By Jonathan D. Grinstein, PhD

Not all drug targets are created equal. For those that result in a tissue-specific gain-of-function, the strategy can be not-so-straightforward.

That’s exactly what’s going on in some forms of amyotrophic lateral sclerosis (ALS), such as those with a mutation in the ubiquitous splicing protein TDP-43, which causes an alteration in motor neuron gene expression and also forms a toxic amyloid structure when misfolded. The result is a highly aggressive form of ALS, with patients typically reaching a fatal outcome 2–5 years from the onset of symptoms.

How then do you target a ubiquitous protein with an essential neuronal function that has a toxic gain-of-function activity in a specific tissue or cell-type?

For VectorY CEO Sander van Deventer, MD, PhD, the answer is antibody technology.

“With antibodies, you can target specifically misfolded or aggregated proteins because they can recognize epitopes that are the result of misfolding, only targeting confirmational epitopes,” Deventer told GEN Edge. “This is what we started doing three years ago when we founded the company, and we got surprisingly successful results with TDP-43.”

But VectorY isn’t just systemically dosing with antibodies; they’re using AAV technology to target specific cells, akin to what is being done in gene therapy approaches.

So far, their preclinical data shows that this approach is working well. In fact, the data from VectorY—named after their technology, with the “Y” representing an antibody—has been so successful that the Dutch company just announced that it had raised one of Europe’s largest Series A rounds of 2023, the equivalent of $138 million to advance their vectorized antibodies for neurodegenerative disease treatment.

EQT Life Sciences and the Forbion Growth Opportunities Fund co-led the round. New and existing investors also participated in the financing, including MRL Ventures Fund (a corporate venture arm of Merck), Insight Partners, ALS Investment Fund, Forbion Ventures, and BioGeneration Ventures (BGV).

Vectorized antibody treatment

While VectorY has not disclosed the exact targeting mechanism of its candidate for TDP-43 in ALS, it is targeting an epitope specific to the misfolded protein. This isn’t straightforward, as the protein forms amyloid aggregates that can bury the target site.

Deventer said that an important thing to measure is TDP-43 cell compartmentalization. The splicing protein is typically found in the nucleus, but misfolding and aggregation tend to cause the accumulation of TDP-43 in the cytoplasm. So, for Deventer, it is not enough to just get rid of mutated TDP-43 but to make sure that the nuclear levels stay within the range seen in homeostatic conditions.

VectorY is using an AAV5 variant to target the roughly 500,000 motor neurons in humans, a small slice of the 100 billion or so total neurons. The vectorized antibody treatment is administered into the spinal cord so that it can reach both the peripheral and central nervous system (CNS). This is similar to how Zolgenzma, a gene therapy drug for spinal muscular atrophy, is usually administered.

According to Denever, their approach is applicable to other programs at VectorY that require deep brain penetration. Along these lines, VectorY isn’t keeping their vectorized antibody treatment approach to themselves and is working with other pharma companies that are interested in using the technology for other diseases of the nervous system, such as dementia and Huntington’s disease.

VectorY is working with two pharma companies, Eli Lily and Merck, and is fielding interest from other companies interested in the CNS space. Denever said that this attraction has to do with data from VectorY showing that their vectorized antibody technology can cross the blood-brain barrier.

However, there will have to be a bit of innovation when it comes to getting the vectorized antibody treatments to be applicable to pathologies with intracellular and extracellular targets, which is something that Denever said VectorY is looking at.

Gearing up for clinical and commercial stages

Denever said that the main goal of this impressive funding round is to get their lead program, VTX-002, into the clinic with a clinical readout.

VectorY will begin its clinical endeavors in the United States. Denever said that they are soon having a pre-IND (investigational new drug) meeting with the FDA, and he expects an IND meeting by the end of 2024, which, for gene therapies, calls for 12 months of rodent data and 6 months of nonhuman primate data. VectorY hopes to begin clinical trials at the start of 2025.

In that time, Denever said VectorY will sort out their clinical readout, which Denever said will lean heavily on biomarkers.

“There’s a wealth of biomarkers that are directly linked to the splicing that you can measure,” said Denever. “You can actually see whether you have a therapeutic effect by measuring proteins in the cerebrospinal fluid (CSF) or blood because those splice proteins you can basically quantify.”

One thing that VectorY sorted out early on was their manufacturing approach. From the start, the company worked on the manufacturing, showing that they could get an excellent product, according to Denever. VectorY is set to start toxicity studies for their vectorized antibodies at the start of 2024 and is already scaling up manufacturing to supply commercial levels of product.

“I want to be the owner of the processes and materials,” said Denever. “We actually own the process. There’s a lot of know-how and knowledge—there’s some IP around it. Actually, a CDMO came to visit us to see how it needed to be done.”

Perhaps what is considered against the grain is that VectorY uses an insect cell-based process, which Denever said has excellent quality parameters.

“There’s a whole lot of discussion about mammalian and insect cell-based manufacturing,” said Denever. “To cut a long story short, the people who publish bad things about insect cell manufacturing haven’t done the molecular engineering to make it work in insect cells. That’s our main conclusion. We actually bring [insect cell-based manufacturing] to the next level.”

Although the company was founded in Amsterdam, VectorY has been putting down roots in Boston, building out their clinical development prior to initiating clinical trials. However, their first trial, which is non-interventional, will investigate their biomarker strategy and is set to take place in December in the Netherlands. Accordingly, VectorY has already begun regulatory interactions in Europe, and they will be moving ahead there as well. 

Dime a dozen or needle in a haystack

There are currently seven drugs approved by the FDA to treat ALS and its symptoms, but only the most recent one, Biogen’s Qalsody (tofersen), treats the genetic root of the disease. As the name suggests, Qalsody is used to treat people with ALS who have a mutation in the SOD1 gene (SOD1-ALS).

VTX-002 will be the first of these drugs to directly target TDP-43, which has been difficult to drug. While Takeda recently obtained an exclusive, worldwide license to AcuraStem’s investigational therapies for potential treatment for ALS, the drug candidate AS-202 targets the PIKfyve enzyme, which ultimately aims to lower toxic TDP-43 protein buildup in nerve cells.

Even with this healthy Series A round, VectorY is still flying a bit under the radar, with much attention being garnered by cell and gene therapies. But their vectorized antibody therapies are a reminder that there is no one-size-fits-all solution for medicine.

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