From α to Epsilon: Which is the more effective SARS-CoV-2 spike protein Spike antibody?

 Scientists from the LA JOLLA Institute of Immunology (LJI) have released a detailed map of the binding of human antibodies to SARS-CoV-2.

These findings drove COVID-19 research in three key areas:

• Hundreds of antibodies provided by more than 50 different organizations around the world are classified and mapped

  
  

• The researchers described the neutralization strength or potency of each antibody, and the likelihood of each antibody providing protection against virus mutations

  
  

• Antibodies with similar binding sites on Spike are classified as "populations"

  
  

"We can map the S spike protein and understand which antibodies bind to which sites

In fact, the researchers discovered three different sets of antibodies that can resist mutations in the SARS-CoV-2 spike protein

"We now have a framework for choosing a durable antibody cocktail for COVID-19 treatment," Sapphire said

Collect powerful antibodies

CoVIC includes 370 antibodies from 59 different development projects, covering a wide range: from academic laboratories, small biotech companies to large international pharmaceutical companies

"CoVIC was established to analyze a large number of monoclonal antibody cohorts on an equal basis," said Dr.

The co-first author of the study and LJI postdoctoral doctor Li Haoyang (transliteration) added: "CoVIC contributors used different strategies to discover these antibodies

Systematic research on a large number of antibody libraries is a difficult task

This global collaboration, coordinated by the project leader, Dr.

Looking for an antibody "all star"

There is a key site on Spike called the receptor binding domain (RBD), which is like a protruding rock.
Scientists in the Sapphire laboratory use mountaineering terms to describe its structure
.
The inner and outer facades of the RBD are connected by a central "valley"
.
Next to it is a "mountain peak" and a "Pingdingshan" tower
.
Head over Pingdingshan and look down at the "cliff" below
.

By observing where the antibody binds to RBD, researchers divide potential antibodies into different "groups
.
"

"A population is a group of antibodies that have the same behavior, which means that they can/cannot bind to the Spike protein at the same time as other antibodies," Schendel said
.

Antibodies know how to recognize a specific virus structure, they see the target and grab it to prevent the virus from infecting the cell
.
But what if their target is mutated, and the environment recognized by the antibody suddenly looks a bit different?

"The mutation may be discovered a few weeks after it appears-this is an endless catch-up game," Sapphire said
.
"We need to know which antibodies in our antibody library can continue to exist in the coming months and years
.
"

Researchers need to find antibodies that target "conserved" sites in RBD
.
These conserved sites are very important to the life cycle of the virus.
If they mutate, the virus may not be able to function
.
The most effective antibodies are those directed against these conserved sites
.

In order to find durable antibodies, Hastie produced a series of Spike proteins with different point mutations
.
These structures reflect those seen in variants such as Alpha, Gamma, and Delta
.

For some antibodies, one or two mutations in Spike are enough to make them ignore the target
.
"We can see which antibody was escaped by which mutation," Hastie said
.
"Knowing this is really useful, because we can see these mutations in the mutant strains we worry about in the real world
.
"

For example, scientists know that the Beta variant has a mutation site called K417N
.
"We can now identify antibodies that are affected by mutations at this site, but we can also identify antibodies that still work at other sites in the Spike protein of the Beta variant," Hastie said
.

Schendel and Hastie worked closely with Dr.
Daniel Bedinger of Carterra, a Salt Lake City biotechnology company, which developed the LSA instrument and epitope classification analysis software, which was critical to the analysis
.
Bedinger created a network diagram that allows scientists to compare how more than 250 antibodies bind to SARS-CoV-2
.
These network diagrams show which antibodies will bind in the presence of each other-in other words, which antibodies will "get along" with other antibodies
.
The goal of the researchers is to find the best antibodies from different groups and combine them into an all-star team to eliminate the virus
.

"Carterra voluntarily does this work on a free basis," Hastie said
.
"I want to pay tribute to Daniel and Carterra
.
"

At the same time, Li led the structural research
.
The team used LJI's cryo-electron microscope equipment to image the RBD-bound antibody structure
.
Through his work, Li has assembled a "hit map" of antibodies against viruses
.
This figure shows that there are 7 antibody populations against variable or conserved regions on Spike
.
In addition, unlike the structure of the Fab version used in traditional research, this work uses intact IgG to simulate and reveal how these antibodies protect cells from infection
.
Some IgGs target the S spike protein of SARS-CoV-2 in a  bivalent-binding manner, which increases the affinity and potency of the antibody, while others tend to cross-linking S Spike protein to inactivate virus particles
.
"This is new information for the scientific community and a good example of why we need more detailed antibody analysis," Li said
.

Not only did Li lead the work of structural biology, he also made sure that these structural diagrams were accessible-whether in the paper or storing structural information in a public database so that other scientists could access the data
.
Schendel said: "Hao Yang is the driving force behind obtaining these structural drawings
.
" "His efforts are true heroes
.
"

Finally, the researchers assembled a fascinating library of color-coded antibodies
.
This work shows which antibodies can be used in combination in monoclonal antibody therapy
.
This study also shows: what antibodies will be produced by future vaccines to maximize protection from SARS-CoV-2 mutations
.

Science with global impact

Three of the populations proved to be able to identify various mutations in RBD and are particularly useful
.
"These antibodies are indeed good candidates for monoclonal antibody therapy," Hastie said
.
"If you're making an antibody cocktail, you want to have at least one antibody in it, because they may remain effective against most variants
.
"

Some COVID-19 patients can already get a cocktail of monoclonal antibodies
.
As Schendel explained, the current cocktail has limitations: it works best before severe symptoms appear, and it must be administered intravenously under clinical conditions
.

Through this new research, CoVIC is one step closer to the development of more effective antibody therapies, which may protect against SARS-CoV-2 mutations
.
Schendel said that more effective antibody therapies may also be effective at lower doses, which makes them an option in countries where healthcare is harder to obtain
.
She hopes that one day, monoclonal antibody therapy can be used as a simple injection
.
: "In the United States and around the world, a large number of people are not vaccinated
.
" "If we can design better monoclonal antibody therapies, there will be therapies available to them
.
"

The CoVIC team is currently conducting animal protection research with partners
.
Other CoVIC researchers are working to understand how neutralizing antibodies coordinate with the immune system's response
.