG1の定常部及びCκをコードしている発現ベクターによりクローン化させた。IMGTデータベースを参照し、FI6変異体2に関係する生殖細胞系の配列を特定した。合成(Genscript、Piscatawy、NJ)又は部位特異的変異導入(Promega)により、単一の又は複数の生殖細胞系列変異が生殖系列に復帰している抗体変異体を産生し、配列を確認した。ヒト細胞における発現を最適化させるため、GenScriptのOptimumGene(商標)システムを使用し、すべての変異体の配列をコドン最適化させた。懸濁培養したFreestyle 293細胞(インビトロジェン)に、PEIにより一過性形質移入を行い、モノクローナル抗体を産生させた。培養開始から7日後に形質移入細胞由来の上清を回収し、プロテインAクロマトグラフィー(GEヘルスケア)によりIgGをアフィニティー精製し、PBSにより脱塩した。複数回の独立試験により、一過性発現系における産生性を評価した。中央値を図1に示す。図1に示すとおり、FI6変異体2は13.5μg/mLの力価で産生され、FI6変異体3は46.3μg/mLの力価で産生され、FI6変異体4は60.7μg/mLの力価で産生され、かつFI6変異体5は61.6μg/mLの力価で産生される。したがって、我々は、FI6変異体3、4及び5の産生力価を、FI6変異体2と比較してそれぞれ3.4倍、4.5倍、及び4.6倍に上昇させることができた。
FI6変異体3により第1群及び第2群のHA上で認識されるエピトープを特定し、抗体及びその標的とする抗原間の分子相互作用について説明するため、我々はFI6変異体3 Fab断片と、H1(第1群)及びH3(第2群)HAホモ三量体とからなる複合体を結晶化させた。FI6変異体3/H1ホモ三量体HA複合体を結晶化するため、H1 HA0の外部ドメインをSf9昆虫細胞で発現させた。GP67分泌シグナルを組み込んだBioFocus発現ベクターに、残基11〜329(HA1)及び1〜176(HA2)(H3付番による)に相当するcDNAをクローン化し、発現したタンパク質を培養培地に分泌させた。クローン化したcDNAを、C末端の三量体形成フォルドン配列(foldon sequence)と融合させて、H1 HA0の三量体を形成させた。結晶化前にフォルドンタグを除去するために、HA2のフォルドン配列とC末端との間にトロンビン切断配列を導入し、かつアフィニティー精製の際に使用する6−Hisタグを、発現させるポリペプチド配列のC末端の最も外側に組み込んだ。
A型インフルエンザウイルスの感染に関するマウスモデルにより、FI6変異体3のもつ予防効果について生体内試験を行った。6週齢及び8週齢の雌性BALB/cマウスに、1〜16mg/kgの濃度で濃度を変えて精製抗体を静脈内注射(i.v.)した。3時間後、マウスを昏睡させ、10 MLD50(マウスの50%致死量)のH1N1 A/PR/8/34を鼻腔内投与(i.n.)した。治療の設定として、マウスには鼻腔内投与から1、2又は3日後に抗体を投与した。マウスの生存及び体重の減少について、感染後(p.i.)14日目まで毎日モニタリングした。実験開始時から体重が25%以上減少したマウスは、動物実験プロトコルを順守し安楽死させた。
FI6抗体のもつ予防効果を評価することを目的とした生体内試験に際し、我々は、補体結合(FI6−v2 KA)又は補体及びFcR結合(FI6−v2 LALA)を欠損しているFI6変異体2 Fc変異体を作製した。これらの抗体は、FI6変異体2と同様の結合及び生体外中和特性、並びに生体内試験に匹敵する半数致死期間を示した(FI6−v2、FI6−v2 KA及びFI6−v2 LALAの平均半数致死期間は、それぞれ、3.3、3.4及び3.5日間)。致死的にA/Puerto Rico/8/34(H1N1)ウイルスを感染させたマウスにおいてこれらの抗体の予防効果を試験した。FI6.v2は、4mg/kgで投与した場合にはマウスの死亡を完全に予防し、2mg/kgで投与した場合にはマウスのうち80%の死亡を予防した(図8F)。10mg/kgで投与した場合、FI6−v2及びFI6−v2 KAは完全に予防したのに対し、FI6−v2 LALAの活性はかなり減少し、40%のマウスでのみ予防することができた(図8F)。この効果の減少は、特に抗体変異体を3mg/kgの限界濃度で投与した場合に顕著であった(図8G)。
