ジャーナル: Cell Res / 年: 2021 タイトル: Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection. 著者: Hangping Yao / Yao Sun / Yong-Qiang Deng / Nan Wang / Yongcong Tan / Na-Na Zhang / Xiao-Feng Li / Chao Kong / Yan-Peng Xu / Qi Chen / Tian-Shu Cao / Hui Zhao / Xintian Yan / Lei Cao / Zhe Lv ...著者: Hangping Yao / Yao Sun / Yong-Qiang Deng / Nan Wang / Yongcong Tan / Na-Na Zhang / Xiao-Feng Li / Chao Kong / Yan-Peng Xu / Qi Chen / Tian-Shu Cao / Hui Zhao / Xintian Yan / Lei Cao / Zhe Lv / Dandan Zhu / Rui Feng / Nanping Wu / Wenhai Zhang / Yuhao Hu / Keda Chen / Rong-Rong Zhang / Qingyu Lv / Shihui Sun / Yunhua Zhou / Run Yan / Guan Yang / Xinglu Sun / Chanjuan Liu / Xiangyun Lu / Linfang Cheng / Hongying Qiu / Xing-Yao Huang / Tianhao Weng / Danrong Shi / Weidong Jiang / Junbin Shao / Lei Wang / Jie Zhang / Tao Jiang / Guojun Lang / Cheng-Feng Qin / Lanjuan Li / Xiangxi Wang / 要旨: Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a ...Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.
ダウンロード / ファイル: emd_30482.map.gz / 形式: CCP4 / 大きさ: 244.1 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
ボクセルのサイズ
X=Y=Z: 1.04 Å
密度
表面レベル
登録者による: 0.00502 / ムービー #1: 0.01
最小 - 最大
-0.023895668 - 0.056485415
平均 (標準偏差)
0.000119217126 (±0.001506104)
対称性
空間群: 1
詳細
EMDB XML:
マップ形状
Axis order
X
Y
Z
Origin
0
0
0
サイズ
400
400
400
Spacing
400
400
400
セル
A=B=C: 416.0 Å α=β=γ: 90.0 °
CCP4マップ ヘッダ情報:
mode
Image stored as Reals
Å/pix. X/Y/Z
1.04
1.04
1.04
M x/y/z
400
400
400
origin x/y/z
0.000
0.000
0.000
length x/y/z
416.000
416.000
416.000
α/β/γ
90.000
90.000
90.000
start NX/NY/NZ
-225
-225
-225
NX/NY/NZ
450
450
450
MAP C/R/S
1
2
3
start NC/NR/NS
0
0
0
NC/NR/NS
400
400
400
D min/max/mean
-0.024
0.056
0.000
-
添付データ
-
試料の構成要素
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全体 : Complex of SARS-CoV-2 spike protein and Fab P17 with one RBD in c...
全体
名称: Complex of SARS-CoV-2 spike protein and Fab P17 with one RBD in closed state and two RBDs in open state.
要素
複合体: Complex of SARS-CoV-2 spike protein and Fab P17 with one RBD in closed state and two RBDs in open state.
複合体: SARS-CoV-2 spike protein
タンパク質・ペプチド: Spike glycoprotein
複合体: Fab P17
タンパク質・ペプチド: Fab P17 heavy chain
タンパク質・ペプチド: Fab P17 light chain
リガンド: 2-acetamido-2-deoxy-beta-D-glucopyranose
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超分子 #1: Complex of SARS-CoV-2 spike protein and Fab P17 with one RBD in c...
超分子
名称: Complex of SARS-CoV-2 spike protein and Fab P17 with one RBD in closed state and two RBDs in open state. タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3