Redirecting immune cells against cancer

An emerging approach to target cancer cells

Traditional targeted immunotherapies engage antigens on the surface of tumour cells, which account for 10-15% of the human proteome. However, many tumour antigens are inside the cell and therefore not reachable by such approaches.

This is where soluble TCRs provide a targeting advantage: by recognising small peptides derived from intracellular antigens that are processed and displayed on tumour cells. “Our approach is both very promising and technically challenging”, says Rodrigo. “It is very difficult to engineer soluble TCRs that bind a tumour antigen very strongly but that have no safety liabilities. It’s like trying to find a needle in a haystack.”

How do the technologies work and what is unique about them?

Engimmune Therapeutics’ technologies enable them to display hundreds of millions of TCR variants. Rodrigo adds: “We select them based on how strongly and specifically they recognise a tumour antigen. Moreover, we can also sequence them to get the identity of the TCRs and generate large data sets.” The data is then used to create machine-learning models that can distinguish between good and bad TCRs. Essentially, this procedure enables the startup to screen for very specific TCRs both in the lab and on the computer, which massively increases their chances of success. 

The technologies coupling protein engineering and machine learning were initially developed in Professor Sai Reddy’s lab at ETH. Over the past 18 months, Engimmune’s team has built on this foundation to develop additional technologies that not only improve the binding strength and specificity of soluble TCRs but also enhance their manufacturability, expand their function, and expedite their safety screening. 

Lars adds: “Our approach is also unique in that we not only engineer the targeting portion of the soluble TCR drug but also the portion that redirects immune cells for tumour killing. Our team has developed technologies in which such portions, also called immunoligands, are designed in multiple configurations and screened at high throughput. This opens the possibility of engineering soluble TCRs in a biology-driven manner, including adding novel functionalities with potential in autoimmune disease, which is a very exciting prospect.”

An added benefit of the new approach is the cost aspect. Related TCR-based cell therapies are extremely costly and difficult to scale. By contrast, soluble TCRs are an off-the-shelf product that reduces the cost of manufacturing and time-to-patient dosing significantly.

What are the next steps?

Last year’s seed financing round brought 15.5 million Swiss Francs with Switzerland-based Pureos Bioventures and Denmark’s Novo Holdings as the main investors. This allowed Engimmune Therapeutics to validate its technologies and advance its oncology pipeline closer to the clinic. They are targeting clinical entry with their lead program across multiple cancer indications in late 2025 and are currently engaging with investors, pharma partners and biotech companies.