A molecular platform for reprogramming immune responses has been designed by researchers from the Children’s Hospital of Philadelphia (CHOP) and Stanford University. TRACeR-I can be used to develop cancer treatments by either directly modifying immune cells, such as T cells, or by creating proteins that help immune cells locate cancer cells. The platform uses high affinity, specific binders to peptide-MHC complexes.
Their findings were published last week in the journal Nature Biotechnology. The lead authors are Haotian Du and Jingjia Liu, department of chemistry, Stanford University.
There is lots of work going on now applying immunotherapy to treating cancer, autoimmune diseases and viral infections, but its effectiveness depends on its ability to specifically target disease cells. Monoclonal antibodies are often used because they can target antigens on the surface of diseased cells, but uniquely expressed antigens found on the surface are sparse.
Also, fragments of these proteins may appear on the tumor cell surface through the presentation of peptides on MHCs, which display pieces of suspicious material like parts of a virus or cancer cells on the surface of cells. There are more than 30,000 different versions of MHC-I proteins in humans, which makes it very challenging to develop treatments that can recognize these peptides across large groups of patients and treat a variety of diseases.
Researchers at Stanford made the first breakthrough with the development of TRACeRs, platforms that recognize many different versions of these MHC proteins. TRACeRs act as “master keys” that can open a variety of “locks” posed by these MHC proteins and then treat the appropriate diseased cells while sparing healthy cells.
“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 overcomes 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.
He added that, “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 better understand the potential of the TRACeR-I platform, researchers from CHOP then used x-ray crystallography to show how the platform attaches to parts of the MHC-I complex that stay the same across different versions while continuing to recognize the peptides that indicate cancer cells or other dangerous material being displayed 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.”
