Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove

Abstract

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6–36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Genetic and Epigenetic Mechanisms of Psoriasis

“…The substantial wealth of knowledge obtained through genetic research has provided essential insights into the biology of psoriasis, allowing for the development of increasingly effective therapeutic agents for psoriasis [ 61 ]. The genetic polymorphisms responsible for treatment response to the different available psoriasis treatment options have been identified [ 62 , 63 , 64 ], including those related to the risk of developing antidrug antibodies [ 65 ], and have been found to correspond in many cases with type I HLA molecules. At the same time, genetic susceptibility to adverse drug reactions has also been described [ 64 , 66 ].…”