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Twist Bioscience Corporation today reported that its internally-discovered antibody candidate TB202-3 (CoVIC-094), demonstrated potent binding to diverse SARS-CoV-2 variant mutations, including strains with the E484K, N501Y, D614G, Y453F and K417N mutations in pseudovirus assays, indicating this therapeutic antibody may be effective in treating many strains of COVID-19.
The Coronavirus Immunotherapy Consortium (CoVIC) is an academic-industry-non-profit collaboration research group, conducted the analysis blinded, and confirmed that TB202-3 was able to completely block SARS’s CoV-2 Spike protein in its binding with the human ACE2. The findings were reported by Science today. the journal Science The journal today.today
CoVIC analyzed over 250 therapeutic antibodies from 46 groups, in an effort to identify the most effective treatment approaches for patients with COVID-19. TB202-3 binds to a specific area (RBD-4) of the SARS-CoV-2 spike protein that has not been impacted by most viral mutations. This makes it an important and viable candidate for clinical testing in combination with other antibody therapeutics.”Erica Ollmann Saphire PhD, Director and Professor, La Jolla Institute for Immunology
CoVIC analyzed over 250 therapeutic antibodies from 46 groups, in an effort to identify the most effective treatment approaches for patients with COVID-19. TB202-3 binds to a specific area (RBD-4) of the SARS-CoV-2 spike protein that has not been impacted by most viral mutations. This makes it an important and viable candidate for clinical testing in combination with other antibody therapeutics.”
Erica Ollmann Saphire PhD, Director and Professor, La Jolla Institute for Immunology
CoVIC utilized high-throughput surface plasmon resonance analysis as well as cryo-EM structural determination to determine the sorting of antibodies that react with the receptor binding domain (RBD) into seven different “communities” (RBD-1 up to RBD-7). Antibodies belonging to the RBD-4 community are able to bind to the outside of RBD and are able to do this by either “up” as well as the “down” RBD conformation. Monoclonal antibodies targeting RBD-4 attach to the outside edges of the motif for receptors. They may inhibit binding to ACE2 on human cells, which is the entrance point to the virus. Specific properties of the RBD-4 antibodies suggest that they be more potent against the virus.
COVID-19 is constantly evolving leading to new mutations and virus strains. The TB202-3 antibody binds to the majority of mutations that are known however, it is not able to bind to the L452R mutation, which is present on both the Delta as well as Epsilon variants. Twist has developed a novel VHH monodomain antibody TB339-331 that has a similar structure and the same potency as TB202-3. It can also neutralize those of the Delta as well as Epsilon variants. It is now in the final stages of research and validation tests.
SARS-CoV-2, an RNA virus, is a threat to human health. Viruses reproduce in their intended hosts, in the case of SARS CoV-2, that is humans. In the process of replication there’s often an error that causes the process of copying. This could be the reason for mutation. The majority of the time mutations are not able to affect the virus. However, sometimes mutations can make the virus more transmissible , or more dangerous. Based on the site that the change occurs, it can decrease the effectiveness for the therapeutic antibody that attach to the affected location. Therapeutic antibodies that are able to bind to the virus in a location that isn’t affected by mutations may be effective in treating the broadest variety of COVID-19 variant strains effectively.
“Applying our own proprietary technology for optimizing and discovering drugs We identified and developed TB202-3 by conducting preclinical studies. We then the antibody was submitted to CoVIC for extensive testing with respect to other antibodies,” said Emily M. Leproust, Ph.D. co-founder and CEO of Twist Bioscience. “With the constant development of new strains of SARS, antibodies that are able to bind to regions that are not in the zones where mutations are frequent are crucial in the continuous global response. While the term “broad-spectrum” is typically used with regard to antibiotics but it also applies on Twist’s antibodies, since they are effective in neutralizing a broad range of variants of SARS-CoV-2.”
“These thorough results indicate that TB202-3 could be more resistant to selection pressure driven by receptors and that Twist antibodies could help in the fight against new SARS-CoV-2 variants” said Dr. Leproust. “In addition to binding site and neutralization efficiency due to its compact size, selectivity and preliminary effectiveness, Twist antibodies could be superior to traditional antibodies because they are an integral part of a bispecific antigen or may be utilized in conjunction alongside other antibodies. COVID-19 continues to spread all over the world and new treatment options will be needed to treat the newer variations.”
Previous studies of TB202-3 an individual Domain VHH “nanobody” showed the ability to prevent weight loss, which is a crucial measure of disease severity with the lowest dosage of just 1 mg/kg for a preliminary hamster-challenge model. The study was conducted by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) immune-suppressed animals received 1, 5, or 10 mg/kg one of the Twist antibodies and screened to determine if they had lost weight. Animals who received all doses of the TB202-3 antibody were protected from weight loss, whereas the control animals lost a median of 11.7 percent in bodyweight. The validation and late-stage research studies continue for TB339-011.
Hastie, K. M., et al. (2021) Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study. Science. doi.org/10.1126/science.abh2315.