Your immune system constantly scans for threats, using molecular tags on cell surfaces to distinguish friend from foe. This process – antigen presentation – underpins how the body detects infections, cancers, and even its own misfiring immune signals. But the immune system can only fight what it can see.
Cells continuously break down proteins and present antigen fragments – in the form of peptides – on their surface via major histocompatibility complex class I (MHC-I) molecules. These act as cellular ID badges that tell immune cells what belongs and what doesn’t. If a peptide looks suspicious – perhaps it comes from a virus, a tumor or even a normal cell in the case of autoimmune diseases – it can trigger an immune attack.
But what happens when dangerous cells manage to slip past this surveillance system? Some tumors, for example, evade detection because they do not display enough recognizable antigens. Some viruses can suppress antigen presentation to hide inside cells undetected. And in autoimmune diseases, the immune system gets the wrong message entirely and mistakenly targets healthy tissue.
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Even when the immune system detects a threat, it doesn’t always stay in the fight. T cells can launch an initial attack, but if they keep encountering the same antigen without success, they burn out – a process called exhaustion. At the same time, the immune system can become tolerant, where they treat persistent antigens as harmless. In cancer and chronic infections, this means the immune response stalls, and disease takes hold. The way to reignite immunity in this case is a fresh set of antigens – new targets that reset recognition, restart immune pressure, and put tumors or infections back on the hit list. “We want to tackle these two problems at the source.” Says Peter Joyce, CEO & Co-founder at èAV Therapeutics, “By modulating how cells process and present antigens, we can change how cells interact with T cells to guide the immune system.
"This will open up a host of new treatment possibilities for cancer, autoimmune disorders and infectious disease.“
Why some cells become invisible to the immune system
The immune system relies on antigen presentation to distinguish normal cells from threats – you can think of antigen presentation as the body’s internal security surveillance system. We refer to the complete set of peptides presented on a cell’s surface by MHC-I molecules as the immunopeptidome. If a T cell recognizes an antigen as foreign, it triggers an immune response.
But many cells, likes tumors for example, can remain invisible to this system. Why? Two reasons – either a lack of recognizable antigens, or, because of chronic exposure, T cells have become exhausted and tolerant to the antigen.
“Neoantigens are peptide fragments produced by tumor-specific mutations. Because they exist only in cancer cells, they make ideal immunotherapy targets as they give the immune system a way to strike tumors while sparing healthy tissue,” continues Peter. “The more neoantigens a tumor displays, the greater the chance of an effective immune response – both in triggering an initial attack and in preventing T cell exhaustion.”
A lack of effective neoantigen recognition happens through a few different mechanisms:
- Low tumor mutational burden (TMB). Some cancers simply don’t harbor enough mutations to produce neoantigens in the first place, making them less likely to be detected by the immune system. Research supports the idea that patients with low TMB respond poorly to checkpoint inhibitor therapies, since their tumors are less likely to present recognizable immune targets (1)
- Peptide competition. Some higher affinity or stronger binding peptides outcompete neoantigen peptides for MHC-I binding, which further skews antigen presentation in a way that helps tumors evade detection.
- T cells have become tolerant to the cancer neoantigens through chronic exposure.
- Impaired antigen processing. Even when neoantigens exist, they may not be properly trimmed, transported or loaded onto MHC-I molecules and so aren’t on display for the immune system to see.
Immune checkpoint inhibitors, like anti-PD-1 therapies, only work if T cells have something to recognize in the first place. For years, researchers have focused on Signals 2 and 3 – co-stimulation and cytokine signaling – to boost immune responses. But without proper antigen recognition (Signal 1), these efforts can be wasted. Based on what we’ve learned about tumor antigen presentation, we can start to apply this principle to other diseases.
This is where antigen modulation approaches come in. Instead of just boosting T cell activation, we change how cells process and display antigens to make sure the immune system has something to spot and attack.
ERAP1 and antigen modulation
Once a protein is broken down into peptides, they’re moved to the endoplasmic reticulum, processed, loaded onto MHC-I molecules and sent to the cell surface for immune inspection. Central to this sequence is endoplasmic reticulum aminopeptidase 1 (ERAP1), an enzyme that trims peptides to the right length for MHC-I presentation.
Blocking ERAP1 reshapes the immunopeptidome to create a new set of neoantigens that the immune system has never encountered before.
"This will open up a host of new treatment possibilities for cancer, autoimmune disorders and infectious disease.“
èAV inhibit ERAP1 to guide the immune system. We’ve developed a novel ERAP1 inhibitor that alters the diversity of neoantigens displayed on tumor cells. Blocking ERAP1 modifies the immunopeptidome by enabling new neoantigens to be presented that weren’t previously displayed.
This idea of antigen modulation isn’t just theory – our preclinical work (2) has shown that ERAP1 inhibition
- Alters the immunopeptidome. Human and mouse peptide profiling of cancer cell lines showed major changes in the antigen repertoire across diverse HLA genotypes and cancer backgrounds.
- Drives CD8+ T cell activation with a resulting increase in T cell infiltration into syngeneic tumors.
- Diversifies the T cell receptor (TCR) repertoire, indicative of an early and sustained impact on immune surveillance.
- Leads to significant tumor growth inhibition, especially when combined with anti-PD-1 immunotherapy in multiple syngeneic mouse models.
Preclinical data is good, but does it translate to human patients? Early data from a first-in-human trial of GRWD5769, our ERAP1 inhibitor, suggests the answer is yes (3).
In this Phase 1 proof-of-mechanism study, we gave GRWD5769 to patients with advanced solid tumors. And we’re over-joyed to say that ERAP1 inhibition did exactly what it was designed to do:
- Changed the antigenic repertoire that is presented. Patients' peripheral PBMC samples showed a clear shift in the peptide population and length distribution, with a decrease in 9-mer peptides and an increase in 10–14-mer – exactly the pharmacodynamic pattern expected from ERAP1 inhibition.
- Showed dose-dependent effects. At 50