Our pipeline
First-in-class treatments and discovery programs to target unmet need.
ONCOLOGY
AUTOIMMUNITY
VIROLOGY
TARGET
DISCOVERY & VALIDATION
IND/CTA ENABLING
PHASE 1/2
LATE-STAGE
WHOLLY-OWNED
ERAP1
Phase 1/2
NAME
GRWD5769
INDICATION
Solid tumor types with moderate to high TMB or virally driven tumors
EXECUTIVE SUMMARY
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:
1) Allowing T cell recognition of tumors that were previously ‘invisible’ to the immune system.
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.
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:
1) Allowing T cell recognition of tumors that were previously ‘invisible’ to the immune system.
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.
NOVEL TARGET
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.
CLOSE
Ind/CTA enabling
NAME
GRWD0715
INDICATION
Axial spondyloarthritis and other autoimmune indications
EXECUTIVE SUMMARY
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.
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.
NOVEL TARGET
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.
CLOSE
Discovery & Validation