Despite being founded just last June, Belgian biotech ExeVir is making serious headway in the race to develop effective antibodies against Covid-19. The company’s llama-derived antibody, XVR011, is currently being trialled in healthy individuals and hospitalised Covid-19 patients – and the data so far looks promising.

The antibodies were originally extracted from a llama named Winter, who is now being left to his own devices at a private animal park in Belgium as the antibodies can be synthesised in a lab. The small, llama-derived nanobodies have demonstrated strong neutralising activity against Covid-19 and all of its variants of concern.

ExeVir, which was spun out from the Flanders Institute for Biotechnology, has moved its lead candidate from laboratory tests to human clinical trials at an impressive pace, and beyond the current pandemic, the firm is hoping to build a broader platform for the treatment of infectious diseases of all kinds, both viral and bacterial.

We speak to ExeVir CEO Torsten Mumenbrauer about the company’s research and why XVR011 has the edge over other Covid-neutralising antibody programmes.

Darcy Jimenez:

How did research into this therapeutic candidate begin, and why were llama-derived antibodies chosen?

Torsten Mummenbrauer:

The technology as such is pretty old. It had been invented at the University of Brussels almost 20 years ago, then the Flanders Institute for Biotechnology (VIB) in Ghent took it on board and continue to develop the technology.

The big benefit of the technology is the small size of the nanobodies and the resulting advantages. In our special case, we have a very specific epitope on the spike protein, which is targeted by our lead candidate. And because the molecule is so much smaller than human antibodies, it can bind in this small groove or niche, and that makes it special.

It’s applicable for any use – that’s why we believe it’s a platform technology that can be used broadly in infectious disease development.

The fact that the nanobody is that much smaller also makes it applicable for different presentation in humans – so you can consider inhaled versions, we will develop a subcutaneous version, and you can fuse it to the Fc receptor to make it look like a human antibody.

That’s what we have done with our lead molecule, specifically to stabilise it. When it’s fused to an Fc, it’s roughly only half of the size of a human antibody, so if you put a certain amount per dose in your therapeutic approach, you have roughly double the number of molecules in the patient.

Then you can think about future variations or design changes. The FDA advised, for Covid-19 products, to go for a combination product – that’s what we see with the Regeneron product, which is a combination of two [monoclonal antibodies], and Lilly’s as well.

In our case, we could simply fuse two different nanobodies to one molecule or on one Fc and mimic the combination approach, but keep all the advantages of the technology.

What have studies shown so far about the antibody’s efficacy against Covid-19?

We started off against the wild type, the Wuhan strain, of course, and we showed efficacy in picomolar range in the hamster model. We have done the same experiment against Alpha, Beta, Gamma and Delta variants, and we see no change. We have very much the same potency against all variants which are [circulating] so far. We are looking at the variants of interest, and we’ll follow up and test these as well.

The key importance here is the epitope of your binder. If this epitope starts to mutate, then that allows the virus to escape. And this is what happens on the antibodies from Regeneron, which were originally derived from plasma from convalescent patients. They are all binding to the outer part of the RBD (receptor binding domain), and this is where you find the mutation hotspots of the virus.

We are on a side niche, and we are not impacted by any of these mutations; we have a crystal structure, and we can clearly show that these mutation hotspots are in other areas of the virus. We have shown on sequencing data that our epitope is very highly conserved over the SARS-COV virus family.

An interesting aspect is that originally, our llama Winter had been immunised against SARS-COV-1 already four or five years ago – that’s the reason why the company could be that fast. The library against SARS-COV-1 existed already in February last year when the SARS-COV-2 sequence was published.

We immediately did a screen, and we found 100% cross-reactive binders, and that resulted in our lead candidate. That’s probably another reason why we have this highly conserved and very stable epitope because it’s conserved on the whole virus family.

We of course are looking into the sequencing database available for all virus isolates worldwide, and there you can see the mutation hotspots coming. In our binding area, there is extremely limited mutation frequency, so it seems that this highly conserved epitope is important for the viability of the virus itself, and that’s probably the reason why it’s so stable.

Dosing of Phase I trial participants began last month, and hospitalised Covid-19 patients were also dosed recently. Are you confident about the antibody being studied in a hospital setting?

We decided a while ago to silence our Fc component, and I’ve mentioned that we’ve fused the Fc of the antibody to the nanobody – that’s specifically for safety reasons.

It’s one of our key differentiators compared to other antibodies, where you have the concern of antibody-derived enhancement of the disease, because of the activation of the immune system through the antibody. Our Fc is silenced, so we just neutralise the virus and we do not activate the immune system.

We’re extremely confident about [the study], and we strongly believe that the early-stage, mild-to-moderate hospitalised patients have the highest medical need, because there you want to avoid progression of the disease and ICU, of course.

To add on to that, the first cohort in Phase I – healthy subjects – have been completely dosed without any severe side effects. There is a bit of redness at the infusion site, which is normal for antibodies, and the same [was found] for the first hospital patient who has been dosed.

Developing a promising candidate to help combat the pandemic is an impressive feat for a company that was founded only last year. What else is ExeVir working on that you’re particularly excited about?

This is our lead candidate; we were focusing very much over the last year on the lead, otherwise it wasn’t going to happen. We were always thinking, if you want to make a difference in a disease like Covid-19, in a crisis, you need to be extremely fast. And so that has to be the focus, but we definitely see this as a platform technology to fight infectious diseases, and there we split that into two parts.

One is the future of pandemic preparedness: I strongly believe that people have realised that vaccines, in the case of a pandemic outbreak, are an important component of a response, but it also requires therapeutics.

If you want to ringfence a local outbreak, a therapeutic is much more efficacious. You don’t need to wait for the onset of immunity, you can use antibodies in prophylactic and therapeutic settings, and I think we have proven with the pre-immunisation of the llama that you can be very fast with this technology.

We definitely want to be part of pandemic preparedness of the future, but that’s not where you can really build the commercial future of a company in my view, because you don’t know if or when your pre-developed product might be required. We are also working on a pipeline for infectious diseases with high medical need, and we are in the last step, I would say, of the process to come up with a shortlist of candidates.

It will target infectious diseases with the highest medical need and hospitalisation relevance, so the technology can be used against bacterial diseases as well as viral. There is an ongoing programme on universal flu at VIB, which is very exciting for us, so there will be definitely a strong pipeline path for the next year beyond Covid-19.

We are really proud to demonstrate with [XVR011] that you can bring a molecule from early R&D and preclinical to a patient within a year. And for a small company, under all the circumstances of the pandemic, we believe that’s a really cool achievement.

Main image: Winter the llama. Credit: ExeVir