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Source: COVID-19 News  Nov 29, 2020  3 years, 4 months, 2 weeks, 1 hour, 1 minute ago

BREAKING! COVID-19 News: Researchers Discover New Monoclonal Antibody HB27 That Is Highly Potent Against SARS-CoV-2 In A Variety Of Ways

BREAKING! COVID-19 News: Researchers Discover New Monoclonal Antibody HB27 That Is Highly Potent Against SARS-CoV-2 In A Variety Of Ways
Source: COVID-19 News  Nov 29, 2020  3 years, 4 months, 2 weeks, 1 hour, 1 minute ago
COVID-19 News: A new Chinese study led by researchers from the Chinese Academy of Sciences-Beijing along with a variety of other Chinese research institutions and biotech companies have discovered a new promising monoclonal antibody called HB27 that was found to have two distinct mechanisms of action inhibiting the virus-host cell interaction and subsequent infection and because of this unique mechanism, the SARS-CoV-02 coronavirus was most unlikely to develop antibody resistant strains to it.


 
The new monoclonal antibody HB27 provides both effective prophylactic and therapeutic results.
 
Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by the SARS-CoV-2 virus. Halting these steps can cure COVID-19.
 
The study team has identified and characterized a potent human monoclonal antibody, HB27,  that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10-fold of effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the RBD, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19.
 
The study results are published on a preprint server and are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.11.24.393629v1
 
SARS-CoV-2, the causative pathogen of COVID-19 has infected over 62.2 million individuals worldwide and caused over 1.45 million deaths.
 
While researchers continue to probe for effective pharmaceutical interventions against SARS-CoV-2, this new study reports a very promising monoclonal antibody, HB27, that appears to have two distinct mechanisms of action inhibiting the virus-host cell interaction and subsequent infection. This could therefore be a "promising candidate for immuno-therapies against COVID-19," says study team.
 
The SARS-CoV-2 coronavirus gains entry to host cells via its spike protein, a two-subunit protein that engages the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane. This exposes the protein to host cell proteases, which then triggers a massive change in conformation from pre-fusion to post-fusion stages. This leads to the fusion of the viral and host cell membranes to allow the virus to enter the cytosol of the host cell.
 
The spike or S protein exists as a trimer in nature, but has a receptor-accessible and -inaccessible state, wherein the RBDs are open (one or more) or closed (all). These states are possible because of the hinge-like movement at the RBD mediated by complex protein-protein interactions with host cells.
 
Although numerous neutralizing antibodies (NAb) have been identified, some, l ike CR3022, fail to prevent infection with the SARS-CoV-2 coronavirus. This is probably due to the flexible conformation of the neutralizing epitopes, which enable the infection to proceed despite the presence of NAbs. On the other hand, other antibodies that are being discovered which appear to neutralize the virus, do so without blocking the ACE2 receptor.
 
Currently, several cross-reactive mAbs, including CR3022, H014 and S309, screened from convalescent SARS patients or via immunization using SARS-CoV RBD, show distinct neutralizing activities against SARS-CoV-2. Structural analysis reveals that all these mAbs recognize conserved patches either distal from or proximal to the edge of the RBM, but not in the RBM. Interestingly, the corresponding epitope in both open and closed RBDs is accessible to S309, but accessible to H014 only in open RBDs, and can only be accessed by CR3022 when at least two RBDs are in the open conformation. The stoichiometric binding of Fab to the S trimer might correlate with the neutralizing activities, probably explaining the weak neutralization efficiency observed for CR3022. HB27 targets the less conserved edge of the RBM core with a full occupancy for all RBDs. This structural observation supports the observed specificity of HB27 for SARS-CoV-2 and its highly potent neutralization of SARS-CoV-2. https://www.nature.com/articles/s41586-020-2349-y
 
https://pubmed.ncbi.nlm.nih.gov/32245784/
 
This research aimed at understanding the mechanism of neutralization of SARS-CoV-2 by a newly identified monoclonal antibody. The NAb was identified from an antibody library obtained from mice immunized with recombinant SARS-CoV-2 RBD, and was a chimeric one, named MHB27.
 
As this had powerful binding and neutralizing activity against the virus, a humanized form was generated, called HB27.
 
Interestingly both the IgG and HB27 forms of this antibody bind to the RBD of SARS-CoV-2 at low and very low nanomolar affinity, but not to the RBD of the earlier SARS-CoV and MERS-CoV.
 
Its half-maximal inhibitory concentration (IC50) is also in the very low nanomolar range. It was further tested against the wildtype virus in a plaque reduction neutralization test (PRNT), and showed a nanomolar neutralizing concentration.
 
It was found that in susceptible mice, a single dose of HB27 was able to prevent infection with the mouse-adapted SARS-CoV-2, MASCp6, when given either before or after exposure to the virus, with the viral load being reduced by over 99.9% in lungs and trachea.

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The study team then tested the ability of HB27 to prevent SARS-CoV-2 infection in a mouse model adapted to express human ACE2 receptors. They found, again, that this molecule was able to reduce viral loads in the lungs and trachea at 5 days following challenge with the virus, if the antibody was administered either before or after exposure. However, preventive dosing was more powerful, with the lung viral levels being reduced over a thousand-fold.
 
It was found that the low levels of viral RNA seen in the lungs and trachea at days 3 and 5 post-infection may be because of the intranasal challenge, where IgG antibodies cannot bind to the virus directly, allowing it to enter the lungs and trachea. However, no infectious virions could be found in these tissues at these time points, as shown by a PRNT.
 
The control mice showed signs of moderate interstitial pneumonia while the HB27-treated mice had minimal or very mild inflammatory infiltrates, showing the ability of the NAb to prevent or treat the infection following exposure to SARS-CoV-2.
 
The study team also tested the antibody's toxicity by giving it at a single high dose, intravenously, at 10 times the estimated effective dose in humans, to the non-human primate (NHP) model, rhesus macaques. Of the four tested animals, none showed any signs of toxicity, and the half-life was found to be about 10 days, on average. Interestingly, this period is probably adequate for its therapeutic efficacy, since at 5 days, there was a 99.9% reduction in viral load. The results indicated its safety in NHPs.
 
The team then investigated the mechanism of neutralization, and found that HB27 completely prevented soluble ACE2-trimeric S interaction. Not only so, already bound soluble ACE2 was replaced by HB27, because the latter has a thousand times stronger binding affinity to the spike protein.
 
However, much higher concentrations are required to neutralize this binding when the ACE2 receptor is on the cell surface, perhaps because it is dimeric.
 
Upon testing by real-time polymerase chain reaction reverse transcription (RT-PCR), the researchers confirmed that cells treated with HB27 before and after virus attachment at below-micromolar concentrations could displace already bound virions at a concentration of about 2.5 nM.
 
Also, the study team found that HB27 also inhibits fusion of viral and host cell membranes. They used a spike-mediated cell-cell fusion system with a cell line that expresses SARS-CoV-2 and a GFP tag as the effector cells that propagate infection, and Vero E6 cells as the target cells that suffer infection. They found that when both cell types were incubated, hundreds of cells fused to form a large syncytial cell. However, the pres