048 The anti-drug antibody response is associated with amino acid variation within the HLADRB1 peptide-binding groove

Abstract

Targeted biologic therapies can elicit an undesirable host immune response characterised by the development of anti-drug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is the TNF inhibitor adalimumab. This genome-wide association study aimed to identify genetic predictors of developing ADA in psoriasis patients on their first course of adalimumab. Within the BSTOP bioresource, 784 psoriasis patients had ADA data 6-36 months after starting adalimumab (discovery cohort), 232 patients had ADA data <6 months after starting adalimumab (early ADA cohort), and 716 patients had only clinical data available (clinical outcome cohort). We genotyped and imputed 10,917,604 SNPs genome-wide and performed HLA imputation. We tested for association between genetic variation and development of ADA (logistic regression), as well as treatment failure (stopping adalimumab due to ineffectiveness [Cox proportional hazards]). We observed a genome-wide association with ADA within the Major Histocompatibility Complex (rs9268628, OR 3.44, 95% CI 2.21-5.36, p=4.93 x10-8) that mapped to the presence of tryptophan at position 9 (OR 0.34, 95% CI 0.25-0.45, p=1.76x10-12) and lysine at position 71 (OR 0.39, 95% CI 0.28-0.55, p=5.77x10-8) within the HLA-DRB1 peptide-binding groove, explaining 20% of ADA heritability. The protective effect of these residues on early ADA development was also observed in the second cohort of 232 patients. Underscoring their clinical relevance, these HLA-DRB1 residues were protective against treatment failure in the third cohort of 716 patients (HR 0.73, 95% CI 0.57-0.94, p=0.013). We suggest that pre-treatment HLA-DRB1 typing could direct clinical decision-making in terms of biologic selection and immunosuppressant co-therapy. Our findings also provide fundamental insight into the mechanisms by which amino acids within MHC Class II subunits play a critical role in selection of drug antigens displayed to the T-cell receptor, thereby determining the immune response to biologics.