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国際公開第00/52031号
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Claims (15)
- 配列番号59のアミノ酸配列を含む重鎖可変領域及び配列番号57のアミノ酸配列を含む軽鎖可変領域;又は配列番号59のアミノ酸配列を含む重鎖可変領域及び配列番号61のアミノ酸配列を含む軽鎖可変領域;又は配列番号55のアミノ酸配列を含む重鎖可変領域及び配列番号57のアミノ酸配列を含む軽鎖可変領域;又は配列番号55のアミノ酸配列を含む重鎖可変領域及び配列番号61のアミノ酸配列を含む軽鎖可変領域を含む単離抗体又はそれらの抗原結合断片であって、前記抗体が、A型インフルエンザウイルスの第1群亜型及び第2群亜型を中和する、単離抗体又はそれらの抗原結合断片。
- 前記抗体が、A型インフルエンザ赤血球凝集素(HA)三量体のステム領域に存在するエピトープに特異的に結合し、この際、前記抗体の重鎖及び軽鎖又はそれらの抗原結合断片は、最初に近位のモノマー中のアミノ酸に接触し、次に、前記HA三量体の遠位右側のモノマーのアミノ酸と接触する、
a.抗体又はそれらの抗原結合断片であって、前記抗体の重鎖又はそれらの抗原結合断片が、前記近位のモノマー中のアミノ酸残基に接触し、その際、前記抗体の軽鎖又はそれらの抗原結合断片が、前記近位のモノマー中のアミノ酸残基に接触し、かつ前記HA三量体の遠位右側モノマー中のアミノ酸残基に接触する、抗体又はそれらの抗原結合断片;及び
b.A型インフルエンザHA三量体のステム領域にあるエピトープに特異的に結合する抗体又はそれらの抗原結合断片であって、前記HA三量体中の前記第一又は第二のモノマーが未切断のものである又は切断されたものである、抗体又はそれらの抗原結合断片、
からなる群から選択される、請求項1に記載の抗体又はそれらの抗原結合断片。 - 前記抗体が、A型インフルエンザ赤血球凝集素(HA)三量体のステム領域に存在するエピトープに特異的に結合し、この際、前記抗体の重鎖及び軽鎖又はそれらの抗原結合断片は、最初に近位のモノマー中のアミノ酸に接触し、次に、前記HA三量体の遠位右側のモノマーのアミノ酸と接触する、
a.抗体又はそれらの抗原結合断片であって、前記抗体の重鎖又はそれらの抗原結合断片が、前記第1又は第2モノマーのHA1における第318番目のアミノ酸、及びHA2における第18、19、20、21、38、41、42、45、49、53、及び57番目のアミノ酸残基に接触し、前記モノマーが未切断のものである又は切断されたものである抗体又はそれらの抗原結合断片;
b.抗体又はそれらの抗原結合断片であって、前記抗体の軽鎖又はそれらの抗原結合断片が、前記近位モノマーのHA2における第38、39及び43番目のアミノ酸残基並びに遠位右側モノマーのHA1における第327、328及び329番目のアミノ酸残基及びHA2における第1、2、3及び4番目のアミノ酸残基と接触し、前記近位及び前記遠位右側モノマーが未切断のものである、抗体又はそれらの抗原結合断片;
c.抗体又はそれらの抗原結合断片であって、前記抗体の軽鎖又はそれらの抗原結合断片が、前記近位モノマーのHA2における第38、39、42及び46番目のアミノ酸残基並びに遠位右側モノマーのHA1における第321及び323番目のアミノ酸残基、及びHA2における第7及び11番目のアミノ酸残基と接触し、前記近位及び前記遠位右側モノマーが切断されたものである、抗体又はそれらの抗原結合断片;
d.前記近位モノマーのHA1の第318番目のアミノ酸及びHA2の第18、19、20、21、38、39、41、42、43、45、48、49、53、56及び57番目のアミノ酸残基、並びに前記遠位右側モノマーのHA1の第327、328、329番目のアミノ酸残基及びHA2の第1、2、3及び4番目のアミノ酸残基を含むエピトープに特異的に結合する抗体又はそれらの抗原結合断片であって、前記近位及び前記遠位右側モノマーが未切断のものである、抗体又はそれらの抗原結合断片;
e.前記近位モノマーのHA1の第318番目のアミノ酸及びHA2の第18、19、20、21、38、39、41、42、45、46、49、52、53及び57番目のアミノ酸残基、並びに前記遠位右側モノマーのHA1の第321及び323番目のアミノ酸残基及びHA2の第7及び11番目のアミノ酸残基を含むエピトープに特異的に結合する、抗体又はそれらの抗原結合断片であって、前記近位及び前記遠位右側モノマーが切断されたものである、抗体又はそれらの抗原結合断片;並びに
f.HA1の第329番目のアミノ酸及びHA2の第1、2、3及び4番目のアミノ酸残基を含むエピトープに特異的に結合する、抗体又はそれらの抗原結合断片であって、前記HA1及びHA2が、前記HA三量体の未切断モノマー中に存在する、抗体又はそれらの抗原結合断片、
からなる群から選択される、請求項1に記載の抗体又はそれらの抗原結合断片。 - 前記抗体が、ヒト抗体、モノクローナル抗体、精製抗体、一本鎖抗体、Fab、Fab’、F(ab’)2、Fv又はscFvである、請求項1〜3のいずれか一項に記載の抗体又はそれらの抗原結合断片。
- 前記抗体又はそれらの抗原結合断片が、A型インフルエンザのHA亜型のH1、H2、H3、H4、H5、H6、H7、H8、H9、H10、H11、H12、H13、H14、H15及びH16に特異的に結合する、請求項1〜4のいずれか一項に記載の抗体又はそれらの抗原結合断片。
- A型インフルエンザウイルスの感染を処置するための、請求項1〜5のいずれか一項に記載の抗体又はそれらの抗原結合断片。
- 請求項1〜6のいずれか一項に記載の抗体又はそれらの抗原結合断片をコードしているポリヌクレオチドを含む核酸分子。
- 前記ポリヌクレオチドが、配列番号60及び58;又は配列番号60及び62;又は配列番号56及び58;又は配列番号56及び62に示す通りの配列を含む、請求項7に記載の核酸分子。
- 請求項7又は8に記載の核酸分子を含むベクター。
- 請求項1〜6のいずれか一項に記載の抗体、又はそれらの抗原結合断片を発現するか、または請求項9に記載のベクターを含む、細胞。
- 請求項1〜6のいずれか一項に記載の抗体又はそれらの抗原結合断片、請求項7又は8に記載の核酸、請求項9に記載のベクター、又は請求項10に記載の細胞、及び製薬上許容可能な希釈剤又は担体を含む、医薬組成物。
- A型インフルエンザウイルスの感染を処置するための薬剤の製造における、請求項1〜6のいずれか一項に記載の抗体又はそれらの抗原結合断片、請求項7又は8に記載の核酸、請求項9に記載のベクター、請求項10に記載の細胞、又は請求項11に記載の医薬組成物の使用。
- 抗A型インフルエンザウイルスワクチンの抗原が適切な立体構造をとっている特定のエピトープを含有していることを確認することにより、前記抗A型インフルエンザウイルスワクチンの品質をモニタリングするための、請求項1〜6のいずれか一項に記載の抗体又はそれらの抗原結合断片の使用。
- A型インフルエンザウイルスの感染を減少させる又はA型インフルエンザウイルスの感染リスクを低下させるための医薬組成物であって、予防又は治療に有効な量の請求項1〜6のいずれか一項に記載の抗体又はそれらの抗原結合断片を含む、医薬組成物。
- A型インフルエンザウイルスの感染診断のための使用における、請求項1〜6のいずれか一項に記載の抗体又はそれらの抗原結合断片、請求項7又は8に記載の核酸、請求項9に記載のベクター、請求項10に記載の細胞、又は請求項11に記載の医薬組成物。
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JP2012521786A (ja) | 2009-03-30 | 2012-09-20 | モウント シナイ スクール オフ メディシネ | インフルエンザウイルスワクチン及びその使用 |
NZ597401A (en) | 2009-06-24 | 2013-09-27 | Medicago Inc | Chimeric influenza virus-like particles comprising hemagglutinin |
HUE044089T2 (hu) * | 2011-07-18 | 2019-09-30 | Inst Res Biomedicine | Neutralizáló anti-influenza A antitestek és alkalmazásaik |
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