W146 - Therapeutic development for Axial Spondyloarthritis: ERAP-1 inhibition by GRWD0715 results in auto-antigen loss on HLA-B*27 and the inhibition of cognate CD8+ T cell responses.

Abstract Text: HLA-B27+ axial spondyloarthritis (axSpA) is a progressive autoimmune disease with a prevalence ranging from 0.1 to 1.4%. It is managed with anti-inflammatory agents, but fewer than 50% patients achieve remission that is rarely curative, leaving a high unmet need. The association of endoplasmic reticulum amino peptidase 1 (ERAP1) with axSpA is strong (p < 10-50) increasing to p=6x10-54 in epistasis with HLA-B*27. ERAP1 activity determines which antigenic peptides are available for adaptive immunity, trimming longer peptides to ~9 amino acids (a.a). An hypomorphic allele of ERAP1 is highly protective for HLA-B*27+ axSpA, supporting ERAP1 inhibition in axSpA. It’s hypothesised ERAP1 inhibition will prevent auto-antigen generation and pathogenic CD8+ T cell activation leading to disease resolution. Our highly potent and selective ERAP1 inhibitor GRWD0715 will start testing in the second half of 2025. Here we demonstrate ERAP1 cleavage of putative axSpA auto-antigen precursors derived from GLRB, HelQ and SEC14L2, with GRWD0715 inhibiting the formation of auto-antigens at an IC50 ranging from 60-400 pM. 7-9 a.a. peptides were significantly down regulated on HLA-B*27 molecules expressed on joint-relevant cell lines exposed to GRWD0715. GRWD0715 suppressed the activation of axSpA-associated-TCR+ CD8+ T cells in an HLA-B*27-autopeptide-dependent manner. We present in silico analysis that implicates

GRWD0715-mediated loss of auto-antigen-HLA-B*27 resulted from the derivation of incompatible a.a. residues at the P2 anchor position. Together these data support the development of GRWD0715 as a disease-modifying therapy for axSpA and other HLA-B*27-associated autoimmune disease through the removal of HLA-I-presented autoantigens and the inhibition of auto-reactive CD8+ T cell responses.