SARS-CoV-2 Antibodies For COVID-19 Therapeutics Properly Identified By Caltech Scientist In The First Ever Proper Detailed Antibody Study So Far
: A new research recently conducted by scientist from California Institute of Technology (Caltech) which can be described as the first properly detailed SARS-CoV-2 antibody study ever conducted so far has properly identified a series of antibodies that can actually be effective as therapeutics against the COVID-19 disease.
The research findings were published in the journal: Nature https://www.nature.com/articles/s41586-020-2852-1
The study team has characterized a multitude of antibodies to the virus that causes COVID-19 and identified those that are most effective at neutralizing the virus.
Antibodies are proteins produced by the body in response to infection. Ultimately, it is hoped that potent antibodies like the ones described in this study can be given as treatment or prevention for COVID-19.
The research was led by Dr Christopher Barnes, senior postdoctoral fellow in Biology and Biological Engineering and Howard Hughes Medical Institute Hanna Gray Fellow.
The detailed study was conducted in the laboratory of Dr Pamela Björkman, the David Baltimore Professor of Biology and Bioengineering, and utilized Caltech's cryo-electron microscopy and protein expression facilities.
It must be noted that an individual can produce hundreds or thousands of different variants of antibodies against any pathogen or foreign substance, including viruses, leading to a wide diversity of antibodies in a single person and in the human population.
However only some of these antibodies are better at blocking a virus than others. Think of the numerous ways that a boxer can engage with an opponent: a punch to the face is more likely to knock out the opponent than a glancing punch to the leg. When an antibody effectively renders a virus unable to infect cells ie knocking it out, so to speak it is called "neutralizing."
Dr Barnes told Thailand Medical News, "An ideal treatment would be a combination or 'cocktail' of different antibodies that attack the virus in different, but still effective, ways
. With a combination of antibodies, it's less likely that a virus can evolve to escape them."
(It should be noted that certain pharmaceutical giants that started research and development on single antibody drugs at the beginning of the COVID-19 pandemic are now trying to unscrupulously getting regulatory approvals to push these in the market after making a huge stockpile despite knowing that there are potential problems associated with these single use antibody protocols) as emerging reports are showing)
From the beginning of the SARS-CoV-2 Dr Barnes and Dr Björkman have been studying the antibodies of individuals who have recovered from the disease, in search of those that are the most neutralizing. They utilize structural biology techniques to image the interactions between SARS-CoV-2 proteins and individual antibodies.
For some background knowledge: every individual SARS-CoV-2 virus has large, spiky protein structures on its surface that, in cross-section, make it resemble a cartoon sun with rays ("corona,"
the Latin word for "crown," is also the scientific term for the wisps of plasma that spread outward from the sun). At the tip of each of these so-called spike proteins is a tripod of protein regions, each called a receptor-binding domain (RBD). An RBD can flip from a "down" position on the spike to an "up" position, which reveals a hidden site called the receptor-binding motif.
The binding target where SARS-CoV-2 latches onto a human cell is called the angiotensin-converting enzyme 2 (ACE2) receptor. Normally, this cell-surface receptor functions to regulate blood pressure, but SARS-CoV-2 has co-opted it as a means to gain entry into cells in the lungs and other organs. The receptor-binding motif acts as a grappling hook, grabbing onto the ACE2 receptor.
Upon attaching to a cell, the virus can fuse with the cell's membrane and invade the cell, turning the infected cell into a factory to make new viruses. An antibody that could block the receptor-binding motif or prevent fusion using a different mechanism would thus be very effective in preventing the virus from entering cells.
Dr Barnes and his team aimed to discover how antibodies interact with the spike RBDs, in both their open (RBD "up") and closed (RBD "down") conformations.
The study team collaborated with the laboratory of Dr Michel Nussenzweig at The Rockefeller University to study individual antibodies (so-called monoclonal antibodies) collected from individuals who had recovered from COVID-19.
Utilizing the collection of monoclonal antibodies discovered at Rockefeller by their collaborators, the Caltech team used microscopy techniques that are able to image proteins with single-atom resolution to discover precisely where the various antibodies bound to SARS-CoV-2 spike proteins.
Dr Barnes then worked with Dr Björkman lab graduate students and microscopists from other Caltech labs to quickly solve eight new structures that show how neutralizing antibodies against SARS-CoV-2 block the RBDs on spike proteins to prevent the virus from entering cells.
The team found a variety of recognition modes: some antibodies bound spikes with three "up" RBDs, some bound to both "up" and "down" RBDs on the same spike, and some bound only to "down" RBDs.
Based on analyses of these structures, the study team proposed four classes of anti-RBD antibodies based on whether they bound "up," "down," or both RBD conformations; whether their binding overlapped with the ACE2 binding site; and other criteria such as their potencies and derivation from particular antibody gene families. From these structures, the researchers proposed different mechanisms for virus neutralization.
Schema illustrating the binding regions for the different classes of SARS-CoV-2 neutralizing antibodies that target the RBD (gray surface). Credit: C. Barnes (the identified antibodies are represented by their codes for example C102 in Class 1)
Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to “up” RBDs, (2) ACE2-blocking hNAbs that bind both “up” and “down” RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize “up” and “down” RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only “up” RBDs.
Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent “down” RBDs, thereby locking the spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.
As an example, the team found a particularly interesting antibody that binds simultaneously to adjacent RBDs, clamping all three RBDs into "down" positions that would lock the spike into a conformation that cannot open to expose the "grappling hook."
Dr Björkman added, "First, I want to say how happy I am to see the high level of cooperation and collaboration within our lab and other Caltech labs to investigate these antibodies. We think these structures will facilitate choices of the most effective combinations of monoclonal antibodies to be used for treatment of COVID-19 or to prevent viral infection of people in high-risk groups."
He added, "In addition knowing the structures of these antibodies can facilitate the design of antibodies that bind more tightly to RBDs, thereby increasing their efficacy and lowering the dose needed for treatment. And finally, mapping where these antibodies bind is necessary information for structure-based design of vaccines to elicit the most potent classes of neutralizing antibodies."
Dr Barnes said, "Our work provides the basis for future studies into patient-derived neutralizing antibodies from recovered COVID-19 individuals, in collaboration with the team at Rockefeller, we are now working on characterizing temporal changes in antibodies isolated from the same donors. We hope that this future work will aid in our understanding of the potential for long-term protection against SARS-CoV-2 infection."
The details of the identified antibodies can be found via link on the article linking to the actual published study.
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