23 November 2020 - - US-based synthetic biology and genomics company Twist Bioscience Corp. (NASDAQ: TWST) has released preclinical data for three of its proprietary antibodies against the S1 protein in SARS-CoV-2, the virus that causes COVID-19, the company said.

The data show that TB202-3 and TB202-63, both single domain VHH "nanobodies," protect against weight loss, a key indicator of disease severity, at the lowest dose of 1 mg/kg in a preclinical hamster challenge model.

In addition, TB181-36, an IgG antibody discovered through Twist's collaboration with Vanderbilt University Medical Center, was found to protect against weight loss at 5 mg/kg and 10 mg/kg.

Preclinical studies of TB202-63, TB202-3 and TB181-36 were 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 TB202-63 and TB202-3 were protected against weight loss, whereas control animals lost a mean of 11.7% of their body weight.

Animals treated with the higher two doses of TB181-36 were protected against weight loss.

TB202-63 and TB202-3 are single domain VHH "nanobody" candidates identified by Twist Biopharma, a division of Twist Bioscience, by screening its proprietary synthetic antibody discovery libraries each containing more than 10 bn single domain antibody sequences.

These antibodies potently neutralize SARS-CoV-2 live virus in vitro by binding the S1 receptor binding domain and directly blocking its binding to ACE2 receptors found in humans and other susceptible animals such as mink and cats.

TB181-36 is an IgG antibody based upon antibodies identified in individuals who recovered from COVID-19 in a collaborative research project with Vanderbilt University Medical Center researchers James E. Crowe, Jr and Robert Carnahan in the Vanderbilt Vaccine Center.

The intellectual property covering such antibodies was later licensed by Vanderbilt University to Twist Biopharma for use in product development.

Because the human immune system naturally generates a variety of antibodies against specific foreign invaders, including SARS-CoV-2, the virus that causes COVID-19, antibodies from recovered individuals have the potential to treat other people infected with the virus.

Twist Biopharma built a proprietary synthetic antibody discovery library based on these sequences to identify the antibodies, one of which is TB181-36, which also neutralizes live SARS-CoV-2 virus in vitro. 

Unlike its single domain leads that directly block ACE2 binding, this antibody binds a unique epitope on the N terminal domain of S1 and neutralizes the virus through an alternate mechanism.

Twist intends to explore opportunities for further development of all three antibodies both internally and potentially with partners.

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.

For over 50 years, USAMRIID has provided leading edge medical capabilities to deter and defend against current and emerging biological threat agents.

The Institute is the only laboratory in the Department of Defense equipped to safely study highly hazardous viruses requiring maximum containment at Biosafety Level 4.

Research conducted at USAMRIID leads to medical solutions vaccines, drugs, diagnostics, information, and training programs that benefit both military personnel and civilians.

Established in 1969, the Institute plays a key role as the lead military medical research laboratory for the Defense Threat Reduction Agency's Joint Science and Technology Office for Chemical and Biological Defense. USAMRIID is a subordinate laboratory of the US Army Medical Research and Development Command.