Illustration of cancer cells dividing. Cancer cells are able to divide uncontrollably and often display irregular shapes and sizes when compared to healthy cells
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A novel class of antibodies can identify cancer proteins on tumor cell surfaces, introducing a novel approach to targeting previously unreachable mutations.
Many cancers exhibit a common vulnerability: a solitary alteration in a pivotal protein can permanently activate cell growth signals. KRAS, for example, is a protein crucial for cell growth regulation and is often mutated in pancreatic, colorectal, and lung cancers. A prevalent mutation in KRAS involves changing one amino acid, transforming the normal protein into a version that continuously promotes cell division.
KRAS has long been a formidable target in cancer treatment. The mutated protein resides inside the cell, out of reach for traditional antibodies. A new study proposes an alternative method. Instead of attempting to transport the antibody inside the cell, newly engineered antibodies detect a fragment of mutant KRAS that is naturally presented on the cell surface.
This technique enables antibodies to differentiate between cancer cells with the KRAS mutation and those with normal KRAS, adapting a system typically used by the immune system to recognize viruses and other threats for targeting cancer.
How Cells Reveal What’s Inside
Cells possess an inherent mechanism to display their internal state to the immune system. As proteins break down naturally, small fragments are transported to the cell surface by display proteins, allowing immune cells to examine them. This mechanism enables the immune system to detect hidden elements, including virus parts and abnormal proteins.
T cells, a type of immune cell responsible for identifying and eradicating infected or abnormal cells, usually conduct this examination. They recognize protein fragments shown by surface display proteins and can eliminate cells carrying fragments indicating an infection or other irregularity.
The system is extremely selective: different surface display proteins exhibit different protein fragments, and even minor changes in a protein can determine whether a fragment is displayed. This means a cancer-inducing mutation can form a new target on the cancer cell surface while the original protein remains inside the cell.
From Recognition to Treatment
The subsequent question was whether these antibodies could prompt immune cells to attack cancer cells. One antibody version was integrated into a drug linking cancer cells to T cells. The antibody detects the mutant KRAS fragment on the cancer cell, while the other end connects to a T cell, facilitating direct contact and directing the immune cell to attack.
The antibody was also used to modify T cells to recognize the same mutant KRAS target. Both strategies selectively targeted cells with the KRAS mutation, leaving cells with normal KRAS largely unaffected.
The findings indicate that a cancer-inducing mutation need not be exposed on a protein’s exterior to become a target. The immune system’s own protein-display mechanism can present a hidden mutation fragment on the cell surface for antibody recognition.
Beyond KRAS
This approach’s significance extends beyond a single mutation. Many cancer-driving proteins reside inside cells, making them difficult or impossible to target with conventional antibody drugs.
Surface display proteins offer a solution. Cells already present protein fragments on their surfaces, potentially creating targets for antibodies against proteins previously deemed unreachable.
This method will not apply to every mutation. The altered protein must produce a displayable fragment, and that fragment must be shown by a surface display protein type compatible with the patient. Different mutations and surface display protein types may necessitate different antibodies.
Nevertheless, the study showcases a new cancer-targeting method. Researchers might leverage the cell’s surveillance system to reveal internal events instead of figuring out how to deliver an antibody inside a cancer cell. Mutations once concealed from antibody drugs could become visible targets for the immune system.
