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. 2020 Nov 13;11(1):5752.
doi: 10.1038/s41467-020-19568-1.

Characterization of neutralizing antibody with prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys

Shuang Wang  1   2 , Yun Peng  3 , Rongjuan Wang  1   2 , Shasha Jiao  1   2 , Min Wang  1 , Weijin Huang  4 , Chao Shan  5 , Wen Jiang  1 , Zepeng Li  1 , Chunying Gu  1 , Ben Chen  1 , Xue Hu  5 , Yanfeng Yao  3 , Juan Min  6 , Huajun Zhang  3 , Ying Chen  3 , Ge Gao  3 , Peipei Tang  1 , Gang Li  1 , An Wang  1 , Lan Wang  4 , Jinchao Zhang  1 , Shuo Chen  7 , Xun Gui  8 , Zhiming Yuan  9 , Datao Liu  10
Affiliations

Characterization of neutralizing antibody with prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys

Shuang Wang et al. Nat Commun. .

Abstract

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19.

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Conflict of interest statement

X.G., S.W., R.W., S.J., W.J., and C.G. are listed as inventors on the licensed patents for MW05 and MW07. S.W., R.W., S.J., M.W., W.J., Z.L., C.G., B.C., P.T., J.Z., X.G., and D.L. are employees of Mabwell (Shanghai) Bioscience Co., Ltd, and may hold shares in Mabwell (Shanghai) Bioscience Co., Ltd. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. MW05 and MW07 disrupting the interaction of SARS-CoV-2 RBD with hACE2 receptor.
a The binding abilities of MW05 and MW07 to SARS-CoV-2 RBD recombinant protein were assessed by ELISA. b, c The abilities of MW05 and MW07 to block SARS-CoV-2 RBD interaction with ACE2 were evaluated by competition ELISA. d The binding of MW05 and MW07 to SARS-CoV-2 S protein expressed on HEK293 cells was measured by FACS. e The dissociation constants (Kd) of MW05 and MW07 to SARS-CoV-2 S1 recombinant protein were measured using a BIAcore S200 system. f The cross-reactivities of MW05 and MW07 to SARS-CoV-CoV-2, SARS-CoV, and MERS-CoV recombinant S1 subunit of spike proteins (S1) were tested by ELISA. g The binding of MW05 and MW07 to RBD recombinant proteins of SARS-CoV-2-mutated strains.
Fig. 2
Fig. 2. Neutralizing activities of MW05 and MW07.
a, b SARS-CoV-2 pseudovirus neutralizing activities of MW05 and MW07 were evaluated on Huh7 cells. Fifty percent neutralization titer (NT50) was calculated by fitting the luciferase activities from serially diluted antibodies to a sigmoidal dose–response curve. The average ± SD from two independent experiments with technical duplicates is shown. c, d SARS-CoV-2 authentic virus-neutralizing activities of MW05 and MW07 were evaluated using Vero E6 cells. One hundred percent neutralization titer (NT100) was labeled accordingly.
Fig. 3
Fig. 3. Crosslinking of Fc and FcγR contributing to ADE activities of MW05.
a, b ADE activities of MW05 and MW07 were assessed using SARS-CoV-2 pseudovirus. Pseudoviruses pre-incubated with serially diluted mAb mixtures were added to Raji, THP-1, and K562 cells to evaluate their ability to enhance infection. RPMI 1640 media containing 10% FBS was used as a negative control. c The expression level of FcγRs on Raji, THP-1, and K562 cells were checked by FACS. All cells except debris were gated and analyzed based on FSC-A/SSC-A plot. d ADE activities of MW05 on Raji cells pre-treated with media or 400 µg/ml irrelevant hIgG1 were assessed using SARS-CoV-2 pseudovirus. Statistical significance was calculated via unpaired two-tailed t-test. *P < 0.05. e ADE activities of MW05 pre-incubated with media or 80 µg/ml FcγRIA were assessed on Raji cells using SARS-CoV-2 pseudovirus. Statistical significance was calculated via unpaired two-tailed t-test. *P < 0.05. f The ADE activities of MW05 and MW05/LALA on Raji cells were compared using SARS-CoV-2 pseudovirus. Statistical significance was calculated via unpaired two-tailed t-test. *P < 0.05. g The pseudovirus neutralizing activities of MW05 and MW05/LALA on Huh7 cells were measured. The average ± SD from two independent experiments with technical duplicates is shown.
Fig. 4
Fig. 4. Prophylactic and therapeutic effects of MW05/LALA.
a A schematic of the experimental in vivo set up. Nine rhesus monkeys were divided into pre-challenge (prophylactic), post-challenge (therapeutic), and control groups with three animals in each group. Before virus challenge, the monkeys in the pre-challenge group were injected intravenously with a single dose of 20 mg/kg MW05/LALA. One day later, all monkeys were challenged with 1 × 105 TCID50 SARS-CoV-2 via intratracheal intubation. A single dose of 40 mg/kg MW05/LALA was administered to each animal in the post-challenge group on day 1 post-challenge. Monkeys in the control group were given 20 mg/kg irrelevant hIgG1 one day before virus challenge. b Viral titers of oropharyngeal swabs at the indicated time points were evaluated using qRT-PCR. Data are average values from three monkeys (n = 3) for the first 5 days, from two monkeys (n = 2) for 6 dpi, and from one monkey (n = 1) for 7 dpi. The dotted line for limit of detection (200 copies/ml) is labeled. Statistical significance was calculated via unpaired two-tailed t-test. P values at different time points are labeled. c Viral titer of rectal swabs at the indicated time points were evaluated by qRT-PCR. C indicates the control group, PA the pre-challenge group, and AC the post-challenge group. The dotted line for limit of detection (200 copies/ml) is labeled. d Histopathology and immunohistochemical examination of lung tissues from pre-challenge, post-challenge, and control monkeys. Two biological replicates were performed. e Immunofluorescence analysis of SARS-CoV-2 protein expression in lung tissues from pre-challenge, post-challenge, and control monkeys. Four fields were checked for each group. The average ± SD of n = 4 from two independent experiments is shown. Two biological replicates were performed. f Viral load analysis of trachea, bronchus, and lung tissues of experimental animals. L-Bronchus left bronchus, R-Bronchus right bronchus. The dotted line for limit of detection (103.5 copies/g) is labeled.
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