To treat viral diseases that have no working vaccine, a group of researchers have engineered immune cells to spit out specific antibodies that can fight off a host of infections, including respiratory syncytial virus (RSV) and HIV (Sci. Immunol. 2019, DOI: 10.1126/sciimmunol.aax0644).
Engineering these immune cells, called B cells, has been no small feat, say scientists who spoke to C&EN. B cells naturally produce the diverse array of antibodies that make up the front lines of the immune system by randomly mixing and matching different antibody genes. Creating a high-yield system that overrides that natural programming so that the cell reliably produces a specific antibody and not one that is mixed has been a challenge, says Richard James, who works on B cell engineering at Seattle Children’s Research Institute, but who was not involved in the paper. “They solved one of the key problems,” James says.
Justin Taylor and his team at the Fred Hutchinson Cancer Research Center decided to target RSV to validate their B cell engineering system. RSV strikes children, the elderly, and people whose immune systems are compromised, such as those who have had a stem cell transplant. The infection can be deadly, and therapy sometimes includes monthly infusions of a monoclonal antibody called palivizumab.
The research team took the DNA that encodes palivizumab and used CRISPR to add it to a specific region of a chromosome involved in creating antibodies in human B cells. These engineered cells expressed the whole palivizumab antibody that could bind antigens from RSV. They repeated the procedure in mouse B cells and then infused those engineered cells back into mice infected with RSV. Mice carrying the engineered B cells fought off the infection; mice without the engineered B cells stayed infected. But the effect was transient. The antibody from the engineered cells disappeared after about three weeks.
People who undergo stem cell transplants are at acute risk of RSV infection because their immune systems are compromised. Taylor and his team tried to recreate that deficiency in mice to test whether the engineered B cells would continue to produce the specific RSV antibody. Compromised mice receiving the engineered cells maintained sufficient levels of the antibody for 40 days, and even after its levels declined, the mice could still fight off infection. The engineered B cells had successfully converted to a long-lived type that could still produce the antibody and a memory type that could recognize RSV quickly and help the animals’ immune systems mount a response.
It’s exciting work, says James Voss, who is trying to engineer B cells to fight HIV at Scripps Research’s California campus, and who was not involved in the new study. He points out that when other groups have tried to engineer B cells, the efficiency of getting the cells to take up antibody DNA has been low. Taylor’s group achieved 60% efficiency, which is “extremely encouraging,” Voss says. He thinks that getting the introduced antibody to last longer in an uncompromised immune system and getting those B cells to transform into memory cells are the next big steps for Taylor, and the field.
Seattle Children’s Research Institute’s James says that the field also needs to work on a manufacturing process, much like the one that exists for T cell cancer therapies.
Taylor agrees. His team is now working to improve the longevity of the antibody, and figuring out how to scale up the system to make the billions of engineered B cells a human might need to fight off an infection.
And while the research team has made engineered B cells that respond to RSV, HIV, influenza, and the mononucleosis culprit Epstein Barr virus, Taylor says engineered B cells could be used to fight other types of disease. “What we’ve developed isn’t limited to viral infections at all,” he says.