JP5683752B2 - 系統グループ1及び系統グループ2のインフルエンザa型ウイルス、並びにインフルエンザb型ウイルスを中和することが可能なヒト結合分子 - Google Patents
系統グループ1及び系統グループ2のインフルエンザa型ウイルス、並びにインフルエンザb型ウイルスを中和することが可能なヒト結合分子 Download PDFInfo
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Description
本願明細書における「含まれる」又は「含む」という用語は、「限定されることなく」という語が続くものとみなされる。
本発明に従う結合分子は、例えば、試料中又は懸濁液中等の可溶性の形態の、インフルエンザウイルス又はその断片に対して結合してよく、又は、例えば、マイクロタイタープレート、膜、及びビーズ等の担体(キャリア)又は基材に対して結合又は付着したインフルエンザウイルス又はその断片に結合してもよい。担体又は基材は、ガラス、プラスチック(例えば、ポリスチレン)、多糖類、ナイロン、ニトロセルロース、又はテフロン等でできていてよい。そのような支持体の表面は、中実(中空でない)又は多孔質、及びあらゆる好便な形状としてよい。更に、結合分子は、精製/単離された、又は未精製/未単離の形態の、インフルエンザウイルスに対して結合してよい。
a)配列番号:133の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、配列番号:135の重鎖CDR3領域を含む結合分子、
b)配列番号:139の重鎖CDR1領域、配列番号:140の重鎖CDR2領域、配列番号:141の重鎖CDR3領域を含む結合分子、
c)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、配列番号:145の重鎖CDR3領域を含む結合分子、
d)配列番号:139の重鎖CDR1領域、配列番号:151の重鎖CDR2領域、配列番号:152の重鎖CDR3領域を含む結合分子、
e)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、配列番号:152の重鎖CDR3領域を含む結合分子、
f)配列番号:139の重鎖CDR1領域、配列番号:151の重鎖CDR2領域、配列番号:161の重鎖CDR3領域を含む結合分子、
g)配列番号:139の重鎖CDR1領域、配列番号:151の重鎖CDR2領域、配列番号:162の重鎖CDR3領域を含む結合分子、
h)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、配列番号:141の重鎖CDR3領域を含む結合分子、
からなる群から選択される。
a)配列番号:133の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:135の重鎖CDR3領域、並びに、配列番号:136の軽鎖CDR1領域、配列番号:137の軽鎖CDR2領域、及び配列番号:138の軽鎖CDR3領域を含む、結合分子、
b)配列番号:139の重鎖CDR1領域、配列番号:140の重鎖CDR2領域、及び配列番号:141の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:144の軽鎖CDR3領域を含む、結合分子、
c)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:145の重鎖CDR3領域、並びに、配列番号:146の軽鎖CDR1領域、配列番号:174の軽鎖CDR2領域、及び配列番号:147の軽鎖CDR3領域を含む、結合分子、
d)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:145の重鎖CDR3領域、並びに、配列番号:148の軽鎖CDR1領域、配列番号:149の軽鎖CDR2領域、及び配列番号:150の軽鎖CDR3領域を含む、結合分子、
e)配列番号:139の重鎖CDR1領域、配列番号:151の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:153の軽鎖CDR1領域、配列番号:154の軽鎖CDR2領域、及び配列番号:155の軽鎖CDR3領域を含む、結合分子、
f)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:148の軽鎖CDR1領域、配列番号:149の軽鎖CDR2領域、及び配列番号:150の軽鎖CDR3領域を含む、結合分子、
g)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:156の軽鎖CDR1領域、配列番号:157の軽鎖CDR2領域、及び配列番号:158の軽鎖CDR3領域を含む、結合分子、
h)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:148の軽鎖CDR1領域、配列番号:159の軽鎖CDR2領域、及び配列番号:160の軽鎖CDR3領域を含む、結合分子、
i)配列番号:139の重鎖CDR1領域、配列番号:151の重鎖CDR2領域、及び配列番号:161の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:144の軽鎖CDR3領域を含む、結合分子、
j)配列番号:139の重鎖CDR1領域、配列番号:151の重鎖CDR2領域、及び配列番号:162の重鎖CDR3領域、並びに、配列番号:163の軽鎖CDR1領域、配列番号:164の軽鎖CDR2領域、及び配列番号:165の軽鎖CDR3領域を含む、結合分子、
k)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:166の軽鎖CDR1領域、配列番号:167の軽鎖CDR2領域、及び配列番号:168の軽鎖CDR3領域を含む、結合分子、
l)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:169の軽鎖CDR1領域、配列番号:149の軽鎖CDR2領域、及び配列番号:150の軽鎖CDR3領域を含む、結合分子、
m)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:141の重鎖CDR3領域、並びに、配列番号:169の軽鎖CDR1領域、配列番号:163の軽鎖CDR2領域、及び配列番号:170の軽鎖CDR3領域を含む、結合分子、
n)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:171の軽鎖CDR1領域、配列番号:164の軽鎖CDR2領域、及び配列番号:172の軽鎖CDR3領域を含む、結合分子、
o)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:145の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:173の軽鎖CDR3領域を含む、結合分子、
p)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:144の軽鎖CDR3領域を含む、結合分子、
からなる群から選択される。
a)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:145の重鎖CDR3領域、並びに、配列番号:146の軽鎖CDR1領域、配列番号:174の軽鎖CDR2領域、及び配列番号:147の軽鎖CDR3領域を含む、結合分子、
b)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:171の軽鎖CDR1領域、配列番号:164の軽鎖CDR2領域、及び配列番号:172の軽鎖CDR3領域を含む、結合分子、
c)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:145の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:173の軽鎖CDR3領域を含む、結合分子、
d)配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:144の軽鎖CDR3領域を含む、結合分子、
からなる群から選択される。
a)配列番号:2の重鎖可変領域を含む結合分子、
b)配列番号:6の重鎖可変領域を含む結合分子、
c)配列番号:10の重鎖可変領域を含む結合分子、
d)配列番号:14の重鎖可変領域を含む結合分子、
e)配列番号:18の重鎖可変領域を含む結合分子、
f)配列番号:22の重鎖可変領域を含む結合分子、
g)配列番号:26の重鎖可変領域を含む結合分子、
h)配列番号:30の重鎖可変領域を含む結合分子、
i)配列番号:34の重鎖可変領域を含む結合分子、
j)配列番号:38の重鎖可変領域を含む結合分子、
k)配列番号:42の重鎖可変領域を含む結合分子、
l)配列番号:46の重鎖可変領域を含む結合分子、
m)配列番号:50の重鎖可変領域を含む結合分子、
n)配列番号:54の重鎖可変領域を含む結合分子、
o)配列番号:58の重鎖可変領域を含む結合分子、及び
p)配列番号:62の重鎖可変領域を含む結合分子、
からなる群から選択される。
a)配列番号:2の重鎖可変領域及び配列番号:4の軽鎖可変領域を含む結合分子、
b)配列番号:6の重鎖可変領域及び配列番号:8の軽鎖可変領域を含む結合分子、
c)配列番号:10の重鎖可変領域及び配列番号:12の軽鎖可変領域を含む結合分子、
d)配列番号:14の重鎖可変領域及び配列番号:16の軽鎖可変領域を含む結合分子、
e)配列番号:18の重鎖可変領域及び配列番号:20の軽鎖可変領域を含む結合分子、
f)配列番号:22の重鎖可変領域及び配列番号:24の軽鎖可変領域を含む結合分子、
g)配列番号:26の重鎖可変領域及び配列番号:28の軽鎖可変領域を含む結合分子、
h)配列番号:30の重鎖可変領域及び配列番号:32の軽鎖可変領域を含む結合分子、
i)配列番号:34の重鎖可変領域及び配列番号:36の軽鎖可変領域を含む結合分子、
j)配列番号:38の重鎖可変領域及び配列番号:40の軽鎖可変領域を含む結合分子、
k)配列番号:42の重鎖可変領域及び配列番号:44の軽鎖可変領域を含む結合分子、
l)配列番号:46の重鎖可変領域及び配列番号:48の軽鎖可変領域を含む結合分子、
m)配列番号:50の重鎖可変領域及び配列番号:52の軽鎖可変領域を含む結合分子、
n)配列番号:54の重鎖可変領域及び配列番号:56の軽鎖可変領域を含む結合分子、
o)配列番号:58の重鎖可変領域及び配列番号:60の軽鎖可変領域を含む結合分子、及び
p)配列番号:62の重鎖可変領域及び配列番号:64の軽鎖可変領域を含む結合分子、
からなる群から選択される。
末梢血をEDTA抗凝固サンプルチューブに静脈穿刺(venapuncture、venipuncture)によって通常の健康なドナーから収集した。参照により本願明細書に援用する国際公開第2008/028946号に記載されるようにscFvファージディスプレイライブラリーを得た。RNAを末梢血単核球から単離し、cDNAを調製した。表1及び2に示されるプライマーセットを用いて、2ラウンドのPCR増幅の手法を用いて、免疫グロブリンVH及びVL領域をそれぞれのドナーレパートリーから単離した。
抗体フラグメントを、実質的に上記の通り構築した抗体ファージディスプレイライブラリー、及び一般的なファージディスプレイ技術、並びに、実質的に、米国特許第6265150号明細書、及び国際公開第98/15833号(その両方を参照により本願明細書に援用する)に記載される、MABSTRACT(登録商標)技術を用いて、セレクションした。また、国際公開第02/103012号(参照により本願明細書に援用する)に記載される方法及びヘルパーファージを、本発明において用いた。
上記のスクリーニングで得られた一本鎖ファージ抗体を含むセレクションされた上澄みを、特異性、すなわち、異なるHAの抗原に対する結合についてのELISAで検証した。この目的のために、バキュロウイルスが発現した、組換え型のH1(A/ニューカレドニア/20/99)、H3(A/ウィスコンシン/67/2005)、H5(A/トリ/ベトナム/28/2003)、H7(A/オランダ/219/2003)、及びB(B/オハイオ/01/2005)HAs(Protein Sciences、CT、米国)を、Maxisorp(登録商標)ELISAプレートに対してコーティングした。コーティング後、プレートを、0.1%v/vのTween−20を含むPBSで3回洗浄し、3%BSA又は2%ELKを含むPBS中で、室温で1時間ブロックした。セレクションされた一本鎖ファージ抗体を、等量の4%ELKを含むPBS中で1時間インキュベートして、ブロックされたファージ抗体を得た。プレートを空にし、PBS/0.1%Tween−20で3回洗浄し、ブロックされた一本鎖ファージ抗体をウェルに加えた。インキュベーションを1時間なし、プレートをPBS/0.1%のTween−20で洗浄し、結合したファージ抗体を、抗M13抗体コンジュゲートペルオキシダーゼを用いて検出した(OD492nmでの測定を用いた)。コントロールとして、この操作を、一本鎖ファージ抗体なしと、関係のないネガティブコントロールの単鎖ファージ抗体とで、同時に行った。ファージライブラリを用いた異なるHAの抗原に対するセレクションから、組換え型のインフルエンザA型のH1、H3、H5、H7、及びインフルエンザB型のHAに特異的に結合する、13のユニークな一本鎖ファージ抗体を得た(SC09−003、SC09−004、SC09−005、SC09−006、SC09−007、SC09−008、SC09−009、SC09−010、SC09−011、SC09−030、SC09−112、SC09−113、及びSC09−114)。表5参照。
選択された特異的な単鎖ファージ抗体(scFv)クローンから、プラスミドDNAを取得し、ヌクレオチド及びアミノ酸配列を、標準的な手法に従って決定した。scFvsの重鎖及び軽鎖の可変領域を、発現のため、IgG発現ベクターpIg−C911−HCガンマ1(配列番号:175参照)、PIG−C909−Cカッパ(配列番号:176参照)、又はpIg−C910−Cラムダ(配列番号:177参照)中に、制限酵素消化により直接的にクローン化した。scFvsのうち、VH及びVL遺伝子の同一性(Tomlinson IMら、V−BASE Sequence Directory.Cambridge United Kingdom:MRC Centre for Protein Engineering(1997))を決定した(表7参照)。
上記の5つのIgG抗体パネル、CR9005、CR9030、CR9112、CR9113、及びCR9114を、結合特異性、すなわち、異なるHA抗原に対する結合について、ELISAで検証した。この目的のために、バキュロウイルスが発現した、組換え型のH1(A/ニューカレドニア/20/99)、H3(A/ウィスコンシン/67/2005)、H5(A/トリ/ベトナム/28/2003)、H7(A/オランダ/219/2003)、及びH9(A/ホンコン/1073/99)HAs(Protein Sciences、CT、米国)を、Maxisorp(登録商標)ELISAプレートに対してコーティングした。コーティング後、プレートを、0.1%v/vのTween−20を含むPBSで3回洗浄し、3%BSA又は2%ELKを含むPBS中で、室温で1時間ブロックした。プレートを空にし、PBS/0.1%Tween−20で3回洗浄し、IgG抗体をウェルに加えた。インキュベーションを1時間なし、プレートをPBS/0.1%のTween−20で洗浄し、結合したファージ抗体を、抗−ヒトIgG抗体コンジュゲートペルオキシダーゼを用いて検出した(OD492nmでの測定を用いた)。コントロールとして、関係のないIgG CR4098を用いた。
セレクションされたIgGsが、複数のインフルエンザA型株をブロックすることが可能であったかどうかを決定するために、追加のインビトロでのウイルス中和アッセイ(VNA)を行った。VNAを、MDCK細胞(ATCC CCL−34)上で行った。MDCK細胞を、MDCK細胞培養培地(抗生物質、20mMのHEPES、及び0.15%(w/v)の重炭酸ナトリウムを添加し、10%(v/v)のウシ胎仔血清を添加した、MEM培地(完全MEM培地))中で培養した。アッセイで用いた、H1(A/WSN/33、A/ニューカレドニア/20/1999、A/ソロモン諸島/IVR−145(A/カリフォルニア/07/2009の高増殖の再集合体))、H2(A/Env/MPU3156/05)、H3(A/ホンコン/1/68、A/ヨハネスブルク/33/94、A/パナマ/2000/1999、A/広島/52/2005、A/ウィスコンシン/67/2005、及びA/ブリスベン/10/2007)、H4(A/WF/HK/MPA892/06)、H5(PR8−H5N1−HK97(A/ホンコン/156/97とA/PR/8/34との6:2の再集合体)、及びA/ユーラシアンウィジョン/MPD411/07)、H7(NIBRG−60(A/マドリード/オランダ/12/2000の6:2の再集合体)、及びPR8−H7N7−NY(A/ニューヨーク/107/2003(H7N7)とA/PR/8/34)との7:1の再集合体))、H8(A/ユーラシアンウィジョン/MPH571/08)、H9(A/ホンコン/1073/99、及びA/ニワトリ/HK/SSP176/09)、H10(A/ニワトリ/ドイツ/N/49)、及びH14(PR8−H14N5(A/マドリード/アストラカン/263/1982(H14N5)、及びA/PR/8/34の6:2の再集合体)株は、全て、Spearman及びKarberの方法に従って計算された力価で、5,7×103TCID50/mL(mL当たり50%組織培養感染量)の力価となるように希釈した。