A new chapter in cell therapy: engineered B cells reach the clinic for the first time

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Engineered B cells

Cell therapy has drastically improved the scope of treatment for a number of diseases in the last few years. Now, engineered B cells are the latest approach in the field of cell therapy, having recently made it into clinical trials. 

But what exactly are B cells and how can they be engineered to treat diseases?

What are engineered B cells?

B cells protect us from infection by making immune system proteins called antibodies. Similar to T cells, they are a type of white blood cell called lymphocytes. However, B cells and T cells differ in the sense that B cells produce antibodies to attack invading bacteria, viruses, and toxins, while T cells destroy the body’s own cells that have already been infected or turned cancerous.

Sean Ainsworth, chief executive officer (CEO) of engineered B cell company Immusoft, said: “B cells – plasma cells, more specifically, which are a subset of B cells – are an excellent cell type because they produce massive amounts of protein per cell, releasing thousands of antibodies into the bloodstream per second, and they naturally engraft in the bone marrow. It has been observed in the clinic that plasma cells can engraft and produce antibodies for more than a decade.”

The idea behind genetically engineered B cells is to harness the B cells’ ability to produce huge amounts of proteins and program them to produce other proteins – instead of antibodies – that will hold a therapeutic benefit.

Theoretically, engineered B cells could be used to treat a number of diseases. “We believe we can address a multitude of conditions for which circulating protein or peptide therapeutics have application – from lysosomal storage diseases to obesity/diabetes, CNS disorders, oncology, and beyond,” commented Ainsworth. 

Ainsworth also explained that one of the main benefits of engineered B cells is that, because B cells naturally reside in the bone marrow, they don’t require the preconditioning regimen associated with gene-modified stem cells. “That regimen is extremely toxic and disruptive to the patient’s life.”

Immusoft: the first company to advance engineered B cells into the clinic

Based in Seattle, biotech company Immusoft has been pioneering the use of B cells as biofactories for therapeutic protein delivery for several years, ever since it was set up in 2009. 

The company’s lead candidate, ISP-001, is designed to treat mucopolysaccharidosis type I (MPS I), a rare condition in which a person’s body does not produce enough of an essential enzyme called alpha-L-iduronidase, which is needed to break down long chains of sugar molecules called glycosaminoglycans. As a result, these molecules then build up in different parts of the body. MPS I is a life-threatening disease; patients have cloudy eyes, respiratory problems, cognitive issues, and enlarged organs. Children with the most severe form of the disease are likely to die by the age of 10. 

“A current therapeutic for MPS I is enzyme replacement therapy, which requires weekly infusions due to a very short half-life of the enzyme,” said Ainsworth. “This results in what is referred to as a ‘sawtooth effect’ – patients have very high enzyme levels for a short period of time, which drop off quickly. This leaves significant unmet need and Immusoft believes that consistent enzyme delivery could yield better outcomes for these patients.”

By genetically engineering a person’s B cells, Immusoft’s aim is to prompt their B cells to make alpha-L-iduronidase instead. And if a patient’s B cells could provide a continuous supply of  alpha-L-iduronidase, it could completely eliminate the need for regular infusions.

In order to get the B cells to produce the missing enzyme, scientists had to add new genetic instructions to them in the lab, before packaging those instructions into a transposon, which is a DNA sequence that can naturally integrate into a cell’s genome using a cut-and-paste mechanism.

Immusoft also uses a non-viral delivery system. Ainsworth noted that this removes the need for immunosuppression associated with viral delivery. “Some clinical trials have shown numerous serious adverse events from the immunosuppression regimen alone.”

On December 15, 2023, in a milestone achievement, Immusoft administered an engineered B cell to a human for the very first time. The phase 1 trial of ISP-001 is taking place at M Health Fairview University of Minnesota Medical Center. 

“In the process of getting to this stage we have also contributed greatly to the understanding of the biology,” commented Ainsworth. “This is a huge milestone for not just Immusoft, but also, the broader fields of cell and gene therapy.”

Concerns around safety of engineered B cells 

Engineered B cells have only just entered the clinic, and so, not only does efficacy still need to be demonstrated, but there is also the question of safety to consider. Regulators are still learning about the safety of CAR-T cell therapies, which have been around for several years now. 

According to an article in WIRED, Paul Orchard, the doctor running Immusoft’s B cell therapy trial at the University of Minnesota Medical School, said the original plan was to treat children with ISP-001, as it is always easier to prevent complications instead of reversing them. But the U.S. Food and Drug Administration (FDA) has initially limited the team to working with adults until the therapy is known to be safe. 

Orchard said that one concern the FDA has with engineering B cells is the possibility that they could turn cancerous, giving rise to lymphoma or leukemia. He said that the transposon system Immunosoft uses inserts the new genetic material in a random fashion, meaning there is a theoretical risk that it could do so near a cancer-causing gene – a risk also associated with current CAR-T therapies. 

Immusoft’s initial trial is meant to test the safety of its engineered B cell approach, so we should know a bit more about the safety of these types of cells soon. The phase 1 trial is expected to be completed in 2025, according to Ainsworth.

Engineered B cells: what lies ahead?

Once the safety has been tested, the next step for Immusoft’s engineered B cell trial is to take patients off the infusions to see whether the engineered B cells are doing what they are supposed to do. One of the major questions that the team of scientists is hoping to answer is just how long the B cells will stay in the body for. This will determine whether ISP-001 will be a one-time therapy or whether patients will need to be re-dosed. 

Only time will tell how effective engineered B cells can be, but Ainsworth believes they have enormous potential. “We believe engineered B cells have tremendous potential across a multitude of indications. This is because the B cell can be deployed as a biofactory to deliver therapeutic peptides and proteins; from antibodies, to enzymes, signaling proteins, and beyond. Considering just lysosomal storage diseases, there is a greater than $5 billion market opportunity across several separate indications.”

And it is not just Immusoft that is focusing its attention on engineered B cells. Companies like Be Biopharma and Walking Fish Therapeutics also want to harness these cells to treat serious rare diseases. 

As more attention is paid to the therapeutic potential of engineered B cells, could this new class of medicine become the next big breakthrough in cell therapy? We will just have to wait and see.

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