USC scientists have discovered a way to turn the body’s B cells into tiny surveillance machines and antibody factories that can pump out specially designed antibodies to destroy cancer cells or HIV, two of medicine’s most formidable enemies.
The research, published today in Nature Biomedical Technology, describes a technique for editing the genes of immune cells called B cells, turbocharging them to fight even the most insidious invaders. The work is a significant advance in harnessing the power of antibodies to treat conditions ranging from Alzheimer’s disease to arthritis.
“In some diseases or conditions, the natural antibodies made by B cells are simply not good enough,” said senior author Paula Cannon, a distinguished professor of Molecular Microbiology and Immunology at the Keck School of Medicine of USC. “HIV is a very good example of this. It is constantly mutating and staying one step ahead of the antibodies thrown at it. We thought that a checkmate move might convince B cells to make an antibody so broad in its ability to ‘see HIV that HIV couldn’t easily mutate around it.’
The beauty of the technique, according to the researchers, is that it can be adapted to produce a wide range of different antibodies.
“It’s a B cell reprogramming technology that can be applied to just about anything you can think of when you’re dealing with an antibody,” said first author Geoffrey Rogers, research associate and senior postdoctoral fellow in Cannon’s lab . “We think we can completely customize everything about the antibody.”
For this project, the researchers were inspired by chimeric antigen receptor (CAR) T cells, “living drugs” designed to target specific things. They have revolutionized the treatment of blood cancers such as leukemia and lymphoma. In CAR T treatment, T cells (sister cells to B cells) are removed from a patient’s blood and genetically modified to identify cancer cells by recognizing a marker on their surface. Millions of cells are then injected into the patient’s body, where they fight disease and then fade away.
B cells behave differently, making them more suitable for fighting chronic conditions. They function as both a security system and an antibody factory, residing for long periods in the bone marrow, lymph nodes and spleen – springing up when needed.
To create these little fighters, Cannon and Rogers used CRISPR gene editing methods to place the instructions for custom antibodies at the exact location in the B cell’s DNA where antibodies are naturally made. This trick means that B cells can be reprogrammed as biofactories that make the modified antibodies. And just as regular antibodies respond to vaccination, the reprogrammed B cells could also be stimulated to increase their production.
Researchers were able to observe the antibodies at work using tonsil tissue to replicate an immune system in a dish.
The researchers are working with the USC Stevens Center for Innovation to license the technology for commercial use. The USC Stevens Center helps scientists take their discoveries from the laboratory to the market.
“We are very excited to help bring this to biotech companies,” said Erin Overstreet, executive director of the USC Stevens Center. “This could be a fundamental change in the way we approach certain diseases.”
In addition to Cannon and Rogers, other authors of the paper include Chun Huang, Atishay Mathur, Xiaoli Huang, Hsu-Yu Chen, Kalya Stanten, Heidy Morales, Chan-Hua Chang and Eric Kezirian, all from USC.
The work was supported by grants from the National Institutes of Health (HL156274, AI164561, AI164556, and MH130178).
