In some tumors, B cells form germinal centers and actively secrete antibodies that can recognize tumor-associated antigens. Now a new study by researchers at the University of Southern California (USC) demonstrates how reprogramming B cells into tiny surveillance machines and antibody factories that can pump out specially designed antibodies to destroy cancer cells and a range of diseases such as HIV and Alzheimer’s disease.
The findings are published in the journal Nature Biomedical Engineering.
“The immunoglobulin locus of B cells can be reprogrammed by genome editing to produce custom or non-natural antibodies that are not induced by immunization,” the researchers wrote. “However, current strategies for antibody reprogramming require complex expression cassettes and do not allow for customization of the constant region of the antibody. Here we show that human B cells can be edited at the immunoglobulin heavy-chain locus to express heavy-chain-only antibodies that support alterations to both the fragment crystallizable domain and the antigen-binding domain, which can be based on both antibody and non-antibody components.”
“In some diseases or conditions, the natural antibodies made by B cells are just not good enough,” said senior author Paula Cannon, PhD, a distinguished professor of molecular microbiology & immunology at the Keck School of Medicine of USC. “HIV is a very good example of that. It mutates constantly, keeping one step ahead of whichever antibodies are being thrown at it. We thought a checkmate move might be persuading B cells to make an antibody that was so broad in its ability to ‘see’ HIV that HIV couldn’t easily mutate around it.”
“It’s a technology for reprogramming B cells that could be applied to almost anything you can imagine dealing with an antibody,” said first author Geoffrey Rogers, PhD, a research associate and senior postdoctoral fellow in Cannon’s lab. “We think we’ll be able to completely customize everything about the antibody.”
For this project, the researchers took inspiration from chimeric antigen receptor (CAR) T cells, “living drugs” designed to target specific things. They’ve revolutionized treatment for blood cancers like leukemia and lymphoma. With 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 the cells are then infused 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 antibody factory, residing long-term in the bone marrow, lymph nodes, and spleen—and firing up when needed.
To make these tiny fighters, Cannon and Rogers used CRISPR gene editing methods to place the instructions for custom antibodies at the exact site in the B cell’s DNA where antibodies are naturally made. This trick means that B cells can be reprogrammed as biofactories making the custom antibodies. And just as regular antibodies respond to vaccination, the reprogrammed B cells could also be stimulated to increase their output.
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 shepherd their discoveries from the lab to the market.
“We’re really excited to help try and bring this to biotech companies,” said Erin Overstreet, executive director of the USC Stevens Center. “This could be a fundamental shift in how we approach certain diseases.”
