In a World First, a Patient’s Antibody Cells Were Just Genetically Engineered

B cells are prolific producers of antibodies, but for the first time, scientists have modified them to make other proteins to counteract a serious genetic disease.

Our B cells help prevent us from getting sick. Their job is to make antibodies, immune system proteins that fight off viruses and other foreign invaders. And they make a lot of antibodies—thousands of them every second. What if these antibody factories could be harnessed to make other things the body needs?

That’s the idea behind a trial launched by Seattle-based biotech company Immusoft. The company announced today that its scientists have genetically programmed a patient’s B cells and put them back in his body in an effort to treat disease. It’s the first time engineered B cells have been tested in a person.

The patient has a genetic disorder known as mucopolysaccharidosis type I, or MPS I. His body doesn’t produce an essential enzyme that helps to break down long-chain sugars inside cells. Without this enzyme, these sugars build up in the eyes, heart, bones, and elsewhere.

The effects are life-threatening. Patients have cloudy eyes, respiratory problems, cognitive issues, and enlarged organs. Those with the most severe form of the disease die in childhood. Others may live to their twenties or thirties.

Patients are currently treated with weekly infusions of the enzyme their body lacks. The therapy must be given for the entirety of a patient’s life. Typically, a gene called IDUA provides instructions for making this enzyme, but people with MPS I have a mutation in this gene. Immusoft’s aim is to override this problem by prompting a person’s B cells to make the enzyme instead. B cells appealed to Immusoft because of their ability to pump out lots of proteins. If a person’s B cells could provide a continuous supply of this enzyme, it could eliminate the need for regular infusions.

Sean Ainsworth, CEO of Immusoft, says the initial patient is doing well after receiving the experimental therapy in mid-November. “So far, so good,” he says.

Researchers at the company collected the patient’s B cells using a machine that removes blood, separates out a particular component, then returns the rest to circulation. There are billions of B cells in the body; Immusoft uses only a portion. “The body is constantly regenerating and producing new B cells,” Ainsworth says.

To get the B cells to produce the missing enzyme in addition to antibodies, scientists had to add new genetic instructions to them in the lab. They packaged those instructions into a transposon, a DNA sequence that can naturally integrate into a cell’s genome using a cut-and-paste mechanism.

Several commercially available therapies involve genetically engineering a patient’s cells outside the body to treat disease. A newly approved treatment for sickle cell disease uses Crispr to edit a patient’s blood-forming stem cells. And a type of “living drug” known as CAR-T cell therapy supercharges a patient’s T cells against cancer. No current therapies use a person’s B cells.

“It seems to me it was the obvious thing to move from T cells to B cells,” says Abla Creasey, vice president of therapeutics development at the California Institute for Regenerative Medicine, which has awarded $12 million in grants to Immusoft. She says B cells represent an exciting new strategy to treat disorders in which the body doesn’t make enough of a certain protein or enzyme.

The field is still new, says David Rawlings, an immunologist at Seattle Children’s Hospital who is working on engineered B cell therapies. That’s in part because B cells proved more difficult to manipulate than other types of cells. His lab is using Crispr to modify B cells, and he cofounded a company, Be Biopharma, to further develop them.

“The uses are really broad because you can think of them as a drug-secreting platform that lasts for a long time,” Rawlings says.

Existing engineered cell therapies have shown miraculous effects, but they come with downsides. In the case of the Crispr treatment, patients first undergo chemotherapy, which can cause hair loss, nausea, and other unpleasant side effects. After treatment, they must then stay in the hospital for weeks while their edited stem cells take up residence in the bone marrow. With CAR-T cell therapy, serious immune or nervous system effects can occur, so patients must be monitored in the hospital.

By contrast, Immusoft’s engineered B cells are given as an IV infusion in an outpatient procedure, Ainsworth says.

Paul Orchard, the doctor running the trial at the University of Minnesota Medical School, says the original plan was to treat children with the disease. “It’s easier to prevent complications than it is to reverse them after they’ve already happened,” he says. “If you can identify kids and intervene relatively early in life, they’re more likely to get benefits.” However, the US Food and Drug Administration has limited the team to working with adults initially, until the therapy is shown to be safe.

He says one concern the FDA has with engineering B cells is the possibility that they could turn cancerous, giving rise to lymphoma or leukemia. The transposon system Immunosoft uses inserts the new genetic material in a random fashion, so Orchard says there’s a theoretical risk that it could do so near a cancer-causing gene. This is also a known risk with current CAR-T cell therapies, which use viruses to deliver new genetic material to cells. Scientists can’t precisely control where in the genome viruses drop off their payload.

Immusoft’s initial trial is meant to test safety of its engineered B cell approach, so patients will continue receiving their usual enzyme infusions for now. The next step will be to take patients off the infusions to see whether the modified B cells are doing what they’re supposed to do. Orchard says they’ll measure enzyme levels in the blood and also look for improvement in patients’ symptoms, including movement and heart function.

One big question investigators are hoping to answer is how long the engineered B cells stick around in the body. Some B cells last for decades, Orchard says. “We’ll have to see. Obviously, it would be better if it's a definitive therapy and a one-time administration.”

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