Cell Discovery: "Lock Up" Omicron! Chinese scientists have developed bispecific antibodies that can target all new crown variants to prevent and treat both

Recently, Chinese scientists published a paper in the journal Cell Discovery [1], proposing a new bispecific antibody that can effectively bind to 16 new coronavirus variants tested, including the widely circulating BA.
2 and BA.
5
.
The corresponding authors of the paper are Zhao Jincun, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Liu Zheng, Cryo-EM Center, Southern University of Science and Technology, Dou Changlin, Boan Biotechnology, and Wang Lan
, National Institute of Food and Drug Control.

Thesis title map

In order to obtain antibodies with wider effectiveness, the researchers used RBD or S proteins of multiple variants such as β, γ, Kappa, and Delta to conduct 4-5 rounds of immunization of humanized mice, extract antibodies from them and establish corresponding phage libraries
.

After immunoscreening, a total of 177 meaningful single-stranded variable fragments (ScFvs) were obtained and their blocking activity
against ACE2 was tested.

177 ScFvs blocking activity against ACE2

The researchers also converted ScFvs into IgG1 antibodies, conducted neutralization experiments with pseudoviruses, and finally selected four strong "candidates", BA7054, BA7208, BA7134 and BA7125
.

Of the 19 coronavirus variants involved, Lota, Eta, and AZ.
5 have only one mutation, RBD E484K, so they are no longer tested
separately.

Mutations of all variants included in the experiment

For the remaining 16 variants and the original D614G strain, BA7208 is only inactive against Mu, BA7125 is powerless against Omicron, and BA7054 and BA7134 are equally unable to cope with all variants
.

IC50 for 16 variants, candidate antibody

Interestingly, the researchers examined the binding ability of these antibodies to different RBDs and found that BA7208 and BA7125 are likely to have completely different binding epitopes, which means that their binding should complement each other and combine
strongly.

So the researchers constructed BA7208/7125 bispecific antibodies
through knobs into holes.

Sure enough, BA7208/7125 showed effective neutralizing activity for all variants, binding to BA.
1 RBD 3.
7 times that of BA7208 and 3.
6 times
that of Mu RBD than BA7125.

Cryo-EM analysis showed that BA7208 and BA7125 had different binding epitopes with RBD

So can BA7208/7125 play a preventive and therapeutic role?

Experimental results in hACE2 transgenic mice showed that for Omicron BA.
1 and BA.
2, intraperitoneal injection of BA7208/7125 or BA7208 before and after exposure had few or only mild symptoms, the virus titers detected in the lungs were significantly reduced, and the infectious virus was below the detection limit (LOD).

Experimental methods and viral titer after 1 day of infection

Considering that the respiratory tract is currently the target of the new coronavirus, the researchers also tested the effect of
respiratory administration.
The results showed that nasal administration and aerosol administration were effective in preventing infection in mice, and no live virus particles
were detected in the treatment group.

Respiratory administration can also achieve good results

In addition, the half-lives of BA7208, BA7125 and BA7208/7125 are also quite long, reaching ~94 hours, 128 hours and 100 hours
, respectively.

Unfortunately, this study failed to test
against the recently circulating XBB and BQ variants.
However, with the method of rapid screening, I believe that scientists will also be able to come up with effective solutions
for emerging mutations as soon as possible.

Resources:

[1] Wang Yan, Yan, A.
, Song, D.
et al.
The antibody BA7208/7125 can effectively neutralize SARS-CoV-2 variants, including Omicron BA.
1-BA.
5.
Cell Dikoff 9,3 (2023).
https://doi.
org/10.
1038/s41421-022-00509-9