A new gene therapy based on antibody cells is about to be tested in humans
Genetically-engineered B cells, the cells that make our bodies' antibodies, will be harnessed to treat a rare disease.
During the covid-19 pandemic, antibodies played a front-and-center role. We took vaccines in the hope our bodies would make more. In home test kits, antibodies stuck to paper strips helped spot the virus and tell us if we were infected.
Less attention was paid to B cells, the immune-system cells that actually make antibodies, churning out as many as 10,000 a second—and which, after an infection, can persist for years inside your bone marrow.
Now a biotechnology company based in Seattle says the US Food and Drug Administration has agreed to let it move forward with the first study in humans of a new type of gene therapy, using genetically engineered B cells. The company, Immusoft, plans to harness B cells to treat a rare inherited disease called MPS-1.
“I feel 100% confident in stating we are the first to get the green light to enter clinical trials,” says Sean Ainsworth, the CEO of Immusoft.
The concept is to engineer B cells so that they manufacture other proteins instead of antibodies. For MPS, what’s needed is an enzyme whose absence causes diverse and devastating symptoms.
Patients with the illness are currently treated with weekly infusions of the missing enzyme, but it’s not enough to cure the disease outright. Immusoft says it can engineer B cells to produce the enzyme instead.
The proposed MPS treatment, which is set to be tested sometime in the next six months at the University of Minnesota Medical School, is the latest example of an approach in which researchers carry out gene therapy on cells in the blood, genetically programming them to give them entirely novel functions.
The advantage of using blood-system cells to add new genes to a person’s body is that they can be removed from a patient, engineered in the lab, and then returned to the same person through an IV drip.
Of the approximately 15 gene therapies approved by regulators in the US or Europe, more than half involve adding gene cargo either to bone marrow stem cells (which make all red blood and immune cells) or to white blood cells called T lymphocytes.
According to the National Cancer Institute, six approved gene-therapy treatments for blood cancers in the US involve engineering T cells. Other gene therapies, like one for sickle-cell disease, involve completely replacing a person’s bone marrow with genetically corrected blood stem cells.
So far, B cells haven’t gotten the same attention—indeed, genetically engineered versions have never been tested in a human. That’s partly because “engineering B cells is not that easy,” says Xin Luo, a professor at Virginia Tech who in 2009 demonstrated how to generate B cells that have an added gene.
That early work, carried out at Caltech, explored whether the cells could be directed to make antibodies against HIV, perhaps becoming a new form of vaccination.
While that idea didn’t pan out, now biotech companies like Immusoft, Be Biopharma, and Walking Fish Therapeutics want to harness the cells as molecular factories to treat serious rare diseases. “These cells are powerhouses for secreting protein, so that’s something they want to take advantage of,” says Luo.
Immusoft licensed the Caltech technology and got an early investment from Peter Thiel’s biotech fund, Breakout Labs. Company founder Matthew Scholz, a software developer, boldly predicted in 2015 that a trial could start immediately. However, the technology the company terms “immune-system programming” didn’t turn out to be as straightforward as coding a computer.
Ainsworth says Immusoft had to first spend several years working out reliable ways to add genes to B cells. Instead of using viruses or gene editing to make genetic changes, the company now employs a transposon—a molecule that likes to cut and paste DNA segments.
It also took time to convince the FDA to allow the trial. That’s because it’s known that if added DNA ends up near cancer-promoting genes, it can sometimes turn them on.
“The FDA is concerned if you are doing this in a B cell, could you develop a leukemia situation? That is something that they are going to watch pretty closely,” says Paul Orchard, the doctor at the University of Minnesota who will be recruiting patients and carrying out the study.
The first human test could resolve some open questions about the technology. One is whether the enhanced cells will take up long-term residence inside people’s bone marrow, where B cells typically live. In theory, the cells could survive decades—even the entire life of the patient. Another question is whether they’ll make enough of the missing enzyme to help stall MPS, which is a progressive disease.
“I don’t know if they are going to be successful, but it’s exciting for all of us that they have gotten permission to start a trial,” says Richard James, whose lab at the University of Washington is also developing approaches to engineering B cells.
James says a key advantage of the technology is that engineered cells won’t cause an immune reaction. By contrast, it’s believed that when gene therapies use viruses to get new DNA into the body, the patient will develop immunity to the treatment. That means if such therapies wear off—and there are mounting signs from medical studies that they do—poeple can’t get a second dose.
“With cells, you can re-dose ad nauseam, because they aren’t immunogenic. You can give the patient a certain amount, add more, or don’t add more,” says James. The treatment also isn’t as grueling and intensive as replacing a person’s bone marrow.
If the treatment works for MPS, researchers have ideas for what diseases could be next. It has to be a condition where free-floating proteins in the blood, the kind pushed out by B cells, make a difference. Ainsworth says Immusoft is interested in using the cells to deliver follistatin, a gene that causes muscle growth, as a potential treatment for sarcopenia, or body wasting. Producing the clotting factors missing in hemophilia patients is another possible application.
“The home run is to have a delivery system that is as safe as possible,” says Orchard. “We’ll have to wait and see.”
Correction: The original version of this article misstated the role of antibodies in Covid-19 test kits used at home. The tests do not detect antibodies. Instead, the tests use antibodies to detect the SARS-CoV-2 virus.
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