New Antibody Targets Mutant Cancer Protein with Minimal Side Effects
For some proteins, a single mutation can be the tipping point between normal function and cancer development. However, these slightly altered proteins often resemble their healthy counterparts so closely that traditional treatments designed to target them can harm healthy cells.
A Breakthrough in Targeted Cancer Therapy
Researchers at NYU Langone Health and its Perlmutter Cancer Center have developed a promising new biologic, a drug derived from natural biological systems, that targets a mutant cancer protein called HER2 without affecting its healthy counterpart. This innovative approach could lead to more effective cancer therapies with fewer side effects for patients with HER2 mutations.
Targeting a Single Amino Acid Change
“Developing an antibody that could recognize a single change in the 600 amino acid building blocks of the exposed part of the HER2 protein was considered very difficult,” said Shohei Koide, PhD, lead study author and professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine. “The fact that we were able to detect this difference so cleanly was a surprise.”
Understanding HER2 and Cancer
HER2 is a protein found on the surface of many cell types, playing a crucial role in cell growth signaling pathways. When a single amino acid swap occurs in the HER2 gene, it can lock the protein into an “always-active” state, leading to uncontrolled cell division and cancer development.
Existing therapies like trastuzumab and pertuzumab target HER2, but they work at the cell surface level where mutant HER2 is present in low amounts. This makes it challenging to distinguish cancer cells from healthy ones. Additionally, these therapies often lack the specificity to differentiate between mutant and normal HER2, increasing the risk of harming healthy cells.
A Novel Antibody Engineering Approach
The researchers utilized a unique protein-engineering technique to develop antibodies that specifically recognize mutant HER2. These antibodies, large Y-shaped proteins, bind to specific targets and trigger the immune system to destroy them. Through multiple rounds of mutation and selection, the team identified antibodies that selectively targeted mutant HER2 without binding to its normal counterpart. Cryo-electron microscopy allowed them to visualize the precise interaction between the antibodies and HER2, further refining their design.
Boosting Antibody Effectiveness with T-Cell Engagement
To enhance the effectiveness of their antibodies, the researchers transformed them into bispecific T cell engagers. These molecules combine an antibody targeting mutant HER2 with another antibody that binds and activates T cells, a type of immune cell. This dual-action mechanism allows the antibody to simultaneously attach to mutant HER2 on cancer cells and activate T cells to destroy them.
Promising Results in Preclinical Studies
Preclinical testing in mice with mutant HER2 tumors demonstrated significant tumor growth reduction with minimal side effects. Although further research is needed to confirm these findings in humans, the results are encouraging.
Dr. Koide notes that future studies will focus on further refining the antibody and exploring additional treatment options. The team also plans to apply their antibody engineering technique to develop therapies targeting other mutant proteins that contribute to cancer development.
**Learn more about this groundbreaking research and the potential for personalized cancer treatments by visiting the NYU Langone Health website.**