A recent investigation has detailed the creation of a biologic drug, which is a type of medication derived from natural biological sources. This drug specifically targets a mutated cancer protein known as HER2 (human epidermal growth factor receptor 2), while leaving its almost indistinguishable normal counterpart in healthy cells unharmed.
For certain proteins, even a single mutation in their DNA can cause a shift that leads from normal function to cancerous behavior. Although these slight mutations can lead to serious illnesses, they often resemble their normal forms so closely that treatment strategies aimed at the mutants could also damage healthy cells.
Conducted by scientists at NYU Langone Health and the Perlmutter Cancer Center, this new study showcases the creation of a biologic that targets a variant of the cancer-associated HER2 protein without also affecting its very similar normal version found on healthy cells. Although this work is in its early stages, researchers indicate that it could pave the way for innovative cancer therapies for patients with HER2 mutations, all while minimizing side effects.
According to lead author Dr. Shohei Koide, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine and a member of the Perlmutter Cancer Center, “Our goal was to design an antibody capable of recognizing a specific alteration among the 600 amino acid units that comprise the exposed section of the HER2 protein, which is generally regarded as a significant challenge. We were surprised by how effectively we identified the difference brought about by a single amino acid.”
The research findings focus on HER2, a protein present on the surfaces of numerous cell types that initiates signaling pathways responsible for cell growth. A singular alteration in an amino acid can cause the protein to enter an “always-active” state, which leads to uncontrolled cell division and proliferation.
Cancer can also develop when cells inadvertently make multiple copies of the DNA that encode the normal HER2 protein, resulting in increased protein levels on their surfaces. Although some therapies approved by the FDA, such as trastuzumab and pertuzumab, can treat this form of cancer, these treatments operate at the HER2 level on the cell’s exterior, where the mutated version is present only in small amounts. “This means we can’t identify cancer cells just by examining HER2 levels,” stated Dr. Koide, who is also the director of cancer biologics at NYU Langone. Since many existing treatments are unable to differentiate between mutant and normal HER2, they can inadvertently damage healthy cells expressing the normal version.
Published in the journal Nature Chemical Biology on October 22, this study illustrates how the researchers employed a novel protein-engineering technique to create antibodies that specifically recognize only the mutant form of HER2. These antibodies are large, Y-shaped proteins that attach to designated targets and signal immune cells to destroy them.
In a process that emulates natural antibody development, the researchers subjected their antibodies to several rounds of mutation and selection, searching for variants that could identify mutant HER2 without binding to the normal version. By capturing atomic images using a cryo-electron microscope, the team observed how their newly developed antibodies interacted with HER2 in space (preventing the interaction of two HER2 molecules that would trigger signaling), which allowed them to consistently refine their antibody designs.
However, the ability to selectively identify mutant HER2 was only part of creating an effective cancer treatment since antibodies need to cooperate with the immune system to eliminate cancerous cells. A significant hurdle arises when cancer cells only express low levels of the mutant HER2 on their surfaces, limiting the antibodies’ ability to attach.
To tackle this issue, the researchers transformed their antibody into a bispecific T cell engager. This structure links the antibody that targets the mutant HER2 to another antibody that recruits and activates immune T cells. One end of the antibody latches onto the mutant HER2 found on a cancer cell while the other side stimulates T cells to destroy the cancer cell. Subsequent tests confirmed that this approach was effective in killing mutant HER2 cancer cells in vitro while sparing normal cells.
When tested on mice with tumors harboring mutant HER2, the T-cell engagers notably inhibited tumor growth without causing weight loss or visible signs of illness in the mice. This suggests minimal side effects from the treatment. However, Dr. Koide mentioned that due to differences between mouse and human proteins, the absence of noticeable side effects might be because the antibody binds to mouse wild-type HER2 even less than to the human variant. Further studies are necessary to clarify this.
Looking ahead, Dr. Koide expressed the researchers’ intention to continue refining their antibody with the aim of commercializing a treatment. He noted that while the T cell engager was the most effective approach they’ve tested thus far, there may be other potentially better options that they have yet to explore. Additionally, they plan to utilize their antibody engineering technique to create highly specific antibodies that could target other mutant proteins responsible for various cancers.
In addition to Dr. Koide, the work involved contributions from NYU Langone researchers, including lead author Injin Bang, as well as Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, and Akiko Koide. Other collaborators included Ken Geles and Elizabeth Buck from Black Diamond Therapeutics in New York City. This research was funded by a grant from the National Institutes of Health (P30CA01608).
Dr. Bang, Dr. Hattori, Dr. Leloup, Dr. A. Koide, Dr. Geles, Dr. Buck, and Dr. S. Koide are listed as inventors on a patent application related to this therapy, which may offer them financial benefits. Dr. S. Koide is a co-founder and holds equity in both Aethon Therapeutics and Revalia Bio, receiving consulting fees from Aethon Therapeutics as well. He has also received research support from Aethon Therapeutics, argenx BVBA, Black Diamond Therapeutics, and PureTech Health. Dr. Geles and Dr. Buck possess equity interests in Black Diamond Therapeutics. All these relationships have been managed following NYU Langone’s established policies.
