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Solid tumor types with moderate to high TMB or virally driven tumors

GRWD5769 has the potential of producing clinically meaningful improvements in the anti-tumor immune response in both anti-PD-1 naïve and resistant patients.

Inhibiting ERAP1 allows modulation of the antigenic repertoire displayed on tumor cells to potentially allow recognition of novel tumor antigens by the immune system. This provides two crucial opportunities to address central mechanisms of resistance to checkpoint inhibitors by:
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1) Allowing T cell recognition of tumors that were previously ‘invisible’ to the immune system.
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2) Addressing T-cell exhaustion caused by chronic exposure to tumor antigens.

By cycling ERAP1 inhibition on and off, it is possible to alternately display two different antigenic repertoires (one repertoire in the inhibited, and one in the uninhibited state) on the surface of the tumor cell. This approach potentially allows two complementary repertoires of T cells to reciprocally engage in tumor cell killing and introduces a rest period between repeat antigenic repertoire exposures, to avoid exhaustion mediated by chronic tumor antigen exposure.

Endoplasmic Reticulum Associated Protease 1 (ERAP1) is a key protein in the antigen presentation pathway that plays a critical role in shaping the antigen repertoire displayed on tumor cells, including tumor neoantigens. Pre-clinical models and genome-wide association studies provide strong evidence that tumors can utilise ERAP1 activity to hide neo-antigens from immune recognition and that ERAP1 is also over expressed in multiple tumor types.

Axial spondyloarthritis and other autoimmune indications

Whilst current therapies seek to suppress the various inflammatory mediators, we're taking a markedly different approach with our GRWD0715 programme – aiming to prevent the inflammation occurring in the first place.

Many autoimmune diseases have strong genetic associations with both particular HLA subtypes and ERAP1, indicating that the presentation of autoantigens on MHC class I is central to the development of many autoimmune diseases (so called ‘MHC-I-opathies'). Axial spondyloarthritis (axSpA) has a very strong association with both HLA-B*27 and ERAP1, and specific T-cells clones that recognise autoantigenic peptides on HLA-B*27 have now been identified. Given the implied central role of ERAP1 in processing these autoantigenic peptides, there is the potential to use ERAP1 inhibition to prevent generation and presentation of these autoantigens. This would remove the antigenic stimulus driving self-reactive T cell activation, potentially stopping autoimmune attack of the axial skeleton and so preventing further damage and disease progression.

ERAP1 is a key protein in the antigen presentation pathway that plays a critical role in the selective presentation of antigens on normal healthy cells, including immunogenic autoantigens that drive autoimmune disease. Genome-wide association studies (GWAS) provide strong evidence that ERAP1 is instrumental in the development and severity of autoimmune diseases associated with MHC-1 haplotypes, such as HLA-B*27 in the case of axial spondyloarthritis.

Virology

While classical HLA-I alleles are highly polymorphic, the non-classical HLA-E allele has few haplotypes. Novel disease-relevant antigens presented by HLA-E following ERAP inhibition can be directly targeted with immunotherapies for the eradication of chronic viral infections. Importantly, these therapeutics will have broad applicability across multiple patients (>90%) due to conservation of the HLA-E protein sequences.

Endoplasmic Reticulum Associated Proteases (ERAP) 1 and 2 are crucial proteins in the antigen presentation pathway and a number of studies have demonstrated that they are control factors for several infectious organisms. Alteration or loss of ERAPs function significantly changes the antigens presented by MHC I molecules, impacting the activation of both NK and CD8+ T cells.

Autoimmunity

The human ERAP2 gene has two major haplotypes called A and B. Haplotype A encodes a functional enzyme located in the endoplasmic reticulum where ERAP2 processes peptides for presentation in the context of MHC class I. On the other hand, haplotype B includes nucleotide base changes that promote the nonsense-mediated decay of the RNA transcript. About 25% of the human population are homozygous for haplotype B and are devoid of functional ERAP2 enzyme. Genetic analysis has shown that loss of ERAP2 function is associated with beneficial clinical outcomes for both cancer and several autoimmune diseases, including birdshot chorioretinopathy.

Endoplasmic Reticulum Associated Protease 2 (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 leads to entirely novel effects on the immunopeptidome.

Virology

While classical HLA-I alleles are highly polymorphic, the non-classical HLA-E allele has few haplotypes. Novel disease-relevant antigens presented by HLA-E following ERAP inhibition can be directly targeted with immunotherapies for the eradication of chronic viral infections. Importantly, these therapeutics will have broad applicability across multiple patients (>90%) due to conservation of the HLA-E protein sequences.

Endoplasmic Reticulum Associated Proteases (ERAP) 1 and 2 are crucial proteins in the antigen presentation pathway and a number of studies have demonstrated that they are control factors for several infectious organisms. Alteration or loss of ERAPs function significantly changes the antigens presented by MHC I molecules, impacting the activation of both NK and CD8+ T cells.

Oncology

Novel disease-relevant antigens presented in the context of classical HLA-I alleles, including A*02 and A*24, following ERAP inhibition can be directly targeted for killing of cancer cells and/or eradication of chronic viral infections. The combination of a proprietary machine learning (ML/AI) algorithm with a state-of-the-art discovery platform provides a unique opportunity to discover ERAP inhibition (ERAPi)-dependent antigens. Novel therapeutics focused at destroying cells presenting the disease-relevant antigens will be developed using proven technologies.

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

Oncology

While classical HLA-I alleles are highly polymorphic, the non-classical HLA-E allele has few haplotypes. Novel disease-relevant antigens presented by HLA-E following ERAP inhibition can be directly targeted with immunotherapies for killing of cancer cells and/or eradication of chronic viral infections. Importantly, these therapeutics will have broad applicability across multiple patients (>90%) due to conservation of the HLA-E protein sequences.