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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.

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. “91��ɫ want to tackle these two problems at the source.” Says Peter Joyce, CEO & Co-founder at 91��ɫ 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. 91��ɫ 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.“

91��ɫ inhibit ERAP1 to guide the immune system. 91��ɫ’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 mg, twice daily, we saw consistent shifts in the immunopeptidome, with higher doses showing even greater modulation of antigen presentation.

• Was well tolerated and showed early signs of clinical activity. The best response so far has been a stable disease, with some patients remaining on treatment for over a year without serious drug-related adverse effects. This supports a favorable safety profile and warrants further clinical investigation.

Tom Lillie, our Chief Medical Officer, has been leading the current clinical trials. "91��ɫ’ve been able to show for the first time, in patients, that ERAP1 inhibition is well tolerated and can change the antigen repertoire.  

“It’s a giant leap toward unlocking the full potential of antigen modulation in treating disease."

ERAP1 inhibition’s clinical and preclinical work debut was a success – it’s inspiring to see biological effects translated from the lab to real patients. And there’s more: these studies also allowed us to identify biomarkers that could be used to track responses in clinical trials. Changes in peptide length in the immunopeptidome, for example, serve as a proof-of-mechanism biomarker demonstrating ERAP1 inhibitor activity.  

Tumor immunohistochemistry alongside TCR repertoire analysis can be used as indicators of tumor immune engagement. And RNA sequencing profiles capture broad immune activation effects. Biomarkers like these could help select responsive patient populations and provide early signals of clinical efficacy.

Applications beyond cancer

Autoimmunity

The versatility and power of ERAP1 inhibitions rests in the fact that antigen presentation also underpins autoimmune disease and chronic infections.

In autoimmune diseases, the problem isn’t a lack of antigen presentation, it’s the wrong antigens being presented. Many therapies aim to suppress immune activity, which often leads to broad immunosuppression and an increased infection risk. However, ERAP inhibition doesn’t carry the same risks. “By inhibiting ERAP1, we could tackle the problem at the source by preventing the generation of pathogenic antigens that trigger autoimmune responses.” says Tom. “Axial spondyloarthritis (axSpA), for example, is strongly associated with ERAP1 function – conferring a relative attributable risk of axSpA of around 25% (4) – and so by modulating its activity we could prevent the immune system from mistakenly attacking healthy tissue.”

And axSpA is just the tip of the iceberg. ERAP1 function is genetically validated in multiple autoimmune diseases, meaning it has a far higher likelihood of translating into clinical success. This could be the first treatment to directly attempt to ‘turn off’ the harmful impact of self-reactive CD8⁺ cytotoxic T cells, an immune cell type that current therapies largely target using immunosuppressive approaches. From inflammatory bowel disease to multiple sclerosis, ERAP1 inhibition could represent a new frontier in autoimmune treatment.

"91��ɫ’ve been able to show for the first time, in patients, that ERAP1 inhibition is well tolerated and can change the antigen repertoire. It’s a giant leap toward unlocking the full potential of antigen modulation in treating disease."

Virology

The unmet need in chronic viral infection ​remains a functional cure.

Chronic viral infections, like hepatitis B (5) and HIV (6) persist because viruses both downregulate antigen presentation and chronic viral antigen exposure, which leads to T cell exhaustion. This prevents infected cells from triggering an immune response. Viral antigen modulation through ERAP1 inhibition could impact virology treatment development in several ways:

• Vaccine innovation: Antigen modulation can expose hidden viral reservoirs to make infected cells more detectable or even boost vaccine efficacy – particularly for rapidly mutating viruses. It can even steer us in the direction of new vaccine targets as ERAP inhibition generates novel viral antigens that have not previously been presented for immune recognition, which enables completely new vaccine designs against viral epitopes that can sidestep T-cell exhaustion.

