Researchers from the Children’s Hospital of Philadelphia (CHOP) and Stanford University have unveiled the molecular structure of TRACeR-I, a protein framework designed for reprogramming immune reactions.
Gaining deeper insights into its structure may enhance design optimizations for the platform, which can be utilized to create cancer therapies by either directly altering immune cells or by producing proteins that assist immune cells in targeting cancer cells.
Immunotherapy represents an exciting frontier in the fight against cancer, autoimmune disorders, and viral infections, with its efficacy strongly linked to accurately targeting diseased cells. Monoclonal antibodies have emerged as powerful tools in this arena because they specifically hone in on antigens—proteins produced by cancer cells that provoke an immune response—on the surfaces of unhealthy cells. However, a significant challenge remains: uniquely expressed antigens on these cell surfaces are often few and far between.
A particularly promising target for cancer treatment lies in the fragments of proteins presented on tumor cell surfaces through peptides on the major histocompatibility complex (MHC). This complex serves as a display for suspicious materials, such as viral components or cancerous cells, on our cell surfaces.
There are more than 30,000 different versions of MHC-I proteins in humans, making it incredibly challenging to develop treatments that can recognize these peptides across large patient groups and address a variety of diseases.
Researchers at Stanford have achieved a breakthrough with their development of TRACeRs, platforms designed to recognize a wide range of MHC protein variants. TRACeRs function as “master keys” capable of unlocking many different “locks” created by these MHC proteins, allowing for the targeted treatment of diseased cells while protecting healthy ones.
“Our TRACeR-I and TRACeR-II platforms unlock the potential for targeting disease-associated class I and class II MHC antigens through novel binding mechanisms that overcome many of the hurdles that have historically limited the broader development of MHC-targeting molecules,” said senior author Possu Huang, PhD, an assistant professor in the Department of Bioengineering at Stanford University. “Our platforms have high peptide-focused specificity, broad compatibility with a variety of antigens, and simpler development that significantly expand the accessibility of targetable MHC biomarkers.”
To gain a deeper insight into the capabilities of the TRACeR-I platform, researchers from CHOP employed x-ray crystallography to demonstrate precisely how the platform binds to the stable regions of the MHC-I complex while still being able to identify the peptides that signal the presence of cancer cells or other harmful substances being presented on the surface.
“We revealed TRACeR-I’s novel binding mechanism and how the structure of this platform is able to help it recognize surface proteins that indicate cancer cells,” said Nikolaos Sgourakis, PhD, Associate Professor in the Center for Computational and Genomic Medicine at CHOP. “With this collaborative work, we were able to take the Huang lab’s designs and help realize their exciting therapeutic potential.”
Journal reference:
- Haotian Du, et al. Targeting peptide antigens using a multiallelic MHC I-binding system. Nature Biotechnology, 2024; DOI: 10.1038/s41587-024-02505-8