The breakthroughs in immunotherapy have been ground-breaking in oncology, leading to durable responses in patients with advanced disease. However, 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 a particular cancer will respond.
Tumours presenting a high number of non-self cell surface markers (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. In order to make the next step change in oncology therapy there is an absolute requirement for a new generation therapies that address the tumour visibility problem.
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 potential overexpression in certain tumour types.
Grey Wolf has demonstrated that prophylactic and therapeutic dosing of different ERAP1 inhibitors can lead to tumour growth inhibition, in combination with anti-PD-1 in the CT26 syngeneic tumour model. 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, in vitro and in vivo.
The comprehensive drug discovery screening cascade and preclinical program developed by Grey Wolf has led to the nomination of an ERAP1 inhibitor development candidate that is now progressing through non-clinical development.
Modulators of ERAP1 activity have the potential to offer a new treatment paradigm in oncology, significantly altering the neoantigen presentation on the surface of tumour cells, leading to greater recognition and destruction by the immune system.
Grey Wolf is also developing inhibitors that target the aminopeptidase Endoplasmic Reticulum Associated Protease 2 (ERAP2), a homologue of ERAP1. The activity of ERAP2 is thought to compliment ERAP1 due to distinct differences in substrate specificity.
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 is therefore likely to lead to entirely novel effects on the immunopeptidome.
ERAP2 is less well characterised compared to ERAP1, due to its absence in rodent models. In humans, there are two common alleles of ERAP2, one of which leads to a shortened form of the enzyme and is surprisingly prevalent in persons of European descent, suggesting the two alleles are maintained in balancing selection.
Recent data suggests that the shortened form of ERAP2 provides protection from viral infection such as 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.
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, University of Southampton and Sygnature Discovery. Grey Wolf is a preclinical stage company focused on understanding the potential of modulating ERAP in immuno-oncology.