Bioengineered antibodies target mutant HER2 proteins

For some proteins, a simple mutation or change in the instructions of its DNA is enough to tip the scales between its normal functioning and the appearance of cancer. But although they cause serious disease, these mildly mutated proteins can resemble their normal versions so closely that treatments designed to target the mutants could also harm healthy cells.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, a new study describes the development of a biologic, a drug derived from natural biological systems, that targets a mutant cancer protein called HER2 (growth factor receptor 2 human epidermal) without attacking its almost identical normal counterpart on healthy cells.

The study was published in the journal Nature Chemical Biology on October 22.

Although still in its early stages, this technique could lead to new treatments to treat cancer patients with HER2 mutations with minimal side effects, the researchers say.

“We set out to create an antibody that could recognize a single change in the 600 amino acids that make up the exposed part of the HER2 protein, which conventional wisdom says is very difficult,” said the lead author of the study. study, Shohei Koide, PhD, professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine and member of the Perlmutter Cancer Center.

“The fact that we were able to detect the difference between a single amino acid so clearly was a surprise.”

The new findings revolve around HER2, a protein found on the surface of many cell types that activates signaling pathways that control cell growth. This can cause cancer when a single amino acid exchange locks the protein in “always on” mode, causing cells to divide and multiply out of control.

Cancer can also occur when cells accidentally make extra copies of the DNA instructions that code for the normal version of HER2 and express higher levels of the protein on their surface.

There are a few FDA-approved therapies, including trastuzumab and pertuzumab, that can treat this type of cancer, but these therapies all work at the level of HER2 on the cell surface, where only low levels of the mutated version of HER2 occur.

“This means we can’t mark cancer cells just by looking at HER2 levels,” said Dr. Koide, who is also director of cancer biologics at NYU Langone. Additionally, because some approved treatments cannot differentiate between mutant HER2 and normal HER2, they are more likely to harm healthy cells expressing normal HER2.

The study shows how the researchers exploited their new protein engineering technique to develop antibodies that recognize only mutant HER2. Antibodies are large, Y-shaped proteins that bind to specific targets and signal immune cells to destroy those targets.

In a process that mimics the natural development of antibodies, the researchers subjected the antibodies to several rounds of mutation and selection, looking for variants that recognized mutant HER2 but not the normal version.

By taking atomic images with a cryo-electron microscope, the team saw how their new antibodies interacted spatially with HER2 (blocked two HER2 molecules from interacting to signal), which allowed the team to continually refine their antibody designs. ‘antibody.

But selective recognition of mutant HER2 was only part of developing an effective cancer treatment, since antibodies must work with the immune system to kill cancer cells. A particular challenge is the case in which cancer cells have only a small number of mutant HER2s on their surface to which an antibody can attach.

To address this challenge, the researchers converted their antibody into a bispecific T cell engager, a molecule in which the antibody targeting the mutant protein is fused to another antibody that binds to and activates immune cells called T cells.

One end of the antibody sticks to the mutant HER2 on a cancer cell, while the other triggers the T cells to destroy the cancer cell. Further testing showed that this method killed the mutant HER2 cancer cells in the dishes. but spared normal cells.

When the researchers tested their T cell activators in mice with HER2 mutant tumors, the treatment significantly reduced tumor growth. It did so without causing weight loss or visible disease in the mice, suggesting that the treatment had few side effects on the animals.

However, Dr. Koide noted that because of the differences between the murine and human proteins, it is possible that the lack of obvious side effects stems from the fact that the antibody binds even less to mouse wild-type HER2 than the human version. Future studies will tell.

Moving forward, Dr. Koide said researchers will continue to refine their antibody with the goal of developing a treatment. Although the T-cell engagement molecule is the most powerful of the things they’ve tried, he said, there might be better options that they haven’t tested yet. Additionally, they plan to apply their antibody engineering technique to develop highly specific antibodies that could treat other cancer-causing mutant proteins.

In addition to Dr. Koide, other NYU Langone researchers involved in this study include lead author Injin Bang, as well as Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, and Akiko Koide.