Therapy Areas: Respiratory
Twist Bioscience Internally-Discovered Single Domain Antibody TB202-3 Shows Potent Binding to Multiple Strains of SARS-CoV-2, Including Alpha, Beta, and Gamma Strains, in Preclinical Studies
24 September 2021 - - US-based synthetic biology and genomics company Twist Bioscience Corp's (NASDAQ: TWST) 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 company said.

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.

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 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.

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 US 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.

About 75 % of the antibodies in the blood are IgGs. IgGs are made up of two heavy protein chains and two light protein chains that must pair together and cooperate to specifically recognize a target, in this case the Spike Protein on SARS-CoV-2.

This specific targeting affords our immune systems "memory," allowing it to selectively and precisely eliminate pathogenic threats.

Target recognition by VHH single domains, on the other hand, requires just a single domain found on heavy chain only antibody.

With VHH-based antibodies able to exhibit pharmaceutically-relevant properties comparable to IgGs, they are a promising therapeutic with several advantages over their bulkier, more complex counterparts.

The small size of VHH antibodies means they can squeeze into spaces and bind or block to parts of molecules that would otherwise be inaccessible to human IgG antibodies.

They are also more thermally and chemically stable, making VHH-based therapeutics good candidates to address respiratory infections, administered by inhaler directly to the respiratory tract where the infection is concentrated.

In addition, the small size simplifies manufacturing of VHH antibodies.

In addition to SARS-CoV-2, Twist Biopharma discovers and develops IgG and VHH antibodies to numerous different targets for partners and internal development.

CoVIC is an academic-industry, non-profit collaborative research effort that brought together scientists from around the world and enabled them to share and evaluate candidate SARS-CoV-2 anti-S protein antibodies side-by-side in a blinded, multidisciplinary analysis.

Together, they are identifying ideal therapeutic combinations, the assays that best predict efficacy, and the features that provide protection.

Twist Bioscience is a synthetic biology and genomics company that has developed a disruptive DNA synthesis platform to industrialize the engineering of biology.

The core of the platform is a proprietary technology that pioneers a new method of manufacturing synthetic DNA by "writing" DNA on a silicon chip.

Twist is leveraging its unique technology to manufacture a broad range of synthetic DNA-based products, including synthetic genes, tools for next-generation sequencing preparation, and antibody libraries for drug discovery and development.

Twist said it is also pursuing longer-term opportunities in digital data storage in DNA and biologics drug discovery. Twist makes products for use across many industries including healthcare, industrial chemicals, agriculture and academic research.
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