Certain proteins can go from functioning normally to causing cancer with just a single mutation or alteration in their DNA instructions.
However, even though these mutated proteins can lead to serious illnesses, they bear such a striking resemblance to their normal counterparts that therapies aimed at targeting the mutants may inadvertently harm healthy cells as well.
Researchers at NYU Langone Health and its Perlmutter Cancer Center have made a significant breakthrough in developing a biologic drug that specifically targets a mutant cancer protein known as HER2.
The drug is designed to selectively attack the mutated protein without harming its normal counterpart found in healthy cells. This innovative approach could potentially revolutionize cancer treatment and improve patient outcomes.
New therapies
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The researchers are in the early stages of development, but they believe that this technique has the potential to revolutionize cancer treatment for patients with HER2 mutations. They are hopeful that it could lead to new therapies that have minimal side effects.
“We aimed to develop an antibody that has the ability to identify a single alteration in the 600 amino acid units that compose the visible segment of the HER2 protein, despite the commonly held belief that this is a challenging task,” stated Shohei Koide, PhD, who is the lead author of the study, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine, and a member of Perlmutter Cancer Center.
“We were pleasantly surprised by our ability to accurately detect the subtle distinction of a single amino acid.”
Sometimes, cancer can occur when cells unintentionally produce additional copies of the DNA instructions that encode for the regular HER2 version, leading to higher levels of the protein on their surfaces.
Saving healthy cells
Dr. Koide, the director of cancer biologics at NYU Langone, emphasized that merely examining HER2 levels is insufficient for identifying cancer cells accurately.
In a recent study published in the journal Nature Chemical Biology, researchers have demonstrated their innovative protein-engineering technique that enables the development of antibodies capable of targeting mutant HER2 exclusively. The findings highlight the potential of this novel approach in antibody design and its implications for targeted therapies.
Antibodies, which are large proteins shaped like a Y, have the ability to bind to specific targets. These proteins then signal immune cells to eliminate the identified targets.
The process
The researchers conducted a series of mutations and selection rounds on antibodies, replicating the natural process of antibody development. Their goal was to identify variants that could recognize the mutant form of HER2 while ignoring the normal version.
Recognizing mutant HER2 selectively was just one aspect of creating an efficient cancer treatment. It is crucial for antibodies to collaborate with the immune system in order to eliminate cancer cells.
When cancer cells have a low amount of mutant HER2 on their surfaces, it becomes a significant challenge for the antibodies to attach to them.
The researchers tackled this challenge by transforming their antibody into a bispecific T cell engager. In this molecule, the antibody that targets the mutant protein is fused with another antibody that binds to and activates T cells, which are immune cells.
The antibody attaches to the mutant HER2 on the cancer cell and activates T cells to eliminate the cancer cell. Subsequent experiments demonstrated that this approach effectively eradicated mutant HER2 cancer cells while leaving normal cells unharmed.
The researchers observed a substantial decrease in tumor growth after administering the T cell engagers to mice with mutant HER2 tumors.
The treatment successfully accomplished this in the mice, without causing any weight loss or visible sickness. This indicated that the treatment had minimal side effects on the animals.
Dr. Koide acknowledged that there may be disparities between mouse and human proteins, leading to the possibility that the absence of noticeable side effects could be attributed to the antibody binding even less to the mouse wild-type HER2 compared to the human counterpart. Further research will shed light on this matter.
