ExeVir Bio and its scientific founders at Belgium’s VIB have announced the publication of a preprint paper by De Cae et al., entitled “Ultrapotent SARS coronavirus-neutralising single-domain antibodies that bind a conserved membrane-proximal epitope of the spike”.
Nearly all SARS-CoV-2 neutralising antibodies that have been used in the clinic show substantial loss of potency against currently circulating variants. The bioRxiv preprint details a novel, highly potent, anti-S2 camelid single-domain antibody, discovered at the VIB-UGent Center for Medical Biotechnology, and developed as a candidate drug molecule by ExeVir as XVR013.
It targets a conserved region in the spike S2 subunit that is essential for viral entry. It neutralises 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 neutralise 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.
The S2 subunit of the SARS-CoV-2 spike mediates membrane fusion, an essential step during virus entry. XVR013 prevents this membrane fusion and potently protects against SARS-CoV-2 infection in vitro and in an in vivo model.
ExeVir’s COVID-19 pipeline includes XVR012, which is a combination product of the S2-targeting single-domain antibody-based XVR013 reported in the preprint paper, and XVR014, a bispecific single-domain-based antibody construct which targets two conserved epitopes in the S1 subunit, using an innovative design that will be reported in the future. XVR012 has demonstrated very high neutralisation 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.
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
Dr Torsten Mummenbrauer, CEO of ExeVir, said: “The pandemic isn’t over; it is an ongoing challenge for immunocompromised patients, who total around 3%1 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 preprint 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.”
Mummenbrauer continued: “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.”
Dr 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 neutralisation 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 finalising 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.”
The new S2-binding camelid single domain antibodies described in the bioRxiv preprint paper by Sieglinde De Cae were identified and characterised in the lab of Xavier Saelens by the team of Bert Schepens (VIB-UGent Center for Medical Biotechnology). A hybrid molecule based on these camelid single domain antibodies and a human antibody was designed and built in the lab of Nico Callewaert (also VIB-UGent Center for Medical Biotechnology).
The interaction between these single domain antibodies and the S2 protein was characterised by Inge Van Molle in the lab of Han Remaut (VIB-VUB Center for Structural Biology). Together these labs form VIB's pandemic drug development response team, which was assembled by the Center for Medical Biotechnology in January 2020. The pharmacodynamic and safety properties of candidate drug molecules based on these S2-binding single domain antibodies were extensively evaluated in vitro and in vivo by ExeVir Bio.