• Broader immune responses: By improving the breadth and efficacy of immune targeting, this approach can lead to an increased reduction in viral load. Data from our oncology trials have demonstrated that a more comprehensive array of antigens are presented through ERAP inhibition, which helps overcome the challenge of viral diversity and immune evasion - such as escape mutations.​

Unlike Signal 2 and 3-based treatments – that work outside the cell – Signal 1-based ERAP inhibition works within cells to treat at the source.

A new class of immunotherapies

The new wave of immunotherapies has dramatically shifted how we tackle disease – but only for cells that already present antigens. Many diseases, from hidden cancers to chronic infections and autoimmune disorders, hinge on one fundamental issue: how cells present antigens.

Antigen modulation changes the way we look at this. By rewiring antigen presentation, we can improve immune recognition of tumors and infected cells, whilst unlocking new ways to redirect the immune responses in autoimmune disease. In cancer, it means invigorating entirely new immune responses and making immunotherapy work where it previously failed. In autoimmunity, it means stopping the immune system from targeting healthy tissue in error. In viral infections, it means forcing hidden reservoirs of infection into the immune system’s crosshairs.

As Peter Joyce puts it, "91��ɫ approach is orthogonal to a broad range of immunotherapy modalities – this goes way beyond oncology and allows us to harness antigen presentation to reshape immune responses across disease areas.”

Antigen modulation isn’t a tweak – it’s a shift in how we control immune visibility at the most fundamental level. When ERAP1 inhibitors and other antigen-modulating therapies deliver in clinical trials, they won’t just complement existing treatments, they’ll rewrite immunotherapy.

References

1. R. Cristescu, R. Mogg, M. Ayers, A. Albright, E. Murphy, J. Yearley, X. Sher, X. Q. Liu, H. Lu, M. Nebozhyn, C. Zhang, J. K. Lunceford, A. Joe, J. Cheng, A. L. 91��ɫbber, N. Ibrahim, E. R. Plimack, P. A. Ott, T. Y. Seiwert, A. Ribas, T. K. McClanahan, J. E. Tomassini, A. Loboda, D. Kaufman, Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy. Science 362, eaar3593 (2018). DOI: .

2. P. Joyce, M. Quibell, J. Shiers, C. Tong, K. Clark, N. Ternette, K. Anderton, J. Sette, W. Paes, A. Leishman, 553 First-in-class inhibitors of ERAP1 alter the immunopeptidome of cancer, driving a differentiated T cell response leading to tumor growth inhibition. J Immunother Cancer 9 (2021). DOI: .

3. T. Lillie, G. Kichenadasse, J. (Jenny) Liu, T. Hernandez Guerrero, E. Calvo, H. Jakobsson, V. Moreno, H. K. Gan, P. Joyce, N. Hyland, M. Giovannetti, T. Palmer, C. McAlpine, D. Green, S. N. Symeonides, EMITT-1: Proof-of-mechanism immunopeptidome (ImPD) effects at target PK exposure, in a phase 1 study of GRWD5769 (a first-in-class inhibitor of Endoplasmic Reticulum Aminopeptidase 1 [ERAP1]) in patients with solid malignancies. JCO 42, 2589–2589 (2024). DOI: .

4. F. W. Tsui, H. W. Tsui, A. Akram, N. Haroon, R. D. Inman, The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl Clin Genet 7, 105–115 (2014). DOI: .

5. H. Liu, B. Hu, J. Huang, Q. Wang, F. Wang, F. Pan, L. Chen, Endoplasmic Reticulum Aminopeptidase 1 Is Involved in Anti-viral Immune Response of Hepatitis B Virus by Trimming Hepatitis B Core Antigen to Generate 9-Mers Peptides. Front Microbiol 13, 829241 (2022). DOI: .

6. P. Stumptner-Cuvelette, S. Morchoisne, M. Dugast, S. Le Gall, G. Raposo, O. Schwartz, P. Benaroch, HIV-1 Nef impairs MHC class II antigen presentation and surface expression. Proc Natl Acad Sci U S A 98, 12144–12149 (2001). DOI: