JP2022540427A - シュードモナス菌PcrVを特異的に認識する抗体及びその使用 - Google Patents
シュードモナス菌PcrVを特異的に認識する抗体及びその使用 Download PDFInfo
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Abstract
Description
前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、(xvi)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:30を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、(xvii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:8を含むHC-CDR1と、アミノ酸配列SEQ ID NO:14を含むHC-CDR2と、アミノ酸配列SEQ ID NO:31を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、或いは(xviii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:7を含むHC-CDR1と、アミノ酸配列SEQ ID NO:13を含むHC-CDR2と、アミノ酸配列SEQ ID NO:29を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:38を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含む、上記のいずれか1つの単離された抗PcrV抗体を提供する。
定義
抗PcrV抗体
核酸
誘導性プロモーター
抗PcrV抗体の調製
完全ヒト抗体及びヒト化抗体
抗PcrV抗体変異体
a、疎水性アミノ酸:ノルロイシンノルロイシンNorleucine、メチオニンMet、アラニンAla、バリンVal、ロイシンLeu、イソロイシンIle;
b、中性親水性アミノ酸:システインCys、セリンSer、スレオニンThr、アスパラギンAsn、グルタミンGln;
c、酸性アミノ酸:アスパラギン酸Asp、グルタミン酸Glu;
d、塩基性アミノ酸:ヒスチジンHis、リジンLys、アルギニンArg;
e、鎖の方向に影響を与えるアミノ酸:グリシンGly、プロリンPro;
f、芳香族アミノ酸:トリプトファンTrp、チロシンTyr、フェニルアラニンPhe。
Fc領域変異体
グリコシル化変異体
システイン操作変異体
誘導体
医薬組成物
抗PcrV抗体を使用する治療方法又は予防方法
抗PcrV抗体抗体の投与量及び方法
製品及び試薬キット
実施例
実施例1:組換えシュードモナス菌PcrVの調製及び抗PcrV一本鎖抗体(scFv)のスクリーニング
組換えシュードモナス菌PcrVの調製
ビオチン化PcrV抗原の調製
抗PcrV一本鎖抗体(scFv)のスクリーニング
PcrV結合による抗PcrV一本鎖抗体(scFv)のスクリーニング
RBC溶解阻害による抗PcrV scFv候補の分析
実施例2:全長のヒトPcrV抗体の調製及び特性評価
全長のヒトPcrV抗体の調製
A549又はU937溶解阻害による抗PcrV候補の分析
マウス急性肺炎モデルによる抗PcrV候補の分析
13-42モノクローナル抗体をリード抗体としての更なる最適化
実施例3:最適化された全長の抗PcrV抗体の調製及び特性評価
最適化された抗PcrV抗体の、緑膿菌によるRBC及びA549細胞溶解への阻害
最適化された抗PcrV抗体の、RBC溶解への阻害
最適化された抗体とPcrVとの結合親和性
抗PcrV抗体の特異性
実施例5:最適化された全長の抗PcrV抗体広範囲の緑膿菌菌株の中和
最適化された抗PcrV抗体によるRBC溶解阻害
最適化された抗PcrV抗体によるA549細胞溶解阻害
実施例6:最適化された抗PcrV抗体の緑膿菌感染の予防的治療の使用
抗PcrV抗体によるマウス肺炎モデルの生存率の改善
抗PcrV抗体を投与したマウス肺炎モデルにおける臓器負荷
抗PcrV抗体を投与したマウス腹腔内感染モデルの生存率の改善
抗PcrV抗体を投与した免疫不全マウス肺炎モデルの生存率の改善
実施例7:最適化された抗PcrV抗体の緑膿菌感染の治療の使用
最適化された抗PcrV抗体によるマウス肺炎モデルの生存率の改善
実施例8:最適化された抗PcrV抗体と抗生物質とを併用する緑膿菌感染の治療
抗生物質と組み合わせる抗PcrV抗体によるマウス腹腔内感染モデルの生存率の改善
実施例9:最適化された抗PcrV抗体の薬物動態学
実施例10:最適化された抗体によって認識されるエピトープ
抗PcrV抗体のエピトープのスクリーニング
Claims (31)
- 単離された抗PcrV抗体であって、シュードモナス菌PcrV上のエピトープに特異的に結合しており、
前記エピトープは、シュードモナス菌PcrVのアミノ酸残基であるGln160、Asp165、Asp170、Asp173、Thr175及びSer202を含む、単離された抗PcrV抗体。 - 前記抗PcrV抗体が前記シュードモナス菌PcrVに結合するKd値は、約0.1pM~1nMである、
請求項1に記載の単離された抗PcrV抗体。 - 重鎖可変ドメイン(VH)及び軽鎖可変ドメイン(VL)を含む単離された抗PcrV抗体であって、
前記重鎖可変ドメイン(VH)は、
X1X2X3MS(SEQ ID NO:39)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がD又はSであり、X2がY又はNであり、X3がP、H、Y又はSである重鎖相補性決定領域(HC-CDR)1と、
X1ISESGGSTX2X3ADSVKG(SEQ ID NO:40)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がG又はVであり、X2がN又はYであり、X3がD又はYであるHC-CDR2と、
GRFX1X2X3X4X5X6FX7RAVYGMDV(SEQ ID NO:41)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がS又はCであり、X2がT、G、D、Y、Q又はAであり、X3がS、D、N、E、L、A又はYであり、X4がS、T、Y又はAであり、X5がS、H、Q、A、R、K、G、E、Y又はDであり、X6がH又はCであり、X7がF又はYであるHC-CDR3とを含み、
前記軽鎖可変ドメイン(VL)は、
RASQGIX1SYLA(SEQ ID NO:42)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がS又はRである軽鎖相補性決定領域(LC-CDR)1と、
AASTLQS(SEQ ID NO:34)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むLC-CDR2と、
