Imagine being able to turn a cell’s behavior ON or OFF, just like flipping a light switch. That’s exactly what scientists have achieved with the innovative technology presented in this paper published in the journal Cell Chemical Biology. This technology uses modified antibody fragments to control biological processes with small, harmless molecules.
What’s the Big Idea?
In this innovative study, researchers from the CTGCT and the Department of Synthetic Biology and Immunology at the National Institute of Chemistry in Slovenia, developed what they call Fv-CID switches. Antibodies can be tuned to bind against almost any biological molecules or drugs and this can give them the ability to regulate biological processes through biological molecules or drugs, which could be very useful for biomedicine.
They took parts of human antibodies, in fact, only the variable fragments (Fvs) that recognize and bind to specific targets and split them into two pieces. These pieces only come together when a specific small molecule (or ligand) against which this specific antibody has been generated, is added. Think of the ligand as a key that unlocks the ability of these fragments to reassemble and activate a cellular process.
Key Terms to Know
- Antibody: A protein produced by the immune system that binds to specific targets, such as viruses or toxins.
- Variable Fragment (Fv): The part of an antibody responsible for recognizing and binding to its target.
- Ligand: A small molecule that attaches to a protein, triggering a response.
- Fluorescein: A safe, FDA-approved dye used in this study as the trigger and ligand to activate the Fv-CID system.
- Chemically Induced Dimerization (CID): A method where two separate protein pieces come together and become active only when a specific small molecule is present.
- Fv-CID Switches: New tools, presented in this paper, that use antibody fragments to control cell functions by assembling only in the presence of a chosen ligand.
- Chimeric Antigen Receptor (CAR) T Cells: Engineered immune cells designed to target and kill cancer cells.
- BiTE (Bispecific T Cell Engager): A protein that connects T cells (a type of immune cells) to cancer cells to help trigger the body’s immune response.
- Gene Expression: The process where information from a gene is used to produce a protein.
Why Does This Matter?
Gene- and cell-based therapies, such as CAR T cells which are used to fight cancer, are incredibly powerful. However, if these treatments work uncontrollably, they can also harm healthy tissues. By integrating Fv-CID switches, scientists can externally control these therapies. For example, the study shows that when an FDA-approved dye called fluorescein is added, the split antibody fragments join together to activate the therapeutic cells or molecules. This method can turn on gene expression or trigger immune cells only when needed, reducing the risk of side effects and improving treatment safety.
How It Works
The process begins by splitting an antibody’s binding region into two fragments, where each fragment is inactive on its own. When a small molecule, such as fluorescein, is introduced, it acts as a bridge that brings these fragments together. This reassembly is key because it could trigger the activation of various cellular functions. In the study, once the fragments rejoined, they successfully turned on genes and controlled the activity of immune cells, demonstrating a new way to regulate biological processes in therapies like cancer treatment.
The images below show first how a conventional CAR receptor would look like on the surface of a T cell (a). The second part of the image (b) shows the off state of the receptor when both fragments are separated, then in the presence of fluorescein the fragments assemble into a functional CAR receptor, on state (c). Once this is achieved, in the last image (d), the T cell is capable of attacking the target cell.
Real-World Impact
By integrating these chemical switches into cell-based therapies, treatments like CAR T cells and BiTEs can be made more controllable. The ability to precisely turn therapies ON or OFF with a small molecule like fluorescein not only potentially improves the safety but also opens the door for dynamic treatment regimens that can be finely tuned in real time according to the state of the disease or patient.
This new approach shows great promise in enhancing the effectiveness of therapies while reducing their risks. With further research and development, these Fv-CID switches could become key components in next-generation treatments for cancer and other diseases. We believe this technology illustrates how re-engineering our natural defense mechanisms could lead to smarter, safer medical treatments.
If you find this research interesting and would be interested in working towards the translation of gene and cell therapies, do not hesitate to contact us. The CTGCT is expanding its team this year!