Surfacing a Solution: Extracellular-Domain Mutations as New Cancer Targets

Using antibodies against cell surface antigen to zero in for focused cancer therapy.

In cancer research, some of the most promising targets are hiding in plain sight – right there on the surface of the cell. Take human epidermal growth factor receptor 2 (HER2), a protein that’s been under scrutiny in cancer research for decades. But while HER2’s overexpression has been the obvious focus and target for drugs, new research from Bang et al. (2024) (1) suggests that focusing on specific mutations in its extracellular domain could offer a more selective, precise approach to tackling cancers, even without the telltale overexpression.

The Extracellular Advantage

HER2 mutations, particularly in the extracellular domain, are a tantalizing target for antibody-based therapies because proteins on the cell surface are uniquely accessible to circulating antibodies. But such a therapy would only work if – and it’s a big if – you can distinguish proteins with a pinpoint mutation from the wild-type version. And up until now, designing antibodies with this level of nuance has been challenging to say the least. This is why antibody-based therapies have been relatively non-specific: they bind any HER2 they find, mutant or not, which can lead to serious side effects and limit a therapies’ efficacy.

Here’s where Bang’s team comes in. They engineered antibodies that are specifically binding to HER2’s most common mutations in the extracellular domain, S310F and S310Y, without reacting to the wild-type (WT) HER2. Using a methodical approach of library sorting and structure-guided design, they effectively trained these antibodies to ignore the WT protein while still locking onto the mutated form. These antibodies are selective to the point that they can disrupt HER2’s dimerization – essentially putting a stop to the hyperactive signaling that drives tumorigenesis in cancerous cells carrying these mutations. And, in a T cell engager format these antibodies have been demonstrated to effectively kill cancerous cells.

Why Extracellular-Specific Matters

Traditional antibody therapies, like trastuzumab, target HER2 indiscriminately and focus more on quantity (overexpression) than quality (mutation). That approach works well in cancers where HER2 is amplified but misses the mark in cancers where the issue isn’t the amount of expression but the structural change due to mutations. With extracellular domain-specific antibodies, Bang’s team has come up with a way to take out the mutant without bringing collateral damage to healthy cells. This kind of precision not only spares non-cancerous cells but opens up antibody therapeutics to a new subset of cancers.

For scientists, this is a great news because it shows that extracellular-specific antibodies can be tailored to recognize and bind unique mutant antigens on the cell surface. As well as therapeutics, these antibodies could work as diagnostic tools to identify these cell surface ‘oncogenic flags’ in mutation-driven cancers that traditional diagnostics might overlook. 

Extracellular Experts

At Alomone Labs we’ve a long track record of developing antibodies that specifically target the specific extracellular domain of membrane proteins. We give you the precise peptide sequence of the immunogen we used in the development and tell you which amino acid residues this corresponds to. You can also choose these extracellular antibodies conjugated directly to a fluorophore, making them ideal for live cell and flow cytometry work.

Take a look at our range of extracellular domain antibodies for yourself.

Reference

1. I. Bang, T. Hattori, N. Leloup, A. Corrado, A. Nyamaa, A. Koide, K. Geles, E. Buck, S. Koide, Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain. Nat Chem Biol, 1–10 (2024). DOI: https://doi.org/10.1038/s41589-024-01751-w.