QQLX1SYPLX2(SEQ ID NO:43)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がS、N又はKであり、X2がS又はTであるLC-CDR3とを含む、単離された抗PcrV抗体。 - 前記抗PcrV抗体は、VH及びVLを含み、
前記VHは、
DX1X2MS(SEQ ID NO:44)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がN又はYであり、X2がP、H又はYであるHC-CDR1と、
X1ISESGGSTNYADSVKG(SEQ ID NO:45)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がG又はVであるHC-CDR2と、
GRFSTX1SX2HFX3RAVYGMDV(SEQ ID NO:46)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がN、S、D又はLであり、X2がS又はAであり、X3がF又はYであるHC-CDR3とを含み、
前記VLは、
RASQGISSYLA(SEQ ID NO:32)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むLC-CDR1と、
AASTLQS(SEQ ID NO:34)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むLC-CDR2と、
QQLSSYPLX1(SEQ ID NO:47)又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含み、X1がS又はTであるLC-CDR3とを含む、
請求項3に記載の単離された抗PcrV抗体。 - VH及びVLを含む単離された抗PcrV抗体であって、
前記VHは、
アミノ酸配列SEQ ID NOs:1~8のいずれか1つ又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むHC-CDR1と、
アミノ酸配列SEQ ID NOs:9~14のいずれか1つ又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むHC-CDR2と、
アミノ酸配列SEQ ID NOs:15~31のいずれか1つ又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むHC-CDR3とを含み、
前記VLは、
アミノ酸配列SEQ ID NOs:32~33のいずれか1つ又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むLC-CDR1と、
アミノ酸配列SEQ ID NO:34又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むLC-CDR2と、
アミノ酸配列SEQ ID NOs:35~38のいずれか1つ又はその変異体を含み、前記変異体が最大約3個のアミノ酸置換を含むLC-CDR3とを含む、単離された抗PcrV抗体。 - VH及びVLを含む単離された抗PcrV抗体であって、
前記VHは、アミノ酸配列SEQ ID NOs:48~64のいずれか1つで示されるVHに含まれるHC-CDR1、HC-CDR2及びHC-CDR3を含み、
前記VLは、アミノ酸配列SEQ ID NOs:65~70のいずれか1つで示されるVLに含まれるLC-CDR1、LC-CDR2及びLC-CDR3を含む、単離された抗PcrV抗体。 - (i)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:9を含むHC-CDR2と、アミノ酸配列SEQ ID NO:15を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(ii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:2を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:16を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(iii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:9を含むHC-CDR2と、アミノ酸配列SEQ ID NO:17を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:36を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(iv)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:3を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:18を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(v)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:3を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:19を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(vi)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:3を含むHC-CDR1と、アミノ酸配列SEQ ID NO:11を含むHC-CDR2と、アミノ酸配列SEQ ID NO:20を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(vii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:4を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:21を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(viii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:5を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:22を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(ix)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:6を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:23を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(x)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:12を含むHC-CDR2と、アミノ酸配列SEQ ID NO:24を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:33を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(xi)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:2を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:25を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(xii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:9を含むHC-CDR2と、アミノ酸配列SEQ ID NO:26を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(xiii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:3を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:27を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(xiv)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:28を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(xv)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:7を含むHC-CDR1と、アミノ酸配列SEQ ID NO:13を含むHC-CDR2と、アミノ酸配列SEQ ID NO:29を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(xvi)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:30を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(xvii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:8を含むHC-CDR1と、アミノ酸配列SEQ ID NO:14を含むHC-CDR2と、アミノ酸配列SEQ ID NO:31を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、或いは
(xviii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:7を含むHC-CDR1と、アミノ酸配列SEQ ID NO:13を含むHC-CDR2と、アミノ酸配列SEQ ID NO:29を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:38を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含む、
請求項1~6のいずれか1項に記載の単離された抗PcrV抗体。 - (i)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:3を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:18を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(ii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:3を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:19を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、
(iii)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:1を含むHC-CDR1と、アミノ酸配列SEQ ID NO:10を含むHC-CDR2と、アミノ酸配列SEQ ID NO:28を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:35を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含むか、或いは
(iv)VH又は前記VHの変異体及びVL又は前記VLの変異体を含み、前記VHは、アミノ酸配列SEQ ID NO:7を含むHC-CDR1と、アミノ酸配列SEQ ID NO:13を含むHC-CDR2と、アミノ酸配列SEQ ID NO:29を含むHC-CDR3とを含み、前記VHの変異体がHC-CDRsにおいて最大約5個のアミノ酸置換を含み、前記VLは、アミノ酸配列SEQ ID NO:32を含むLC-CDR1と、アミノ酸配列SEQ ID NO:34を含むLC-CDR2と、アミノ酸配列SEQ ID NO:37を含むLC-CDR3とを含み、前記VLの変異体がLC-CDRsにおいて最大約5個のアミノ酸置換を含む、
請求項7に記載の単離された抗PcrV抗体。 - VH及びVLを含み、
前記VHは、アミノ酸配列SEQ ID NOs:48~64のいずれか1つ又はその変異体を含み、前記変異体がアミノ酸配列SEQ ID NOs:48~64のいずれか1つと少なくとも約90%の配列同一性を有し、
前記VLは、アミノ酸配列SEQ ID NOs:65~70のいずれか1つ又はその変異体を含み、前記変異体がアミノ酸配列SEQ ID NOs:65~70のいずれか1つと少なくとも約90%の配列同一性を有する、
請求項1~8のいずれか1項に記載の単離された抗PcrV抗体。 - VH及びVLを含み、
前記VHは、アミノ酸配列SEQ ID NOs:51~52及び61~62のいずれか1つ又はその変異体を含み、前記変異体がアミノ酸配列SEQ ID NOs:51~52及び61~62のいずれか1つと少なくとも約90%の配列同一性を有し、
前記VLは、アミノ酸配列SEQ ID NO:65若しくは67又はその変異体を含み、前記変異体がアミノ酸配列SEQ ID NO:65若しくは67と少なくとも約90%の配列同一性を有する、
請求項9に記載の単離された抗PcrV抗体。 - (i)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:48を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(ii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:49を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(iii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:50を含み、前記VLは、アミノ酸配列SEQ ID NO:66を含むか、
