A new therapeutic branch
Our approach
T-cell activation requires a chain of three signals, but all current approaches are focused on changing the later steps in the signaling cascade - Signals 2 & 3.
We are the first to explore the untapped potential of changing Signal 1, despite its fundamental importance in T cell activation.
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Signal 3
Guiding how T cells target threats
Cytokine-mediated differentiation and expansion
Signal 2
Enhancement of the immune response
Co-stimulation of non-antigen presenting molecules
Signal 1 – Antigen recognition
Initial detection of a cell by a T cell
Signal 1 is crucial to T-cell activation, yet the potential of changing it is yet to be explored.
This completely new approach has enabled us to develop first-in-class antigen modulators that aim to treat disease by controlling T cells.
We make cancer more visible to the immune system, aiming to
activate new T cells.
The immune system does not always recognise tumors as threats, and even when it does, cancers can still enter the 'escape phase' and continue to grow due to T-cell exhaustion by suppressive cytokines or prolonged T-cell receptor stimulation by antigens. Our antigen modulators aim to make cancer cells more visible to the immune system in two key ways:
Visibility
By modulating the antigens that present on the cell surface we hope to increase the number of tumor antigens (neoantigens) that appear on their surface to make them identifiable as threats by T cells.
Targetability
New antigens offer new sources of stimulation for T-cell receptors to revive a waning immune response.
We eliminate autoantigens at the source to control T cells.
Inhibiting ERAP aims to halt the production of autoantigens in autoimmune disease.
By blocking the presentation of these antigens, which trigger the incorrect immune response, we seek to stop T cells from attacking healthy cells.
Unlike Signal 2 & 3 based treatments, that work outside the cell, Signal 1 based ERAP inhibition works within cells to treat at the source – potentially delivering the first disease-modifying treatment for an autoimmune disorder.
Our focus
Validation of the vital role of ERAP in autoimmunity where we can address significant unmet need. Our initial disease of focus is axial spondyloarthritis.
We expose new viral antigens in infected cells, making them detectable to the immune system.
Chronic viral infections are adept at evading the immune system, hiding in plain sight from T cells.
While current treatments focus on suppressing viral load and managing viral replication, they do not address the immune system evasion that allows viral infection to persist.
Our antigen modulators aim to increase the presentation of viral antigens on infected cells, making them easier for the immune system to recognize and target, offering the potential of functional cures in viral diseases of global significant impact.
Our novel targets
T-cell control through ERAP inhibition – a novel mechanism of action.
Central to our approach is endoplasmic reticulum aminopeptidases (ERAPs), enzymes located in the antigen processing and presentation pathway and vital for antigen recognition.
ERAP is located in the manufacturing and transportation hub of a cell – the endoplasmic reticulum (ER) - and trims peptides prior to binding to MHC-I molecules. MHC-I molecules then present these peptides as antigens on the cell for recognition by T cells.
Video: Antigen modulation to increase the visibility and targetability of tumor cells
ERAP1
Endoplasmic Reticulum Associated Protease 1 (ERAP1) is a key protein in the antigen presentation pathway that has been shown to edit the antigen repertoire within tumor cells. Genome-wide association studies provide strong support for the role of ERAP1 in antigen modulation in disease and overexpression in certain tumor types.
We have demonstrated that oral dosing of different ERAP1 inhibitors leads to tumor growth inhibition, in combination with standard of care therapies, including immune checkpoint inhibitors, across several different syngeneic tumor models. Single antigen systems and state-of-the-art immunopeptidomic analyses show clear dose responsive effects of ERAP1 modulation on antigen presentation across species, cell types and genetic backgrounds both in vitro and in vivo. Critically, ERAP1 inhibition leads to the generation of novel neoantigens (non-self cell surface markers) and upregulation of pre-existing neoantigens.
The ability for ERAP1 inhibition to reveal novel tumor antigens to the immune system represents a key potential solution to the shortcomings of current immunotherapies. While recent advances in immunotherapy have been groundbreaking in oncology, leading to durable responses in some patients with advanced disease, the sad fact remains that most cancers do not respond to these therapies. Clinical data generated over the last few years have shown that the visibility of a tumor to the immune system is one of the key determinants of whether cancer will respond to treatment.
Tumors presenting a high number of neoantigens are exquisitely sensitive to T cell checkpoint therapy because they are more likely to be recognized as ‘foreign’. However, the vast majority of cancers have low neoantigen expression and, as such, are non-responsive to immunotherapy. To create the next step change in oncology therapy there is an absolute requirement for a new generation of therapies that address the tumor visibility problem.
ERAP1 also plays a central role in other immunologically-driven diseases, particularly autoimmune disorders. We are leading pioneering research into the biological role of ERAP in autoimmunity, which is supported by compelling human genetic associations. Recently published research that strongly suggest that auto-antigens produced by ERAP1 are responsible for triggering the activation of cytotoxic T cells that drive various autoimmune diseases. This opens up a novel disease modifying therapeutic approach for autoimmune disorders by blocking the production of these pathogenic auto-antigens with targeted ERAP1 inhibition to prevent CD8 T-cell activation and resultant tissue inflammation and damage.
ERAP2
ERAP1 typically processes peptides that contain hydrophobic residues at the N-terminus, whereas ERAP2 has been shown to process shorter peptides, with a preference for positively charged Lys and Arg residues at the N-terminus. Inhibition of ERAP2, therefore leads to entirely novel effects on the immunopeptidome.
The activity of ERAP2 complements ERAP1 due to distinct differences in substrate specificity. As such, they are non-redundant enzymes in the antigen presentation pathway, meaning inhibition of one enzyme cannot be compensated for by the activity of the other.
MHC-I
The generation of novel cancer antigens through ERAP inhibition unlocks an entirely new area of major histocompatibility complex (MHC) class I or MHC-I directed therapeutic targets - only accessible following ERAP inhibition. This approach provides a unique therapeutic platform for the generation of ERAP inhibitor and MHC-I directed therapy combinations.
Compelling preclinical proof-of-concept data have clearly demonstrated the potential of combining ERAP inhibition with specific MHC-I directed therapies, such as soluble T-cell receptor (TCR), TCR mimic bispecifics or vaccines. By mining a wealth of proprietary immunopeptidomic data, we are selecting key cancer antigen targets for therapeutic development in combination with ERAP1 inhibition.