Novel antibody candidate shows potent binding to diverse SARS-CoV-2 variant mutations

Reviewed by Emily Henderson, B.Sc.Sep 25 2021

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), an academic-industry, non-profit collaborative research effort, performed the blinded analysis, confirming that TB202-3 completely blocked SARS-CoV-2 spike protein from binding to human ACE2. The results were published in Science 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 used high-throughput surface plasmon resonance analysis and cryo-EM structural determination, sorting antibodies that react within the SARS-CoV-2 receptor binding domain (RBD) into 7 different "communities" (RBD-1 through RBD-7). Antibodies in the RBD-4 community bind to the outer face of the RBD and can do so in either the "up" or "down" RBD conformation. Monoclonal antibodies that target RBD-4 bind towards the outer edge of the receptor binding motif and can block binding to ACE2 on human cells, the entry point for the virus. Select properties of RBD-4 antibodies indicate they may have increased potency against the virus.

COVID-19 continues to evolve, spurring additional mutations and viral strains. TB202-3 binds to a majority of known mutations, with the exception of the L452R mutation present in the Delta and Epsilon variants. Twist developed a new VHH single domain antibody, TB339-031, with a similar structure and potency to TB202-3, which also binds and neutralizes the Delta and Epsilon variants, that is now advancing through late-stage discovery and validation testing.

SARS-CoV-2 is an RNA virus. Viruses survive by replicating in their target host, in the case of SARS-CoV-2 this is humans. During the replication process, there is often an error that results in the copying process, which is the definition of a mutation. Most of the time, mutations do not make a difference in the virus. Sometimes, however, a mutation makes the virus more transmissible or more deadly. Depending on the location of the mutation, it may reduce the efficacy of therapeutic antibodies that bind at the mutated location. Therapeutic antibodies that bind to the virus in a place that is not impacted by mutations can treat the widest range of COVID-19 variant strains successfully.

"Applying our proprietary drug discovery and optimization platform, we identified and advanced TB202-3 through preclinical studies and submitted this antibody to CoVIC for comprehensive testing in comparison to others," said Emily M. Leproust, Ph.D., CEO and co-founder of Twist Bioscience. "With the continuous emergence of variant strains of SARS-CoV-2, antibodies that bind to regions away from the areas of frequent mutation will be critical to the ongoing global response. While broad-spectrum is a term used most often in relation to antibiotics, it applies here to Twist's antibodies, as they show efficacy in neutralizing a wide range of SARS-CoV-2 variants."

"These comprehensive results show that TB202-3 may be more resistant to receptor-driven selection pressure and Twist antibodies may work therapeutically against emerging SARS-CoV-2 variants," continued Dr. Leproust. "In addition to binding location and neutralization efficacy, due to its small size, selectivity and preclinical efficacy, Twist antibodies may offer an advantage over traditional antibodies as they can be an integral component of a bispecific antibody or can be used with other antibodies. COVID-19 infection continues to spread throughout the world, and new therapeutic options will be required to treat emerging variants."

Previous studies of TB202-3, a single domain VHH "nanobody", demonstrated protection against weight loss, a key indicator of disease severity, at the lowest dose of 1 mg/kg in a preclinical hamster challenge model. Conducted at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), immunosuppressed animals were given 1, 5 or 10 mg/kg of each of the Twist antibodies and were assessed for weight loss. Animals treated with all doses of TB202-3 were protected against weight loss, whereas control animals lost a mean of 11.7% of their body weight. Validation and late-stage discovery studies continue for TB339-031.