(iv)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:51を含み、前記VLは、アミノ酸配列SEQ ID NO:67を含むか、
(v)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:52を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(vi)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:53を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(vii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:54を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(viii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:55を含み、前記VLは、アミノ酸配列SEQ ID NO:67を含むか、
(ix)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:56を含み、前記VLは、アミノ酸配列SEQ ID NO:67を含むか、
(x)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:57を含み、前記VLは、アミノ酸配列SEQ ID NO:68を含むか、
(xi)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:58を含み、前記VLは、アミノ酸配列SEQ ID NO:69を含むか、
(xii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:59を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(xiii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:60を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(xiv)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:61を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(xv)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:62を含み、前記VLは、アミノ酸配列SEQ ID NO:67を含むか、
(xvi)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:63を含み、前記VLは、アミノ酸配列SEQ ID NO:65を含むか、
(xvii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:64を含み、前記VLは、アミノ酸配列SEQ ID NO:67を含むか、或いは
(xviii)VH及びVLを含み、前記VHは、アミノ酸配列SEQ ID NO:62を含み、前記VLは、アミノ酸配列SEQ ID NO:70を含む、
請求項9に記載の単離された抗PcrV抗体。 - 請求項1~11のいずれか1項に記載の単離された抗PcrV抗体と競合的にPcrVに特異的に結合するか、或いは
請求項1~11のいずれか1項に記載の単離された抗PcrV抗体と同じエピトープに特異的に結合する、単離された抗PcrV抗体。 - 前記抗PcrV抗体は、Fcフラグメントを含む、
請求項1~12のいずれか1項に記載の単離された抗PcrV抗体。 - 前記抗PcrV抗体は、全長のIgG抗体である、
請求項13に記載の単離された抗PcrV抗体。 - 前記抗PcrV抗体は、全長のIgG1又はIgG4抗体である、
請求項14に記載の単離された抗PcrV抗体。 - 前記抗PcrV抗体は、キメラ抗体、ヒト抗体又はヒト化抗体である、
請求項1~15のいずれか1項に記載の単離された抗PcrV抗体。 - 前記抗PcrV抗体は、Fab、Fab’、F(ab)’2、Fab’-SH、一本鎖抗体(scFv)、Fvフラグメント、dAb、Fd、及びダイアボディからなる群から選択される抗原結合性フラグメントである、
請求項1~12のいずれか1項に記載の単離された抗PcrV抗体。 - 請求項1~17のいずれか1項に記載の単離された抗PcrV抗体をコードする、単離された核酸分子。
- 請求項18に記載の単離された核酸分子を含む、ベクター。
- 請求項1~17のいずれか1項に記載の単離された抗PcrV抗体、請求項18に記載の単離された核酸分子、又は請求項19に記載のベクターを含む、単離された宿主細胞。
- 単離された抗PcrV抗体を調製する方法であって、
a)抗PcrV抗体を有効に発現する条件で請求項20に記載の単離された宿主細胞を培養すること、及び
b)前記宿主細胞から、発現された抗PcrV抗体を得ることを含む、単離された抗PcrV抗体の調製方法。 - 請求項1~17のいずれか1項に記載の単離された抗PcrV抗体、請求項18に記載の単離された核酸分子、請求項19に記載のベクター、又は請求項20に記載の単離された宿主細胞と、薬学的に許容される担体とを含む、医薬組成物。
- 有効量の請求項22に記載の医薬組成物を個体へ投与することを含む、必要とする個体における疾患又は病症を治療する方法。
- 前記疾患又は病症は、病原菌感染である、
請求項23に記載の方法。 - 前記感染は、グラム陰性菌感染である、
請求項24に記載の方法。 - 前記細菌は、緑膿菌である、
請求項25に記載の方法。 - 前記疾患又は病症は、緑膿菌感染による症状の一種又は複数種を含む、
請求項23~26のいずれか1項に記載の方法。 - 前記症状は、熱、悪寒、疲労、筋肉及び関節の痛み、関節の腫れ、頭痛、下痢、皮膚発疹、創傷の膿、細菌血症、急性肺炎、腹腔内感染、呼吸器感染、敗血症性ショック、化膿性関節炎、腸炎、皮膚及び軟組織感染、***、腸感染、潰瘍性角膜炎、慢性化膿性中耳炎、乳様突起炎、副鼻腔炎、及び心内膜炎のうちの一種又は複数種を含む、
請求項27に記載の方法。 - 治療薬の一種又は複数種を投与することをさらに含む、
請求項23~28のいずれか1項に記載の方法。 - 前記治療薬の少なくとも一種は、抗生物質である、
請求項29に記載の方法。 - 前記抗生物質は、イミペネム、トブラマイシン、シプロフロキサシン、メロペネム、及びアズトレオナムのうちの一種又は複数種である、
請求項30に記載の方法。
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