New therapy for prevention and treatment of COVID-19

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ExeVir Bio, and its scientific founders at Belgium’s VIB, Flanders’ leading life sciences institute, have published a pre-print paper by De Cae et al., entitled “Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that bind a conserved membrane-proximal epitope of the spike.” 

Nearly all SARS-CoV-2 neutralizing antibodies used in the clinic show substantial loss of potency against the currently-circulating variants. The pre-print details a novel, highly potent, anti-S2 camelid single-domain antibody, discovered at the VIB-UGent Center for Medical Biotechnology, which was developed as a candidate drug molecule by ExeVir Bio as XVR013. 

It targets a conserved region in the spike S2 subunit that is essential for viral entry. It neutralizes all previous and current variants of concern and the currently most frequently circulating variants, including XBB, XBB.1.5, BQ.1.1 and BF.7. 

These single-domain antibodies bypass the highly immunogenic spots on the S1 part of the COVID-19 virus, which were the targets of all first-generation anti-SARS-CoV-2 antibodies in the clinic. In addition, the anti-S2 single domain antibodies directly neutralize the virus without relying on the patient’s own immune system, potentially providing protection for immunocompromised patients who typically do not, or only poorly, respond to COVID-19 vaccines. 

Llamas and camelids

The antibodies, discovered in llamas and other camelids, are smaller, more precise, and more stable than regular human antibodies. 

The ‘nanobodies’ produced by camelids are about a quarter of the size of human antibodies, and their simple structure allows them to be manufactured easily. More importantly, they are able to bind to very small and specific antigens in the invading organism that are inaccessible to regular antibodies.

Exevir Bio’s XVR013 preventing fusion

It’s the S2 subunit of the SARS-CoV-2 spike that mediates membrane fusion, an essential step during virus entry. XVR013 prevents the membrane fusion, and protects against SARS-CoV-2 infection in vitro and in an in vivo model.

ExeVir Bio’s COVID-19 pipeline includes XVR012, a combination product of the S2-targeting single-domain antibody-based XVR013 reported in the pre-print paper, and XVR014, a bispecific single-domain-based antibody construct that targets two conserved epitopes in the S1 subunit. XVR012 has demonstrated very high neutralization activity against all previous and current variants of concern and the currently most frequently circulating variants, and is advancing towards clinical trials for COVID-19. 

‘Pandemic isn’t over’ according to ExeVir Bio’s CEO

Torsten Mummenbrauer, CEO of ExeVir Bio, said: “The pandemic isn’t over; it is an ongoing challenge for immunocompromised patients, who total around 3% of the world population and remain at high risk of severe COVID-19 disease despite availability of current vaccines. We are therefore delighted to share our positive results in this pre-print paper with our VIB colleagues. 

“It highlights XVR013’s unique and powerful mode of action targeted to a highly conserved epitope of the coronavirus spike protein. This is but one asset in our arsenal of multiple epitope binders which offer the potential of multi-specific binders to the spike protein in one molecule or as a cocktail. XVR013 is a super potent molecule with a single digit nanomolar IC50 against virtually all circulating known variants. It could add an additional layer of protection for the most vulnerable in our population who are unable to build an adequate immune response with current vaccines.” 

COVID weak spot

Bert Schepens of VIB, said: “As there is currently a strong need for antibodies that work against the newest omicron variants, we think it is useful to rapidly communicate to our scientific colleagues about the discovery that targeting this novel membrane-proximal S2 epitope can yield such strong neutralization of SARS-CoV-2. We will be submitting a comprehensive paper for peer review soon. 

“As researchers, it is very motivating that ExeVir, who we have been working closely with, is finalizing the preclinical package to move into the clinic. Together we are enabling great strides towards bringing a long-lasting biologic to treat and protect immuno-compromised and elderly people. Our research, part of which is pre-printed today, has unveiled weak spots in the SARS-CoV-2 spike; a true Achilles’ heel that requires spears with a small tip to reach them well, in the form of our new single domain antibodies.”

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