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Modulating antigen presentation to combat immune dysfunction

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Modulating the presentation of antigens to the human immune system to address the source of immune dysfunction in oncology and autoimmunity.

Grey Wolf has developed and is advancing a unique therapeutic strategy that leverages the ability to effectively modulate the presentation of target antigens to the human immune system to upregulate or downregulate immune cell activity for specific therapeutic outcomes.

This is achieved through oral delivery of a targeted inhibitor of the endoplasmic reticulum aminopeptidases (ERAP1 or ERAP2), which has the potential to: (1) drive the generation and presentation of novel and potent antigens to elicit targeted immune activity in cancer; and (2) block the production of disease-causing auto-antigens to prevent pathogenic immune responses that drive autoimmune diseases.

ERAP1 and ERAP2 are enzymes that trim peptides loaded into the classical and non-classical MCHI molecules.

ANTIGEN PRESENTATION PATHWAY

The targeted Inhibition of ERAP1 or ERAP2 has the potential to unlock novel therapeutics in the areas of oncology and autoimmune disease.

In cancer, inhibiting ERAP1 and ERAP2 reveals novel tumour antigens, resulting in the mobilisation of an entirely novel anti-cancer T cell response that increases tumor visibility, and bypasses the challenge faced by current immunotherapy when once anti-tumourigenic T cells become irreversibly exhausted and hence ineffective.

In autoimmunity, ERAP inhibition blocks the production of specific auto-antigens, which are the source of the unwanted pathogenic immune responses that drive autoimmune diseases.

Grey Wolf is developing novel, first-in-class ERAP inhibitors that directly impact the presentation of antigens to the immune system, unlocking new treatment approaches in immunologically-driven diseases.

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TARGETING
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 tumour cells. Genome-wide association studies provide strong support for the role of ERAP1 in antigen modulation in disease and overexpression in certain tumour types.

Grey Wolf Therapeutics has demonstrated that oral dosing of different ERAP1 inhibitors leads to tumour growth inhibition, in combination with standard of care therapies, including immune checkpoint inhibitors, across several different syngeneic tumour 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 tumour 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 tumour to the immune system is one of the key determinants of whether cancer will respond to treatment.

Tumours 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 tumour visibility problem.

To address this problem, Grey Wolf is advancing its lead ERAP1 inhibitor, GRWD5769, as a potentially first-in-class immuno-oncology agent.  The compound is currently being evaluated in a Phase 1/2 clinical trial.

ERAP1 also plays a central role in other immunologically-driven diseases, particularly autoimmune disorders. As such, Grey Wolf is 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.

Grey Wolf is developing a second ERAP1 inhibitor, GRWD0715, focused on autoimmune disease. The company intends to move the compound through investigational new drug (IND)-enabling studies with the goal of entering the clinic in 2025.

SEE OUR SCIENCE IN ACTION

TARGETING
ERAP2

Grey Wolf is also developing inhibitors that target Endoplasmic Reticulum Associated Protease 2 (ERAP2), a homologue of ERAP1. 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.

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.

ERAP2 is less well characterised compared to ERAP1 due to its absence in rodents. In humans, there are two common alleles of ERAP2, one of which leads to a functional knockout of the enzyme and is surprisingly prevalent in persons of European descent, suggesting the two alleles are maintained in balancing selection.

Recent data suggest that the shortened form of ERAP2 provides protection from viral infection such as COVID-19 and influenza. The importance of ERAP2 is further highlighted by its genetic association with cancer and immune-related diseases such as ankylosing spondylitis (AS), birdshot chorioretinopathy, and psoriasis.

NOVEL MHCI-DIRECTED
THERAPIES

 

The generation of novel cancer antigens following ERAP inhibition unlocks an entirely new area of major histocompatibility complex (MHC) class I or MHCI-directed therapeutic targets, that are only accessible following ERAP inhibition. This approach provides a unique therapeutic platform for the generation of ERAP inhibitor and MHCI-directed therapy combinations.

Compelling preclinical proof-of-concept data have clearly demonstrated the potential of combining ERAP inhibition with specific MHCI-directed therapies, such as soluble T cell receptor (TCR), TCR mimic bispecifics or vaccines. By mining a wealth of proprietary immunopeptidomic data, Grey Wolf is working on the selection of key cancer antigen targets for therapeutic development in combination with ERAP1 inhibition.

EXECUTION

Grey Wolf’s core team of drug discovery and development professionals is further strengthened by a network of collaborations with experts in immuno-oncology, antigen presentation and drug discovery across world leading academic institutions and CROs, including University of Oxford, Monash University, University of Southampton and Sygnature Discovery. Grey Wolf is pioneering an antigen presentation technology, through ERAP inhibition, for disease-modifying therapies in immuno-oncology and autoimmune diseases. Phase I/II clinical trials for the lead oncology program are ongoing with sites in the UK, Spain and Australia, and the lead autoimmune program is expected to enter the clinic in 2025.

We regularly present our latest scientific data around the world for peer review. Please click below to download a copy.