4つ一組のウェルにおいて、完全MEM培地中で、IgG調製物(200μg/mL)を連続的に2倍に希釈した(1:2〜1:512)。それぞれのIgG希釈物の25μLを、25μLのウイルス懸濁液(100 TCID50/25μL)と混合し、37℃で1時間インキュベートした。この懸濁液をその後、50μLの完全MEM培地中のコンフルエントのMDCK培養物を含む、96ウェルプレート上に4つ一組で移した。使用前に、MDCK細胞を、ウェル当たり3×104細胞で、MDCK細胞培養培地に播種し、細胞がコンフルエントに達するまで生育させ、300〜350μLのPBS、pH7.4で洗浄し、最後に、50μLの完全MEM培地を各ウェルに加えた。播種した細胞を、37℃で3〜4日間培養し、細胞変性効果(CPE)の進展について、毎日観察した。CPEをポジティブコントロールと比較した。
選択されたIgGがHA分子の融合前又は後の形態に結合することが可能かどうかを決定するために、インビトロのpHシフト実験を行った。この目的のため、インフルエンザA型サブタイプH1(A/ニューカレドニア/20/99)、H3(A/ウィスコンシン/67/2005)、H5(A/ベトナム/1203/04)、H7(A/オランダ/219/03)、及びH9(A/ホンコン/1073/99)のHAを、PER.C6細胞上に発現した。異なる構造のHAの形態に対して結合するmAbを測定するため、細胞をPBS−EDTAを用いてプラスチック氏辞退から剥離し、その後、トリプシン(TrypLE(登録商標) Select、Gibco)で室温で5分間処理し、洗浄(1%のBSAのPBS溶液)し、クエン酸−リン酸ナトリウム緩衝溶液(pH4.9)中で15分間インキュベートした。各処理ステップ(トリプシン処理せず/HA0;トリプシン処理/HA1−HA2;pH4.9/融合HA)の後、細胞試料を確保、各処理の画分をmAb CR9114で1時間インキュベートした。細胞をその後、1%BSA中のフィコエリトリン−コンジュゲート−抗−ヒトIgG(Southern Biotech)で30分間インキュベートした。染色した細胞を、FACS Diva ソフトウェアを備えたFACS Canto(Becton Dickinson)を用いて分析した。HAが発現された表面に対するIgGのFACSでの結合は、トリプシン及びpH4.9緩衝培地による連続的処理後のものとし、未処理のHAに(A)に対する結合の割合として表した。図1A参照のこと。
昆虫細胞中でバキュロウイルスベクターを用いて生産された、A/ニューカレドニア/20/1999(H1)、A/ブリスベン/59/2007(H1)、A/ウィスコンシン/67/2005(H3)、A/ブリスベン/10/2007(H3)、B/フロリダ/4/2006(B)、B/ブリスベン/60/2008(B)、及びB/マレーシア/2506/2004(B)の組換え型可溶性HAを、Protein Science Corp(CT、米国)から購入し、EZ−link sulfo−NHS−LC−LC−biotin (Pierce)を用いて、室温(RT)で40分間ビオチン化した。バッファをPBSに交換するステップを、Amicon Ultra 0.5mL Centrifugal Filters(Millipore)を用いて行った。ビオチン化したHAを37℃で1200秒間ストレプトアビジンセンサーに結合させた。センサーを1×キネティックバッファ中の100nM抗体に曝すことによって、CR9005、CR9112、CR9113、及びCR9114のFab断片の集合を、Octet QK(ForteBio)で、37℃で700秒間測定した。CR9005、CR9112、CR9113、及びCR9114のFab断片の全てが、H1、H2及びインフルエンザBのHAに対してマイクロ〜ピコモラーの親和性で結合した。
昆虫細胞中でバキュロウイルスベクターを用いて生産された、A/ニューカレドニア/20/1999(H1N1)、及びA/ウィスコンシン/67/2005(H3N2)の組換え型可溶性HAを、Protein Science Corp(CT、米国)から購入し、EZ−link sulfo−NHS−LC−LC−biotin (Pierce)を用いて、室温(RT)で40分間ビオチン化した。バッファをPBSに交換するステップを、Amicon Ultra 0.5mL Centrifugal Filters(Millipore)を用いて行った。ビオチン化したHAを37℃で1200秒間ストレプトアビジンセンサーに結合させた。センサーを1×キネティックバッファ中の100nM抗体に曝すことによって、抗体CR9114及びCR6261のH1のHAに対する集合を、Octet QK(ForteBio)で、37℃で700秒間測定し、その後、追加的結合の程度を、センサーを一次抗体(100nM)の存在下で、二次抗体(1×キネティックバッファ中で100nM)に、37℃で700秒間曝すことによって評価した。コントロールとして、H1の球状頭部に対して結合する、mAb CR9020を共に用いた。抗体CR9114及びCR8020のH3のHAに対する集合を、Octet QK(ForteBio)で、37℃で900秒間測定し、その後、追加的結合の程度を、センサーを一次抗体(100nM)の存在下で、二次抗体(1×キネティックバッファ中で100nM)に37℃で900秒間曝すことによって評価した。コントロールとして、H3の球状頭部に対して結合する、mAb CR8057を共に用いた。
インビボにおけるヒトIgGモノクローナル抗体CR9114のインフルエンザBの致死的攻撃に対する予防活性を試験するための研究を行った。MAb CR9114を、インフルエンザB/フロリダ/04/2006ウイルス(Central Veterinary Institute (CVI), Lelystad, The Netherlands)に罹患させたマウスを用いたマウス致死的攻撃モデルにおいて、予防活性について試験した。B/フロリダ/04/2006ウイルスを、5回の肺対肺(lung−to−lung)継代後、マウスに罹患させた。マウスに罹患させたインフルエンザBの5継代目のウイルスは、CVI’sラボラトリーで、孵化鶏卵において増殖させた。全てのマウス(Balb/c、雌、6〜8週齢、グループ当たりn=10)を、実験の開始前少なくとも4日間順応させ、維持した。MAb CR9114を、攻撃1日前に、尾静脈(vena coccygeus)において静脈内に15mg/kgで投与した。マウス当たり平均重量18gであり、所定投与量は0.2mLであった。共に用いるコントロールグループにはビヒクルコントロールを投与した。マウスを、その後、経鼻接種により、25LD50のB/フロリダ/04/2006インフルエンザウイルスで、0日目に攻撃した。臨床的徴候及び体重を、攻撃1日前から8日目まで毎日測定した。臨床的徴候は、スコアリングシステム(0=臨床徴候なし;1=ラフコート、2=ラフコート、取扱いの間低反応、3=ラフコート、ロールドアップ、呼吸困難(laboured breathing)、取扱いの間低反応、4=ラフコート、ロールアップ、呼吸困難、操作/取扱いに対して低反応。)を用いてスコアした。
(1)Air MA (1981), Sequence relationships among the hemagglutinin genes of 12 subtypes of influenza A virus. Proc Natl Acad Sci USA 78(12):7639−7643.
(2)De Kruif J et al. (1995), Rapid selection of cell subpopulation−specific human monoclonal antibodies from a synthetic phage antibody library. Proc Natl Acad Sci USA 92:3938.
(3)Ferguson et al., (2003), Nature 422:428−443.
(4)Fouchier AM et al. (2005), Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black−headed gulls. J Virol 79(5):2814−2822.
(5)The World Health Organization Global Influenza Program Surveillance Network (2005), Evolution of H5N1 Avian Influenza Viruses in Asia. Emerg Infect Dis 11:1515−1521.
Claims (6)
- 系統グループ1のインフルエンザA型ウイルスのサブタイプ、及び系統グループ2のインフルエンザA型ウイルスのサブタイプのヘマグルチニンタンパク質(HA)のステム領域中のエピトープに対して特異的に結合することができ、且つ、H1、H2、H5、H6、H8、H9、及びH11サブタイプのHAを含むインフルエンザA型ウイルスからなる群から選択される、少なくとも1種又は複数種のグループ1のインフルエンザA型ウイルスのサブタイプ、及び、H3、H4、H7、及びH10サブタイプのHAを含むインフルエンザA型ウイルスからなる群から選択される、少なくとも1種又は複数種のグループ2のインフルエンザA型ウイルスのサブタイプを中和することができる、単離された抗体又はその抗原結合性の断片であり、
インフルエンザB型ウイルスのサブタイプのヘマグルチニンタンパク質(HA)に対して特異的に結合することもできる
ことを特徴とし、
配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:145の重鎖CDR3領域、並びに、配列番号:146の軽鎖CDR1領域、配列番号:174の軽鎖CDR2領域、及び配列番号:147の軽鎖CDR3領域を含む、抗体又はその抗原結合性の断片、
配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:145の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:173の軽鎖CDR3領域を含む、抗体又はその抗原結合性の断片、
配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:171の軽鎖CDR1領域、配列番号:164の軽鎖CDR2領域、及び配列番号:172の軽鎖CDR3領域を含む、抗体又はその抗原結合性の断片、および
配列番号:139の重鎖CDR1領域、配列番号:134の重鎖CDR2領域、及び配列番号:152の重鎖CDR3領域、並びに、配列番号:142の軽鎖CDR1領域、配列番号:143の軽鎖CDR2領域、及び配列番号:144の軽鎖CDR3領域を含む、抗体又はその抗原結合性の断片、
からなる群から選択される、
単離された抗体又はその抗原結合性の断片。 - 前記抗体又はその抗原結合性の断片は、赤血球凝集抑制活性を有しない、請求項1に記載の抗体又はその抗原結合性の断片。
- 請求項1または2に記載の抗体又はその抗原結合性の断片をコード化する核酸分子。
- 医薬用の、請求項1または2に記載の抗体又はその抗原結合性の断片、及び/又は請求項3に記載の核酸分子。
- インフルエンザ感染の予防及び/又は治療用の、請求項4に記載の抗体又はその抗原結合性の断片。
- 請求項1または2に記載の抗体若しくはその抗原結合性の断片、及び/又は請求項3に記載の核酸分子、並びに薬学的に許容可能な賦形剤を含む、薬学的組成物。
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PCT/EP2012/063637 WO2013007770A1 (en) | 2011-07-14 | 2012-07-12 | Human binding molecules capable of neutralizing influenza a viruses of phylogenetic group 1 and phylogenetic group 2 and influenza b viruses |
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US9593159B2 (en) | 2017-03-14 |
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MX2014000373A (es) | 2014-03-31 |
CA2838999A1 (en) | 2013-01-17 |
CN103906763A (zh) | 2014-07-02 |
EP2731967B1 (en) | 2016-10-12 |
DK2731967T3 (en) | 2017-01-16 |
EA201490288A1 (ru) | 2014-05-30 |
IL230222A (en) | 2017-09-28 |
KR20140095017A (ko) | 2014-07-31 |
BR112014000263B1 (pt) | 2022-01-18 |
MX346206B (es) | 2017-03-09 |
EP2731967A1 (en) | 2014-05-21 |
KR101941724B1 (ko) | 2019-01-23 |
US20150274811A1 (en) | 2015-10-01 |
ES2608321T3 (es) | 2017-04-07 |
MY166282A (en) | 2018-06-25 |
IN2014CN00953A (ja) | 2015-04-10 |
CN103906763B (zh) | 2016-10-12 |
BR112014000263A2 (pt) | 2017-02-14 |
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